Since 2008, the US Food and Drug Administration (FDA) has required new diabetes drugs to demonstrate cardiovascular safety, resulting in large and lengthy clinical trials. Under the new regulations, several dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular safety, with some demonstrating superior cardiovascular efficacy. In 2016, the SGLT-2 inhibitor empagliflozin became the first (and as of this writing, the only) diabetes drug approved by the FDA for a clinical outcome indication, ie, to reduce the risk of cardiovascular death.

DIABETES DRUG DEVELOPMENT

Changing priorities

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was formed in 1990 as a collaborative effort across global regulatory agencies and coordinated by the World Health Organization to universalize criteria for drug development. The ICH standards for type 2 diabetes drug development included the following requirements for patient exposure to investigational products to satisfy new drug application requirements:

• 1,500 individuals total (including single-dose exposure)
• 300–600 patients for 6 months
• 100 patients for 1 year.

Thus, just 250 patient-years of exposure were needed for approval of a drug that patients might take for decades. These standards were unlikely to reveal rare, serious complications and had no ability to assess clinical outcomes efficacy for either microvascular or macrovascular disease complications.

Since 1995, when metformin was approved in the United States, a new class of antihyperglycemic medication has been approved about once every 2 years, so that by 2008, 12 classes of medications had become available for the treatment of type 2 diabetes. This extraordinary rate of drug development has now yielded more classes of medications to treat type 2 diabetes than we presently have for the treatment of hypertension.

This proliferation of new treatments resolved much of the pressure of the unmet medical need, over a period of increasing awareness of the cardiovascular complications of type 2 diabetes, along with numerous examples of adverse cardiovascular effects observed with some of the drugs. In this context, the FDA (and in parallel the European Medicines Agency) made paradigm-shifting changes in the requirements for the development of new type 2 diabetes drugs, requiring large-scale randomized clinical outcome data to assess cardiovascular safety of the new drugs. In December 2008, the FDA published a Guidance for Industry,¹ recommending that sponsors of new drugs for type 2 diabetes demonstrate that therapy would not only improve glucose control, but also that it would, at a minimum, not result in an unacceptable increase in cardiovascular risk.¹ To better assess new diabetes drugs, the requirement for patient-years of exposure to the studied drug was increased by over 60-fold from 250 patient-years to more than 15,000.

INCRETIN MODULATORS

The incretin system, a regulator of postprandial glucose metabolism, is an attractive target for glycemic control, as it promotes early satiety and lowers blood glucose.

After a meal, endocrine cells in the distal small intestine secrete the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP), among others, which reduce gastric motility, stimulate the pancreas to augment glucose-appropriate insulin secretion, and decrease postprandial glucagon release. GLP-1 also interacts with the satiety center of the hypothalamus, suppressing appetite. GLP-1 and GIP are rapidly inactivated by the circulating protease DPP-4. Injectable formulations of GLP-1 receptor agonists that are resistant to DPP-4 degradation have been developed.

Ten incretin modulators are now available in the United States. The 4 available DPP-4 inhibitors are all once-daily oral medications, and the 6 GLP-1 receptor agonists are all injectable (Table 1).

Small studies in humans and animals suggest that DPP-4 inhibitors and GLP-1-receptor agonists may have multiple favorable effects on the cardiovascular system independent of their glycemic effects. These include reducing myocardial infarct size,^2–5 improving endothelial function,⁶ reducing inflammation and oxidative stress,⁷ reducing atherosclerotic plaque volume,⁸ improving left ventricular function, ^9,10 and lowering triglyceride levels.¹¹ However, large clinical trials are needed to determine clinical effectiveness.

DPP-4 INHIBITORS: NOT INFERIOR TO PLACEBO 

Saxagliptin

Saxagliptin, a DPP-4 inhibitor, was found in a meta-analysis of phase 2B and early phase 3 trial data involving almost 5,000 patients to be associated with a dramatic 56% relative risk reduction in cardiovascular death, heart attack, and stroke. However, this analysis was limited by the extremely low number of events to analyze, with only 41 total patients with cardiovascular events in that dataset.¹²

The SAVOR-TIMI 53 trial¹³ subsequently compared saxagliptin and placebo in a randomized, double-blind trial conducted in 26 countries with nearly 16,500 patients with type 2 diabetes. All patients continued their conventional diabetes treatment at the discretion of their physicians.

During an average follow-up of 2 years, 1,222 events of cardiovascular death, myocardial infarction, or stroke occurred. No significant difference in event rates was found between the saxagliptin and placebo groups. This did not demonstrate the expected cardiovascular benefit based on prior meta-analysis of phase 2B and phase 3 data presented above, but saxagliptin did not increase cardiovascular risk and was the first diabetes drug to earn this distinction of robustly statistically proven cardiovascular safety.

Further analysis of the SAVOR-TIMI 53 trial data revealed a 27% increased relative risk of heart failure hospitalization with saxagliptin compared with placebo.¹⁴ Although the risk was statistically significant, the absolute difference in heart failure incidence between the drug and placebo groups was only 0.7% (3.5% vs 2.8%, respectively). As the average follow-up in the trial was 2 years, the absolute incremental risk of heart failure seen with saxagliptin is 0.35% annually—almost identical in magnitude to the increased heart failure risk with pioglitazone. The increased risk of heart failure was seen within the first 6 months of the trial and persisted throughout the trial, indicating an increased up-front risk of heart failure.

Alogliptin

The EXAMINE trial¹⁵ compared the DPP-4 inhibitor alogliptin and placebo in 5,380 patients with type 2 diabetes who had had a recent acute coronary event.¹⁵ Over the 30 months of the trial, more than 600 primary outcome events of cardiovascular death, myocardial infarction, or stroke occurred, with no significant difference between drug and placebo groups with established nominal statistical noninferiority. A numerically higher incidence of heart failure was noted in patients who received alogliptin than with placebo, but the difference was not statistically significant.¹⁶ However, this study was not powered to detect such an increased risk. In patients entering the trial with no history of heart failure, the risk of hospitalization for heart failure was 76% higher in the alogliptin group than in the placebo group, with a nominally significant P value less than .05 in this subgroup.

These analyses led the FDA in 2016 to mandate label warnings for saxagliptin and alogliptin regarding the increased risk of heart failure.¹⁷

Sitagliptin

The TECOS trial¹⁸ tested the DPP-4 inhibitor sitagliptin and, unlike the SAVOR or EXAMINE trials, included hospitalization for unstable angina in the composite end point. Nearly 15,000 patients with type 2 diabetes and established cardiovascular disease were enrolled, and almost 2,500 events occurred. No significant difference was found between the 2 groups.

In a series of analyses prospectively planned, sitagliptin was not associated with an increased risk of hospitalization for heart failure.¹⁹ But despite these robust analyses demonstrating no incremental heart failure risk with sitagliptin, in August 2017, the US product label for sitagliptin was modified to include a warning that other DPP-4 inhibitors have been associated with heart failure and to suggest caution. The label for linagliptin had the same FDA-required changes, with no data yet available from outcomes trials with linagliptin.

GLP-1 RECEPTOR AGONISTS

Lixisenatide: Noninferior to placebo

The ELIXA trial²⁰ assessed the cardiovascular safety of the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes who recently had an acute coronary event. The study enrolled 6,068 patients from 49 countries, and nearly 1,000 events (cardiovascular death, myocardial infarction, stroke, or unstable angina) occurred during the median 25 months of the study. Results showed lixisenatide did not increase or decrease cardiovascular events or adverse events when compared with placebo.

Liraglutide: Evidence of benefit

The LEADER trial²¹ randomized 9,340 patients with or at increased risk for cardiovascular disease to receive the injectable GLP-1 receptor agonist liraglutide or placebo. After a median of 3.8 years of follow-up, liraglutide use was associated with a statistically significant 13% relative reduction in major adverse cardiovascular events, mostly driven by a 22% reduction in cardiovascular death.

Semaglutide: Evidence of benefit

The SUSTAIN-6 trial²² found a statistically significant 26% relative risk reduction in cardiovascular outcomes comparing once-weekly semaglutide (an injectable GLP-1 receptor agonist) and placebo in 3,297 patients with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or risk factors for cardiovascular disease. The significant reduction in the incidence of nonfatal stroke with semaglutide was the main driver of the observed benefit.

Taspoglutide: Development halted

Taspoglutide was a candidate GLP-1 receptor agonist that underwent clinical trials for cardiovascular outcomes planned to involve about 8,000 patients. The trials were stopped early and drug development was halted after about 600 patient-years of exposure because of antibody formation in about half of patients exposed to taspoglutide, with anaphylactoid reactions and anaphylaxis reported.²³

SGLT-2 INHIBITORS

The renal glomeruli filter about 180 g of glucose every day in normal adults; nearly all of it is reabsorbed by SGLT-2 in the proximal tubules, so that very little glucose is excreted in the urine.^24–26 The benign condition hereditary glucosuria occurs due to loss-of-function mutations in the gene for SGLT-2. Individuals with this condition rarely if ever develop type 2 diabetes or obesity, and this observation led pharmaceutical researchers to probe SGLT-2 as a therapeutic target.

Inhibitors of SGLT-2 block glucose reabsorption in the renal proximal tubules and lead to glucosuria. Patients treated with an SGLT-2 inhibitor have lower serum glucose levels and lose weight. Inhibitors also reduce sodium reabsorption via SGLT-2 and lead to increased sodium excretion and decreased blood pressure.²⁷

Three SGLT-2 antagonists are available in the United States: canagliflozin, dapagliflozin, and empagliflozin (Table 1). Ertugliflozin is currently in a phase 3B trial, and cardiovascular outcomes trials are in the planning phase for sotagliflozin, a dual SGLT-1/SGLT-2 inhibitor with SGLT-1 localized to the gastrointestinal tract.²⁸

Empaglifozin: Evidence of benefit

The EMPA-REG OUTCOME trial²⁹ randomized more than 7,200 patients with type 2 diabetes and atherosclerotic vascular disease to receive the SGLT-2 inhibitor empagliflozin or placebo as once-daily tablets, with both groups receiving off-study treatment for glycemic control at the discretion of their own care providers. Two doses of empagliflozin were evaluated in the trial (10 and 25 mg per day), with the 2 dosing groups pooled for all analyses as prospectively planned.

Patients taking empagliflozin had a 14% relative risk reduction of the composite outcome (cardiovascular death, myocardial infarction, and stroke) vs placebo, with no difference in effect between the 2 randomized doses. The improvement in the composite outcome was seen early in the empagliflozin group and persisted for the 4 years of the study.

This was the first trial of newly developed diabetes drugs that showed a statistically significant reduction in cardiovascular risk. The study revealed a 38% relative risk reduction in cardiovascular death in the treatment group. The risk reduction occurred early in the trial and improved throughout the duration of the study. This is a dramatic finding, unequaled even in trials of drugs that specifically target cardiovascular disease. Both doses of empagliflozin studied provided similar benefit over placebo, reinforcing the validity of the findings. Interestingly, in the empagliflozin group, there was a 35% relative risk reduction in heart failure hospitalizations.

Canaglifozin: Evidence of benefit

The CANVAS Program consisted of two sister trials, CANVAS and CANVAS-R, and examined the safety and efficacy of canagliflozin.³⁰ More than 10,000 participants with type 2 diabetes and atherosclerotic disease or at increased risk of cardiovascular disease were randomized to receive canagliflozin or placebo. Canagliflozin led to a 14% relative risk reduction in the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, but there was a statistically significant doubling in the incidence of amputations. Unlike empagliflozin, canagliflozin did not demonstrate a significant reduction in death from cardiovascular causes, suggesting that this may not be a class effect of SGLT-2 inhibitors. As with empagliflozin, canagliflozin led to a 33% relative risk reduction in heart failure hospitalizations.

Cardiovascular benefits independent of glucose-lowering

The cardiovascular benefits of empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS were observed early, suggesting that the mechanism may be due to the direct effects on the cardiovascular system rather than glycemic modification.

Improved glycemic control with the SGLT-2 inhibitor was seen early in both studies, but with the trials designed for glycemic equipoise encouraging open-label therapy targeting hemoglobin A_1c to standard-of-care targets in both groups, the contrast in hemoglobin A_1c between groups diminished throughout the trial after its first assessment. Although hemoglobin A_1c levels in the SGLT-2 inhibitor groups decreased in the first 12 weeks, they increased over time nearly to the level seen in the placebo group. The adjusted mean hemoglobin A_1c level in the placebo groups remained near 8.0% throughout the studies, a target consistent with guidelines from the American Diabetes Association and the European Association for the Study of Diabetes³¹ for the high-risk populations recruited and enrolled.

Blood pressure reduction and weight loss do not explain cardiovascular benefits

SGLT-2 inhibitors lower blood pressure independent of their diuretic effects. In the EMPA-REG OUTCOME trial, the adjusted mean systolic blood pressure was 3 to 4 mm Hg lower in the treatment groups than in the placebo group throughout the trial.²⁹ This level of blood pressure lowering translates to an estimated 10% to 12% relative risk reduction for major adverse cardiovascular events, including heart failure. Although the risk reduction from blood pressure lowering is not insignificant, it does not explain the 38% reduction in cardiovascular deaths seen in the trial. Canagliflozin led to a similar 4-mm Hg reduction in systolic pressure compared with the placebo group.³⁰

Weight loss was seen with both empagliflozin and canagliflozin but was not dramatic and is unlikely to account for the described cardiovascular benefits.

Theories of cardiovascular benefit

Several mechanisms have been proposed to help explain the observed cardiovascular benefits of SGLT-2 inhibitors.³²

Ketone-body elevation. Ferrannini et al³³ found that the blood concentration of the ketone-body beta-hydroxybutyrate is about twice as high in patients with type 2 diabetes in the fasting state who are chronically taking empagliflozin as in  patients not receiving the drug. Beta-hydroxybutyrate levels peak after a meal and then return to baseline over several hours before rising again during the fasting period. Although the ketone elevation is not nearly as extreme as in diabetic ketoacidosis (about a 1,000-fold increase), the observed increase may reduce myocardial oxygen demand, as beta-hydroxybutyrate is among the most efficient metabolic substrates for the myocardium.       

Red blood cell expansion. Perhaps a more likely explanation of the cardiovascular benefit seen with SGLT-2 inhibitor therapy is the increase in hemoglobin and hematocrit levels. At first attributed to hemoconcentration secondary to diuresis, this has been disproven by a number of studies. The EMPA-REG OUTCOME trial²⁹ found that within 12 weeks of exposure to empagliflozin, hematocrit levels rose nearly 4% absolutely compared with the levels in the placebo group. This increase is equivalent to transfusing a unit of red blood cells, favorably affecting myocardial oxygen supply.

Reduction in glomerular hypertension. The kidneys regulate glomerular filtration in a process involving the macula densa, an area of specialized cells in the juxtaglomerular apparatus in the loop of Henle that responds to sodium concentration in the urine. Normally, SGLT-2 receptors upstream from the loop of Henle reabsorb sodium and glucose into the bloodstream, reducing sodium delivery to the macula densa, which senses this as a low-volume state. The macula densa cells respond by releasing factors that dilate afferent arterioles and increase glomerular filtration. People with diabetes have more glucose to reabsorb and therefore also reabsorb more sodium, leading to glomerular hypertension.

SGLT-2 inhibitors block both glucose and sodium reuptake at SGLT-2 receptors, normalizing the response at the macula densa, restoring a normal glomerular filtration rate, and alleviating glomerular hypertension. As the kidney perceives a more normal volume status, renin-angiotensin-aldosterone stimulation is attenuated and sympathetic nervous system activity improves.^27,34 If this model of SGLT-2 inhibitor effects on the kidney is correct, these drugs have similar effects as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid antagonists, and beta-blockers combined.

 

 

Kidney benefits

Empagliflozin³⁵ and canagliflozin³⁰ both reduced the rate of progression of kidney dysfunction and led to fewer clinically relevant renal events compared with placebo. Treatment and placebo groups also received standard care, so many patients were treated with renin-angiotensin-aldosterone system inhibitors and with good blood pressure control, making the finding that SGLT-2 inhibitors had a significant beneficial effect even more dramatic. Beneficial effects on markers of kidney function were seen early on, suggesting a more favorable hemodynamic effect on the kidney rather than improved glycemic control attenuating microvascular disease.

Empagliflozin approved to reduce clinical events

In December 2016, the FDA approved the indication for empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes,³⁶ the first-ever clinical outcome indication for a type 2 diabetes medication. The European Society of Cardiology guidelines now include empagliflozin as preferred therapy for type 2 diabetes, recommending it to prevent the onset of heart failure and prolong life.³⁷ This recommendation goes beyond the evidence from the EMPA-REG OUTCOME trial on which it is based, as the trial only studied patients with known atherosclerotic vascular disease.

The 2016 European Guidelines on cardiovascular disease prevention also recommend that an SGLT-2 inhibitor be considered early for patients with type 2 diabetes and cardiovascular disease to reduce cardiovascular and total mortality.³⁸ The American Diabetes Association in their 2017 guidelines also endorse empagliflozin for treating patients with type 2 diabetes and cardiovascular disease.³⁹ The fact that the American Diabetes Association recommendation is not based on glycemic control, in line with the product-labeled indication, is a major shift in the association’s guidance.

Cautions with SGLT-2 inhibitors

• Use SGLT-2 inhibitors in patients with low blood pressure with caution, and with increased blood pressure monitoring just following initiation.
• Consider modifying antihypertensive drugs in patients with labile blood pressure.
• Consider stopping or reducing background diuretics when starting an SGLT-2 inhibitor, and reassess volume status after 1 to 2 weeks.
• For patients on insulin, sulfonylureas, or both, consider decreasing dosages when starting an SGLT-2 inhibitor, and reassess glycemic control periodically.
• Counsel patients about urinary hygiene. Although bacterial urinary tract infections have not emerged as a problem, fungal genital infections have, particularly in women and uncircumcised men.
• Consider SGLT-2 inhibitors to be “sick-day” medications. Patients with diabetes must adjust their diabetes medications if their oral intake is reduced for a day or more, such as while sick or fasting. SGLT-2 inhibitors should not be taken on these days. Cases of diabetic ketoacidosis have arisen in patients who reduced oral intake while continuing their SGLT-2 inhibitor.

OTHER DRUGS WITH DEVELOPMENT HALTED

Aleglitazar, a peroxisome proliferator-activated receptor agonist taken orally once daily, raised high expectations when it was found in early studies to lower serum triglycerides and raise high-density lipoprotein cholesterol levels in addition to lowering blood glucose. However, a phase 3 trial in more than 7,000 patients was terminated after a median follow up of 2 years because of increased rates of heart failure, worsened kidney function, bone fractures, and gastrointestinal bleeding.⁴⁰ Development of this drug was stopped.

Fasiglifam, a G-protein-coupled receptor 40 agonist, was tested in a cardiovascular clinical outcomes trial. Compared with placebo, fasiglifam reduced hemoglobin A_1c  levels with low risk of hypoglycemia.⁴¹ However,  safety concerns about increased liver enzyme levels led to the cessation of the drug’s development.⁴²

HOW WILL THIS AFFECT DIABETES MANAGEMENT?

Metformin is still the most commonly prescribed drug for type 2 diabetes but has only marginal evidence for its cardiovascular benefits and may not be the first-line therapy for the management of diabetes in the future. In the EMPA REG OUTCOME, LEADER, and SUSTAIN-6 trials, the novel diabetes medications were given to patients who were already treated with available therapies, often including metformin. Treatment with empagliflozin, liraglutide, and semaglutide may be indicated for patients with diabetes and atherosclerotic vascular disease as first-line therapies in the future.

SGLT-2 inhibitor therapy can cost about $500 per month, and GLP-1 inhibitors are only slightly less expensive. The cost may be prohibitive for many patients. As more evidence, guidelines, and FDA criteria support the use of these novel diabetes drugs, third-party payers and pharmaceutical companies may be motivated to lower costs to help reach more patients who can benefit from these therapies.

Since 2008, the US Food and Drug Administration (FDA) has required new diabetes drugs to demonstrate cardiovascular safety, resulting in large and lengthy clinical trials. Under the new regulations, several dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular safety, with some demonstrating superior cardiovascular efficacy. In 2016, the SGLT-2 inhibitor empagliflozin became the first (and as of this writing, the only) diabetes drug approved by the FDA for a clinical outcome indication, ie, to reduce the risk of cardiovascular death.

DIABETES DRUG DEVELOPMENT

Changing priorities

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was formed in 1990 as a collaborative effort across global regulatory agencies and coordinated by the World Health Organization to universalize criteria for drug development. The ICH standards for type 2 diabetes drug development included the following requirements for patient exposure to investigational products to satisfy new drug application requirements:

• 1,500 individuals total (including single-dose exposure)
• 300–600 patients for 6 months
• 100 patients for 1 year.

Thus, just 250 patient-years of exposure were needed for approval of a drug that patients might take for decades. These standards were unlikely to reveal rare, serious complications and had no ability to assess clinical outcomes efficacy for either microvascular or macrovascular disease complications.

Since 1995, when metformin was approved in the United States, a new class of antihyperglycemic medication has been approved about once every 2 years, so that by 2008, 12 classes of medications had become available for the treatment of type 2 diabetes. This extraordinary rate of drug development has now yielded more classes of medications to treat type 2 diabetes than we presently have for the treatment of hypertension.

This proliferation of new treatments resolved much of the pressure of the unmet medical need, over a period of increasing awareness of the cardiovascular complications of type 2 diabetes, along with numerous examples of adverse cardiovascular effects observed with some of the drugs. In this context, the FDA (and in parallel the European Medicines Agency) made paradigm-shifting changes in the requirements for the development of new type 2 diabetes drugs, requiring large-scale randomized clinical outcome data to assess cardiovascular safety of the new drugs. In December 2008, the FDA published a Guidance for Industry,¹ recommending that sponsors of new drugs for type 2 diabetes demonstrate that therapy would not only improve glucose control, but also that it would, at a minimum, not result in an unacceptable increase in cardiovascular risk.¹ To better assess new diabetes drugs, the requirement for patient-years of exposure to the studied drug was increased by over 60-fold from 250 patient-years to more than 15,000.

INCRETIN MODULATORS

The incretin system, a regulator of postprandial glucose metabolism, is an attractive target for glycemic control, as it promotes early satiety and lowers blood glucose.

After a meal, endocrine cells in the distal small intestine secrete the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP), among others, which reduce gastric motility, stimulate the pancreas to augment glucose-appropriate insulin secretion, and decrease postprandial glucagon release. GLP-1 also interacts with the satiety center of the hypothalamus, suppressing appetite. GLP-1 and GIP are rapidly inactivated by the circulating protease DPP-4. Injectable formulations of GLP-1 receptor agonists that are resistant to DPP-4 degradation have been developed.

Ten incretin modulators are now available in the United States. The 4 available DPP-4 inhibitors are all once-daily oral medications, and the 6 GLP-1 receptor agonists are all injectable (Table 1).

Small studies in humans and animals suggest that DPP-4 inhibitors and GLP-1-receptor agonists may have multiple favorable effects on the cardiovascular system independent of their glycemic effects. These include reducing myocardial infarct size,^2–5 improving endothelial function,⁶ reducing inflammation and oxidative stress,⁷ reducing atherosclerotic plaque volume,⁸ improving left ventricular function, ^9,10 and lowering triglyceride levels.¹¹ However, large clinical trials are needed to determine clinical effectiveness.

DPP-4 INHIBITORS: NOT INFERIOR TO PLACEBO 

Saxagliptin

Saxagliptin, a DPP-4 inhibitor, was found in a meta-analysis of phase 2B and early phase 3 trial data involving almost 5,000 patients to be associated with a dramatic 56% relative risk reduction in cardiovascular death, heart attack, and stroke. However, this analysis was limited by the extremely low number of events to analyze, with only 41 total patients with cardiovascular events in that dataset.¹²

The SAVOR-TIMI 53 trial¹³ subsequently compared saxagliptin and placebo in a randomized, double-blind trial conducted in 26 countries with nearly 16,500 patients with type 2 diabetes. All patients continued their conventional diabetes treatment at the discretion of their physicians.

During an average follow-up of 2 years, 1,222 events of cardiovascular death, myocardial infarction, or stroke occurred. No significant difference in event rates was found between the saxagliptin and placebo groups. This did not demonstrate the expected cardiovascular benefit based on prior meta-analysis of phase 2B and phase 3 data presented above, but saxagliptin did not increase cardiovascular risk and was the first diabetes drug to earn this distinction of robustly statistically proven cardiovascular safety.

Further analysis of the SAVOR-TIMI 53 trial data revealed a 27% increased relative risk of heart failure hospitalization with saxagliptin compared with placebo.¹⁴ Although the risk was statistically significant, the absolute difference in heart failure incidence between the drug and placebo groups was only 0.7% (3.5% vs 2.8%, respectively). As the average follow-up in the trial was 2 years, the absolute incremental risk of heart failure seen with saxagliptin is 0.35% annually—almost identical in magnitude to the increased heart failure risk with pioglitazone. The increased risk of heart failure was seen within the first 6 months of the trial and persisted throughout the trial, indicating an increased up-front risk of heart failure.

Alogliptin

The EXAMINE trial¹⁵ compared the DPP-4 inhibitor alogliptin and placebo in 5,380 patients with type 2 diabetes who had had a recent acute coronary event.¹⁵ Over the 30 months of the trial, more than 600 primary outcome events of cardiovascular death, myocardial infarction, or stroke occurred, with no significant difference between drug and placebo groups with established nominal statistical noninferiority. A numerically higher incidence of heart failure was noted in patients who received alogliptin than with placebo, but the difference was not statistically significant.¹⁶ However, this study was not powered to detect such an increased risk. In patients entering the trial with no history of heart failure, the risk of hospitalization for heart failure was 76% higher in the alogliptin group than in the placebo group, with a nominally significant P value less than .05 in this subgroup.

These analyses led the FDA in 2016 to mandate label warnings for saxagliptin and alogliptin regarding the increased risk of heart failure.¹⁷

Sitagliptin

The TECOS trial¹⁸ tested the DPP-4 inhibitor sitagliptin and, unlike the SAVOR or EXAMINE trials, included hospitalization for unstable angina in the composite end point. Nearly 15,000 patients with type 2 diabetes and established cardiovascular disease were enrolled, and almost 2,500 events occurred. No significant difference was found between the 2 groups.

In a series of analyses prospectively planned, sitagliptin was not associated with an increased risk of hospitalization for heart failure.¹⁹ But despite these robust analyses demonstrating no incremental heart failure risk with sitagliptin, in August 2017, the US product label for sitagliptin was modified to include a warning that other DPP-4 inhibitors have been associated with heart failure and to suggest caution. The label for linagliptin had the same FDA-required changes, with no data yet available from outcomes trials with linagliptin.

GLP-1 RECEPTOR AGONISTS

Lixisenatide: Noninferior to placebo

The ELIXA trial²⁰ assessed the cardiovascular safety of the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes who recently had an acute coronary event. The study enrolled 6,068 patients from 49 countries, and nearly 1,000 events (cardiovascular death, myocardial infarction, stroke, or unstable angina) occurred during the median 25 months of the study. Results showed lixisenatide did not increase or decrease cardiovascular events or adverse events when compared with placebo.

Liraglutide: Evidence of benefit

The LEADER trial²¹ randomized 9,340 patients with or at increased risk for cardiovascular disease to receive the injectable GLP-1 receptor agonist liraglutide or placebo. After a median of 3.8 years of follow-up, liraglutide use was associated with a statistically significant 13% relative reduction in major adverse cardiovascular events, mostly driven by a 22% reduction in cardiovascular death.

Semaglutide: Evidence of benefit

The SUSTAIN-6 trial²² found a statistically significant 26% relative risk reduction in cardiovascular outcomes comparing once-weekly semaglutide (an injectable GLP-1 receptor agonist) and placebo in 3,297 patients with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or risk factors for cardiovascular disease. The significant reduction in the incidence of nonfatal stroke with semaglutide was the main driver of the observed benefit.

Taspoglutide: Development halted

Taspoglutide was a candidate GLP-1 receptor agonist that underwent clinical trials for cardiovascular outcomes planned to involve about 8,000 patients. The trials were stopped early and drug development was halted after about 600 patient-years of exposure because of antibody formation in about half of patients exposed to taspoglutide, with anaphylactoid reactions and anaphylaxis reported.²³

SGLT-2 INHIBITORS

The renal glomeruli filter about 180 g of glucose every day in normal adults; nearly all of it is reabsorbed by SGLT-2 in the proximal tubules, so that very little glucose is excreted in the urine.^24–26 The benign condition hereditary glucosuria occurs due to loss-of-function mutations in the gene for SGLT-2. Individuals with this condition rarely if ever develop type 2 diabetes or obesity, and this observation led pharmaceutical researchers to probe SGLT-2 as a therapeutic target.

Inhibitors of SGLT-2 block glucose reabsorption in the renal proximal tubules and lead to glucosuria. Patients treated with an SGLT-2 inhibitor have lower serum glucose levels and lose weight. Inhibitors also reduce sodium reabsorption via SGLT-2 and lead to increased sodium excretion and decreased blood pressure.²⁷

Three SGLT-2 antagonists are available in the United States: canagliflozin, dapagliflozin, and empagliflozin (Table 1). Ertugliflozin is currently in a phase 3B trial, and cardiovascular outcomes trials are in the planning phase for sotagliflozin, a dual SGLT-1/SGLT-2 inhibitor with SGLT-1 localized to the gastrointestinal tract.²⁸

Empaglifozin: Evidence of benefit

The EMPA-REG OUTCOME trial²⁹ randomized more than 7,200 patients with type 2 diabetes and atherosclerotic vascular disease to receive the SGLT-2 inhibitor empagliflozin or placebo as once-daily tablets, with both groups receiving off-study treatment for glycemic control at the discretion of their own care providers. Two doses of empagliflozin were evaluated in the trial (10 and 25 mg per day), with the 2 dosing groups pooled for all analyses as prospectively planned.

Patients taking empagliflozin had a 14% relative risk reduction of the composite outcome (cardiovascular death, myocardial infarction, and stroke) vs placebo, with no difference in effect between the 2 randomized doses. The improvement in the composite outcome was seen early in the empagliflozin group and persisted for the 4 years of the study.

This was the first trial of newly developed diabetes drugs that showed a statistically significant reduction in cardiovascular risk. The study revealed a 38% relative risk reduction in cardiovascular death in the treatment group. The risk reduction occurred early in the trial and improved throughout the duration of the study. This is a dramatic finding, unequaled even in trials of drugs that specifically target cardiovascular disease. Both doses of empagliflozin studied provided similar benefit over placebo, reinforcing the validity of the findings. Interestingly, in the empagliflozin group, there was a 35% relative risk reduction in heart failure hospitalizations.

Canaglifozin: Evidence of benefit

The CANVAS Program consisted of two sister trials, CANVAS and CANVAS-R, and examined the safety and efficacy of canagliflozin.³⁰ More than 10,000 participants with type 2 diabetes and atherosclerotic disease or at increased risk of cardiovascular disease were randomized to receive canagliflozin or placebo. Canagliflozin led to a 14% relative risk reduction in the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, but there was a statistically significant doubling in the incidence of amputations. Unlike empagliflozin, canagliflozin did not demonstrate a significant reduction in death from cardiovascular causes, suggesting that this may not be a class effect of SGLT-2 inhibitors. As with empagliflozin, canagliflozin led to a 33% relative risk reduction in heart failure hospitalizations.

Cardiovascular benefits independent of glucose-lowering

The cardiovascular benefits of empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS were observed early, suggesting that the mechanism may be due to the direct effects on the cardiovascular system rather than glycemic modification.

Improved glycemic control with the SGLT-2 inhibitor was seen early in both studies, but with the trials designed for glycemic equipoise encouraging open-label therapy targeting hemoglobin A_1c to standard-of-care targets in both groups, the contrast in hemoglobin A_1c between groups diminished throughout the trial after its first assessment. Although hemoglobin A_1c levels in the SGLT-2 inhibitor groups decreased in the first 12 weeks, they increased over time nearly to the level seen in the placebo group. The adjusted mean hemoglobin A_1c level in the placebo groups remained near 8.0% throughout the studies, a target consistent with guidelines from the American Diabetes Association and the European Association for the Study of Diabetes³¹ for the high-risk populations recruited and enrolled.

Blood pressure reduction and weight loss do not explain cardiovascular benefits

SGLT-2 inhibitors lower blood pressure independent of their diuretic effects. In the EMPA-REG OUTCOME trial, the adjusted mean systolic blood pressure was 3 to 4 mm Hg lower in the treatment groups than in the placebo group throughout the trial.²⁹ This level of blood pressure lowering translates to an estimated 10% to 12% relative risk reduction for major adverse cardiovascular events, including heart failure. Although the risk reduction from blood pressure lowering is not insignificant, it does not explain the 38% reduction in cardiovascular deaths seen in the trial. Canagliflozin led to a similar 4-mm Hg reduction in systolic pressure compared with the placebo group.³⁰

Weight loss was seen with both empagliflozin and canagliflozin but was not dramatic and is unlikely to account for the described cardiovascular benefits.

Theories of cardiovascular benefit

Several mechanisms have been proposed to help explain the observed cardiovascular benefits of SGLT-2 inhibitors.³²

Ketone-body elevation. Ferrannini et al³³ found that the blood concentration of the ketone-body beta-hydroxybutyrate is about twice as high in patients with type 2 diabetes in the fasting state who are chronically taking empagliflozin as in  patients not receiving the drug. Beta-hydroxybutyrate levels peak after a meal and then return to baseline over several hours before rising again during the fasting period. Although the ketone elevation is not nearly as extreme as in diabetic ketoacidosis (about a 1,000-fold increase), the observed increase may reduce myocardial oxygen demand, as beta-hydroxybutyrate is among the most efficient metabolic substrates for the myocardium.       

Red blood cell expansion. Perhaps a more likely explanation of the cardiovascular benefit seen with SGLT-2 inhibitor therapy is the increase in hemoglobin and hematocrit levels. At first attributed to hemoconcentration secondary to diuresis, this has been disproven by a number of studies. The EMPA-REG OUTCOME trial²⁹ found that within 12 weeks of exposure to empagliflozin, hematocrit levels rose nearly 4% absolutely compared with the levels in the placebo group. This increase is equivalent to transfusing a unit of red blood cells, favorably affecting myocardial oxygen supply.

Reduction in glomerular hypertension. The kidneys regulate glomerular filtration in a process involving the macula densa, an area of specialized cells in the juxtaglomerular apparatus in the loop of Henle that responds to sodium concentration in the urine. Normally, SGLT-2 receptors upstream from the loop of Henle reabsorb sodium and glucose into the bloodstream, reducing sodium delivery to the macula densa, which senses this as a low-volume state. The macula densa cells respond by releasing factors that dilate afferent arterioles and increase glomerular filtration. People with diabetes have more glucose to reabsorb and therefore also reabsorb more sodium, leading to glomerular hypertension.

SGLT-2 inhibitors block both glucose and sodium reuptake at SGLT-2 receptors, normalizing the response at the macula densa, restoring a normal glomerular filtration rate, and alleviating glomerular hypertension. As the kidney perceives a more normal volume status, renin-angiotensin-aldosterone stimulation is attenuated and sympathetic nervous system activity improves.^27,34 If this model of SGLT-2 inhibitor effects on the kidney is correct, these drugs have similar effects as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid antagonists, and beta-blockers combined.

 

 

Kidney benefits

Empagliflozin³⁵ and canagliflozin³⁰ both reduced the rate of progression of kidney dysfunction and led to fewer clinically relevant renal events compared with placebo. Treatment and placebo groups also received standard care, so many patients were treated with renin-angiotensin-aldosterone system inhibitors and with good blood pressure control, making the finding that SGLT-2 inhibitors had a significant beneficial effect even more dramatic. Beneficial effects on markers of kidney function were seen early on, suggesting a more favorable hemodynamic effect on the kidney rather than improved glycemic control attenuating microvascular disease.

Empagliflozin approved to reduce clinical events

In December 2016, the FDA approved the indication for empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes,³⁶ the first-ever clinical outcome indication for a type 2 diabetes medication. The European Society of Cardiology guidelines now include empagliflozin as preferred therapy for type 2 diabetes, recommending it to prevent the onset of heart failure and prolong life.³⁷ This recommendation goes beyond the evidence from the EMPA-REG OUTCOME trial on which it is based, as the trial only studied patients with known atherosclerotic vascular disease.

The 2016 European Guidelines on cardiovascular disease prevention also recommend that an SGLT-2 inhibitor be considered early for patients with type 2 diabetes and cardiovascular disease to reduce cardiovascular and total mortality.³⁸ The American Diabetes Association in their 2017 guidelines also endorse empagliflozin for treating patients with type 2 diabetes and cardiovascular disease.³⁹ The fact that the American Diabetes Association recommendation is not based on glycemic control, in line with the product-labeled indication, is a major shift in the association’s guidance.

Cautions with SGLT-2 inhibitors

• Use SGLT-2 inhibitors in patients with low blood pressure with caution, and with increased blood pressure monitoring just following initiation.
• Consider modifying antihypertensive drugs in patients with labile blood pressure.
• Consider stopping or reducing background diuretics when starting an SGLT-2 inhibitor, and reassess volume status after 1 to 2 weeks.
• For patients on insulin, sulfonylureas, or both, consider decreasing dosages when starting an SGLT-2 inhibitor, and reassess glycemic control periodically.
• Counsel patients about urinary hygiene. Although bacterial urinary tract infections have not emerged as a problem, fungal genital infections have, particularly in women and uncircumcised men.
• Consider SGLT-2 inhibitors to be “sick-day” medications. Patients with diabetes must adjust their diabetes medications if their oral intake is reduced for a day or more, such as while sick or fasting. SGLT-2 inhibitors should not be taken on these days. Cases of diabetic ketoacidosis have arisen in patients who reduced oral intake while continuing their SGLT-2 inhibitor.

OTHER DRUGS WITH DEVELOPMENT HALTED

Aleglitazar, a peroxisome proliferator-activated receptor agonist taken orally once daily, raised high expectations when it was found in early studies to lower serum triglycerides and raise high-density lipoprotein cholesterol levels in addition to lowering blood glucose. However, a phase 3 trial in more than 7,000 patients was terminated after a median follow up of 2 years because of increased rates of heart failure, worsened kidney function, bone fractures, and gastrointestinal bleeding.⁴⁰ Development of this drug was stopped.

Fasiglifam, a G-protein-coupled receptor 40 agonist, was tested in a cardiovascular clinical outcomes trial. Compared with placebo, fasiglifam reduced hemoglobin A_1c  levels with low risk of hypoglycemia.⁴¹ However,  safety concerns about increased liver enzyme levels led to the cessation of the drug’s development.⁴²

HOW WILL THIS AFFECT DIABETES MANAGEMENT?

Metformin is still the most commonly prescribed drug for type 2 diabetes but has only marginal evidence for its cardiovascular benefits and may not be the first-line therapy for the management of diabetes in the future. In the EMPA REG OUTCOME, LEADER, and SUSTAIN-6 trials, the novel diabetes medications were given to patients who were already treated with available therapies, often including metformin. Treatment with empagliflozin, liraglutide, and semaglutide may be indicated for patients with diabetes and atherosclerotic vascular disease as first-line therapies in the future.

SGLT-2 inhibitor therapy can cost about $500 per month, and GLP-1 inhibitors are only slightly less expensive. The cost may be prohibitive for many patients. As more evidence, guidelines, and FDA criteria support the use of these novel diabetes drugs, third-party payers and pharmaceutical companies may be motivated to lower costs to help reach more patients who can benefit from these therapies.

Since 2008, the US Food and Drug Administration (FDA) has required new diabetes drugs to demonstrate cardiovascular safety, resulting in large and lengthy clinical trials. Under the new regulations, several dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular safety, with some demonstrating superior cardiovascular efficacy. In 2016, the SGLT-2 inhibitor empagliflozin became the first (and as of this writing, the only) diabetes drug approved by the FDA for a clinical outcome indication, ie, to reduce the risk of cardiovascular death.

DIABETES DRUG DEVELOPMENT

Changing priorities

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was formed in 1990 as a collaborative effort across global regulatory agencies and coordinated by the World Health Organization to universalize criteria for drug development. The ICH standards for type 2 diabetes drug development included the following requirements for patient exposure to investigational products to satisfy new drug application requirements:

• 1,500 individuals total (including single-dose exposure)
• 300–600 patients for 6 months
• 100 patients for 1 year.

Thus, just 250 patient-years of exposure were needed for approval of a drug that patients might take for decades. These standards were unlikely to reveal rare, serious complications and had no ability to assess clinical outcomes efficacy for either microvascular or macrovascular disease complications.

Since 1995, when metformin was approved in the United States, a new class of antihyperglycemic medication has been approved about once every 2 years, so that by 2008, 12 classes of medications had become available for the treatment of type 2 diabetes. This extraordinary rate of drug development has now yielded more classes of medications to treat type 2 diabetes than we presently have for the treatment of hypertension.

This proliferation of new treatments resolved much of the pressure of the unmet medical need, over a period of increasing awareness of the cardiovascular complications of type 2 diabetes, along with numerous examples of adverse cardiovascular effects observed with some of the drugs. In this context, the FDA (and in parallel the European Medicines Agency) made paradigm-shifting changes in the requirements for the development of new type 2 diabetes drugs, requiring large-scale randomized clinical outcome data to assess cardiovascular safety of the new drugs. In December 2008, the FDA published a Guidance for Industry,¹ recommending that sponsors of new drugs for type 2 diabetes demonstrate that therapy would not only improve glucose control, but also that it would, at a minimum, not result in an unacceptable increase in cardiovascular risk.¹ To better assess new diabetes drugs, the requirement for patient-years of exposure to the studied drug was increased by over 60-fold from 250 patient-years to more than 15,000.

INCRETIN MODULATORS

The incretin system, a regulator of postprandial glucose metabolism, is an attractive target for glycemic control, as it promotes early satiety and lowers blood glucose.

After a meal, endocrine cells in the distal small intestine secrete the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP), among others, which reduce gastric motility, stimulate the pancreas to augment glucose-appropriate insulin secretion, and decrease postprandial glucagon release. GLP-1 also interacts with the satiety center of the hypothalamus, suppressing appetite. GLP-1 and GIP are rapidly inactivated by the circulating protease DPP-4. Injectable formulations of GLP-1 receptor agonists that are resistant to DPP-4 degradation have been developed.

Ten incretin modulators are now available in the United States. The 4 available DPP-4 inhibitors are all once-daily oral medications, and the 6 GLP-1 receptor agonists are all injectable (Table 1).

Small studies in humans and animals suggest that DPP-4 inhibitors and GLP-1-receptor agonists may have multiple favorable effects on the cardiovascular system independent of their glycemic effects. These include reducing myocardial infarct size,^2–5 improving endothelial function,⁶ reducing inflammation and oxidative stress,⁷ reducing atherosclerotic plaque volume,⁸ improving left ventricular function, ^9,10 and lowering triglyceride levels.¹¹ However, large clinical trials are needed to determine clinical effectiveness.

DPP-4 INHIBITORS: NOT INFERIOR TO PLACEBO 

Saxagliptin

Saxagliptin, a DPP-4 inhibitor, was found in a meta-analysis of phase 2B and early phase 3 trial data involving almost 5,000 patients to be associated with a dramatic 56% relative risk reduction in cardiovascular death, heart attack, and stroke. However, this analysis was limited by the extremely low number of events to analyze, with only 41 total patients with cardiovascular events in that dataset.¹²

The SAVOR-TIMI 53 trial¹³ subsequently compared saxagliptin and placebo in a randomized, double-blind trial conducted in 26 countries with nearly 16,500 patients with type 2 diabetes. All patients continued their conventional diabetes treatment at the discretion of their physicians.

During an average follow-up of 2 years, 1,222 events of cardiovascular death, myocardial infarction, or stroke occurred. No significant difference in event rates was found between the saxagliptin and placebo groups. This did not demonstrate the expected cardiovascular benefit based on prior meta-analysis of phase 2B and phase 3 data presented above, but saxagliptin did not increase cardiovascular risk and was the first diabetes drug to earn this distinction of robustly statistically proven cardiovascular safety.

Further analysis of the SAVOR-TIMI 53 trial data revealed a 27% increased relative risk of heart failure hospitalization with saxagliptin compared with placebo.¹⁴ Although the risk was statistically significant, the absolute difference in heart failure incidence between the drug and placebo groups was only 0.7% (3.5% vs 2.8%, respectively). As the average follow-up in the trial was 2 years, the absolute incremental risk of heart failure seen with saxagliptin is 0.35% annually—almost identical in magnitude to the increased heart failure risk with pioglitazone. The increased risk of heart failure was seen within the first 6 months of the trial and persisted throughout the trial, indicating an increased up-front risk of heart failure.

Alogliptin

The EXAMINE trial¹⁵ compared the DPP-4 inhibitor alogliptin and placebo in 5,380 patients with type 2 diabetes who had had a recent acute coronary event.¹⁵ Over the 30 months of the trial, more than 600 primary outcome events of cardiovascular death, myocardial infarction, or stroke occurred, with no significant difference between drug and placebo groups with established nominal statistical noninferiority. A numerically higher incidence of heart failure was noted in patients who received alogliptin than with placebo, but the difference was not statistically significant.¹⁶ However, this study was not powered to detect such an increased risk. In patients entering the trial with no history of heart failure, the risk of hospitalization for heart failure was 76% higher in the alogliptin group than in the placebo group, with a nominally significant P value less than .05 in this subgroup.

These analyses led the FDA in 2016 to mandate label warnings for saxagliptin and alogliptin regarding the increased risk of heart failure.¹⁷

Sitagliptin

The TECOS trial¹⁸ tested the DPP-4 inhibitor sitagliptin and, unlike the SAVOR or EXAMINE trials, included hospitalization for unstable angina in the composite end point. Nearly 15,000 patients with type 2 diabetes and established cardiovascular disease were enrolled, and almost 2,500 events occurred. No significant difference was found between the 2 groups.

In a series of analyses prospectively planned, sitagliptin was not associated with an increased risk of hospitalization for heart failure.¹⁹ But despite these robust analyses demonstrating no incremental heart failure risk with sitagliptin, in August 2017, the US product label for sitagliptin was modified to include a warning that other DPP-4 inhibitors have been associated with heart failure and to suggest caution. The label for linagliptin had the same FDA-required changes, with no data yet available from outcomes trials with linagliptin.

GLP-1 RECEPTOR AGONISTS

Lixisenatide: Noninferior to placebo

The ELIXA trial²⁰ assessed the cardiovascular safety of the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes who recently had an acute coronary event. The study enrolled 6,068 patients from 49 countries, and nearly 1,000 events (cardiovascular death, myocardial infarction, stroke, or unstable angina) occurred during the median 25 months of the study. Results showed lixisenatide did not increase or decrease cardiovascular events or adverse events when compared with placebo.

Liraglutide: Evidence of benefit

The LEADER trial²¹ randomized 9,340 patients with or at increased risk for cardiovascular disease to receive the injectable GLP-1 receptor agonist liraglutide or placebo. After a median of 3.8 years of follow-up, liraglutide use was associated with a statistically significant 13% relative reduction in major adverse cardiovascular events, mostly driven by a 22% reduction in cardiovascular death.

Semaglutide: Evidence of benefit

The SUSTAIN-6 trial²² found a statistically significant 26% relative risk reduction in cardiovascular outcomes comparing once-weekly semaglutide (an injectable GLP-1 receptor agonist) and placebo in 3,297 patients with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or risk factors for cardiovascular disease. The significant reduction in the incidence of nonfatal stroke with semaglutide was the main driver of the observed benefit.

Taspoglutide: Development halted

Taspoglutide was a candidate GLP-1 receptor agonist that underwent clinical trials for cardiovascular outcomes planned to involve about 8,000 patients. The trials were stopped early and drug development was halted after about 600 patient-years of exposure because of antibody formation in about half of patients exposed to taspoglutide, with anaphylactoid reactions and anaphylaxis reported.²³

SGLT-2 INHIBITORS

The renal glomeruli filter about 180 g of glucose every day in normal adults; nearly all of it is reabsorbed by SGLT-2 in the proximal tubules, so that very little glucose is excreted in the urine.^24–26 The benign condition hereditary glucosuria occurs due to loss-of-function mutations in the gene for SGLT-2. Individuals with this condition rarely if ever develop type 2 diabetes or obesity, and this observation led pharmaceutical researchers to probe SGLT-2 as a therapeutic target.

Inhibitors of SGLT-2 block glucose reabsorption in the renal proximal tubules and lead to glucosuria. Patients treated with an SGLT-2 inhibitor have lower serum glucose levels and lose weight. Inhibitors also reduce sodium reabsorption via SGLT-2 and lead to increased sodium excretion and decreased blood pressure.²⁷

Three SGLT-2 antagonists are available in the United States: canagliflozin, dapagliflozin, and empagliflozin (Table 1). Ertugliflozin is currently in a phase 3B trial, and cardiovascular outcomes trials are in the planning phase for sotagliflozin, a dual SGLT-1/SGLT-2 inhibitor with SGLT-1 localized to the gastrointestinal tract.²⁸

Empaglifozin: Evidence of benefit

The EMPA-REG OUTCOME trial²⁹ randomized more than 7,200 patients with type 2 diabetes and atherosclerotic vascular disease to receive the SGLT-2 inhibitor empagliflozin or placebo as once-daily tablets, with both groups receiving off-study treatment for glycemic control at the discretion of their own care providers. Two doses of empagliflozin were evaluated in the trial (10 and 25 mg per day), with the 2 dosing groups pooled for all analyses as prospectively planned.

Patients taking empagliflozin had a 14% relative risk reduction of the composite outcome (cardiovascular death, myocardial infarction, and stroke) vs placebo, with no difference in effect between the 2 randomized doses. The improvement in the composite outcome was seen early in the empagliflozin group and persisted for the 4 years of the study.

This was the first trial of newly developed diabetes drugs that showed a statistically significant reduction in cardiovascular risk. The study revealed a 38% relative risk reduction in cardiovascular death in the treatment group. The risk reduction occurred early in the trial and improved throughout the duration of the study. This is a dramatic finding, unequaled even in trials of drugs that specifically target cardiovascular disease. Both doses of empagliflozin studied provided similar benefit over placebo, reinforcing the validity of the findings. Interestingly, in the empagliflozin group, there was a 35% relative risk reduction in heart failure hospitalizations.

Canaglifozin: Evidence of benefit

The CANVAS Program consisted of two sister trials, CANVAS and CANVAS-R, and examined the safety and efficacy of canagliflozin.³⁰ More than 10,000 participants with type 2 diabetes and atherosclerotic disease or at increased risk of cardiovascular disease were randomized to receive canagliflozin or placebo. Canagliflozin led to a 14% relative risk reduction in the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, but there was a statistically significant doubling in the incidence of amputations. Unlike empagliflozin, canagliflozin did not demonstrate a significant reduction in death from cardiovascular causes, suggesting that this may not be a class effect of SGLT-2 inhibitors. As with empagliflozin, canagliflozin led to a 33% relative risk reduction in heart failure hospitalizations.

Cardiovascular benefits independent of glucose-lowering

The cardiovascular benefits of empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS were observed early, suggesting that the mechanism may be due to the direct effects on the cardiovascular system rather than glycemic modification.

Improved glycemic control with the SGLT-2 inhibitor was seen early in both studies, but with the trials designed for glycemic equipoise encouraging open-label therapy targeting hemoglobin A_1c to standard-of-care targets in both groups, the contrast in hemoglobin A_1c between groups diminished throughout the trial after its first assessment. Although hemoglobin A_1c levels in the SGLT-2 inhibitor groups decreased in the first 12 weeks, they increased over time nearly to the level seen in the placebo group. The adjusted mean hemoglobin A_1c level in the placebo groups remained near 8.0% throughout the studies, a target consistent with guidelines from the American Diabetes Association and the European Association for the Study of Diabetes³¹ for the high-risk populations recruited and enrolled.

Blood pressure reduction and weight loss do not explain cardiovascular benefits

SGLT-2 inhibitors lower blood pressure independent of their diuretic effects. In the EMPA-REG OUTCOME trial, the adjusted mean systolic blood pressure was 3 to 4 mm Hg lower in the treatment groups than in the placebo group throughout the trial.²⁹ This level of blood pressure lowering translates to an estimated 10% to 12% relative risk reduction for major adverse cardiovascular events, including heart failure. Although the risk reduction from blood pressure lowering is not insignificant, it does not explain the 38% reduction in cardiovascular deaths seen in the trial. Canagliflozin led to a similar 4-mm Hg reduction in systolic pressure compared with the placebo group.³⁰

Weight loss was seen with both empagliflozin and canagliflozin but was not dramatic and is unlikely to account for the described cardiovascular benefits.

Theories of cardiovascular benefit

Several mechanisms have been proposed to help explain the observed cardiovascular benefits of SGLT-2 inhibitors.³²

Ketone-body elevation. Ferrannini et al³³ found that the blood concentration of the ketone-body beta-hydroxybutyrate is about twice as high in patients with type 2 diabetes in the fasting state who are chronically taking empagliflozin as in  patients not receiving the drug. Beta-hydroxybutyrate levels peak after a meal and then return to baseline over several hours before rising again during the fasting period. Although the ketone elevation is not nearly as extreme as in diabetic ketoacidosis (about a 1,000-fold increase), the observed increase may reduce myocardial oxygen demand, as beta-hydroxybutyrate is among the most efficient metabolic substrates for the myocardium.       

Red blood cell expansion. Perhaps a more likely explanation of the cardiovascular benefit seen with SGLT-2 inhibitor therapy is the increase in hemoglobin and hematocrit levels. At first attributed to hemoconcentration secondary to diuresis, this has been disproven by a number of studies. The EMPA-REG OUTCOME trial²⁹ found that within 12 weeks of exposure to empagliflozin, hematocrit levels rose nearly 4% absolutely compared with the levels in the placebo group. This increase is equivalent to transfusing a unit of red blood cells, favorably affecting myocardial oxygen supply.

Reduction in glomerular hypertension. The kidneys regulate glomerular filtration in a process involving the macula densa, an area of specialized cells in the juxtaglomerular apparatus in the loop of Henle that responds to sodium concentration in the urine. Normally, SGLT-2 receptors upstream from the loop of Henle reabsorb sodium and glucose into the bloodstream, reducing sodium delivery to the macula densa, which senses this as a low-volume state. The macula densa cells respond by releasing factors that dilate afferent arterioles and increase glomerular filtration. People with diabetes have more glucose to reabsorb and therefore also reabsorb more sodium, leading to glomerular hypertension.

SGLT-2 inhibitors block both glucose and sodium reuptake at SGLT-2 receptors, normalizing the response at the macula densa, restoring a normal glomerular filtration rate, and alleviating glomerular hypertension. As the kidney perceives a more normal volume status, renin-angiotensin-aldosterone stimulation is attenuated and sympathetic nervous system activity improves.^27,34 If this model of SGLT-2 inhibitor effects on the kidney is correct, these drugs have similar effects as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid antagonists, and beta-blockers combined.

 

 

Kidney benefits

Empagliflozin³⁵ and canagliflozin³⁰ both reduced the rate of progression of kidney dysfunction and led to fewer clinically relevant renal events compared with placebo. Treatment and placebo groups also received standard care, so many patients were treated with renin-angiotensin-aldosterone system inhibitors and with good blood pressure control, making the finding that SGLT-2 inhibitors had a significant beneficial effect even more dramatic. Beneficial effects on markers of kidney function were seen early on, suggesting a more favorable hemodynamic effect on the kidney rather than improved glycemic control attenuating microvascular disease.

Empagliflozin approved to reduce clinical events

In December 2016, the FDA approved the indication for empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes,³⁶ the first-ever clinical outcome indication for a type 2 diabetes medication. The European Society of Cardiology guidelines now include empagliflozin as preferred therapy for type 2 diabetes, recommending it to prevent the onset of heart failure and prolong life.³⁷ This recommendation goes beyond the evidence from the EMPA-REG OUTCOME trial on which it is based, as the trial only studied patients with known atherosclerotic vascular disease.

The 2016 European Guidelines on cardiovascular disease prevention also recommend that an SGLT-2 inhibitor be considered early for patients with type 2 diabetes and cardiovascular disease to reduce cardiovascular and total mortality.³⁸ The American Diabetes Association in their 2017 guidelines also endorse empagliflozin for treating patients with type 2 diabetes and cardiovascular disease.³⁹ The fact that the American Diabetes Association recommendation is not based on glycemic control, in line with the product-labeled indication, is a major shift in the association’s guidance.

Cautions with SGLT-2 inhibitors

• Use SGLT-2 inhibitors in patients with low blood pressure with caution, and with increased blood pressure monitoring just following initiation.
• Consider modifying antihypertensive drugs in patients with labile blood pressure.
• Consider stopping or reducing background diuretics when starting an SGLT-2 inhibitor, and reassess volume status after 1 to 2 weeks.
• For patients on insulin, sulfonylureas, or both, consider decreasing dosages when starting an SGLT-2 inhibitor, and reassess glycemic control periodically.
• Counsel patients about urinary hygiene. Although bacterial urinary tract infections have not emerged as a problem, fungal genital infections have, particularly in women and uncircumcised men.
• Consider SGLT-2 inhibitors to be “sick-day” medications. Patients with diabetes must adjust their diabetes medications if their oral intake is reduced for a day or more, such as while sick or fasting. SGLT-2 inhibitors should not be taken on these days. Cases of diabetic ketoacidosis have arisen in patients who reduced oral intake while continuing their SGLT-2 inhibitor.

OTHER DRUGS WITH DEVELOPMENT HALTED

Aleglitazar, a peroxisome proliferator-activated receptor agonist taken orally once daily, raised high expectations when it was found in early studies to lower serum triglycerides and raise high-density lipoprotein cholesterol levels in addition to lowering blood glucose. However, a phase 3 trial in more than 7,000 patients was terminated after a median follow up of 2 years because of increased rates of heart failure, worsened kidney function, bone fractures, and gastrointestinal bleeding.⁴⁰ Development of this drug was stopped.

Fasiglifam, a G-protein-coupled receptor 40 agonist, was tested in a cardiovascular clinical outcomes trial. Compared with placebo, fasiglifam reduced hemoglobin A_1c  levels with low risk of hypoglycemia.⁴¹ However,  safety concerns about increased liver enzyme levels led to the cessation of the drug’s development.⁴²

HOW WILL THIS AFFECT DIABETES MANAGEMENT?

Metformin is still the most commonly prescribed drug for type 2 diabetes but has only marginal evidence for its cardiovascular benefits and may not be the first-line therapy for the management of diabetes in the future. In the EMPA REG OUTCOME, LEADER, and SUSTAIN-6 trials, the novel diabetes medications were given to patients who were already treated with available therapies, often including metformin. Treatment with empagliflozin, liraglutide, and semaglutide may be indicated for patients with diabetes and atherosclerotic vascular disease as first-line therapies in the future.

SGLT-2 inhibitor therapy can cost about $500 per month, and GLP-1 inhibitors are only slightly less expensive. The cost may be prohibitive for many patients. As more evidence, guidelines, and FDA criteria support the use of these novel diabetes drugs, third-party payers and pharmaceutical companies may be motivated to lower costs to help reach more patients who can benefit from these therapies.

Since the first successful pregnancy in a kidney transplant recipient in 1958,¹ hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, lead­ing to anovulation and infertility. However, within 6 months of kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal,² and the renal allograft is able to adapt to the various physiologic changes of pregnancy.³

Successful pregnancy after kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.⁴

Below are answers to questions often asked by renal transplant recipients who wish to become pregnant.

WHAT IS THE IDEAL TIME TO BECOME PREGNANT AFTER KIDNEY TRANSPLANT?

Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion. Data on sirolimus from clinical studies are limited, but in animal studies it is associated with delay in ossification of skeletal structure and with an increase in fetal mortality.⁷

WHAT INCREASES THE RISK OF A POOR PREGNANCY OUTCOME AFTER RENAL TRANSPLANT?

Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and at conception is associated with better pregnancy outcome.^5,8

WHAT ARE THE POSSIBLE MATERNAL COMPLICATIONS?

Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%.^9,10 The risk of cesarean delivery is 5 times higher  than in the general population, and the incidence rate is 43% to 64%.^10,11

Low-dose aspirin reduces the risk of preeclampsia and should be prescribed to all pregnant women who are kidney transplant recipients. Angiotensin-converting enzyme inhibitors are contraindicated due to the risk of teratogenic effects, ie, pulmonary hypoplasia and oligohydramnios.⁴

 

 

WHAT ARE THE POSSIBLE FETAL COMPLICATIONS?

Women who become pregnant after kidney transplant are at greater risk of preterm delivery (40% to 60% higher risk), having a baby with low birth weight (42% to 46% higher risk), and intrauterine growth restriction (30% to 50% higher risk). But the risk of perinatal mortality is not increased in the absence of the above-mentioned risk factors.^10,11

DOES PREGNANCY INCREASE THE RISK OF GRAFT FAILURE?

Pregnancy does not increase the risk of allograft loss as long as the patient has a prepregnancy serum creatinine below 1.4 mg/dL, no hypertension, and urine protein excretion less than 500 mg/24 hours.¹²

WHAT CHANGES TO IMMUNE SUPPRESSION ARE REQUIRED BEFORE AND DURING PREGNANCY?

Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects.

As stated above, mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone.

A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in metabolic activity of cytochrome P450 and an increase in the volume of distribution.^5,6,13 However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

DOES PREGNANCY INCREASE THE RISK OF INFECTION?

Because of their immunosuppressed state, renal transplant recipients are prone to infection; the incidence rate of urinary tract infection is as high as 40% due to mild reflux and pregnancy-related dilation of ureters and collecting ducts.⁶ Women should be screened for urinary tract infection at every visit with urine dipstick testing and with urine culture every 4 weeks. Antibiotics such as nitrofurantoin, amoxicillin, and cephalexin are safe to treat urinary tract infection during pregnancy.⁶

IS BREAST-FEEDING SAFE IN RENAL TRANSPLANT RECIPIENTS?

Breast-feeding is considered safe for women with renal transplant who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breast-feeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate.¹⁴

Since the first successful pregnancy in a kidney transplant recipient in 1958,¹ hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, lead­ing to anovulation and infertility. However, within 6 months of kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal,² and the renal allograft is able to adapt to the various physiologic changes of pregnancy.³

Successful pregnancy after kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.⁴

Below are answers to questions often asked by renal transplant recipients who wish to become pregnant.

WHAT IS THE IDEAL TIME TO BECOME PREGNANT AFTER KIDNEY TRANSPLANT?

Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion. Data on sirolimus from clinical studies are limited, but in animal studies it is associated with delay in ossification of skeletal structure and with an increase in fetal mortality.⁷

WHAT INCREASES THE RISK OF A POOR PREGNANCY OUTCOME AFTER RENAL TRANSPLANT?

Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and at conception is associated with better pregnancy outcome.^5,8

WHAT ARE THE POSSIBLE MATERNAL COMPLICATIONS?

Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%.^9,10 The risk of cesarean delivery is 5 times higher  than in the general population, and the incidence rate is 43% to 64%.^10,11

Low-dose aspirin reduces the risk of preeclampsia and should be prescribed to all pregnant women who are kidney transplant recipients. Angiotensin-converting enzyme inhibitors are contraindicated due to the risk of teratogenic effects, ie, pulmonary hypoplasia and oligohydramnios.⁴

 

 

WHAT ARE THE POSSIBLE FETAL COMPLICATIONS?

Women who become pregnant after kidney transplant are at greater risk of preterm delivery (40% to 60% higher risk), having a baby with low birth weight (42% to 46% higher risk), and intrauterine growth restriction (30% to 50% higher risk). But the risk of perinatal mortality is not increased in the absence of the above-mentioned risk factors.^10,11

DOES PREGNANCY INCREASE THE RISK OF GRAFT FAILURE?

Pregnancy does not increase the risk of allograft loss as long as the patient has a prepregnancy serum creatinine below 1.4 mg/dL, no hypertension, and urine protein excretion less than 500 mg/24 hours.¹²

WHAT CHANGES TO IMMUNE SUPPRESSION ARE REQUIRED BEFORE AND DURING PREGNANCY?

Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects.

As stated above, mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone.

A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in metabolic activity of cytochrome P450 and an increase in the volume of distribution.^5,6,13 However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

DOES PREGNANCY INCREASE THE RISK OF INFECTION?

Because of their immunosuppressed state, renal transplant recipients are prone to infection; the incidence rate of urinary tract infection is as high as 40% due to mild reflux and pregnancy-related dilation of ureters and collecting ducts.⁶ Women should be screened for urinary tract infection at every visit with urine dipstick testing and with urine culture every 4 weeks. Antibiotics such as nitrofurantoin, amoxicillin, and cephalexin are safe to treat urinary tract infection during pregnancy.⁶

IS BREAST-FEEDING SAFE IN RENAL TRANSPLANT RECIPIENTS?

Breast-feeding is considered safe for women with renal transplant who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breast-feeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate.¹⁴

Since the first successful pregnancy in a kidney transplant recipient in 1958,¹ hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, lead­ing to anovulation and infertility. However, within 6 months of kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal,² and the renal allograft is able to adapt to the various physiologic changes of pregnancy.³

Successful pregnancy after kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.⁴

Below are answers to questions often asked by renal transplant recipients who wish to become pregnant.

WHAT IS THE IDEAL TIME TO BECOME PREGNANT AFTER KIDNEY TRANSPLANT?

Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion. Data on sirolimus from clinical studies are limited, but in animal studies it is associated with delay in ossification of skeletal structure and with an increase in fetal mortality.⁷

WHAT INCREASES THE RISK OF A POOR PREGNANCY OUTCOME AFTER RENAL TRANSPLANT?

Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and at conception is associated with better pregnancy outcome.^5,8

WHAT ARE THE POSSIBLE MATERNAL COMPLICATIONS?

Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%.^9,10 The risk of cesarean delivery is 5 times higher  than in the general population, and the incidence rate is 43% to 64%.^10,11

Low-dose aspirin reduces the risk of preeclampsia and should be prescribed to all pregnant women who are kidney transplant recipients. Angiotensin-converting enzyme inhibitors are contraindicated due to the risk of teratogenic effects, ie, pulmonary hypoplasia and oligohydramnios.⁴

 

 

WHAT ARE THE POSSIBLE FETAL COMPLICATIONS?

Women who become pregnant after kidney transplant are at greater risk of preterm delivery (40% to 60% higher risk), having a baby with low birth weight (42% to 46% higher risk), and intrauterine growth restriction (30% to 50% higher risk). But the risk of perinatal mortality is not increased in the absence of the above-mentioned risk factors.^10,11

DOES PREGNANCY INCREASE THE RISK OF GRAFT FAILURE?

Pregnancy does not increase the risk of allograft loss as long as the patient has a prepregnancy serum creatinine below 1.4 mg/dL, no hypertension, and urine protein excretion less than 500 mg/24 hours.¹²

WHAT CHANGES TO IMMUNE SUPPRESSION ARE REQUIRED BEFORE AND DURING PREGNANCY?

Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects.

As stated above, mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone.

A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in metabolic activity of cytochrome P450 and an increase in the volume of distribution.^5,6,13 However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

DOES PREGNANCY INCREASE THE RISK OF INFECTION?

Because of their immunosuppressed state, renal transplant recipients are prone to infection; the incidence rate of urinary tract infection is as high as 40% due to mild reflux and pregnancy-related dilation of ureters and collecting ducts.⁶ Women should be screened for urinary tract infection at every visit with urine dipstick testing and with urine culture every 4 weeks. Antibiotics such as nitrofurantoin, amoxicillin, and cephalexin are safe to treat urinary tract infection during pregnancy.⁶

IS BREAST-FEEDING SAFE IN RENAL TRANSPLANT RECIPIENTS?

Breast-feeding is considered safe for women with renal transplant who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breast-feeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate.¹⁴

Azithromycin is prescribed for a variety of acute respiratory and nonrespiratory infections. However, it is also used in several chronic respiratory diseases.

MECHANISM OF ACTION

Macrolide antibiotics like azithromycin inhibit bacterial growth and replication by interrupting protein synthesis. But azithromycin also has immunomodulatory properties.¹

In the acute phase of inflammation, azithromycin exerts an initial neutrophil degranulation effect and enhances the oxidative response that is primed by particulate stimulus, which could facilitate its antibacterial effects. In the late phase, it down-regulates the oxidative burst and increases apoptosis of neutrophils to promote healing without compromising immunity. Azithromycin also attenuates airway mucus hypersecretion, improves ciliary function, and promotes pulmonary epithelial cell healing.^2,3

Collectively, these effects make the drug effective in many chronic inflammatory lung conditions (Table 1).

CYSTIC FIBROSIS

Cystic fibrosis is a genetic disease affecting many organs, but its effect on the upper and lower airways has the greatest impact on quality of life and survival. Impaired mucociliary clearance and repeated respiratory infections contribute to chronic inflammation and a progressive decline in lung function.^4,5

A 2012 Cochrane review of 5 studies in 549 patients found that, compared with those taking placebo, patients taking azithromycin 250–500 mg 3 times a week had improvement in forced expiratory volume in 1 second (FEV₁). The mean difference at 6 months was 3.97% (95% cofidence interval [CI] 1.74– 6.19). Patients on azithromycin were free from pulmonary exacerbation approximately twice as long as patients on placebo (odds ratio 1.96, 95% CI 1.15–3.33).^6,7

The Cystic Fibrosis Foundation recommends long-term azithromycin therapy to improve lung function and reduce exacerbations in patients age 6 or older who have persistent Pseudomonas aeruginosa airway cultures (level of evidence: fair).⁸

DIFFUSE PANBRONCHIOLITIS

Diffuse panbronchiolitis, or diffuse chronic inflammatory bronchiolitis and sinusitis, is seen mainly in patients of Asian descent.⁹ In the past, the mortality rate was greater than 90%, but between 1970 and 1979 the 10-year survival rate increased by more than 40% with chronic macrolide therapy, ie, with erythromycin.^10,11

Later retrospective studies of azithromycin 500 mg 3 times a week showed results comparable to those with erythromycin, with improvement in symptoms, lung function, arterial partial pressure of oxygen, and radiologic findings, as well as fewer adverse effects.¹² These benefits justify the current recommendation for azithromycin as the mainstay of therapy in diffuse panbronchiolitis.

BRONCHIOLITIS OBLITERANS SYNDROME

Bronchiolitis obliterans syndrome is an airflow limitation that arises without infection or imaging evidence of bronchiolitis in patients who received allogeneic hematopoietic stem cell or lung transplant. It occurs in 50% of lung transplant recipients as a form of chronic graft rejection and in 6% to 20% of allogeneic stem cell transplant recipients as a manifestation of chronic graft-vs-host disease.^13,14

Azithromycin has been used in its management. A meta-analysis of lung transplant recipients found a significant improvement in the survival rate and overall lung function after an average of 7 months of treatment with azithromycin, with a mean increase in FEV₁ of 8.8% (95% CI 5.1–12.47, P < .001).¹⁴ The evidence currently supports long-term azithromycin 250 mg 3 times a week after lung transplant to reduce any decline in lung function and to lower the mortality rate.^14,15

In allogeneic stem cell transplant recipients, the evidence for long-term azithromycin treatment is sparse. A recent prospective multicenter study evaluated the effect of an azithromycin-based regimen (fluticasone, azithromycin, and montelukast, plus a steroid pulse) in stem cell recipients with bronchiolitis obliterans syndrome during the first 3 months after diagnosis. In the treated group, 6% had a drop in FEV₁ of more than 10% at 3-month follow-up compared with 40% of historical controls (95% CI 1%–19%, P < .001). Also, treatment resulted in a 50% reduction in the dose of systemic steroids and a substantial improvement in functional status.¹⁶

Given the limited options in the management of these patients and until further studies are available, azithromycin 3 times weekly is suggested.

NON-CYSTIC FIBROSIS BRONCHIECTASIS

Non-cystic fibrosis bronchiectasis is a chronic inflammatory lung condition characterized by irreversible dilation of the bronchi and bronchioles due to a variety of causes including recurrent or old infection, immunodeficiency, autoimmune conditions, and connective tissue disease; it can also be idiopathic.¹⁷

Altenburg et al,¹⁸ in a randomized, double-blind, placebo-controlled trial, found that azithromycin 250 mg 3 times a week for 12 months reduced the number of exacerbations  from a median number of 2 per patient with placebo to 0 per patient with azithromycin (P < .001). At 3 months, the FEV₁ as a percent of predicted had increased by 1.03% in the azithromycin group and decreased by 0.10% in the placebo group (P = .047). The number needed to treat with azithromycin to maintain clinical stability was 3.0.

Wong et al¹⁹ randomized patients to receive azithromycin 500 mg 3 times a week or placebo for 6 months. The rate of exacerbations was 0.59 per patient in the azithromycin group and 1.57 per patient in the placebo group (P < .0001). The FEV₁ remained unchanged from baseline in the azithromycin group while decreasing in the placebo group, but the difference was not significant.

EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of death, poor quality of life, and healthcare expenditures.²⁰ Prevention is therefore of the utmost importance.

Several studies have shown that azithromycin prophylaxis can reduce acute exacerbations of COPD. A recent meta-analysis showed that long-term macrolide prophylaxis significantly reduced exacerbations compared with rates in controls (risk ratio = 0.70, 95% CI 0.56–0.87, P < .01) and increased the median time to first COPD exacerbation by more than 90 days (P < .01).²¹ Long-term azithromycin therapy may be considered in selected patients who have frequent exacerbations despite optimal maintenance inhaler therapy.

PROPHYLAXIS IN IMMUNODEFICIENCY

Disseminated Mycobacterium avium complex (MAC) is an opportunistic infection most commonly occurring in patients with acquired immunodeficiency syndrome with CD4 counts below 50 cells/µL.^22,23

In a double-blinded, randomized trial, patients who received azithromycin had a 47% reduction in the incidence of MAC infection.

Given the long half-life of azithromycin, it is effective with once-weekly dosing of 1,200 mg.²³ Ideally, patients are placed on a prophylactic agent for disseminated MAC infection until the CD4 count reaches 100 cells/µL and remains at or above this level for 3 consecutive months.²⁴

ADVERSE EFFECTS AND PRECAUTIONS

Long-term azithromycin therapy may produce bacterial resistance; the risk has been estimated at 2.7 times greater in patients who are on long-term azithromycin treatment.²⁵ Also, patients at risk for MAC infection, such as those with cystic fibrosis, should be screened for it before starting treatment in order to prevent resistance to azithromycin.

The US Food and Drug Administration warns that azithromycin can lead to a prolonged corrected QT interval and potential fatal arrhythmias such as torsades de pointes. Major reviews have largely agreed that arrhythmias are more pronounced in patients with a coexisting cardiac risk factor such as existing QT-interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or arrhythmias, or who are on class IA and III antiarrhythmic drugs.^26–28

Other potential adverse effects of long-term azithromycin treatment are gastrointestinal symptoms and hearing impairment.^29,30 A review of potential drug interactions is advised when patients are placed on long-term azithromycin therapy.

Although azithromycin is generally well tolerated, long-term treatment should be individualized and the benefits weighed against the risks. Patients should be monitored during treatment for any of the above adverse effects.

Azithromycin is prescribed for a variety of acute respiratory and nonrespiratory infections. However, it is also used in several chronic respiratory diseases.

MECHANISM OF ACTION

Macrolide antibiotics like azithromycin inhibit bacterial growth and replication by interrupting protein synthesis. But azithromycin also has immunomodulatory properties.¹

In the acute phase of inflammation, azithromycin exerts an initial neutrophil degranulation effect and enhances the oxidative response that is primed by particulate stimulus, which could facilitate its antibacterial effects. In the late phase, it down-regulates the oxidative burst and increases apoptosis of neutrophils to promote healing without compromising immunity. Azithromycin also attenuates airway mucus hypersecretion, improves ciliary function, and promotes pulmonary epithelial cell healing.^2,3

Collectively, these effects make the drug effective in many chronic inflammatory lung conditions (Table 1).

CYSTIC FIBROSIS

Cystic fibrosis is a genetic disease affecting many organs, but its effect on the upper and lower airways has the greatest impact on quality of life and survival. Impaired mucociliary clearance and repeated respiratory infections contribute to chronic inflammation and a progressive decline in lung function.^4,5

A 2012 Cochrane review of 5 studies in 549 patients found that, compared with those taking placebo, patients taking azithromycin 250–500 mg 3 times a week had improvement in forced expiratory volume in 1 second (FEV₁). The mean difference at 6 months was 3.97% (95% cofidence interval [CI] 1.74– 6.19). Patients on azithromycin were free from pulmonary exacerbation approximately twice as long as patients on placebo (odds ratio 1.96, 95% CI 1.15–3.33).^6,7

The Cystic Fibrosis Foundation recommends long-term azithromycin therapy to improve lung function and reduce exacerbations in patients age 6 or older who have persistent Pseudomonas aeruginosa airway cultures (level of evidence: fair).⁸

DIFFUSE PANBRONCHIOLITIS

Diffuse panbronchiolitis, or diffuse chronic inflammatory bronchiolitis and sinusitis, is seen mainly in patients of Asian descent.⁹ In the past, the mortality rate was greater than 90%, but between 1970 and 1979 the 10-year survival rate increased by more than 40% with chronic macrolide therapy, ie, with erythromycin.^10,11

Later retrospective studies of azithromycin 500 mg 3 times a week showed results comparable to those with erythromycin, with improvement in symptoms, lung function, arterial partial pressure of oxygen, and radiologic findings, as well as fewer adverse effects.¹² These benefits justify the current recommendation for azithromycin as the mainstay of therapy in diffuse panbronchiolitis.

BRONCHIOLITIS OBLITERANS SYNDROME

Bronchiolitis obliterans syndrome is an airflow limitation that arises without infection or imaging evidence of bronchiolitis in patients who received allogeneic hematopoietic stem cell or lung transplant. It occurs in 50% of lung transplant recipients as a form of chronic graft rejection and in 6% to 20% of allogeneic stem cell transplant recipients as a manifestation of chronic graft-vs-host disease.^13,14

Azithromycin has been used in its management. A meta-analysis of lung transplant recipients found a significant improvement in the survival rate and overall lung function after an average of 7 months of treatment with azithromycin, with a mean increase in FEV₁ of 8.8% (95% CI 5.1–12.47, P < .001).¹⁴ The evidence currently supports long-term azithromycin 250 mg 3 times a week after lung transplant to reduce any decline in lung function and to lower the mortality rate.^14,15

In allogeneic stem cell transplant recipients, the evidence for long-term azithromycin treatment is sparse. A recent prospective multicenter study evaluated the effect of an azithromycin-based regimen (fluticasone, azithromycin, and montelukast, plus a steroid pulse) in stem cell recipients with bronchiolitis obliterans syndrome during the first 3 months after diagnosis. In the treated group, 6% had a drop in FEV₁ of more than 10% at 3-month follow-up compared with 40% of historical controls (95% CI 1%–19%, P < .001). Also, treatment resulted in a 50% reduction in the dose of systemic steroids and a substantial improvement in functional status.¹⁶

Given the limited options in the management of these patients and until further studies are available, azithromycin 3 times weekly is suggested.

NON-CYSTIC FIBROSIS BRONCHIECTASIS

Non-cystic fibrosis bronchiectasis is a chronic inflammatory lung condition characterized by irreversible dilation of the bronchi and bronchioles due to a variety of causes including recurrent or old infection, immunodeficiency, autoimmune conditions, and connective tissue disease; it can also be idiopathic.¹⁷

Altenburg et al,¹⁸ in a randomized, double-blind, placebo-controlled trial, found that azithromycin 250 mg 3 times a week for 12 months reduced the number of exacerbations  from a median number of 2 per patient with placebo to 0 per patient with azithromycin (P < .001). At 3 months, the FEV₁ as a percent of predicted had increased by 1.03% in the azithromycin group and decreased by 0.10% in the placebo group (P = .047). The number needed to treat with azithromycin to maintain clinical stability was 3.0.

Wong et al¹⁹ randomized patients to receive azithromycin 500 mg 3 times a week or placebo for 6 months. The rate of exacerbations was 0.59 per patient in the azithromycin group and 1.57 per patient in the placebo group (P < .0001). The FEV₁ remained unchanged from baseline in the azithromycin group while decreasing in the placebo group, but the difference was not significant.

EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of death, poor quality of life, and healthcare expenditures.²⁰ Prevention is therefore of the utmost importance.

Several studies have shown that azithromycin prophylaxis can reduce acute exacerbations of COPD. A recent meta-analysis showed that long-term macrolide prophylaxis significantly reduced exacerbations compared with rates in controls (risk ratio = 0.70, 95% CI 0.56–0.87, P < .01) and increased the median time to first COPD exacerbation by more than 90 days (P < .01).²¹ Long-term azithromycin therapy may be considered in selected patients who have frequent exacerbations despite optimal maintenance inhaler therapy.

PROPHYLAXIS IN IMMUNODEFICIENCY

Disseminated Mycobacterium avium complex (MAC) is an opportunistic infection most commonly occurring in patients with acquired immunodeficiency syndrome with CD4 counts below 50 cells/µL.^22,23

In a double-blinded, randomized trial, patients who received azithromycin had a 47% reduction in the incidence of MAC infection.

Given the long half-life of azithromycin, it is effective with once-weekly dosing of 1,200 mg.²³ Ideally, patients are placed on a prophylactic agent for disseminated MAC infection until the CD4 count reaches 100 cells/µL and remains at or above this level for 3 consecutive months.²⁴

ADVERSE EFFECTS AND PRECAUTIONS

Long-term azithromycin therapy may produce bacterial resistance; the risk has been estimated at 2.7 times greater in patients who are on long-term azithromycin treatment.²⁵ Also, patients at risk for MAC infection, such as those with cystic fibrosis, should be screened for it before starting treatment in order to prevent resistance to azithromycin.

The US Food and Drug Administration warns that azithromycin can lead to a prolonged corrected QT interval and potential fatal arrhythmias such as torsades de pointes. Major reviews have largely agreed that arrhythmias are more pronounced in patients with a coexisting cardiac risk factor such as existing QT-interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or arrhythmias, or who are on class IA and III antiarrhythmic drugs.^26–28

Other potential adverse effects of long-term azithromycin treatment are gastrointestinal symptoms and hearing impairment.^29,30 A review of potential drug interactions is advised when patients are placed on long-term azithromycin therapy.

Although azithromycin is generally well tolerated, long-term treatment should be individualized and the benefits weighed against the risks. Patients should be monitored during treatment for any of the above adverse effects.

Azithromycin is prescribed for a variety of acute respiratory and nonrespiratory infections. However, it is also used in several chronic respiratory diseases.

MECHANISM OF ACTION

Macrolide antibiotics like azithromycin inhibit bacterial growth and replication by interrupting protein synthesis. But azithromycin also has immunomodulatory properties.¹

In the acute phase of inflammation, azithromycin exerts an initial neutrophil degranulation effect and enhances the oxidative response that is primed by particulate stimulus, which could facilitate its antibacterial effects. In the late phase, it down-regulates the oxidative burst and increases apoptosis of neutrophils to promote healing without compromising immunity. Azithromycin also attenuates airway mucus hypersecretion, improves ciliary function, and promotes pulmonary epithelial cell healing.^2,3

Collectively, these effects make the drug effective in many chronic inflammatory lung conditions (Table 1).

CYSTIC FIBROSIS

Cystic fibrosis is a genetic disease affecting many organs, but its effect on the upper and lower airways has the greatest impact on quality of life and survival. Impaired mucociliary clearance and repeated respiratory infections contribute to chronic inflammation and a progressive decline in lung function.^4,5

A 2012 Cochrane review of 5 studies in 549 patients found that, compared with those taking placebo, patients taking azithromycin 250–500 mg 3 times a week had improvement in forced expiratory volume in 1 second (FEV₁). The mean difference at 6 months was 3.97% (95% cofidence interval [CI] 1.74– 6.19). Patients on azithromycin were free from pulmonary exacerbation approximately twice as long as patients on placebo (odds ratio 1.96, 95% CI 1.15–3.33).^6,7

The Cystic Fibrosis Foundation recommends long-term azithromycin therapy to improve lung function and reduce exacerbations in patients age 6 or older who have persistent Pseudomonas aeruginosa airway cultures (level of evidence: fair).⁸

DIFFUSE PANBRONCHIOLITIS

Diffuse panbronchiolitis, or diffuse chronic inflammatory bronchiolitis and sinusitis, is seen mainly in patients of Asian descent.⁹ In the past, the mortality rate was greater than 90%, but between 1970 and 1979 the 10-year survival rate increased by more than 40% with chronic macrolide therapy, ie, with erythromycin.^10,11

Later retrospective studies of azithromycin 500 mg 3 times a week showed results comparable to those with erythromycin, with improvement in symptoms, lung function, arterial partial pressure of oxygen, and radiologic findings, as well as fewer adverse effects.¹² These benefits justify the current recommendation for azithromycin as the mainstay of therapy in diffuse panbronchiolitis.

BRONCHIOLITIS OBLITERANS SYNDROME

Bronchiolitis obliterans syndrome is an airflow limitation that arises without infection or imaging evidence of bronchiolitis in patients who received allogeneic hematopoietic stem cell or lung transplant. It occurs in 50% of lung transplant recipients as a form of chronic graft rejection and in 6% to 20% of allogeneic stem cell transplant recipients as a manifestation of chronic graft-vs-host disease.^13,14

Azithromycin has been used in its management. A meta-analysis of lung transplant recipients found a significant improvement in the survival rate and overall lung function after an average of 7 months of treatment with azithromycin, with a mean increase in FEV₁ of 8.8% (95% CI 5.1–12.47, P < .001).¹⁴ The evidence currently supports long-term azithromycin 250 mg 3 times a week after lung transplant to reduce any decline in lung function and to lower the mortality rate.^14,15

In allogeneic stem cell transplant recipients, the evidence for long-term azithromycin treatment is sparse. A recent prospective multicenter study evaluated the effect of an azithromycin-based regimen (fluticasone, azithromycin, and montelukast, plus a steroid pulse) in stem cell recipients with bronchiolitis obliterans syndrome during the first 3 months after diagnosis. In the treated group, 6% had a drop in FEV₁ of more than 10% at 3-month follow-up compared with 40% of historical controls (95% CI 1%–19%, P < .001). Also, treatment resulted in a 50% reduction in the dose of systemic steroids and a substantial improvement in functional status.¹⁶

Given the limited options in the management of these patients and until further studies are available, azithromycin 3 times weekly is suggested.

NON-CYSTIC FIBROSIS BRONCHIECTASIS

Non-cystic fibrosis bronchiectasis is a chronic inflammatory lung condition characterized by irreversible dilation of the bronchi and bronchioles due to a variety of causes including recurrent or old infection, immunodeficiency, autoimmune conditions, and connective tissue disease; it can also be idiopathic.¹⁷

Altenburg et al,¹⁸ in a randomized, double-blind, placebo-controlled trial, found that azithromycin 250 mg 3 times a week for 12 months reduced the number of exacerbations  from a median number of 2 per patient with placebo to 0 per patient with azithromycin (P < .001). At 3 months, the FEV₁ as a percent of predicted had increased by 1.03% in the azithromycin group and decreased by 0.10% in the placebo group (P = .047). The number needed to treat with azithromycin to maintain clinical stability was 3.0.

Wong et al¹⁹ randomized patients to receive azithromycin 500 mg 3 times a week or placebo for 6 months. The rate of exacerbations was 0.59 per patient in the azithromycin group and 1.57 per patient in the placebo group (P < .0001). The FEV₁ remained unchanged from baseline in the azithromycin group while decreasing in the placebo group, but the difference was not significant.

EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of death, poor quality of life, and healthcare expenditures.²⁰ Prevention is therefore of the utmost importance.

Several studies have shown that azithromycin prophylaxis can reduce acute exacerbations of COPD. A recent meta-analysis showed that long-term macrolide prophylaxis significantly reduced exacerbations compared with rates in controls (risk ratio = 0.70, 95% CI 0.56–0.87, P < .01) and increased the median time to first COPD exacerbation by more than 90 days (P < .01).²¹ Long-term azithromycin therapy may be considered in selected patients who have frequent exacerbations despite optimal maintenance inhaler therapy.

PROPHYLAXIS IN IMMUNODEFICIENCY

Disseminated Mycobacterium avium complex (MAC) is an opportunistic infection most commonly occurring in patients with acquired immunodeficiency syndrome with CD4 counts below 50 cells/µL.^22,23

In a double-blinded, randomized trial, patients who received azithromycin had a 47% reduction in the incidence of MAC infection.

Given the long half-life of azithromycin, it is effective with once-weekly dosing of 1,200 mg.²³ Ideally, patients are placed on a prophylactic agent for disseminated MAC infection until the CD4 count reaches 100 cells/µL and remains at or above this level for 3 consecutive months.²⁴

ADVERSE EFFECTS AND PRECAUTIONS

Long-term azithromycin therapy may produce bacterial resistance; the risk has been estimated at 2.7 times greater in patients who are on long-term azithromycin treatment.²⁵ Also, patients at risk for MAC infection, such as those with cystic fibrosis, should be screened for it before starting treatment in order to prevent resistance to azithromycin.

The US Food and Drug Administration warns that azithromycin can lead to a prolonged corrected QT interval and potential fatal arrhythmias such as torsades de pointes. Major reviews have largely agreed that arrhythmias are more pronounced in patients with a coexisting cardiac risk factor such as existing QT-interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or arrhythmias, or who are on class IA and III antiarrhythmic drugs.^26–28

Other potential adverse effects of long-term azithromycin treatment are gastrointestinal symptoms and hearing impairment.^29,30 A review of potential drug interactions is advised when patients are placed on long-term azithromycin therapy.

Although azithromycin is generally well tolerated, long-term treatment should be individualized and the benefits weighed against the risks. Patients should be monitored during treatment for any of the above adverse effects.

African American, Hispanic, American Indian, and Alaskan Native women continue to be disproportionately affected by cervical cancer compared with white women. From 2006 to 2010, the incidence of cervical cancer in African American women was 10.3 per 100,000; in white women it was 7.2.¹ The mortality rate from cervical cancer in African American women is twice that in white women.¹ Although cervical cancer rates have decreased nationwide, significant racial health disparities persist.

See related editorial

As the first-line healthcare providers for many women, the primary care physician and the general obstetrician-gynecologist are optimally positioned to reduce these disparities.

Cervical cancer is the third most common gynecologic cancer, after uterine and ovarian cancer. Nearly 13,000 new cases are diagnosed each year in the United States, and more than 4,000 women die of it.² Fortunately, cervical cancer can be significantly prevented with adequate screening and vaccination against human papillomavirus (HPV).

WHY ARE BLACK WOMEN MORE LIKELY TO DIE OF CERVICAL CANCER?

Later stage at diagnosis. African American women are more likely to present with advanced cervical cancer than non-Hispanic white women.^3–6

Less-aggressive treatment. African American women are more likely to receive no treatment after a cancer diagnosis.⁶ Differences in treatment may be attributed to comorbid conditions, stage at cancer diagnosis, and patient refusal.^5,7

Less access to care. A study from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute looked at 7,267 women (4,431 non-Hispanic white women, 1,830 Hispanic white women, and 1,006 non-Hispanic African American women) who were diagnosed with primary invasive cervical cancer from 1992 to 1996 and followed through 2000. African American women had a 19% higher mortality rate compared with non-Hispanic white women during follow-up despite adjusting for age, stage, histology, and time of first treatment.⁸

However, a later study from the same program found no such difference after 1995, when the data were adjusted for marital status, disease stage, age, treatment, grade, and histology.⁶  

Equal access to healthcare may eliminate most of the disparity.⁷ A study in women with cervical cancer who sought treatment within the United States military healthcare system found no difference in treatment or 5- and 10-year survival rates between African American and white women.⁵ Equal access to comprehensive healthcare eliminated any disparity once cervical cancer was diagnosed.

CERVICAL CANCER SCREENING

The value of cervical cancer screening and prevention is well established. In 1941, Papanicolau reported that cervical cancer could be detected from vaginal smears.⁹ Since the development and widespread implementation of the “Pap” smear, cervical cancer rates have decreased dramatically in the United States.

Another major advance was the discovery that persistent infection with HPV is necessary for the development of cervical cancer, precancerous lesions, and genital warts.¹⁰

With advancing research, guidelines for cervical cancer screening have changed considerably over the years. Today, combined cervical cytologic and HPV testing is the mainstay. (Isolated HPV testing is generally not available outside clinical trials.)

Who should be screened?

Previous recommendations called for women to undergo Pap testing when they first became sexually active and then every year. However, cervical lesions are likely to regress in young women.¹¹ One study found that 28% of cervical intimal neoplasia (CIN) grade 2 and 3 lesions spontaneously regressed by 15 weeks, although lesions associated with HPV 16 infection were less likely to regress than with other HPV types.¹² A study of college women found that HPV infection persisted in only 9% of women after 24 months.¹³

To minimize unnecessary treatment of young women with dysplasia, the American Society for Colposcopy and Cervical Pathology in 2012 recommended cytologic screening for all women 21 years or older, regardless of age at first sexual encounter.¹⁴ Screening intervals were changed from every year to every 3 years until age 30, at which time cotesting with cytology and HPV testing is performed every 5 years. Routine cotesting is not recommended for women younger than 30, who have a high likelihood of HPV infection and spontaneous regression.

In 2014, the US Food and Drug Administration approved primary HPV screening (ie, testing for HPV first, and then performing cytology in samples that test positive) for women age 25 and older.¹⁵

Patients who need further evaluation and testing should be referred for colposcopy. The current guidelines for patients who have abnormal results on cervical cancer screening¹⁶ can be reviewed at www.asccp.org/asccp-guidelines.

As screening guidelines continue to evolve, primary care physicians will need to stay current and also help educate their patients. For example, many of our patients have undergone annual Pap screening for most of their lives and may not yet know about the new testing intervals.

Are there disparities in screening and follow-up?

Disparities in screening and follow-up may exist, but the evidence is not clear-cut.

In a 2013 National Health Interview Survey report, the rates of cervical cancer screening with Pap tests did not differ between African American and white women.¹⁷ However, the information on Pap testing was based on a single question asking participants if they had had a Pap test in the last 3 years. In our experience, patients may confuse Pap tests with speculum examinations.

Once women are screened, adequate and timely follow-up of abnormal results is key.

In a study from the National Breast and Cervical Cancer Early Detection Program,¹⁸ women who had cytology findings of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions were to undergo repeat Pap testing every 4 to 6 months for 2 years. African American women were the least likely to have a follow-up Pap smear compared with other racial groups.  

On the other hand, there was no difference related to race in follow-up rates of abnormal Pap tests in women ages 47 to 64 in the South Carolina Breast and Cervical Cancer Early Detection Program.¹⁹

In a study in an urban population (predominantly African African), the overall follow-up rate was only 26% at 12 months from an initial abnormal Pap smear. This study did not find any differences in follow-up according to race or ethnicity; however, it had insufficient power to detect a difference because only 15% of the study participants were white.²⁰

 

 

What is in a genotype?

HPV is implicated in progression to both squamous cell carcinoma and adenocarcinoma of the cervix. Worldwide, HPV genotypes 16 and 18 are associated with 73% of cases of invasive cervical cancer; most of the remainder are associated with, in order of decreasing prevalence, genotypes 58, 33, 45, 31, 52, 35, 59, 39, 51, and 56.²¹

High-grade cervical lesions in African American women may less often be positive for HPV 16 and 18 than in white women.^22,23 On the other hand, the proportion of non-Hispanic black women infected with HPV 35 and 58 was significantly higher than in non-Hispanic white women.²² Regardless, HPV screening is recommended for women of all races and ethnicities.

The 2-valent and 4-valent HPV vaccines do not cover HPV 35 or 58. The newer 9-valent vaccine covers HPV 58 (but not 35) and so may in theory decrease any potential disparity related to infection with a specific oncogenic subtype.

THE ROLE OF PREVENTION

HPV vaccination

The Females United to Unilaterally Reduce Endo/Ectocervical Disease study demonstrated that the 4-valent vaccine was highly effective against cervical intraepithelial neoplasia due to HPV 16 and 18.²⁴ In another study, the 2-valent vaccine reduced the incidence of CIN 3 or higher by 87% in women who received all 3 doses and who had no evidence of HPV infection at baseline.²⁵

HPV vaccination is expensive. Each shot costs about $130, plus the cost of administering it. Although the Vaccines for Children program covers the HPV vaccine for uninsured and underinsured children and adolescents under age 19, Medicaid coverage varies from state to state for adults over age 21.

The Advisory Committee on Immunization Practices (ACIP)²⁶ recommends routine vaccination for:

• Males 11 or 12 years old
• Females ages 9 to 26.

In October 2016, the ACIP approved a 2-dose series given 6 to 12 months apart for patients starting vaccination at ages 9 through 14 years who are not immunocompromised. Others should receive a 3-dose series, with the second dose given 1 to 2 months after the first dose and the third dose given 6 months after the first dose.²⁷ Previously, 3 doses were recommended for everyone.

Disparities in HPV vaccination rates

HPV vaccination rates among adolescents in the United States increased from 33.6% in 2013 to 41.7% in 2014.²⁸ However, HPV vaccination rates continue to lag behind those of other routine vaccines, such as Tdap and meningococcal conjugate.

Reagan-Steiner et al²⁸ reported that more black than white girls age 13 through 17 received at least 1 dose of a 3-dose HPV vaccination series, but more white girls received all 3 doses (70.6% vs 61.6%). In contrast, a meta-analysis by Fisher et al²⁹ found African American and uninsured women generally less likely to initiate the HPV vaccination series. Kessels et al³⁰ reported similar findings.

Barriers to HPV vaccination

Barriers to HPV vaccination can be provider-dependent, parental, or institutional.

Malo et al³¹ surveyed Florida Medicaid providers and found that those who participated in the Vaccines for Children program were less likely to cite lack of reimbursement as a barrier to vaccination.

Meites et al³² surveyed sexually transmitted disease clinics and found that common reasons for not offering HPV vaccine were cost, staff time, and difficulty coordinating follow-up visits to complete the series.  

Providers report lack of urgency or lack of perception of cervical cancer as a true public health threat, safety concerns regarding the vaccine, and the inability to coadminister vaccines as barriers.³³

Studies have shown that relatively few parents (up to 18%) of parents are concerned about the effect of the vaccine on sexual activity.³⁴ Rather, they are most likely to cite lack of information regarding the vaccine, lack of physician recommendation, and not knowing where to receive the vaccine as barriers.^35,36

Guerry et al³⁷ determined that the single most important factor in vaccine initiation was physician recommendation, a finding reiterated in other studies.^35,38 A study in North Carolina identified failure of physician recommendation as one of the missed opportunities for vaccination of young women.³⁹

Therefore, the primary care physician, as the initial contact with the child or young adult, holds a responsibility to narrow this gap. In simply discussing and recommending the vaccine, physicians could increase vaccination rates.

REPRODUCTIVE HEALTH

Although 80% of women will be infected with HPV in their lifetime, only a small proportion will develop cervical cancer, suggesting there are other cofactors in the progression to cervical cancer.⁴⁰

Given the infectious etiology of cervical cancer, other contributing reproductive health factors have been described. As expected, the number of sexual partners correlates with HPV infection.^41,42 Younger age at first intercourse has been linked to development of cervical neoplasia, consistent with persistent infection leading to neoplasia.^41,42

Primary care physicians should provide timely and comprehensive sexual education, including information on safe sexual practices and pregnancy prevention.

Human immunodeficiency virus

In 2010, the estimated rate of new human immunodeficiency virus (HIV) infections in African American women was nearly 20 times greater than in white women.⁴³ Previous studies have shown a clear relationship between HIV and HPV-associated cancers, including cervical neoplasia and invasive cervical cancer.^44,45

Women with HIV should receive screening for cervical cancer at the time of diagnosis, 6 months after the initial diagnosis, and annually thereafter.⁴⁶

Conflicting evidence exists regarding the effect of highly active antiretroviral therapy on the incidence of HPV-related disease, so aggressive screening and management of cervical neoplasia is recommended for women with HIV, regardless of CD4+ levels or viral load.^47–49

 

 

Additional infectious culprits

Coinfection with other sexually transmitted infections, specifically Chlamydia, herpes, and HIV, has been associated with cervical neoplasia and invasive cervical cancer. A positive linear association exists between the number of sexually transmitted infections and cervical neoplasia.⁵⁰

C trachomatis is the most common sexually transmitted infection in the United States, with a 6-times higher rate in African American women.⁵¹ Women who are seropositive for C trachomatis are at twofold higher risk of developing squamous cell cervical cancer.^52,53 Women who are seropositive for Chlamydia infection, herpes virus 2, or HPV are at markedly increased risk of invasive cervical cancer.⁵⁰

Tobacco use

The negative impact of smoking on numerous other cancers resulted in investigation of its role in cervical cancer.

Early case-control studies found an association between cervical cancer and smoking,⁵⁴ but because these studies did not account for HPV infection status, they could not establish causality. Subsequently, several studies did control for HPV infection; the risk of squamous cervical cancer was twice as high in women who had ever smoked.⁵⁵ Furthermore, the more cigarettes smoked per day, the higher the risk of  cervical neoplasia.^41,56

According to the US Centers for Disease Control and Prevention in 2014, the highest prevalence of smoking was among American Indian and Alaskan Native women, 32.5% of whom said they smoked every day, compared with 17.2% of white women and 13.7% of African American women.⁵⁷

HOW CAN PRIMARY CARE PHYSICIANS CLOSE THE GAP?

By promoting HPV vaccination to children and young adults, primary care physicians can help prevent cervical cancer. Moreover, primary care physicians will see most adolescents for a nonpreventive health visit, an optimal opportunity to discuss sexual activity practices and HPV vaccination.⁵⁸ Including the HPV vaccine as routine with other vaccinations can close the gap.³⁸

Screening and treatment of sexually transmitted infection during these visits can affect the risk that future HPV infection will progress to neoplasia or cancer. Persistent lifestyle modification counseling, especially smoking cessation through motivational interviewing, can lessen the risk of cervical cancer neoplasia progression.

Additionally, in light of recent changes in cervical cancer screening guidelines, the primary care physician’s role as educator is of utmost importance. In one study, although 99% of women had received a Pap test, 87% could not identify the purpose of the Pap test.⁵⁹ The primary care physician’s role is perhaps the most influential in preventing disease and, as such, has the greatest impact on a patient’s disease process.

African American, Hispanic, American Indian, and Alaskan Native women continue to be disproportionately affected by cervical cancer compared with white women. From 2006 to 2010, the incidence of cervical cancer in African American women was 10.3 per 100,000; in white women it was 7.2.¹ The mortality rate from cervical cancer in African American women is twice that in white women.¹ Although cervical cancer rates have decreased nationwide, significant racial health disparities persist.

See related editorial

As the first-line healthcare providers for many women, the primary care physician and the general obstetrician-gynecologist are optimally positioned to reduce these disparities.

Cervical cancer is the third most common gynecologic cancer, after uterine and ovarian cancer. Nearly 13,000 new cases are diagnosed each year in the United States, and more than 4,000 women die of it.² Fortunately, cervical cancer can be significantly prevented with adequate screening and vaccination against human papillomavirus (HPV).

WHY ARE BLACK WOMEN MORE LIKELY TO DIE OF CERVICAL CANCER?

Later stage at diagnosis. African American women are more likely to present with advanced cervical cancer than non-Hispanic white women.^3–6

Less-aggressive treatment. African American women are more likely to receive no treatment after a cancer diagnosis.⁶ Differences in treatment may be attributed to comorbid conditions, stage at cancer diagnosis, and patient refusal.^5,7

Less access to care. A study from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute looked at 7,267 women (4,431 non-Hispanic white women, 1,830 Hispanic white women, and 1,006 non-Hispanic African American women) who were diagnosed with primary invasive cervical cancer from 1992 to 1996 and followed through 2000. African American women had a 19% higher mortality rate compared with non-Hispanic white women during follow-up despite adjusting for age, stage, histology, and time of first treatment.⁸

However, a later study from the same program found no such difference after 1995, when the data were adjusted for marital status, disease stage, age, treatment, grade, and histology.⁶  

Equal access to healthcare may eliminate most of the disparity.⁷ A study in women with cervical cancer who sought treatment within the United States military healthcare system found no difference in treatment or 5- and 10-year survival rates between African American and white women.⁵ Equal access to comprehensive healthcare eliminated any disparity once cervical cancer was diagnosed.

CERVICAL CANCER SCREENING

The value of cervical cancer screening and prevention is well established. In 1941, Papanicolau reported that cervical cancer could be detected from vaginal smears.⁹ Since the development and widespread implementation of the “Pap” smear, cervical cancer rates have decreased dramatically in the United States.

Another major advance was the discovery that persistent infection with HPV is necessary for the development of cervical cancer, precancerous lesions, and genital warts.¹⁰

With advancing research, guidelines for cervical cancer screening have changed considerably over the years. Today, combined cervical cytologic and HPV testing is the mainstay. (Isolated HPV testing is generally not available outside clinical trials.)

Who should be screened?

Previous recommendations called for women to undergo Pap testing when they first became sexually active and then every year. However, cervical lesions are likely to regress in young women.¹¹ One study found that 28% of cervical intimal neoplasia (CIN) grade 2 and 3 lesions spontaneously regressed by 15 weeks, although lesions associated with HPV 16 infection were less likely to regress than with other HPV types.¹² A study of college women found that HPV infection persisted in only 9% of women after 24 months.¹³

To minimize unnecessary treatment of young women with dysplasia, the American Society for Colposcopy and Cervical Pathology in 2012 recommended cytologic screening for all women 21 years or older, regardless of age at first sexual encounter.¹⁴ Screening intervals were changed from every year to every 3 years until age 30, at which time cotesting with cytology and HPV testing is performed every 5 years. Routine cotesting is not recommended for women younger than 30, who have a high likelihood of HPV infection and spontaneous regression.

In 2014, the US Food and Drug Administration approved primary HPV screening (ie, testing for HPV first, and then performing cytology in samples that test positive) for women age 25 and older.¹⁵

Patients who need further evaluation and testing should be referred for colposcopy. The current guidelines for patients who have abnormal results on cervical cancer screening¹⁶ can be reviewed at www.asccp.org/asccp-guidelines.

As screening guidelines continue to evolve, primary care physicians will need to stay current and also help educate their patients. For example, many of our patients have undergone annual Pap screening for most of their lives and may not yet know about the new testing intervals.

Are there disparities in screening and follow-up?

Disparities in screening and follow-up may exist, but the evidence is not clear-cut.

In a 2013 National Health Interview Survey report, the rates of cervical cancer screening with Pap tests did not differ between African American and white women.¹⁷ However, the information on Pap testing was based on a single question asking participants if they had had a Pap test in the last 3 years. In our experience, patients may confuse Pap tests with speculum examinations.

Once women are screened, adequate and timely follow-up of abnormal results is key.

In a study from the National Breast and Cervical Cancer Early Detection Program,¹⁸ women who had cytology findings of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions were to undergo repeat Pap testing every 4 to 6 months for 2 years. African American women were the least likely to have a follow-up Pap smear compared with other racial groups.  

On the other hand, there was no difference related to race in follow-up rates of abnormal Pap tests in women ages 47 to 64 in the South Carolina Breast and Cervical Cancer Early Detection Program.¹⁹

In a study in an urban population (predominantly African African), the overall follow-up rate was only 26% at 12 months from an initial abnormal Pap smear. This study did not find any differences in follow-up according to race or ethnicity; however, it had insufficient power to detect a difference because only 15% of the study participants were white.²⁰

 

 

What is in a genotype?

HPV is implicated in progression to both squamous cell carcinoma and adenocarcinoma of the cervix. Worldwide, HPV genotypes 16 and 18 are associated with 73% of cases of invasive cervical cancer; most of the remainder are associated with, in order of decreasing prevalence, genotypes 58, 33, 45, 31, 52, 35, 59, 39, 51, and 56.²¹

High-grade cervical lesions in African American women may less often be positive for HPV 16 and 18 than in white women.^22,23 On the other hand, the proportion of non-Hispanic black women infected with HPV 35 and 58 was significantly higher than in non-Hispanic white women.²² Regardless, HPV screening is recommended for women of all races and ethnicities.

The 2-valent and 4-valent HPV vaccines do not cover HPV 35 or 58. The newer 9-valent vaccine covers HPV 58 (but not 35) and so may in theory decrease any potential disparity related to infection with a specific oncogenic subtype.

THE ROLE OF PREVENTION

HPV vaccination

The Females United to Unilaterally Reduce Endo/Ectocervical Disease study demonstrated that the 4-valent vaccine was highly effective against cervical intraepithelial neoplasia due to HPV 16 and 18.²⁴ In another study, the 2-valent vaccine reduced the incidence of CIN 3 or higher by 87% in women who received all 3 doses and who had no evidence of HPV infection at baseline.²⁵

HPV vaccination is expensive. Each shot costs about $130, plus the cost of administering it. Although the Vaccines for Children program covers the HPV vaccine for uninsured and underinsured children and adolescents under age 19, Medicaid coverage varies from state to state for adults over age 21.

The Advisory Committee on Immunization Practices (ACIP)²⁶ recommends routine vaccination for:

• Males 11 or 12 years old
• Females ages 9 to 26.

In October 2016, the ACIP approved a 2-dose series given 6 to 12 months apart for patients starting vaccination at ages 9 through 14 years who are not immunocompromised. Others should receive a 3-dose series, with the second dose given 1 to 2 months after the first dose and the third dose given 6 months after the first dose.²⁷ Previously, 3 doses were recommended for everyone.

Disparities in HPV vaccination rates

HPV vaccination rates among adolescents in the United States increased from 33.6% in 2013 to 41.7% in 2014.²⁸ However, HPV vaccination rates continue to lag behind those of other routine vaccines, such as Tdap and meningococcal conjugate.

Reagan-Steiner et al²⁸ reported that more black than white girls age 13 through 17 received at least 1 dose of a 3-dose HPV vaccination series, but more white girls received all 3 doses (70.6% vs 61.6%). In contrast, a meta-analysis by Fisher et al²⁹ found African American and uninsured women generally less likely to initiate the HPV vaccination series. Kessels et al³⁰ reported similar findings.

Barriers to HPV vaccination

Barriers to HPV vaccination can be provider-dependent, parental, or institutional.

Malo et al³¹ surveyed Florida Medicaid providers and found that those who participated in the Vaccines for Children program were less likely to cite lack of reimbursement as a barrier to vaccination.

Meites et al³² surveyed sexually transmitted disease clinics and found that common reasons for not offering HPV vaccine were cost, staff time, and difficulty coordinating follow-up visits to complete the series.  

Providers report lack of urgency or lack of perception of cervical cancer as a true public health threat, safety concerns regarding the vaccine, and the inability to coadminister vaccines as barriers.³³

Studies have shown that relatively few parents (up to 18%) of parents are concerned about the effect of the vaccine on sexual activity.³⁴ Rather, they are most likely to cite lack of information regarding the vaccine, lack of physician recommendation, and not knowing where to receive the vaccine as barriers.^35,36

Guerry et al³⁷ determined that the single most important factor in vaccine initiation was physician recommendation, a finding reiterated in other studies.^35,38 A study in North Carolina identified failure of physician recommendation as one of the missed opportunities for vaccination of young women.³⁹

Therefore, the primary care physician, as the initial contact with the child or young adult, holds a responsibility to narrow this gap. In simply discussing and recommending the vaccine, physicians could increase vaccination rates.

REPRODUCTIVE HEALTH

Although 80% of women will be infected with HPV in their lifetime, only a small proportion will develop cervical cancer, suggesting there are other cofactors in the progression to cervical cancer.⁴⁰

Given the infectious etiology of cervical cancer, other contributing reproductive health factors have been described. As expected, the number of sexual partners correlates with HPV infection.^41,42 Younger age at first intercourse has been linked to development of cervical neoplasia, consistent with persistent infection leading to neoplasia.^41,42

Primary care physicians should provide timely and comprehensive sexual education, including information on safe sexual practices and pregnancy prevention.

Human immunodeficiency virus

In 2010, the estimated rate of new human immunodeficiency virus (HIV) infections in African American women was nearly 20 times greater than in white women.⁴³ Previous studies have shown a clear relationship between HIV and HPV-associated cancers, including cervical neoplasia and invasive cervical cancer.^44,45

Women with HIV should receive screening for cervical cancer at the time of diagnosis, 6 months after the initial diagnosis, and annually thereafter.⁴⁶

Conflicting evidence exists regarding the effect of highly active antiretroviral therapy on the incidence of HPV-related disease, so aggressive screening and management of cervical neoplasia is recommended for women with HIV, regardless of CD4+ levels or viral load.^47–49

 

 

Additional infectious culprits

Coinfection with other sexually transmitted infections, specifically Chlamydia, herpes, and HIV, has been associated with cervical neoplasia and invasive cervical cancer. A positive linear association exists between the number of sexually transmitted infections and cervical neoplasia.⁵⁰

C trachomatis is the most common sexually transmitted infection in the United States, with a 6-times higher rate in African American women.⁵¹ Women who are seropositive for C trachomatis are at twofold higher risk of developing squamous cell cervical cancer.^52,53 Women who are seropositive for Chlamydia infection, herpes virus 2, or HPV are at markedly increased risk of invasive cervical cancer.⁵⁰

Tobacco use

The negative impact of smoking on numerous other cancers resulted in investigation of its role in cervical cancer.

Early case-control studies found an association between cervical cancer and smoking,⁵⁴ but because these studies did not account for HPV infection status, they could not establish causality. Subsequently, several studies did control for HPV infection; the risk of squamous cervical cancer was twice as high in women who had ever smoked.⁵⁵ Furthermore, the more cigarettes smoked per day, the higher the risk of  cervical neoplasia.^41,56

According to the US Centers for Disease Control and Prevention in 2014, the highest prevalence of smoking was among American Indian and Alaskan Native women, 32.5% of whom said they smoked every day, compared with 17.2% of white women and 13.7% of African American women.⁵⁷

HOW CAN PRIMARY CARE PHYSICIANS CLOSE THE GAP?

By promoting HPV vaccination to children and young adults, primary care physicians can help prevent cervical cancer. Moreover, primary care physicians will see most adolescents for a nonpreventive health visit, an optimal opportunity to discuss sexual activity practices and HPV vaccination.⁵⁸ Including the HPV vaccine as routine with other vaccinations can close the gap.³⁸

Screening and treatment of sexually transmitted infection during these visits can affect the risk that future HPV infection will progress to neoplasia or cancer. Persistent lifestyle modification counseling, especially smoking cessation through motivational interviewing, can lessen the risk of cervical cancer neoplasia progression.

Additionally, in light of recent changes in cervical cancer screening guidelines, the primary care physician’s role as educator is of utmost importance. In one study, although 99% of women had received a Pap test, 87% could not identify the purpose of the Pap test.⁵⁹ The primary care physician’s role is perhaps the most influential in preventing disease and, as such, has the greatest impact on a patient’s disease process.

African American, Hispanic, American Indian, and Alaskan Native women continue to be disproportionately affected by cervical cancer compared with white women. From 2006 to 2010, the incidence of cervical cancer in African American women was 10.3 per 100,000; in white women it was 7.2.¹ The mortality rate from cervical cancer in African American women is twice that in white women.¹ Although cervical cancer rates have decreased nationwide, significant racial health disparities persist.

See related editorial

As the first-line healthcare providers for many women, the primary care physician and the general obstetrician-gynecologist are optimally positioned to reduce these disparities.

Cervical cancer is the third most common gynecologic cancer, after uterine and ovarian cancer. Nearly 13,000 new cases are diagnosed each year in the United States, and more than 4,000 women die of it.² Fortunately, cervical cancer can be significantly prevented with adequate screening and vaccination against human papillomavirus (HPV).

WHY ARE BLACK WOMEN MORE LIKELY TO DIE OF CERVICAL CANCER?

Later stage at diagnosis. African American women are more likely to present with advanced cervical cancer than non-Hispanic white women.^3–6

Less-aggressive treatment. African American women are more likely to receive no treatment after a cancer diagnosis.⁶ Differences in treatment may be attributed to comorbid conditions, stage at cancer diagnosis, and patient refusal.^5,7

Less access to care. A study from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute looked at 7,267 women (4,431 non-Hispanic white women, 1,830 Hispanic white women, and 1,006 non-Hispanic African American women) who were diagnosed with primary invasive cervical cancer from 1992 to 1996 and followed through 2000. African American women had a 19% higher mortality rate compared with non-Hispanic white women during follow-up despite adjusting for age, stage, histology, and time of first treatment.⁸

However, a later study from the same program found no such difference after 1995, when the data were adjusted for marital status, disease stage, age, treatment, grade, and histology.⁶  

Equal access to healthcare may eliminate most of the disparity.⁷ A study in women with cervical cancer who sought treatment within the United States military healthcare system found no difference in treatment or 5- and 10-year survival rates between African American and white women.⁵ Equal access to comprehensive healthcare eliminated any disparity once cervical cancer was diagnosed.

CERVICAL CANCER SCREENING

The value of cervical cancer screening and prevention is well established. In 1941, Papanicolau reported that cervical cancer could be detected from vaginal smears.⁹ Since the development and widespread implementation of the “Pap” smear, cervical cancer rates have decreased dramatically in the United States.

Another major advance was the discovery that persistent infection with HPV is necessary for the development of cervical cancer, precancerous lesions, and genital warts.¹⁰

With advancing research, guidelines for cervical cancer screening have changed considerably over the years. Today, combined cervical cytologic and HPV testing is the mainstay. (Isolated HPV testing is generally not available outside clinical trials.)

Who should be screened?

Previous recommendations called for women to undergo Pap testing when they first became sexually active and then every year. However, cervical lesions are likely to regress in young women.¹¹ One study found that 28% of cervical intimal neoplasia (CIN) grade 2 and 3 lesions spontaneously regressed by 15 weeks, although lesions associated with HPV 16 infection were less likely to regress than with other HPV types.¹² A study of college women found that HPV infection persisted in only 9% of women after 24 months.¹³

To minimize unnecessary treatment of young women with dysplasia, the American Society for Colposcopy and Cervical Pathology in 2012 recommended cytologic screening for all women 21 years or older, regardless of age at first sexual encounter.¹⁴ Screening intervals were changed from every year to every 3 years until age 30, at which time cotesting with cytology and HPV testing is performed every 5 years. Routine cotesting is not recommended for women younger than 30, who have a high likelihood of HPV infection and spontaneous regression.

In 2014, the US Food and Drug Administration approved primary HPV screening (ie, testing for HPV first, and then performing cytology in samples that test positive) for women age 25 and older.¹⁵

Patients who need further evaluation and testing should be referred for colposcopy. The current guidelines for patients who have abnormal results on cervical cancer screening¹⁶ can be reviewed at www.asccp.org/asccp-guidelines.

As screening guidelines continue to evolve, primary care physicians will need to stay current and also help educate their patients. For example, many of our patients have undergone annual Pap screening for most of their lives and may not yet know about the new testing intervals.

Are there disparities in screening and follow-up?

Disparities in screening and follow-up may exist, but the evidence is not clear-cut.

In a 2013 National Health Interview Survey report, the rates of cervical cancer screening with Pap tests did not differ between African American and white women.¹⁷ However, the information on Pap testing was based on a single question asking participants if they had had a Pap test in the last 3 years. In our experience, patients may confuse Pap tests with speculum examinations.

Once women are screened, adequate and timely follow-up of abnormal results is key.

In a study from the National Breast and Cervical Cancer Early Detection Program,¹⁸ women who had cytology findings of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions were to undergo repeat Pap testing every 4 to 6 months for 2 years. African American women were the least likely to have a follow-up Pap smear compared with other racial groups.  

On the other hand, there was no difference related to race in follow-up rates of abnormal Pap tests in women ages 47 to 64 in the South Carolina Breast and Cervical Cancer Early Detection Program.¹⁹

In a study in an urban population (predominantly African African), the overall follow-up rate was only 26% at 12 months from an initial abnormal Pap smear. This study did not find any differences in follow-up according to race or ethnicity; however, it had insufficient power to detect a difference because only 15% of the study participants were white.²⁰

 

 

What is in a genotype?

HPV is implicated in progression to both squamous cell carcinoma and adenocarcinoma of the cervix. Worldwide, HPV genotypes 16 and 18 are associated with 73% of cases of invasive cervical cancer; most of the remainder are associated with, in order of decreasing prevalence, genotypes 58, 33, 45, 31, 52, 35, 59, 39, 51, and 56.²¹

High-grade cervical lesions in African American women may less often be positive for HPV 16 and 18 than in white women.^22,23 On the other hand, the proportion of non-Hispanic black women infected with HPV 35 and 58 was significantly higher than in non-Hispanic white women.²² Regardless, HPV screening is recommended for women of all races and ethnicities.

The 2-valent and 4-valent HPV vaccines do not cover HPV 35 or 58. The newer 9-valent vaccine covers HPV 58 (but not 35) and so may in theory decrease any potential disparity related to infection with a specific oncogenic subtype.

THE ROLE OF PREVENTION

HPV vaccination

The Females United to Unilaterally Reduce Endo/Ectocervical Disease study demonstrated that the 4-valent vaccine was highly effective against cervical intraepithelial neoplasia due to HPV 16 and 18.²⁴ In another study, the 2-valent vaccine reduced the incidence of CIN 3 or higher by 87% in women who received all 3 doses and who had no evidence of HPV infection at baseline.²⁵

HPV vaccination is expensive. Each shot costs about $130, plus the cost of administering it. Although the Vaccines for Children program covers the HPV vaccine for uninsured and underinsured children and adolescents under age 19, Medicaid coverage varies from state to state for adults over age 21.

The Advisory Committee on Immunization Practices (ACIP)²⁶ recommends routine vaccination for:

• Males 11 or 12 years old
• Females ages 9 to 26.

In October 2016, the ACIP approved a 2-dose series given 6 to 12 months apart for patients starting vaccination at ages 9 through 14 years who are not immunocompromised. Others should receive a 3-dose series, with the second dose given 1 to 2 months after the first dose and the third dose given 6 months after the first dose.²⁷ Previously, 3 doses were recommended for everyone.

Disparities in HPV vaccination rates

HPV vaccination rates among adolescents in the United States increased from 33.6% in 2013 to 41.7% in 2014.²⁸ However, HPV vaccination rates continue to lag behind those of other routine vaccines, such as Tdap and meningococcal conjugate.

Reagan-Steiner et al²⁸ reported that more black than white girls age 13 through 17 received at least 1 dose of a 3-dose HPV vaccination series, but more white girls received all 3 doses (70.6% vs 61.6%). In contrast, a meta-analysis by Fisher et al²⁹ found African American and uninsured women generally less likely to initiate the HPV vaccination series. Kessels et al³⁰ reported similar findings.

Barriers to HPV vaccination

Barriers to HPV vaccination can be provider-dependent, parental, or institutional.

Malo et al³¹ surveyed Florida Medicaid providers and found that those who participated in the Vaccines for Children program were less likely to cite lack of reimbursement as a barrier to vaccination.

Meites et al³² surveyed sexually transmitted disease clinics and found that common reasons for not offering HPV vaccine were cost, staff time, and difficulty coordinating follow-up visits to complete the series.  

Providers report lack of urgency or lack of perception of cervical cancer as a true public health threat, safety concerns regarding the vaccine, and the inability to coadminister vaccines as barriers.³³

Studies have shown that relatively few parents (up to 18%) of parents are concerned about the effect of the vaccine on sexual activity.³⁴ Rather, they are most likely to cite lack of information regarding the vaccine, lack of physician recommendation, and not knowing where to receive the vaccine as barriers.^35,36

Guerry et al³⁷ determined that the single most important factor in vaccine initiation was physician recommendation, a finding reiterated in other studies.^35,38 A study in North Carolina identified failure of physician recommendation as one of the missed opportunities for vaccination of young women.³⁹

Therefore, the primary care physician, as the initial contact with the child or young adult, holds a responsibility to narrow this gap. In simply discussing and recommending the vaccine, physicians could increase vaccination rates.

REPRODUCTIVE HEALTH

Although 80% of women will be infected with HPV in their lifetime, only a small proportion will develop cervical cancer, suggesting there are other cofactors in the progression to cervical cancer.⁴⁰

Given the infectious etiology of cervical cancer, other contributing reproductive health factors have been described. As expected, the number of sexual partners correlates with HPV infection.^41,42 Younger age at first intercourse has been linked to development of cervical neoplasia, consistent with persistent infection leading to neoplasia.^41,42

Primary care physicians should provide timely and comprehensive sexual education, including information on safe sexual practices and pregnancy prevention.

Human immunodeficiency virus

In 2010, the estimated rate of new human immunodeficiency virus (HIV) infections in African American women was nearly 20 times greater than in white women.⁴³ Previous studies have shown a clear relationship between HIV and HPV-associated cancers, including cervical neoplasia and invasive cervical cancer.^44,45

Women with HIV should receive screening for cervical cancer at the time of diagnosis, 6 months after the initial diagnosis, and annually thereafter.⁴⁶

Conflicting evidence exists regarding the effect of highly active antiretroviral therapy on the incidence of HPV-related disease, so aggressive screening and management of cervical neoplasia is recommended for women with HIV, regardless of CD4+ levels or viral load.^47–49

 

 

Additional infectious culprits

Coinfection with other sexually transmitted infections, specifically Chlamydia, herpes, and HIV, has been associated with cervical neoplasia and invasive cervical cancer. A positive linear association exists between the number of sexually transmitted infections and cervical neoplasia.⁵⁰

C trachomatis is the most common sexually transmitted infection in the United States, with a 6-times higher rate in African American women.⁵¹ Women who are seropositive for C trachomatis are at twofold higher risk of developing squamous cell cervical cancer.^52,53 Women who are seropositive for Chlamydia infection, herpes virus 2, or HPV are at markedly increased risk of invasive cervical cancer.⁵⁰

Tobacco use

The negative impact of smoking on numerous other cancers resulted in investigation of its role in cervical cancer.

Early case-control studies found an association between cervical cancer and smoking,⁵⁴ but because these studies did not account for HPV infection status, they could not establish causality. Subsequently, several studies did control for HPV infection; the risk of squamous cervical cancer was twice as high in women who had ever smoked.⁵⁵ Furthermore, the more cigarettes smoked per day, the higher the risk of  cervical neoplasia.^41,56

According to the US Centers for Disease Control and Prevention in 2014, the highest prevalence of smoking was among American Indian and Alaskan Native women, 32.5% of whom said they smoked every day, compared with 17.2% of white women and 13.7% of African American women.⁵⁷

HOW CAN PRIMARY CARE PHYSICIANS CLOSE THE GAP?

By promoting HPV vaccination to children and young adults, primary care physicians can help prevent cervical cancer. Moreover, primary care physicians will see most adolescents for a nonpreventive health visit, an optimal opportunity to discuss sexual activity practices and HPV vaccination.⁵⁸ Including the HPV vaccine as routine with other vaccinations can close the gap.³⁸

Screening and treatment of sexually transmitted infection during these visits can affect the risk that future HPV infection will progress to neoplasia or cancer. Persistent lifestyle modification counseling, especially smoking cessation through motivational interviewing, can lessen the risk of cervical cancer neoplasia progression.

Additionally, in light of recent changes in cervical cancer screening guidelines, the primary care physician’s role as educator is of utmost importance. In one study, although 99% of women had received a Pap test, 87% could not identify the purpose of the Pap test.⁵⁹ The primary care physician’s role is perhaps the most influential in preventing disease and, as such, has the greatest impact on a patient’s disease process.

Primary care providers play a crucial role in cancer control, including screening and follow-up.^1,2 In particular, they are often responsible for performing the initial screening and, when necessary, discussing appropriate treatment options. However, cancer screening practices in primary care can vary significantly, leading to disparities in access to these services.³

See related article

Arvizo and Mahdi,⁴ in this issue of the Journal, discuss disparities in cervical cancer screening, noting that African American women have a higher risk of developing and dying of cervical cancer than white women, possibly because they are diagnosed at a later stage and have lower stage-specific survival rates. The authors state that equal access to healthcare may help mitigate these factors, and they also discuss how primary care providers can reduce these disparities.

PRIORITIZING CERVICAL CANCER SCREENING

Even in patients who have access to regular primary care, other barriers to cancer screening may exist. A 2014 study used self-reported data from the Behavioral Risk Factor Surveillance System survey to assess barriers to cervical cancer screening in older women (ages 40 to 65) who reported having health insurance and a personal healthcare provider.⁵ Those who were never or rarely screened for cervical cancer were more likely than those who were regularly screened to have a chronic condition, such as heart disease, chronic obstructive pulmonary disease, arthritis, depression, kidney disease, or diabetes.

This finding suggests that cancer screening may be a low priority during an adult primary care visit in which multiple chronic diseases must be addressed. To reduce disparities in cancer screening, primary care systems need to be designed to optimize delivery of preventive care and disease management using a team approach.

SYSTEMATIC FOLLOW-UP

Arvizo and Mahdi also discuss the follow-up of abnormal screening Papanicolaou (Pap) smears. While appropriate follow-up is a key factor in the management of cervical dysplasia, follow-up rates vary among African American women. System-level interventions such as the use of an electronic medical record-based tracking system in primary care settings⁶ with established protocols for follow-up may be effective.

But even with such systems in place, patients may face psychosocial barriers (eg, lack of health literacy, distress after receiving an abnormal cervical cytology test result⁷) that prevent them from seeking additional care. To improve follow-up rates, providers must be aware of these barriers and know how to address them through effective communication.

VACCINATION FOR HPV

Finally, the association between human papilloma virus (HPV) infection and cervical cancer makes HPV vaccination a crucial step in cervical cancer prevention. Continued provider education regarding HPV vaccination can improve knowledge about the HPV vaccine,⁸ as well as improve vaccination rates.⁹ The recent approval of a 2-dose vaccine schedule for younger girls¹⁰ may also help improve vaccine series completion rates.

The authors also suggest that primary care providers counsel all patients about risk factors for cervical cancer, including unsafe sex practices and tobacco use.

OPTIMIZING SCREENING AND PREVENTION

I commend the authors for their discussion of cervical cancer disparities and for raising awareness of the important role primary care providers play in reducing these disparities. Improving cervical cancer screening rates and follow-up will require providers and patients to be aware of cervical cancer risk factors. Further, system-level practice interventions will optimize primary care providers’ ability to engage patients in cancer screening conversations and ensure timely follow-up of screening tests.

Primary care providers play a crucial role in cancer control, including screening and follow-up.^1,2 In particular, they are often responsible for performing the initial screening and, when necessary, discussing appropriate treatment options. However, cancer screening practices in primary care can vary significantly, leading to disparities in access to these services.³

See related article

Arvizo and Mahdi,⁴ in this issue of the Journal, discuss disparities in cervical cancer screening, noting that African American women have a higher risk of developing and dying of cervical cancer than white women, possibly because they are diagnosed at a later stage and have lower stage-specific survival rates. The authors state that equal access to healthcare may help mitigate these factors, and they also discuss how primary care providers can reduce these disparities.

PRIORITIZING CERVICAL CANCER SCREENING

Even in patients who have access to regular primary care, other barriers to cancer screening may exist. A 2014 study used self-reported data from the Behavioral Risk Factor Surveillance System survey to assess barriers to cervical cancer screening in older women (ages 40 to 65) who reported having health insurance and a personal healthcare provider.⁵ Those who were never or rarely screened for cervical cancer were more likely than those who were regularly screened to have a chronic condition, such as heart disease, chronic obstructive pulmonary disease, arthritis, depression, kidney disease, or diabetes.

This finding suggests that cancer screening may be a low priority during an adult primary care visit in which multiple chronic diseases must be addressed. To reduce disparities in cancer screening, primary care systems need to be designed to optimize delivery of preventive care and disease management using a team approach.

SYSTEMATIC FOLLOW-UP

Arvizo and Mahdi also discuss the follow-up of abnormal screening Papanicolaou (Pap) smears. While appropriate follow-up is a key factor in the management of cervical dysplasia, follow-up rates vary among African American women. System-level interventions such as the use of an electronic medical record-based tracking system in primary care settings⁶ with established protocols for follow-up may be effective.

But even with such systems in place, patients may face psychosocial barriers (eg, lack of health literacy, distress after receiving an abnormal cervical cytology test result⁷) that prevent them from seeking additional care. To improve follow-up rates, providers must be aware of these barriers and know how to address them through effective communication.

VACCINATION FOR HPV

Finally, the association between human papilloma virus (HPV) infection and cervical cancer makes HPV vaccination a crucial step in cervical cancer prevention. Continued provider education regarding HPV vaccination can improve knowledge about the HPV vaccine,⁸ as well as improve vaccination rates.⁹ The recent approval of a 2-dose vaccine schedule for younger girls¹⁰ may also help improve vaccine series completion rates.

The authors also suggest that primary care providers counsel all patients about risk factors for cervical cancer, including unsafe sex practices and tobacco use.

OPTIMIZING SCREENING AND PREVENTION

I commend the authors for their discussion of cervical cancer disparities and for raising awareness of the important role primary care providers play in reducing these disparities. Improving cervical cancer screening rates and follow-up will require providers and patients to be aware of cervical cancer risk factors. Further, system-level practice interventions will optimize primary care providers’ ability to engage patients in cancer screening conversations and ensure timely follow-up of screening tests.

Primary care providers play a crucial role in cancer control, including screening and follow-up.^1,2 In particular, they are often responsible for performing the initial screening and, when necessary, discussing appropriate treatment options. However, cancer screening practices in primary care can vary significantly, leading to disparities in access to these services.³

See related article

Arvizo and Mahdi,⁴ in this issue of the Journal, discuss disparities in cervical cancer screening, noting that African American women have a higher risk of developing and dying of cervical cancer than white women, possibly because they are diagnosed at a later stage and have lower stage-specific survival rates. The authors state that equal access to healthcare may help mitigate these factors, and they also discuss how primary care providers can reduce these disparities.

PRIORITIZING CERVICAL CANCER SCREENING

Even in patients who have access to regular primary care, other barriers to cancer screening may exist. A 2014 study used self-reported data from the Behavioral Risk Factor Surveillance System survey to assess barriers to cervical cancer screening in older women (ages 40 to 65) who reported having health insurance and a personal healthcare provider.⁵ Those who were never or rarely screened for cervical cancer were more likely than those who were regularly screened to have a chronic condition, such as heart disease, chronic obstructive pulmonary disease, arthritis, depression, kidney disease, or diabetes.

This finding suggests that cancer screening may be a low priority during an adult primary care visit in which multiple chronic diseases must be addressed. To reduce disparities in cancer screening, primary care systems need to be designed to optimize delivery of preventive care and disease management using a team approach.

SYSTEMATIC FOLLOW-UP

Arvizo and Mahdi also discuss the follow-up of abnormal screening Papanicolaou (Pap) smears. While appropriate follow-up is a key factor in the management of cervical dysplasia, follow-up rates vary among African American women. System-level interventions such as the use of an electronic medical record-based tracking system in primary care settings⁶ with established protocols for follow-up may be effective.

But even with such systems in place, patients may face psychosocial barriers (eg, lack of health literacy, distress after receiving an abnormal cervical cytology test result⁷) that prevent them from seeking additional care. To improve follow-up rates, providers must be aware of these barriers and know how to address them through effective communication.

VACCINATION FOR HPV

Finally, the association between human papilloma virus (HPV) infection and cervical cancer makes HPV vaccination a crucial step in cervical cancer prevention. Continued provider education regarding HPV vaccination can improve knowledge about the HPV vaccine,⁸ as well as improve vaccination rates.⁹ The recent approval of a 2-dose vaccine schedule for younger girls¹⁰ may also help improve vaccine series completion rates.

The authors also suggest that primary care providers counsel all patients about risk factors for cervical cancer, including unsafe sex practices and tobacco use.

OPTIMIZING SCREENING AND PREVENTION

I commend the authors for their discussion of cervical cancer disparities and for raising awareness of the important role primary care providers play in reducing these disparities. Improving cervical cancer screening rates and follow-up will require providers and patients to be aware of cervical cancer risk factors. Further, system-level practice interventions will optimize primary care providers’ ability to engage patients in cancer screening conversations and ensure timely follow-up of screening tests.

A 40-year-old man was brought to the emergency department with altered mental status. His roommate had found him lying unconscious in snow on the lawn outside his residence. When the emergency medical services team arrived, they recorded a core body temperature of 28.3°C (82.9°F) and instituted advanced cardiac life support.

During transit to the hospital, the patient’s heart rhythm changed from asystole to ventricular fibrillation, and defibrillation was performed twice.

Upon his arrival at the emergency room, advanced life support was continued, resulting in return of spontaneous circulation, with slow, wide-complex QRS rhythm noted on electrocardiography (ECG).

On examination, the patient’s pupils were fixed and dilated. The extremities were cold to palpation. The core body temperature dropped to 27.7°C (81.9°F).

Laboratory test results showed severe acidemia (arterial pH 6.8), elevated aspartate aminotransferase and alanine aminotransferase levels, and elevated creatinine and troponin. The troponin was measured 3 times and rose from 0.8 ng/mL to 0.9 ng/mL. A urine toxicology screen was positive for cannabinoids and cocaine.

ECG revealed J-point elevation (Osborn waves) in the precordial leads (Figure 1). A baseline electrocardiogram in the medical record from a previous admission had been normal.

An aggressive hypothermia protocol was initiated, but the patient died despite resuscitation efforts.

HYPOTHERMIA AND HEART RHYTHMS

Hypothermia—a core body temperature below 35°C (95°F)—causes generalized slowing of impulse conduction through cardiac tissues, shown on ECG as a prolongation of the PR, RR, QRS, and QT intervals.¹

A characteristic feature is elevation of the J point, also called the J wave or Osborn wave, most prominent in precordial leads V₂ to V₅ and caused by abnormal membrane repolarization in the early phase. The degree of hypothermia correlates linearly with the amplitude of the Osborn wave.^2,3

Laboratory tests can identify complications such as rhabdomyolysis, spontaneous bleeding, and lactic acidosis. Moderate to severe hypothermia may cause prolongation of all ECG intervals. Management requires resuscitation and rewarming.

Conditions to consider in the differential diagnosis are Brugada syndrome, hypercalcemia, and early repolarization syndrome.

A 40-year-old man was brought to the emergency department with altered mental status. His roommate had found him lying unconscious in snow on the lawn outside his residence. When the emergency medical services team arrived, they recorded a core body temperature of 28.3°C (82.9°F) and instituted advanced cardiac life support.

During transit to the hospital, the patient’s heart rhythm changed from asystole to ventricular fibrillation, and defibrillation was performed twice.

Upon his arrival at the emergency room, advanced life support was continued, resulting in return of spontaneous circulation, with slow, wide-complex QRS rhythm noted on electrocardiography (ECG).

On examination, the patient’s pupils were fixed and dilated. The extremities were cold to palpation. The core body temperature dropped to 27.7°C (81.9°F).

Laboratory test results showed severe acidemia (arterial pH 6.8), elevated aspartate aminotransferase and alanine aminotransferase levels, and elevated creatinine and troponin. The troponin was measured 3 times and rose from 0.8 ng/mL to 0.9 ng/mL. A urine toxicology screen was positive for cannabinoids and cocaine.

ECG revealed J-point elevation (Osborn waves) in the precordial leads (Figure 1). A baseline electrocardiogram in the medical record from a previous admission had been normal.

An aggressive hypothermia protocol was initiated, but the patient died despite resuscitation efforts.

HYPOTHERMIA AND HEART RHYTHMS

Hypothermia—a core body temperature below 35°C (95°F)—causes generalized slowing of impulse conduction through cardiac tissues, shown on ECG as a prolongation of the PR, RR, QRS, and QT intervals.¹

A characteristic feature is elevation of the J point, also called the J wave or Osborn wave, most prominent in precordial leads V₂ to V₅ and caused by abnormal membrane repolarization in the early phase. The degree of hypothermia correlates linearly with the amplitude of the Osborn wave.^2,3

Laboratory tests can identify complications such as rhabdomyolysis, spontaneous bleeding, and lactic acidosis. Moderate to severe hypothermia may cause prolongation of all ECG intervals. Management requires resuscitation and rewarming.

Conditions to consider in the differential diagnosis are Brugada syndrome, hypercalcemia, and early repolarization syndrome.

A 40-year-old man was brought to the emergency department with altered mental status. His roommate had found him lying unconscious in snow on the lawn outside his residence. When the emergency medical services team arrived, they recorded a core body temperature of 28.3°C (82.9°F) and instituted advanced cardiac life support.

During transit to the hospital, the patient’s heart rhythm changed from asystole to ventricular fibrillation, and defibrillation was performed twice.

Upon his arrival at the emergency room, advanced life support was continued, resulting in return of spontaneous circulation, with slow, wide-complex QRS rhythm noted on electrocardiography (ECG).

On examination, the patient’s pupils were fixed and dilated. The extremities were cold to palpation. The core body temperature dropped to 27.7°C (81.9°F).

Laboratory test results showed severe acidemia (arterial pH 6.8), elevated aspartate aminotransferase and alanine aminotransferase levels, and elevated creatinine and troponin. The troponin was measured 3 times and rose from 0.8 ng/mL to 0.9 ng/mL. A urine toxicology screen was positive for cannabinoids and cocaine.

ECG revealed J-point elevation (Osborn waves) in the precordial leads (Figure 1). A baseline electrocardiogram in the medical record from a previous admission had been normal.

An aggressive hypothermia protocol was initiated, but the patient died despite resuscitation efforts.

HYPOTHERMIA AND HEART RHYTHMS

Hypothermia—a core body temperature below 35°C (95°F)—causes generalized slowing of impulse conduction through cardiac tissues, shown on ECG as a prolongation of the PR, RR, QRS, and QT intervals.¹

A characteristic feature is elevation of the J point, also called the J wave or Osborn wave, most prominent in precordial leads V₂ to V₅ and caused by abnormal membrane repolarization in the early phase. The degree of hypothermia correlates linearly with the amplitude of the Osborn wave.^2,3

Laboratory tests can identify complications such as rhabdomyolysis, spontaneous bleeding, and lactic acidosis. Moderate to severe hypothermia may cause prolongation of all ECG intervals. Management requires resuscitation and rewarming.

Conditions to consider in the differential diagnosis are Brugada syndrome, hypercalcemia, and early repolarization syndrome.

A 41-year-old woman presented with coughing, wheezing, and painful subcutaneous nodules on her legs. She had presented 6 years ago with similar nodules and enlarged retroauricular, occipital, and maxillary lymph nodes. At that time, biopsy study of submaxillary lymph nodes and skin showed nonnecrotizing granulomas, with negative microbiology studies. Chest radiography and spirometry were normal. A diagnosis of sarcoidosis was made. Treatment was offered but refused.

Based on this history, computed tomography of the thorax and abdomen was performed and showed mediastinal and hilar lymphadenopathy, small bilateral lung nodules, and osseous cystic areas in both iliac blades. Magnetic resonance imaging (MRI) showed numerous discrete lesions in both iliac bones (Figure 1). Biopsy study of iliac bone revealed preserved architecture with no evidence of malignancy or granulomas.

Radiography of the hands showed an osseous lytic lesion in the third proximal phalanx of the right hand. No other radiographic abnormalities were noted.

The clinical and radiographic features and the patient’s clinical course were consistent with osseous sarcoidosis. She was started on methotrexate and a low-dose corticosteroid and was symptom-free at 12-month follow-up. Follow-up MRI showed reduction in the lymphadenopathies and stabilization of the bone lesions.

SARCOIDOSIS AND BONE

Sarcoidosis is a systemic granulomatous disease that involves the lung in more than 90% of cases. Skeletal involvement has been reported in 1% to 14% of patients.^1,2 Typical osseous involvement is cystic osteitis of the phalangeal bones of the hands and feet, but any part of the skeleton may be involved.³

Bone sarcoidosis is usually asymptomatic and is discovered incidentally. The diagnosis of sarcoidosis has usually been established clinically before bone lesions are detected on MRI. However, sarcoidosis-related bone lesions resembling bone metastases on MRI may be the initial presentation. The presence of intralesional fat has been described as a feature that excludes malignancy. 

No treatment has been shown to be of benefit.⁴ Sarcoidosis is a diagnosis of exclusion and radiographic lytic bone features are not specific, so a neoplastic cause (such as primary osteoblastoma, metastasis, or multiple myeloma) must always be ruled out, as well as other bone conditions such as osteomyelitis or bone cyst.

A 41-year-old woman presented with coughing, wheezing, and painful subcutaneous nodules on her legs. She had presented 6 years ago with similar nodules and enlarged retroauricular, occipital, and maxillary lymph nodes. At that time, biopsy study of submaxillary lymph nodes and skin showed nonnecrotizing granulomas, with negative microbiology studies. Chest radiography and spirometry were normal. A diagnosis of sarcoidosis was made. Treatment was offered but refused.

Based on this history, computed tomography of the thorax and abdomen was performed and showed mediastinal and hilar lymphadenopathy, small bilateral lung nodules, and osseous cystic areas in both iliac blades. Magnetic resonance imaging (MRI) showed numerous discrete lesions in both iliac bones (Figure 1). Biopsy study of iliac bone revealed preserved architecture with no evidence of malignancy or granulomas.

Radiography of the hands showed an osseous lytic lesion in the third proximal phalanx of the right hand. No other radiographic abnormalities were noted.

The clinical and radiographic features and the patient’s clinical course were consistent with osseous sarcoidosis. She was started on methotrexate and a low-dose corticosteroid and was symptom-free at 12-month follow-up. Follow-up MRI showed reduction in the lymphadenopathies and stabilization of the bone lesions.

SARCOIDOSIS AND BONE

Sarcoidosis is a systemic granulomatous disease that involves the lung in more than 90% of cases. Skeletal involvement has been reported in 1% to 14% of patients.^1,2 Typical osseous involvement is cystic osteitis of the phalangeal bones of the hands and feet, but any part of the skeleton may be involved.³

Bone sarcoidosis is usually asymptomatic and is discovered incidentally. The diagnosis of sarcoidosis has usually been established clinically before bone lesions are detected on MRI. However, sarcoidosis-related bone lesions resembling bone metastases on MRI may be the initial presentation. The presence of intralesional fat has been described as a feature that excludes malignancy. 

No treatment has been shown to be of benefit.⁴ Sarcoidosis is a diagnosis of exclusion and radiographic lytic bone features are not specific, so a neoplastic cause (such as primary osteoblastoma, metastasis, or multiple myeloma) must always be ruled out, as well as other bone conditions such as osteomyelitis or bone cyst.

A 41-year-old woman presented with coughing, wheezing, and painful subcutaneous nodules on her legs. She had presented 6 years ago with similar nodules and enlarged retroauricular, occipital, and maxillary lymph nodes. At that time, biopsy study of submaxillary lymph nodes and skin showed nonnecrotizing granulomas, with negative microbiology studies. Chest radiography and spirometry were normal. A diagnosis of sarcoidosis was made. Treatment was offered but refused.

Based on this history, computed tomography of the thorax and abdomen was performed and showed mediastinal and hilar lymphadenopathy, small bilateral lung nodules, and osseous cystic areas in both iliac blades. Magnetic resonance imaging (MRI) showed numerous discrete lesions in both iliac bones (Figure 1). Biopsy study of iliac bone revealed preserved architecture with no evidence of malignancy or granulomas.

Radiography of the hands showed an osseous lytic lesion in the third proximal phalanx of the right hand. No other radiographic abnormalities were noted.

The clinical and radiographic features and the patient’s clinical course were consistent with osseous sarcoidosis. She was started on methotrexate and a low-dose corticosteroid and was symptom-free at 12-month follow-up. Follow-up MRI showed reduction in the lymphadenopathies and stabilization of the bone lesions.

SARCOIDOSIS AND BONE

Sarcoidosis is a systemic granulomatous disease that involves the lung in more than 90% of cases. Skeletal involvement has been reported in 1% to 14% of patients.^1,2 Typical osseous involvement is cystic osteitis of the phalangeal bones of the hands and feet, but any part of the skeleton may be involved.³

Bone sarcoidosis is usually asymptomatic and is discovered incidentally. The diagnosis of sarcoidosis has usually been established clinically before bone lesions are detected on MRI. However, sarcoidosis-related bone lesions resembling bone metastases on MRI may be the initial presentation. The presence of intralesional fat has been described as a feature that excludes malignancy. 

No treatment has been shown to be of benefit.⁴ Sarcoidosis is a diagnosis of exclusion and radiographic lytic bone features are not specific, so a neoplastic cause (such as primary osteoblastoma, metastasis, or multiple myeloma) must always be ruled out, as well as other bone conditions such as osteomyelitis or bone cyst.

Raynaud phenomenon is an overactive vascular response to cold and emotional stress that results in cutaneous color changes and sensory symptoms of the digits (Figure 1). It can occur in isolation as primary Raynaud phenomenon or secondary to another disease process. It is thought to be triggered by a heightened sympathetic vasoconstrictive response of small arteriovenous anastomoses in the fingers, toes, ears, and tip of the nose. These structures play a key role in maintaining a stable core body temperature by cutaneous thermoregulation.¹

Secondary Raynaud phenomenon can be seen with a wide array of systemic conditions as well as environmental and drug exposures. It is a frequent feature of autoimmune rheumatic conditions such as systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, and dermatomyositis. Less commonly, cryoproteinemias, paraneoplastic syndromes, hypothyroidism, and carpal tunnel syndrome can be associated with or cause Raynaud phenomenon. Vibratory trauma (eg, from using a jackhammer) and drugs (eg, vasopressors, stimulants, ergots, chemotherapeutic agents) can also cause Raynaud phenomenon.¹

A variety of disorders that cause vasospasm or vascular occlusion of the peripheral circulation can mimic typical Raynaud phenomenon, including peripheral nerve injury,² complex regional pain syndrome,³ occlusive vascular disease, vasculitis, acrocyanosis,⁴ and thoracic outlet syndrome.

The prevalence of Raynaud phenomenon is not exactly known, in part due to geographic differences in climate and variation in methods of assessment. However, a 2015 systematic review and meta-analysis of primary Raynaud phenomenon determined a pooled prevalence of 4.85% (95% confidence interval [CI] 2.08%–8.71%) in the general population.⁵ Accordingly, accurate identification and management of this condition is a useful skill for the internist.

COLD SENSITIVITY AND COLOR CHANGES

Because there are no confirmatory diagnostic tests for this condition, there are no formal diagnostic criteria. However, many experts agree that Raynaud phenomenon can be diagnosed clinically when patients report:

• Unusual sensitivity of the fingers to cold, manifesting as pain or paresthesia (eg, tingling, pricking, numbness), and
• Color changes of the fingers when exposed to cold, specifically pale white or blue-black, or both.⁶

Provocative testing such as submerging patients’ hands in cold water is not recommended, as it is distressing to the patient and inconsistent in triggering an event.

Pain is a symptom of critical digital ischemia.

The skin color changes are due to rapid alterations in blood flow in digital skin. The pale white is due to markedly reduced or absent flow secondary to intense vasoconstriction, the blue-black is due to hypoxemic venous stasis, and the red blush is due to hyperemic reperfusion (Figure 1). However, not all patients have all 3 phases of the classic triphasic color changes, and color changes may not follow a set sequence.

Raynaud phenomenon can also occur in other areas of the body that have thermoregulatory vessels, such as the toes, ears, nipples, tongue, and nose. While some patients with Raynaud phenomenon have a finger that is more sensitive than the others, repeated isolated single-digit or asymmetric events without typical progression to all fingers suggest a secondary local structural disease requiring further investigation (see below).

Symptoms related to Raynaud often mimic sensory changes including paresthesias, numbness, aching, and clumsiness of the hand. Abnormal vascular reactivity has been implicated as a causative factor in several disorders, such as migraine headache, preeclampsia, and variant angina. While case reports, case series, and some controlled studies have linked Raynaud phenomenon and these conditions, there is no solid evidence of a systemic vaso­spastic disorder in patients with primary Raynaud phenomenon.

Raynaud phenomenon is triggered by more than just a cold ambient temperature. Provocation can occur during movement from warmer to relatively cooler temperatures, as well as during episodes of elevated sympathetic activity (eg, emotional distress or fear). In fact, maintaining full body warmth as well as emotional equilibrium are the most important strategies to reduce the frequency of attacks.

PRIMARY VS SECONDARY RAYNAUD PHENOMENON

To distinguish between primary and secondary Raynaud phenomenon, a careful history and physical examination are paramount.

Primary Raynaud phenomenon

In uncomplicated primary Raynaud phenomenon, the episodes typically last 15 to 20 minutes after rewarming and usually start in a single finger and spread to other digits symmetrically and bilaterally.⁷ The thumb is often spared, and ischemic digital ulcers do not occur. Vasoconstrictive episodes are mild.

Females under age 20 are most commonly affected. In our experience, a young woman with the above clinical picture, no signs or symptoms suggestive of connective tissue disease (see below), and normal nailfold capillaries can be diagnosed as having primary Raynaud phenomenon without any further workup.

Careful clinical follow-up is recommended, because if an occult secondary process is indeed present, most patients will begin to show additional symptoms or signs of it within 2 years of the onset of Raynaud phenomenon.

Should a clinician be unfamiliar with nailfold capillary examination, or if symptoms (eg, fatigue or arthralgia) or signs (eg, rash, arthritis) suggestive of connective tissue disease are present, referral to a rheumatologist for further evaluation is appropriate. Results of further diagnostic testing dictated by the history and physical such as a screening antinuclear antibody test can be sent before referral.

Secondary Raynaud phenomenon

Several clinical features suggest secondary Raynaud phenomenon and warrant referral to a rheumatologist:

• Age 20 or older at onset
• Frequent severe vasoconstrictive episodes
• Male sex
• Thumb involvement

• 

  Signs of an autoimmune rheumatic disease, eg, sclerodactyly, cutaneous or mucosal matted telangiectasia, inflammatory arthritis, an abnormal lung examination, severe digital ischemia with ulceration or gangrene, or nailfold capillary dilation or dropout (Figure 2)⁸

  Isolated single-limb or 1-finger ischemic events, seen in macrovascular occlusive disease or inflammatory disease mimicking Raynaud phenomenon (eg, atherosclerosis, vasculitis); when isolated acute ischemic events occur in the upper or lower extremity, a further workup is necessary.

Figure 3 shows our approach to evaluation.

NONPHARMACOLOGIC THERAPY

Cold avoidance and stress management are first-line therapies for preventing Raynaud attacks and must be part of any treatment strategy. Digital arteries and thermoregulatory vessels of the skin are predominantly under sympathetic adrenergic control, so temperature changes and emotional stressors trigger vasoconstriction. Patients should be counseled to:

Keep the whole body warm. Patients should wear multiple layers of clothing, a hat, warm gloves, and warm socks. Commercially available hand-warmers can help, especially for patients who live in cold climates.

Learn to avoid or manage stress. Good communication, attention to the patient’s needs, and regular follow-up for reassurance are paramount. For some patients, psychotropic medications to manage mood may help. Behavioral approaches have been suggested for acute stress management. One approach, autogenic training, is a form of relaxation with temperature biofeedback in which finger temperature data are provided to patients to help them learn to relax by monitoring their internal states and changes in temperature. However, there are no strong data to support the routine use of this technique or the use of one behavioral approach over another. Trials have generally been of low quality and limited by small sample size.⁹

Stop smoking!¹⁰

Stop a Raynaud attack should one occur, eg, place the hands under warm water or in a warm part of the body, such as under legs when sitting. This can help speed recovery.

In addition, the physician should:

Eliminate vasoconstricting agents such as nonselective beta-blockers, ergots, triptans, and amphetamines.

PHARMACOLOGIC THERAPY

For many patients, nonpharmacologic interventions are enough to decrease the severity and frequency of attacks. However, if Raynaud phenomenon continues to negatively affect quality of life, drug therapy can be added (Table 1).

Calcium channel blockers

Calcium channel blockers are first-line agents for both primary and secondary Raynaud phenomenon that does not adequately respond to nonpharmacologic interventions. These agents are effective, available, and reasonably inexpensive. 

Dihydropyridine calcium channel blockers such as nifedipine and amlodipine are commonly used. Both drugs are acceptable options, though some patients may respond better to one than the other in terms of symptoms and side effects. Nondihydropyridines such as diltiazem can also be used, but they have less potent vasodilatory effects because they are less selective for vascular smooth muscle.

These medications should be started at the lowest dose and titrated up over several weeks as tolerated to achieve their maximal effect. Intermittent therapy (eg, during the winter months only) is reasonable for primary Raynaud without risk of digital ulceration, as relief of symptoms and improvement in quality of life are the main indications for therapy in this circumstance.

A 2016 Cochrane review and meta-analysis of the use of calcium channel blockers to treat primary Raynaud phenomenon included 7 randomized controlled trials with 296 patients treated with either nifedipine or nicardipine.¹¹ There was moderate-quality evidence that these drugs minimally decreased the frequency of attacks (standardized mean difference of 0.23; 95% CI 0.08–0.38, P = .003). This translated to 1.72 fewer attacks per week with treatment than with no pharmacologic therapy (95% CI 0.60–2.84). When analyzed individually, only nifedipine was effective; nicardipine did not decrease the frequency of attacks.

Unfortunately, calcium channel blockers failed to decrease the severity of attacks (according to unvalidated severity scoring systems) or make any differences in physiologic measurement outcomes. Attacks were not completely eliminated, just less frequent than before treatment.¹¹

Most commonly reported side effects included headache, flushing, hypotension, edema, and, rarely, gastrointestinal reflux. Use of these medications may be limited by hypotension.

The review was limited by the small sample size, short duration of treatment, and relatively low doses of calcium channel blockers used in the available studies.¹¹

A 2005 meta-analysis also indicated a statistically significant decrease of 2.8 to 5 attacks per week with nifedipine treatment, though this study also included some patients with secondary Raynaud phenomenon.¹²

Phosphodiesterase type 5 inhibitors

When calcium channel blockers do not adequately control symptoms, phosphodiesterase type 5 (PDE5) inhibitors can be added or substituted. These medications work by preventing breakdown of cyclic guanosine monophosphate, which induces relaxation in vascular smooth muscle and vasodilation.

Sildenafil can be started at a low dose (20 mg daily) and up-titrated to the maximum dose (20 mg 3 times daily) as tolerated.

A 2014 meta-analysis of 6 randomized controlled trials included 244 patients with secondary Raynaud phenomenon treated with sildenafil, tadalafil, or vardenafil.¹³ These drugs decreased the daily frequency of attacks by about 0.5 per day vs placebo (–0.49,  95% CI –0.71 to –0.28, P <  .0001). PDE5 inhibitors also decreased the severity of attacks (based on the Raynaud’s Condition Score, a popular scoring system) and the duration of attacks by a statistically significant amount.

Almost all patients in these 6 trials were on PDE5 monotherapy. Data on the cumulative benefit of calcium channel blocker and PDE5 inhibitor combination therapy are not yet available. Not all patients tolerate combination therapy, as it can cause symptomatic hypotension, but it can be a successful option in some.

There are also no data showing that either calcium channel blockers or PDE5 inhibitors are superior, though the former are less expensive. A small double-blind, randomized, crossover study of udenafil vs amlodipine in the treatment of secondary Raynaud phenomenon showed that both medications significantly decreased the frequency of attacks and had comparable efficacy.¹⁴

Cost and insurance coverage. We have generally been successful in obtaining coverage for this off-label use of PDE5 inhibitors, though additional effort may be required. No drug (not even a calcium channel blocker) is approved by the US Food and Drug Administration for use in Raynaud phenomenon. In our experience, a letter of appeal outlining the rationale for use and citing supporting publications can lead to successful coverage of a medication. If the drug is still not approved, the patient either pays for it out of pocket or another agent is selected. In certain circumstances, pharmaceutical companies may provide prescription assistance for compassionate use of these drugs in Raynaud phenomenon, although this also takes letter-writing, phone calls, or both on the part of the physician.

Topical nitrates

Patients who have an unsatisfactory response to calcium channel blockers with or without PDE5 inhibitors can try topical nitrates, available as sustained-release transdermal patches, tapes, creams, gels, and ointments.

Small trials have noted slight improvement in the Raynaud Condition Score¹⁵ and finger temperature¹⁶ with these therapies. Another trial noted decreased frequency of attacks and symptoms with the use of sustained-release glyceryl trinitrate patches, but use was limited by intolerable headache.¹⁷

In our experience, topical nitrates are most helpful for patients who have 1 or a few digits that are more severely affected than the others, and we reserve these drugs for this indication. Localized vasodilation can provide targeted rapid relief of more ischemic areas.

Topical nitroglycerin can be applied to the base of the ischemic digit for 6 to 12 hours. Preparations vary, and patients should be closely monitored for dose response and tolerance.

Combining a topical nitrate with a calcium channel blocker is safe, but the use of a nitrate with a PDE5 inhibitor is contraindicated due to the risk of hypotension. The use of topical nitrates may be limited by systemic side effects such as headache and flushing and a lack of benefit over time.

Other therapies

If the aforementioned agents are not tolerated or not effective, there is limited evidence that other therapies reduce the frequency and sometimes the severity of attacks. These are not first-line agents but may be tried when other options have been exhausted and symptoms persist. There are no data to support combining these therapies, but in our experience doing so may help some patients in whom drug-drug interactions are not prohibitive.

Prazosin, an alpha-1-adrenergic receptor antagonist, was reported to improve Raynaud phenomenon in 2 small studies in the 1980s, but we do not use it since better options are available. In addition, the vasoactive blood vessels involved do not have alpha-1 receptors, so there is no theoretical basis for using prazosin.^18,19

Fluoxetine, a selective serotonin reuptake inhibitor, reduced the frequency and severity of attacks in a 6-week crossover study with nifedipine.²⁰

Losartan, an angiotensin II receptor blocker, also reduced the severity and frequency of attacks when compared with nifedipine.²¹

Pentoxifylline, a nonselective phosphodiesterase inhibitor, showed some benefit in a trial in 11 patients with primary Raynaud.²²

Atorvastatin, a lipid-lowering drug, reduced the number of digital ulcers in patients with secondary Raynaud already on first-line vasodilatory therapy, and might be added in this situation.²³

Botulinum toxin A injections have some data to support their use, but evidence is based on uncontrolled case series.²⁴ A controlled trial in scleroderma patients with severe Raynaud phenomenon found botulinum toxin to be no better than placebo.²⁵

Prostacyclin preparations are available. Intermittent intravenous doses of prostacyclin analogues over several days can be used in resistant cases. Oral prostacyclin agents have not shown consistent benefit. New prostacyclin receptor agonists are under investigation.

Overall, we move to other options only in patients with persistent symptoms that impair quality of life, or in patients with recurrent digital ischemic lesions that have not responded to calcium channel blockers and PDE5 inhibitors or nitrates, either alone or in combination.

DIGITAL ULCERATION AND ACUTE DIGITAL ISCHEMIC CRISIS

Patients with secondary Raynaud phenomenon may be at risk of recurrent digital ulceration and acute digital ischemia with gangrene. These patients should be comanaged with a rheumatologist so that the underlying disease process is fully addressed. Digital ulcers should be inspected closely for signs of infection, which may require treatment with antibiotics.

Acute digital ischemia is a medical emergency and should prompt inpatient admission with warming, emotional regulation, and pain control (often with narcotics) to decrease sympathetic vasoconstriction. These patients require aggressive vasodilatory therapy to reverse the ischemic event.

A short-acting calcium channel blocker or combination therapy with a calcium channel blocker and a PDE5 inhibitor or topical nitrate should be started. If there is no benefit, then transient intravenous vasodilatory therapy with a prostacyclin (epoprostenol) or localized digital sympathectomy is used to prevent digital loss.

The endothelin receptor inhibitor bosentan has been shown to decrease recurrent digital ulcers in patients with scleroderma, and while bosentan does not decrease the frequency of Raynaud attacks, it can be used in this select group to prevent new digital ulcers.

Treatment options may be limited by insurance coverage or access to intravenous infusions.

TAKE-HOME RECOMMENDATIONS

For many patients with primary or secondary Raynaud phenomenon, nonpharmacologic interventions are all that are required to decrease the frequency of attacks and improve quality of life. The goal should not be to eliminate attacks completely, as aggressive drug treatment may cause more harm than benefit. From our perspective, the goals of treatment should be to improve quality of life and prevent ischemic complications.

Pharmacologic therapies should be added only if attacks remain poorly controlled with incapacitating symptoms, or if the patient has digital ischemic ulcers. Calcium channel blockers are first-line therapy, given proven efficacy and low cost, and should be titrated to the maximum tolerated dose before adding or substituting other agents.

Raynaud phenomenon is an overactive vascular response to cold and emotional stress that results in cutaneous color changes and sensory symptoms of the digits (Figure 1). It can occur in isolation as primary Raynaud phenomenon or secondary to another disease process. It is thought to be triggered by a heightened sympathetic vasoconstrictive response of small arteriovenous anastomoses in the fingers, toes, ears, and tip of the nose. These structures play a key role in maintaining a stable core body temperature by cutaneous thermoregulation.¹

Secondary Raynaud phenomenon can be seen with a wide array of systemic conditions as well as environmental and drug exposures. It is a frequent feature of autoimmune rheumatic conditions such as systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, and dermatomyositis. Less commonly, cryoproteinemias, paraneoplastic syndromes, hypothyroidism, and carpal tunnel syndrome can be associated with or cause Raynaud phenomenon. Vibratory trauma (eg, from using a jackhammer) and drugs (eg, vasopressors, stimulants, ergots, chemotherapeutic agents) can also cause Raynaud phenomenon.¹

A variety of disorders that cause vasospasm or vascular occlusion of the peripheral circulation can mimic typical Raynaud phenomenon, including peripheral nerve injury,² complex regional pain syndrome,³ occlusive vascular disease, vasculitis, acrocyanosis,⁴ and thoracic outlet syndrome.

The prevalence of Raynaud phenomenon is not exactly known, in part due to geographic differences in climate and variation in methods of assessment. However, a 2015 systematic review and meta-analysis of primary Raynaud phenomenon determined a pooled prevalence of 4.85% (95% confidence interval [CI] 2.08%–8.71%) in the general population.⁵ Accordingly, accurate identification and management of this condition is a useful skill for the internist.

COLD SENSITIVITY AND COLOR CHANGES

Because there are no confirmatory diagnostic tests for this condition, there are no formal diagnostic criteria. However, many experts agree that Raynaud phenomenon can be diagnosed clinically when patients report:

• Unusual sensitivity of the fingers to cold, manifesting as pain or paresthesia (eg, tingling, pricking, numbness), and
• Color changes of the fingers when exposed to cold, specifically pale white or blue-black, or both.⁶

Provocative testing such as submerging patients’ hands in cold water is not recommended, as it is distressing to the patient and inconsistent in triggering an event.

Pain is a symptom of critical digital ischemia.

The skin color changes are due to rapid alterations in blood flow in digital skin. The pale white is due to markedly reduced or absent flow secondary to intense vasoconstriction, the blue-black is due to hypoxemic venous stasis, and the red blush is due to hyperemic reperfusion (Figure 1). However, not all patients have all 3 phases of the classic triphasic color changes, and color changes may not follow a set sequence.

Raynaud phenomenon can also occur in other areas of the body that have thermoregulatory vessels, such as the toes, ears, nipples, tongue, and nose. While some patients with Raynaud phenomenon have a finger that is more sensitive than the others, repeated isolated single-digit or asymmetric events without typical progression to all fingers suggest a secondary local structural disease requiring further investigation (see below).

Symptoms related to Raynaud often mimic sensory changes including paresthesias, numbness, aching, and clumsiness of the hand. Abnormal vascular reactivity has been implicated as a causative factor in several disorders, such as migraine headache, preeclampsia, and variant angina. While case reports, case series, and some controlled studies have linked Raynaud phenomenon and these conditions, there is no solid evidence of a systemic vaso­spastic disorder in patients with primary Raynaud phenomenon.

Raynaud phenomenon is triggered by more than just a cold ambient temperature. Provocation can occur during movement from warmer to relatively cooler temperatures, as well as during episodes of elevated sympathetic activity (eg, emotional distress or fear). In fact, maintaining full body warmth as well as emotional equilibrium are the most important strategies to reduce the frequency of attacks.

PRIMARY VS SECONDARY RAYNAUD PHENOMENON

To distinguish between primary and secondary Raynaud phenomenon, a careful history and physical examination are paramount.

Primary Raynaud phenomenon

In uncomplicated primary Raynaud phenomenon, the episodes typically last 15 to 20 minutes after rewarming and usually start in a single finger and spread to other digits symmetrically and bilaterally.⁷ The thumb is often spared, and ischemic digital ulcers do not occur. Vasoconstrictive episodes are mild.

Females under age 20 are most commonly affected. In our experience, a young woman with the above clinical picture, no signs or symptoms suggestive of connective tissue disease (see below), and normal nailfold capillaries can be diagnosed as having primary Raynaud phenomenon without any further workup.

Careful clinical follow-up is recommended, because if an occult secondary process is indeed present, most patients will begin to show additional symptoms or signs of it within 2 years of the onset of Raynaud phenomenon.

Should a clinician be unfamiliar with nailfold capillary examination, or if symptoms (eg, fatigue or arthralgia) or signs (eg, rash, arthritis) suggestive of connective tissue disease are present, referral to a rheumatologist for further evaluation is appropriate. Results of further diagnostic testing dictated by the history and physical such as a screening antinuclear antibody test can be sent before referral.

Secondary Raynaud phenomenon

Several clinical features suggest secondary Raynaud phenomenon and warrant referral to a rheumatologist:

• Age 20 or older at onset
• Frequent severe vasoconstrictive episodes
• Male sex
• Thumb involvement

• 

  Signs of an autoimmune rheumatic disease, eg, sclerodactyly, cutaneous or mucosal matted telangiectasia, inflammatory arthritis, an abnormal lung examination, severe digital ischemia with ulceration or gangrene, or nailfold capillary dilation or dropout (Figure 2)⁸

  Isolated single-limb or 1-finger ischemic events, seen in macrovascular occlusive disease or inflammatory disease mimicking Raynaud phenomenon (eg, atherosclerosis, vasculitis); when isolated acute ischemic events occur in the upper or lower extremity, a further workup is necessary.

Figure 3 shows our approach to evaluation.

NONPHARMACOLOGIC THERAPY

Cold avoidance and stress management are first-line therapies for preventing Raynaud attacks and must be part of any treatment strategy. Digital arteries and thermoregulatory vessels of the skin are predominantly under sympathetic adrenergic control, so temperature changes and emotional stressors trigger vasoconstriction. Patients should be counseled to:

Keep the whole body warm. Patients should wear multiple layers of clothing, a hat, warm gloves, and warm socks. Commercially available hand-warmers can help, especially for patients who live in cold climates.

Learn to avoid or manage stress. Good communication, attention to the patient’s needs, and regular follow-up for reassurance are paramount. For some patients, psychotropic medications to manage mood may help. Behavioral approaches have been suggested for acute stress management. One approach, autogenic training, is a form of relaxation with temperature biofeedback in which finger temperature data are provided to patients to help them learn to relax by monitoring their internal states and changes in temperature. However, there are no strong data to support the routine use of this technique or the use of one behavioral approach over another. Trials have generally been of low quality and limited by small sample size.⁹

Stop smoking!¹⁰

Stop a Raynaud attack should one occur, eg, place the hands under warm water or in a warm part of the body, such as under legs when sitting. This can help speed recovery.

In addition, the physician should:

Eliminate vasoconstricting agents such as nonselective beta-blockers, ergots, triptans, and amphetamines.

PHARMACOLOGIC THERAPY

For many patients, nonpharmacologic interventions are enough to decrease the severity and frequency of attacks. However, if Raynaud phenomenon continues to negatively affect quality of life, drug therapy can be added (Table 1).

Calcium channel blockers

Calcium channel blockers are first-line agents for both primary and secondary Raynaud phenomenon that does not adequately respond to nonpharmacologic interventions. These agents are effective, available, and reasonably inexpensive. 

Dihydropyridine calcium channel blockers such as nifedipine and amlodipine are commonly used. Both drugs are acceptable options, though some patients may respond better to one than the other in terms of symptoms and side effects. Nondihydropyridines such as diltiazem can also be used, but they have less potent vasodilatory effects because they are less selective for vascular smooth muscle.

These medications should be started at the lowest dose and titrated up over several weeks as tolerated to achieve their maximal effect. Intermittent therapy (eg, during the winter months only) is reasonable for primary Raynaud without risk of digital ulceration, as relief of symptoms and improvement in quality of life are the main indications for therapy in this circumstance.

A 2016 Cochrane review and meta-analysis of the use of calcium channel blockers to treat primary Raynaud phenomenon included 7 randomized controlled trials with 296 patients treated with either nifedipine or nicardipine.¹¹ There was moderate-quality evidence that these drugs minimally decreased the frequency of attacks (standardized mean difference of 0.23; 95% CI 0.08–0.38, P = .003). This translated to 1.72 fewer attacks per week with treatment than with no pharmacologic therapy (95% CI 0.60–2.84). When analyzed individually, only nifedipine was effective; nicardipine did not decrease the frequency of attacks.

Unfortunately, calcium channel blockers failed to decrease the severity of attacks (according to unvalidated severity scoring systems) or make any differences in physiologic measurement outcomes. Attacks were not completely eliminated, just less frequent than before treatment.¹¹

Most commonly reported side effects included headache, flushing, hypotension, edema, and, rarely, gastrointestinal reflux. Use of these medications may be limited by hypotension.

The review was limited by the small sample size, short duration of treatment, and relatively low doses of calcium channel blockers used in the available studies.¹¹

A 2005 meta-analysis also indicated a statistically significant decrease of 2.8 to 5 attacks per week with nifedipine treatment, though this study also included some patients with secondary Raynaud phenomenon.¹²

Phosphodiesterase type 5 inhibitors

When calcium channel blockers do not adequately control symptoms, phosphodiesterase type 5 (PDE5) inhibitors can be added or substituted. These medications work by preventing breakdown of cyclic guanosine monophosphate, which induces relaxation in vascular smooth muscle and vasodilation.

Sildenafil can be started at a low dose (20 mg daily) and up-titrated to the maximum dose (20 mg 3 times daily) as tolerated.

A 2014 meta-analysis of 6 randomized controlled trials included 244 patients with secondary Raynaud phenomenon treated with sildenafil, tadalafil, or vardenafil.¹³ These drugs decreased the daily frequency of attacks by about 0.5 per day vs placebo (–0.49,  95% CI –0.71 to –0.28, P <  .0001). PDE5 inhibitors also decreased the severity of attacks (based on the Raynaud’s Condition Score, a popular scoring system) and the duration of attacks by a statistically significant amount.

Almost all patients in these 6 trials were on PDE5 monotherapy. Data on the cumulative benefit of calcium channel blocker and PDE5 inhibitor combination therapy are not yet available. Not all patients tolerate combination therapy, as it can cause symptomatic hypotension, but it can be a successful option in some.

There are also no data showing that either calcium channel blockers or PDE5 inhibitors are superior, though the former are less expensive. A small double-blind, randomized, crossover study of udenafil vs amlodipine in the treatment of secondary Raynaud phenomenon showed that both medications significantly decreased the frequency of attacks and had comparable efficacy.¹⁴

Cost and insurance coverage. We have generally been successful in obtaining coverage for this off-label use of PDE5 inhibitors, though additional effort may be required. No drug (not even a calcium channel blocker) is approved by the US Food and Drug Administration for use in Raynaud phenomenon. In our experience, a letter of appeal outlining the rationale for use and citing supporting publications can lead to successful coverage of a medication. If the drug is still not approved, the patient either pays for it out of pocket or another agent is selected. In certain circumstances, pharmaceutical companies may provide prescription assistance for compassionate use of these drugs in Raynaud phenomenon, although this also takes letter-writing, phone calls, or both on the part of the physician.

Topical nitrates

Patients who have an unsatisfactory response to calcium channel blockers with or without PDE5 inhibitors can try topical nitrates, available as sustained-release transdermal patches, tapes, creams, gels, and ointments.

Small trials have noted slight improvement in the Raynaud Condition Score¹⁵ and finger temperature¹⁶ with these therapies. Another trial noted decreased frequency of attacks and symptoms with the use of sustained-release glyceryl trinitrate patches, but use was limited by intolerable headache.¹⁷

In our experience, topical nitrates are most helpful for patients who have 1 or a few digits that are more severely affected than the others, and we reserve these drugs for this indication. Localized vasodilation can provide targeted rapid relief of more ischemic areas.

Topical nitroglycerin can be applied to the base of the ischemic digit for 6 to 12 hours. Preparations vary, and patients should be closely monitored for dose response and tolerance.

Combining a topical nitrate with a calcium channel blocker is safe, but the use of a nitrate with a PDE5 inhibitor is contraindicated due to the risk of hypotension. The use of topical nitrates may be limited by systemic side effects such as headache and flushing and a lack of benefit over time.

Other therapies

If the aforementioned agents are not tolerated or not effective, there is limited evidence that other therapies reduce the frequency and sometimes the severity of attacks. These are not first-line agents but may be tried when other options have been exhausted and symptoms persist. There are no data to support combining these therapies, but in our experience doing so may help some patients in whom drug-drug interactions are not prohibitive.

Prazosin, an alpha-1-adrenergic receptor antagonist, was reported to improve Raynaud phenomenon in 2 small studies in the 1980s, but we do not use it since better options are available. In addition, the vasoactive blood vessels involved do not have alpha-1 receptors, so there is no theoretical basis for using prazosin.^18,19

Fluoxetine, a selective serotonin reuptake inhibitor, reduced the frequency and severity of attacks in a 6-week crossover study with nifedipine.²⁰

Losartan, an angiotensin II receptor blocker, also reduced the severity and frequency of attacks when compared with nifedipine.²¹

Pentoxifylline, a nonselective phosphodiesterase inhibitor, showed some benefit in a trial in 11 patients with primary Raynaud.²²

Atorvastatin, a lipid-lowering drug, reduced the number of digital ulcers in patients with secondary Raynaud already on first-line vasodilatory therapy, and might be added in this situation.²³

Botulinum toxin A injections have some data to support their use, but evidence is based on uncontrolled case series.²⁴ A controlled trial in scleroderma patients with severe Raynaud phenomenon found botulinum toxin to be no better than placebo.²⁵

Prostacyclin preparations are available. Intermittent intravenous doses of prostacyclin analogues over several days can be used in resistant cases. Oral prostacyclin agents have not shown consistent benefit. New prostacyclin receptor agonists are under investigation.

Overall, we move to other options only in patients with persistent symptoms that impair quality of life, or in patients with recurrent digital ischemic lesions that have not responded to calcium channel blockers and PDE5 inhibitors or nitrates, either alone or in combination.

DIGITAL ULCERATION AND ACUTE DIGITAL ISCHEMIC CRISIS

Patients with secondary Raynaud phenomenon may be at risk of recurrent digital ulceration and acute digital ischemia with gangrene. These patients should be comanaged with a rheumatologist so that the underlying disease process is fully addressed. Digital ulcers should be inspected closely for signs of infection, which may require treatment with antibiotics.

Acute digital ischemia is a medical emergency and should prompt inpatient admission with warming, emotional regulation, and pain control (often with narcotics) to decrease sympathetic vasoconstriction. These patients require aggressive vasodilatory therapy to reverse the ischemic event.

A short-acting calcium channel blocker or combination therapy with a calcium channel blocker and a PDE5 inhibitor or topical nitrate should be started. If there is no benefit, then transient intravenous vasodilatory therapy with a prostacyclin (epoprostenol) or localized digital sympathectomy is used to prevent digital loss.

The endothelin receptor inhibitor bosentan has been shown to decrease recurrent digital ulcers in patients with scleroderma, and while bosentan does not decrease the frequency of Raynaud attacks, it can be used in this select group to prevent new digital ulcers.

Treatment options may be limited by insurance coverage or access to intravenous infusions.

TAKE-HOME RECOMMENDATIONS

For many patients with primary or secondary Raynaud phenomenon, nonpharmacologic interventions are all that are required to decrease the frequency of attacks and improve quality of life. The goal should not be to eliminate attacks completely, as aggressive drug treatment may cause more harm than benefit. From our perspective, the goals of treatment should be to improve quality of life and prevent ischemic complications.

Pharmacologic therapies should be added only if attacks remain poorly controlled with incapacitating symptoms, or if the patient has digital ischemic ulcers. Calcium channel blockers are first-line therapy, given proven efficacy and low cost, and should be titrated to the maximum tolerated dose before adding or substituting other agents.

Raynaud phenomenon is an overactive vascular response to cold and emotional stress that results in cutaneous color changes and sensory symptoms of the digits (Figure 1). It can occur in isolation as primary Raynaud phenomenon or secondary to another disease process. It is thought to be triggered by a heightened sympathetic vasoconstrictive response of small arteriovenous anastomoses in the fingers, toes, ears, and tip of the nose. These structures play a key role in maintaining a stable core body temperature by cutaneous thermoregulation.¹

Secondary Raynaud phenomenon can be seen with a wide array of systemic conditions as well as environmental and drug exposures. It is a frequent feature of autoimmune rheumatic conditions such as systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, and dermatomyositis. Less commonly, cryoproteinemias, paraneoplastic syndromes, hypothyroidism, and carpal tunnel syndrome can be associated with or cause Raynaud phenomenon. Vibratory trauma (eg, from using a jackhammer) and drugs (eg, vasopressors, stimulants, ergots, chemotherapeutic agents) can also cause Raynaud phenomenon.¹

A variety of disorders that cause vasospasm or vascular occlusion of the peripheral circulation can mimic typical Raynaud phenomenon, including peripheral nerve injury,² complex regional pain syndrome,³ occlusive vascular disease, vasculitis, acrocyanosis,⁴ and thoracic outlet syndrome.

The prevalence of Raynaud phenomenon is not exactly known, in part due to geographic differences in climate and variation in methods of assessment. However, a 2015 systematic review and meta-analysis of primary Raynaud phenomenon determined a pooled prevalence of 4.85% (95% confidence interval [CI] 2.08%–8.71%) in the general population.⁵ Accordingly, accurate identification and management of this condition is a useful skill for the internist.

COLD SENSITIVITY AND COLOR CHANGES

Because there are no confirmatory diagnostic tests for this condition, there are no formal diagnostic criteria. However, many experts agree that Raynaud phenomenon can be diagnosed clinically when patients report:

• Unusual sensitivity of the fingers to cold, manifesting as pain or paresthesia (eg, tingling, pricking, numbness), and
• Color changes of the fingers when exposed to cold, specifically pale white or blue-black, or both.⁶

Provocative testing such as submerging patients’ hands in cold water is not recommended, as it is distressing to the patient and inconsistent in triggering an event.

Pain is a symptom of critical digital ischemia.

The skin color changes are due to rapid alterations in blood flow in digital skin. The pale white is due to markedly reduced or absent flow secondary to intense vasoconstriction, the blue-black is due to hypoxemic venous stasis, and the red blush is due to hyperemic reperfusion (Figure 1). However, not all patients have all 3 phases of the classic triphasic color changes, and color changes may not follow a set sequence.

Raynaud phenomenon can also occur in other areas of the body that have thermoregulatory vessels, such as the toes, ears, nipples, tongue, and nose. While some patients with Raynaud phenomenon have a finger that is more sensitive than the others, repeated isolated single-digit or asymmetric events without typical progression to all fingers suggest a secondary local structural disease requiring further investigation (see below).

Symptoms related to Raynaud often mimic sensory changes including paresthesias, numbness, aching, and clumsiness of the hand. Abnormal vascular reactivity has been implicated as a causative factor in several disorders, such as migraine headache, preeclampsia, and variant angina. While case reports, case series, and some controlled studies have linked Raynaud phenomenon and these conditions, there is no solid evidence of a systemic vaso­spastic disorder in patients with primary Raynaud phenomenon.

Raynaud phenomenon is triggered by more than just a cold ambient temperature. Provocation can occur during movement from warmer to relatively cooler temperatures, as well as during episodes of elevated sympathetic activity (eg, emotional distress or fear). In fact, maintaining full body warmth as well as emotional equilibrium are the most important strategies to reduce the frequency of attacks.

PRIMARY VS SECONDARY RAYNAUD PHENOMENON

To distinguish between primary and secondary Raynaud phenomenon, a careful history and physical examination are paramount.

Primary Raynaud phenomenon

In uncomplicated primary Raynaud phenomenon, the episodes typically last 15 to 20 minutes after rewarming and usually start in a single finger and spread to other digits symmetrically and bilaterally.⁷ The thumb is often spared, and ischemic digital ulcers do not occur. Vasoconstrictive episodes are mild.

Females under age 20 are most commonly affected. In our experience, a young woman with the above clinical picture, no signs or symptoms suggestive of connective tissue disease (see below), and normal nailfold capillaries can be diagnosed as having primary Raynaud phenomenon without any further workup.

Careful clinical follow-up is recommended, because if an occult secondary process is indeed present, most patients will begin to show additional symptoms or signs of it within 2 years of the onset of Raynaud phenomenon.

Should a clinician be unfamiliar with nailfold capillary examination, or if symptoms (eg, fatigue or arthralgia) or signs (eg, rash, arthritis) suggestive of connective tissue disease are present, referral to a rheumatologist for further evaluation is appropriate. Results of further diagnostic testing dictated by the history and physical such as a screening antinuclear antibody test can be sent before referral.

Secondary Raynaud phenomenon

Several clinical features suggest secondary Raynaud phenomenon and warrant referral to a rheumatologist:

• Age 20 or older at onset
• Frequent severe vasoconstrictive episodes
• Male sex
• Thumb involvement

• 

  Signs of an autoimmune rheumatic disease, eg, sclerodactyly, cutaneous or mucosal matted telangiectasia, inflammatory arthritis, an abnormal lung examination, severe digital ischemia with ulceration or gangrene, or nailfold capillary dilation or dropout (Figure 2)⁸

  Isolated single-limb or 1-finger ischemic events, seen in macrovascular occlusive disease or inflammatory disease mimicking Raynaud phenomenon (eg, atherosclerosis, vasculitis); when isolated acute ischemic events occur in the upper or lower extremity, a further workup is necessary.

Figure 3 shows our approach to evaluation.

NONPHARMACOLOGIC THERAPY

Cold avoidance and stress management are first-line therapies for preventing Raynaud attacks and must be part of any treatment strategy. Digital arteries and thermoregulatory vessels of the skin are predominantly under sympathetic adrenergic control, so temperature changes and emotional stressors trigger vasoconstriction. Patients should be counseled to:

Keep the whole body warm. Patients should wear multiple layers of clothing, a hat, warm gloves, and warm socks. Commercially available hand-warmers can help, especially for patients who live in cold climates.

Learn to avoid or manage stress. Good communication, attention to the patient’s needs, and regular follow-up for reassurance are paramount. For some patients, psychotropic medications to manage mood may help. Behavioral approaches have been suggested for acute stress management. One approach, autogenic training, is a form of relaxation with temperature biofeedback in which finger temperature data are provided to patients to help them learn to relax by monitoring their internal states and changes in temperature. However, there are no strong data to support the routine use of this technique or the use of one behavioral approach over another. Trials have generally been of low quality and limited by small sample size.⁹

Stop smoking!¹⁰

Stop a Raynaud attack should one occur, eg, place the hands under warm water or in a warm part of the body, such as under legs when sitting. This can help speed recovery.

In addition, the physician should:

Eliminate vasoconstricting agents such as nonselective beta-blockers, ergots, triptans, and amphetamines.

PHARMACOLOGIC THERAPY

For many patients, nonpharmacologic interventions are enough to decrease the severity and frequency of attacks. However, if Raynaud phenomenon continues to negatively affect quality of life, drug therapy can be added (Table 1).

Calcium channel blockers

Calcium channel blockers are first-line agents for both primary and secondary Raynaud phenomenon that does not adequately respond to nonpharmacologic interventions. These agents are effective, available, and reasonably inexpensive. 

Dihydropyridine calcium channel blockers such as nifedipine and amlodipine are commonly used. Both drugs are acceptable options, though some patients may respond better to one than the other in terms of symptoms and side effects. Nondihydropyridines such as diltiazem can also be used, but they have less potent vasodilatory effects because they are less selective for vascular smooth muscle.

These medications should be started at the lowest dose and titrated up over several weeks as tolerated to achieve their maximal effect. Intermittent therapy (eg, during the winter months only) is reasonable for primary Raynaud without risk of digital ulceration, as relief of symptoms and improvement in quality of life are the main indications for therapy in this circumstance.

A 2016 Cochrane review and meta-analysis of the use of calcium channel blockers to treat primary Raynaud phenomenon included 7 randomized controlled trials with 296 patients treated with either nifedipine or nicardipine.¹¹ There was moderate-quality evidence that these drugs minimally decreased the frequency of attacks (standardized mean difference of 0.23; 95% CI 0.08–0.38, P = .003). This translated to 1.72 fewer attacks per week with treatment than with no pharmacologic therapy (95% CI 0.60–2.84). When analyzed individually, only nifedipine was effective; nicardipine did not decrease the frequency of attacks.

Unfortunately, calcium channel blockers failed to decrease the severity of attacks (according to unvalidated severity scoring systems) or make any differences in physiologic measurement outcomes. Attacks were not completely eliminated, just less frequent than before treatment.¹¹

Most commonly reported side effects included headache, flushing, hypotension, edema, and, rarely, gastrointestinal reflux. Use of these medications may be limited by hypotension.

The review was limited by the small sample size, short duration of treatment, and relatively low doses of calcium channel blockers used in the available studies.¹¹

A 2005 meta-analysis also indicated a statistically significant decrease of 2.8 to 5 attacks per week with nifedipine treatment, though this study also included some patients with secondary Raynaud phenomenon.¹²

Phosphodiesterase type 5 inhibitors

When calcium channel blockers do not adequately control symptoms, phosphodiesterase type 5 (PDE5) inhibitors can be added or substituted. These medications work by preventing breakdown of cyclic guanosine monophosphate, which induces relaxation in vascular smooth muscle and vasodilation.

Sildenafil can be started at a low dose (20 mg daily) and up-titrated to the maximum dose (20 mg 3 times daily) as tolerated.

A 2014 meta-analysis of 6 randomized controlled trials included 244 patients with secondary Raynaud phenomenon treated with sildenafil, tadalafil, or vardenafil.¹³ These drugs decreased the daily frequency of attacks by about 0.5 per day vs placebo (–0.49,  95% CI –0.71 to –0.28, P <  .0001). PDE5 inhibitors also decreased the severity of attacks (based on the Raynaud’s Condition Score, a popular scoring system) and the duration of attacks by a statistically significant amount.

Almost all patients in these 6 trials were on PDE5 monotherapy. Data on the cumulative benefit of calcium channel blocker and PDE5 inhibitor combination therapy are not yet available. Not all patients tolerate combination therapy, as it can cause symptomatic hypotension, but it can be a successful option in some.

There are also no data showing that either calcium channel blockers or PDE5 inhibitors are superior, though the former are less expensive. A small double-blind, randomized, crossover study of udenafil vs amlodipine in the treatment of secondary Raynaud phenomenon showed that both medications significantly decreased the frequency of attacks and had comparable efficacy.¹⁴

Cost and insurance coverage. We have generally been successful in obtaining coverage for this off-label use of PDE5 inhibitors, though additional effort may be required. No drug (not even a calcium channel blocker) is approved by the US Food and Drug Administration for use in Raynaud phenomenon. In our experience, a letter of appeal outlining the rationale for use and citing supporting publications can lead to successful coverage of a medication. If the drug is still not approved, the patient either pays for it out of pocket or another agent is selected. In certain circumstances, pharmaceutical companies may provide prescription assistance for compassionate use of these drugs in Raynaud phenomenon, although this also takes letter-writing, phone calls, or both on the part of the physician.

Topical nitrates

Patients who have an unsatisfactory response to calcium channel blockers with or without PDE5 inhibitors can try topical nitrates, available as sustained-release transdermal patches, tapes, creams, gels, and ointments.

Small trials have noted slight improvement in the Raynaud Condition Score¹⁵ and finger temperature¹⁶ with these therapies. Another trial noted decreased frequency of attacks and symptoms with the use of sustained-release glyceryl trinitrate patches, but use was limited by intolerable headache.¹⁷

In our experience, topical nitrates are most helpful for patients who have 1 or a few digits that are more severely affected than the others, and we reserve these drugs for this indication. Localized vasodilation can provide targeted rapid relief of more ischemic areas.

Topical nitroglycerin can be applied to the base of the ischemic digit for 6 to 12 hours. Preparations vary, and patients should be closely monitored for dose response and tolerance.

Combining a topical nitrate with a calcium channel blocker is safe, but the use of a nitrate with a PDE5 inhibitor is contraindicated due to the risk of hypotension. The use of topical nitrates may be limited by systemic side effects such as headache and flushing and a lack of benefit over time.

Other therapies

If the aforementioned agents are not tolerated or not effective, there is limited evidence that other therapies reduce the frequency and sometimes the severity of attacks. These are not first-line agents but may be tried when other options have been exhausted and symptoms persist. There are no data to support combining these therapies, but in our experience doing so may help some patients in whom drug-drug interactions are not prohibitive.

Prazosin, an alpha-1-adrenergic receptor antagonist, was reported to improve Raynaud phenomenon in 2 small studies in the 1980s, but we do not use it since better options are available. In addition, the vasoactive blood vessels involved do not have alpha-1 receptors, so there is no theoretical basis for using prazosin.^18,19

Fluoxetine, a selective serotonin reuptake inhibitor, reduced the frequency and severity of attacks in a 6-week crossover study with nifedipine.²⁰

Losartan, an angiotensin II receptor blocker, also reduced the severity and frequency of attacks when compared with nifedipine.²¹

Pentoxifylline, a nonselective phosphodiesterase inhibitor, showed some benefit in a trial in 11 patients with primary Raynaud.²²

Atorvastatin, a lipid-lowering drug, reduced the number of digital ulcers in patients with secondary Raynaud already on first-line vasodilatory therapy, and might be added in this situation.²³

Botulinum toxin A injections have some data to support their use, but evidence is based on uncontrolled case series.²⁴ A controlled trial in scleroderma patients with severe Raynaud phenomenon found botulinum toxin to be no better than placebo.²⁵

Prostacyclin preparations are available. Intermittent intravenous doses of prostacyclin analogues over several days can be used in resistant cases. Oral prostacyclin agents have not shown consistent benefit. New prostacyclin receptor agonists are under investigation.

Overall, we move to other options only in patients with persistent symptoms that impair quality of life, or in patients with recurrent digital ischemic lesions that have not responded to calcium channel blockers and PDE5 inhibitors or nitrates, either alone or in combination.

DIGITAL ULCERATION AND ACUTE DIGITAL ISCHEMIC CRISIS

Patients with secondary Raynaud phenomenon may be at risk of recurrent digital ulceration and acute digital ischemia with gangrene. These patients should be comanaged with a rheumatologist so that the underlying disease process is fully addressed. Digital ulcers should be inspected closely for signs of infection, which may require treatment with antibiotics.

Acute digital ischemia is a medical emergency and should prompt inpatient admission with warming, emotional regulation, and pain control (often with narcotics) to decrease sympathetic vasoconstriction. These patients require aggressive vasodilatory therapy to reverse the ischemic event.

A short-acting calcium channel blocker or combination therapy with a calcium channel blocker and a PDE5 inhibitor or topical nitrate should be started. If there is no benefit, then transient intravenous vasodilatory therapy with a prostacyclin (epoprostenol) or localized digital sympathectomy is used to prevent digital loss.

The endothelin receptor inhibitor bosentan has been shown to decrease recurrent digital ulcers in patients with scleroderma, and while bosentan does not decrease the frequency of Raynaud attacks, it can be used in this select group to prevent new digital ulcers.

Treatment options may be limited by insurance coverage or access to intravenous infusions.

TAKE-HOME RECOMMENDATIONS

For many patients with primary or secondary Raynaud phenomenon, nonpharmacologic interventions are all that are required to decrease the frequency of attacks and improve quality of life. The goal should not be to eliminate attacks completely, as aggressive drug treatment may cause more harm than benefit. From our perspective, the goals of treatment should be to improve quality of life and prevent ischemic complications.

Pharmacologic therapies should be added only if attacks remain poorly controlled with incapacitating symptoms, or if the patient has digital ischemic ulcers. Calcium channel blockers are first-line therapy, given proven efficacy and low cost, and should be titrated to the maximum tolerated dose before adding or substituting other agents.

For many patients, Raynaud symptoms are mild enough to not even mention to their primary care provider, and conversely, there is little reason for most clinicians to routinely inquire about such symptoms. So it may surprise some readers to read about the nuances of diagnosis and treatment discussed by Shapiro and Wigley in this issue of the Journal.

To a rheumatologist, Raynaud phenomenon, particularly of recent onset in an adult, raises the specter of an underlying systemic inflammatory disease. The phenomenon is not linked to a specific diagnosis; it is associated with lupus, rheumatoid arthritis, cryoglobulinemia, inflammatory myopathy, Sjögren syndrome, and, in its severe form, with the scleroderma syndromes. We focus on differentiating between these rheumatic disorders once we have discarded nonrheumatic causes such as atherosclerotic arterial disease, carcinoma, embolism, Buerger disease, medications, smoking, or thrombosis.

But rheumatologists are toward the bottom of the diagnostic funnel—we see these patients when an underlying disease is already suspected. The real challenge is for the primary care providers who first recognize the digital vasospasm on examination or are told of the symptoms by their patient. These clinicians need to know which initial reflexive actions are warranted and which can wait, for, as noted by Shapiro and Wigley, there are several options.

The first action is to try to determine the timeline, although Raynaud disease often has an insidious onset or the patient doesn’t recall the onset. New and sudden onset likely has a stronger association with an underlying disease. A focused physical examination should look for digital stigmata of ischemic damage; the presence of digital ulcers or healed digital pits indicates a possible vascular occlusive component in addition to the vascular spasm. This strongly suggests scleroderma or Buerger disease, as tissue damage doesn’t occur in (primary) Raynaud disease or generally even with Raynaud phenomenon associated with lupus or other rheumatic disorders. Sclerodactyly should be looked for: diffuse finger puffiness, skin-tightening, or early signs such as loss of the usual finger skin creases. Telangiectasia (not vascular spiders or cherry angiomata) should be searched for, particularly on the palms, face, and inner lips, as these vascular lesions are common in patients with limited scleroderma. Careful auscultation for basilar lung crackles should be done. Distal pulses should all be assessed, and bruits in the neck, abdomen and inguinal areas should be carefully sought.

Patients should be questioned about any symptom-associated reduction in exercise tolerance and particularly about trouble swallowing, “heartburn,” and symptoms of reflux. Although patients with Raynaud disease may have demonstrable esophageal dysmotility, the presence of significant, new, or worsened symptoms raises the concern of scleroderma. Patients should be asked about symptoms of malabsorption. Specific questioning should be directed at eliciting a history of joint stiffness and especially muscle weakness. The latter can be approached by inquiring about new or progressive difficulty in specific tasks such as walking up steps, brushing hair, and arising from low chairs or the toilet. Distinguishing muscle weakness from general fatigue is not always easy, but it is important.

Shapiro and Wigley discuss the extremely useful evaluation of nailfold capillaries, which can be done with a standard magnifier or ophthalmoscope. This is very valuable to help predict the development or current presence of a systemic rheumatic disease. But this is not a technique that most clinicians are familiar with. A potentially useful surrogate or adjunctive test, especially in the setting of new-onset Raynaud, is the antinuclear antibody (ANA) test; I prefer the immunofluorescent assay. While a positive test alone (with Raynaud) does not define the presence of any rheumatic disease, several older studies suggest that patients with a new onset of Raynaud phenomenon and a positive ANA test are more likely to develop a systemic autoimmune disorder than if the test is negative. Those who do so (and this is far from all) are most likely to have the disease manifest within a few years. Hence, if the ANA test is positive but the history, physical examination, and limited laboratory testing (complete blood cell count with differential, complete metabolic panel, creatine kinase, and urinalysis) are normal, it is reasonable to reexamine the patient in 3 months and then every 6 months for 2 to 3 years, repeating the focused history and physical examination. It is also reasonable at some point to refer these patients to a rheumatologist.

Since Raynaud phenomenon is common, and the associated severe rheumatic disorders associated with it are rare, it is easy to not recognize Raynaud phenomenon as a clue to the onset of a potentially severe systemic disease. Yet with a few simple questions, a focused examination, and minimal laboratory testing, patients who are more likely to harbor a systemic disease can usually be treated symptomatically if necessary, and appropriately triaged to observation or for subspecialty referral.

For many patients, Raynaud symptoms are mild enough to not even mention to their primary care provider, and conversely, there is little reason for most clinicians to routinely inquire about such symptoms. So it may surprise some readers to read about the nuances of diagnosis and treatment discussed by Shapiro and Wigley in this issue of the Journal.

To a rheumatologist, Raynaud phenomenon, particularly of recent onset in an adult, raises the specter of an underlying systemic inflammatory disease. The phenomenon is not linked to a specific diagnosis; it is associated with lupus, rheumatoid arthritis, cryoglobulinemia, inflammatory myopathy, Sjögren syndrome, and, in its severe form, with the scleroderma syndromes. We focus on differentiating between these rheumatic disorders once we have discarded nonrheumatic causes such as atherosclerotic arterial disease, carcinoma, embolism, Buerger disease, medications, smoking, or thrombosis.

But rheumatologists are toward the bottom of the diagnostic funnel—we see these patients when an underlying disease is already suspected. The real challenge is for the primary care providers who first recognize the digital vasospasm on examination or are told of the symptoms by their patient. These clinicians need to know which initial reflexive actions are warranted and which can wait, for, as noted by Shapiro and Wigley, there are several options.

The first action is to try to determine the timeline, although Raynaud disease often has an insidious onset or the patient doesn’t recall the onset. New and sudden onset likely has a stronger association with an underlying disease. A focused physical examination should look for digital stigmata of ischemic damage; the presence of digital ulcers or healed digital pits indicates a possible vascular occlusive component in addition to the vascular spasm. This strongly suggests scleroderma or Buerger disease, as tissue damage doesn’t occur in (primary) Raynaud disease or generally even with Raynaud phenomenon associated with lupus or other rheumatic disorders. Sclerodactyly should be looked for: diffuse finger puffiness, skin-tightening, or early signs such as loss of the usual finger skin creases. Telangiectasia (not vascular spiders or cherry angiomata) should be searched for, particularly on the palms, face, and inner lips, as these vascular lesions are common in patients with limited scleroderma. Careful auscultation for basilar lung crackles should be done. Distal pulses should all be assessed, and bruits in the neck, abdomen and inguinal areas should be carefully sought.

Patients should be questioned about any symptom-associated reduction in exercise tolerance and particularly about trouble swallowing, “heartburn,” and symptoms of reflux. Although patients with Raynaud disease may have demonstrable esophageal dysmotility, the presence of significant, new, or worsened symptoms raises the concern of scleroderma. Patients should be asked about symptoms of malabsorption. Specific questioning should be directed at eliciting a history of joint stiffness and especially muscle weakness. The latter can be approached by inquiring about new or progressive difficulty in specific tasks such as walking up steps, brushing hair, and arising from low chairs or the toilet. Distinguishing muscle weakness from general fatigue is not always easy, but it is important.

Shapiro and Wigley discuss the extremely useful evaluation of nailfold capillaries, which can be done with a standard magnifier or ophthalmoscope. This is very valuable to help predict the development or current presence of a systemic rheumatic disease. But this is not a technique that most clinicians are familiar with. A potentially useful surrogate or adjunctive test, especially in the setting of new-onset Raynaud, is the antinuclear antibody (ANA) test; I prefer the immunofluorescent assay. While a positive test alone (with Raynaud) does not define the presence of any rheumatic disease, several older studies suggest that patients with a new onset of Raynaud phenomenon and a positive ANA test are more likely to develop a systemic autoimmune disorder than if the test is negative. Those who do so (and this is far from all) are most likely to have the disease manifest within a few years. Hence, if the ANA test is positive but the history, physical examination, and limited laboratory testing (complete blood cell count with differential, complete metabolic panel, creatine kinase, and urinalysis) are normal, it is reasonable to reexamine the patient in 3 months and then every 6 months for 2 to 3 years, repeating the focused history and physical examination. It is also reasonable at some point to refer these patients to a rheumatologist.

Since Raynaud phenomenon is common, and the associated severe rheumatic disorders associated with it are rare, it is easy to not recognize Raynaud phenomenon as a clue to the onset of a potentially severe systemic disease. Yet with a few simple questions, a focused examination, and minimal laboratory testing, patients who are more likely to harbor a systemic disease can usually be treated symptomatically if necessary, and appropriately triaged to observation or for subspecialty referral.

For many patients, Raynaud symptoms are mild enough to not even mention to their primary care provider, and conversely, there is little reason for most clinicians to routinely inquire about such symptoms. So it may surprise some readers to read about the nuances of diagnosis and treatment discussed by Shapiro and Wigley in this issue of the Journal.

To a rheumatologist, Raynaud phenomenon, particularly of recent onset in an adult, raises the specter of an underlying systemic inflammatory disease. The phenomenon is not linked to a specific diagnosis; it is associated with lupus, rheumatoid arthritis, cryoglobulinemia, inflammatory myopathy, Sjögren syndrome, and, in its severe form, with the scleroderma syndromes. We focus on differentiating between these rheumatic disorders once we have discarded nonrheumatic causes such as atherosclerotic arterial disease, carcinoma, embolism, Buerger disease, medications, smoking, or thrombosis.

But rheumatologists are toward the bottom of the diagnostic funnel—we see these patients when an underlying disease is already suspected. The real challenge is for the primary care providers who first recognize the digital vasospasm on examination or are told of the symptoms by their patient. These clinicians need to know which initial reflexive actions are warranted and which can wait, for, as noted by Shapiro and Wigley, there are several options.

The first action is to try to determine the timeline, although Raynaud disease often has an insidious onset or the patient doesn’t recall the onset. New and sudden onset likely has a stronger association with an underlying disease. A focused physical examination should look for digital stigmata of ischemic damage; the presence of digital ulcers or healed digital pits indicates a possible vascular occlusive component in addition to the vascular spasm. This strongly suggests scleroderma or Buerger disease, as tissue damage doesn’t occur in (primary) Raynaud disease or generally even with Raynaud phenomenon associated with lupus or other rheumatic disorders. Sclerodactyly should be looked for: diffuse finger puffiness, skin-tightening, or early signs such as loss of the usual finger skin creases. Telangiectasia (not vascular spiders or cherry angiomata) should be searched for, particularly on the palms, face, and inner lips, as these vascular lesions are common in patients with limited scleroderma. Careful auscultation for basilar lung crackles should be done. Distal pulses should all be assessed, and bruits in the neck, abdomen and inguinal areas should be carefully sought.

Patients should be questioned about any symptom-associated reduction in exercise tolerance and particularly about trouble swallowing, “heartburn,” and symptoms of reflux. Although patients with Raynaud disease may have demonstrable esophageal dysmotility, the presence of significant, new, or worsened symptoms raises the concern of scleroderma. Patients should be asked about symptoms of malabsorption. Specific questioning should be directed at eliciting a history of joint stiffness and especially muscle weakness. The latter can be approached by inquiring about new or progressive difficulty in specific tasks such as walking up steps, brushing hair, and arising from low chairs or the toilet. Distinguishing muscle weakness from general fatigue is not always easy, but it is important.

Shapiro and Wigley discuss the extremely useful evaluation of nailfold capillaries, which can be done with a standard magnifier or ophthalmoscope. This is very valuable to help predict the development or current presence of a systemic rheumatic disease. But this is not a technique that most clinicians are familiar with. A potentially useful surrogate or adjunctive test, especially in the setting of new-onset Raynaud, is the antinuclear antibody (ANA) test; I prefer the immunofluorescent assay. While a positive test alone (with Raynaud) does not define the presence of any rheumatic disease, several older studies suggest that patients with a new onset of Raynaud phenomenon and a positive ANA test are more likely to develop a systemic autoimmune disorder than if the test is negative. Those who do so (and this is far from all) are most likely to have the disease manifest within a few years. Hence, if the ANA test is positive but the history, physical examination, and limited laboratory testing (complete blood cell count with differential, complete metabolic panel, creatine kinase, and urinalysis) are normal, it is reasonable to reexamine the patient in 3 months and then every 6 months for 2 to 3 years, repeating the focused history and physical examination. It is also reasonable at some point to refer these patients to a rheumatologist.

Since Raynaud phenomenon is common, and the associated severe rheumatic disorders associated with it are rare, it is easy to not recognize Raynaud phenomenon as a clue to the onset of a potentially severe systemic disease. Yet with a few simple questions, a focused examination, and minimal laboratory testing, patients who are more likely to harbor a systemic disease can usually be treated symptomatically if necessary, and appropriately triaged to observation or for subspecialty referral.

The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.

Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).

Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.

“Our current results may be clinically exploitable. ... Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD, a hematology-oncology fellow at the university.

In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the ... results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”

The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.

For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing (Guardant360) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.

The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.

Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.

Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.

“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.

The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.

aotto@frontlinemedcom.com

The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.

Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).

Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.

“Our current results may be clinically exploitable. ... Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD, a hematology-oncology fellow at the university.

In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the ... results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”

The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.

For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing (Guardant360) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.

The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.

Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.

Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.

“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.

The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.

aotto@frontlinemedcom.com

The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.

Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).

Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.

“Our current results may be clinically exploitable. ... Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD, a hematology-oncology fellow at the university.

In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the ... results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”

The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.

For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing (Guardant360) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.

The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.

Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.

Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.

“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.

The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.

aotto@frontlinemedcom.com