Cardiology

SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.

He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.

In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.

“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.

Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).

Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.

HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.

Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.

bjancin@mdedge.com

SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.

He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.

In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.

“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.

Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).

Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.

HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.

Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.

bjancin@mdedge.com

SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.

He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.

In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.

“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.

Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).

Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.

HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.

Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.

bjancin@mdedge.com

Background: Patients with left-sided infective endocarditis often are treated with prolonged courses of intravenous (IV) antibiotics. The safety of switching from IV to oral antibiotics is unknown.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Background: Patients with left-sided infective endocarditis often are treated with prolonged courses of intravenous (IV) antibiotics. The safety of switching from IV to oral antibiotics is unknown.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Background: Patients with left-sided infective endocarditis often are treated with prolonged courses of intravenous (IV) antibiotics. The safety of switching from IV to oral antibiotics is unknown.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

The association between type 2 diabetes (T2D) and cardiovascular (CV) disease is well-established:

• Type 2 diabetes approximately doubles the risk of coronary artery disease, stroke, and peripheral arterial disease, independent of conventional risk factors¹
• CV disease is the leading cause of morbidity and mortality in patients with T2D
• CV disease is the largest contributor to direct and indirect costs of the health care of patients who have T2D.²

In recent years, new classes of agents for treating T2D have been introduced (TABLE 1). Prior to 2008, the US Food and Drug Administration (FDA) approved drugs in those new classes based simply on their effectiveness in reducing the blood glucose level. Concerns about the CV safety of specific drugs (eg, rosiglitazone, muraglitazar) emerged from a number of trials, suggesting that these agents might increase the risk of CV events.^3,4

All glucose-lowering medications used to treat type 2 diabetes are not equally effective in reducing CV complications.

Consequently, in 2008, the FDA issued guidance to the pharmaceutical industry: Preapproval and postapproval trials of all new antidiabetic drugs must now assess potential excess CV risk.⁵ CV outcomes trials (CVOTs), performed in accordance with FDA guidelines, have therefore become the focus of evaluating novel treatment options. In most CVOTs, combined primary CV endpoints have included CV mortality, nonfatal myocardial infarction (MI), and nonfatal stroke—taken together, what is known as the composite of these 3 major adverse CV events, or MACE-3.

To date, 15 CVOTs have been completed, assessing 3 novel classes of antihyperglycemic agents:

• dipeptidyl peptidase-4 (DPP-4) inhibitors
• glucagon-like peptide-1 (GLP-1) receptor agonists
• sodium–glucose cotransporter-2 (SGLT-2) inhibitors.

None of these trials identified any increased incidence of MACE; 7 found CV benefit. This review summarizes what the CVOTs revealed about these antihyperglycemic agents and their ability to yield a reduction in MACE and a decrease in all-cause mortality in patients with T2D and elevated CV disease risk. Armed with this information, you will have the tools you need to offer patients with T2D CV benefit while managing their primary disease.

Cardiovascular outcomes trials: DPP-4 inhibitors

Four trials. Trials of DPP-4 inhibitors that have been completed and reported are of saxagliptin (SAVOR-TIMI 53⁶), alogliptin (EXAMINE⁷), sitagliptin (TECOS⁸), and linagliptin (CARMELINA⁹); others are in progress. In general, researchers enrolled patients at high risk of CV events, although inclusion criteria varied substantially. Consistently, these studies demonstrated that DPP-4 inhibition neither increased nor decreased (ie, were noninferior) the 3-point MACE (SAVOR-TIMI 53 noninferiority, P < .001; EXAMINE, P < .001; TECOS, P < .001).

Continue to: Rather than improve...

Rather than improve CV outcomes, there was some evidence that DPP-4 inhibitors might be associated with an increased risk of hospitalization for heart failure (HHF). In the SAVOR-TIMI 53 trial, patients randomized to saxagliptin had a 0.7% absolute increase in risk of HHF (P = .98).⁶ In the EXAMINE trial, patients treated with alogliptin showed a nonsignificant trend for HHF.¹⁰ In both the TECOS and CARMELINA trials, no difference was recorded in the rate of HHF.^8,9,11 Subsequent meta-analysis that summarized the risk of HHF in CVOTs with DPP-4 inhibitors indicated a nonsignificant trend to increased risk.¹²

It’s likely that the CV benefits result from mechanisms other than a reduction in the serum glucose level, given the short time frame of the studies and the magnitude of the CV benefit.

From these trials alone, it appears that DPP-4 inhibitors are unlikely to provide CV benefit. Data from additional trials are needed to evaluate the possible association between these medications and heart failure (HF). However, largely as a result of the findings from SAVOR-TIMI 53 and EXAMINE, the FDA issued a Drug Safety Communication in April 2016, adding warnings about HF to the labeling of saxagliptin and alogliptin.¹³

CARMELINA was designed to also evaluate kidney outcomes in patients with T2D. As with other DPP-4 inhibitor trials, the primary aim was to establish noninferiority, compared with placebo, for time to MACE-3 (P < .001). Secondary outcomes were defined as time to first occurrence of end-stage renal disease, death due to renal failure, and sustained decrease from baseline of ≥ 40% in the estimated glomerular filtration rate. The incidence of the secondary kidney composite results was not significantly different between groups randomized to linagliptin or placebo.⁹

Cardiovascular outcomes trials: GLP-1 receptor agonists

ELIXA. The CV safety of GLP-1 receptor agonists has been evaluated in several randomized clinical trials. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial was the first¹⁴: Lixisenatide was studied in 6068 patients with recent hospitalization for acute coronary syndrome. Lixisenatide therapy was neutral with regard to CV outcomes, which met the primary endpoint: noninferiority to placebo (P < .001). There was no increase in either HF or HHF.

Continue to: LEADER

LEADER. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial (LEADER) evaluated long-term effects of liraglutide, compared to placebo, on CV events in patients with T2D.¹⁵ It was a multicenter, double-blind, placebocontrolled study that followed 9340 participants, most (81%) of whom had established CV disease, over 5 years. LEADER is considered a landmark study because it was the first large CVOT to show significant benefit for a GLP-1 receptor agonist.

Liraglutide demonstrated reductions in first occurrence of death from CV causes, nonfatal MI or nonfatal stroke, overall CV mortality, and all-cause mortality. The composite MACE-3 showed a relative risk reduction (RRR) of 13%, equivalent to an absolute risk reduction (ARR) of 1.9% (noninferiority, P < .001; superiority, P < .01). The RRR was 22% for death from CV causes, with an ARR of 1.3% (P = .007); the RRR for death from any cause was 15%, with an ARR of 1.4% (P = .02).

In addition, there was a lower rate of nephropathy (1.5 events for every 100 patient–years in the liraglutide group [P = .003], compared with 1.9 events every 100 patient–years in the placebo group).¹⁵

Results clearly demonstrated benefit. No significant difference was seen in the liraglutide rate of HHF, compared to the rate in the placebo group.

SUSTAIN-6. Evidence for the CV benefit of GLP-1 receptor agonists was also demonstrated in the phase 3 Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6).¹⁶ This was a study of 3297 patients with T2D at high risk of CV disease and with a mean hemoglobin A_1c (HbA_1c) value of 8.7%, 83% of whom had established CV disease. Patients were randomized to semaglutide or placebo. Note: SUSTAIN-6 was a noninferiority safety study; as such, it was not actually designed to assess or establish superiority.

Continue to: The incidence of MACE-3...

The incidence of MACE-3 was significantly reduced among patients treated with semaglutide (P = .02) after median followup of 2.1 years. The expanded composite outcome (death from CV causes, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina or HF), also showed a significant reduction with semaglutide (P = .002), compared with placebo. There was no difference in the overall hospitalization rate or rate of death from any cause.

EXSCEL. The Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL)^17,18 was a phase III/IV, double-blind, pragmatic placebo-controlled study of 14,752 patients at any level of CV risk, for a median 3.2 years. The study population was intentionally more diverse than in earlier GLP-1 receptor agonist studies. The researchers hypothesized that patients at increased risk of MACE would experience a comparatively greater relative treatment benefit with exenatide than those at lower risk. That did not prove to be the case.

EXSCEL did confirm noninferiority compared with placebo (P < .001), but once-weekly exenatide resulted in a nonsignificant reduction in major adverse CV events, and a trend for RRR in all-cause mortality (RRR = 14%; ARR = 1% [P = .06]).

HARMONY OUTCOMES. The Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease study (HARMONY OUTCOMES)¹⁹ was a double-blind, randomized, placebocontrolled trial conducted at 610 sites across 28 countries. The study investigated albiglutide, 30 to 50 mg once weekly, compared with placebo. It included 9463 patients ages ≥ 40 years with T2D who had an HbA_1c > 7% (median value, 8.7%) and established CV disease. Patients were evaluated for a median 1.6 years.

Albiglutide reduced the risk of CV causes of death, nonfatal MI, and nonfatal stroke by an RRR of 22%, (ARR, 2%) (noninferiority, P < .0001; superiority, P < .0006).

Continue to: REWIND

REWIND. The Researching Cardiovascular Events with a Weekly INcretin in Diabetes trial (REWIND),²⁰ the most recently completed GLP-1 receptor agonist CVOT (presented at the 2019 American Diabetes Association [ADA] Conference in June and published simultaneously in The Lancet), was a multicenter, randomized, double-blind placebo-controlled trial designed to assess the effect of weekly dulaglutide, 1.5 mg, compared with placebo, in 9901 participants enrolled at 371 sites in 24 countries. Mean patient age was 66.2 years, with women constituting 4589 (46.3%) of participants.

REWIND was distinct from other CVOTs in several ways:

• Other CVOTs were designed to show noninferiority compared with placebo regarding CV events; REWIND was designed to establish superiority
• In contrast to trials of other GLP-1 receptor agonists, in which most patients had established CV disease, only 31% of REWIND participants had a history of CV disease or a prior CV event (although 69% did have CV risk factors without underlying disease)
• REWIND was much longer (median follow-up, 5.4 years) than other GLP-1 receptor agonist trials (median follow-up, 1.5 to 3.8 years).

In REWIND, the primary composite outcome of MACE-3 occurred in 12% of participants assigned to dulaglutide, compared with 13.1% assigned to placebo (P = .026). This equated to 2.4 events for every 100 person– years on dulaglutide, compared with 2.7 events for every 100 person–years on placebo. There was a consistent effect on all MACE-3 components, although the greatest reductions were observed in nonfatal stroke (P = .017). Overall risk reduction was the same for primary and secondary prevention cohorts (P = .97), as well as in patients with either an HbA_1c value < 7.2% or ≥ 7.2% (P = .75). Risk reduction was consistent across age, sex, duration of T2D, and body mass index.

Dulaglutide did not significantly affect the incidence of all-cause mortality, heart failure, revascularization, or hospital admission. Forty-seven percent of patients taking dulaglutide reported gastrointestinal adverse effects (P = .0001).

Cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.

In a separate analysis of secondary outcomes, ²¹ dulaglutide reduced the composite renal outcomes of new-onset macroalbuminuria (P = .0001); decline of ≥ 30% in the estimated glomerular filtration rate (P = .066); and chronic renal replacement therapy (P = .39). Investigators estimated that 1 composite renal outcome event would be prevented for every 31 patients treated with dulaglutide for a median 5.4 years.

Continue to: Cardiovascular outcomes trials...

Cardiovascular outcomes trials: SGLT-2 inhibitors

EMPA-REG OUTCOME. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) was also a landmark study because it was the first dedicated CVOT to show that an antihyperglycemic agent 1) decreased CV mortality and all-cause mortality, and 2) reduced HHF in patients with T2D and established CV disease.22 In this trial, 7020 patients with T2D who were at high risk of CV events were randomized and treated with empagliflozin, 10 or 25 mg, or placebo, in addition to standard care, and were followed for a median 2.6 years.

In October, the FDA approved dapaglifozin to reduce the risk of hospitalization for heart failure in adults with T2D and established CV disease.

Compared with placebo, empagliflozin resulted in an RRR of 14% (ARR, 1.6%) in the primary endpoint of CV death, nonfatal MI, and stroke, confirming study drug superiority (P = .04). When compared with placebo, the empagliflozin group had an RRR of 38% in CV mortality, (ARR < 2.2%) (P < .001); an RRR of 35% in HHF (ARR, 1.4%) (P = .002); and an RRR of 32% (ARR, 2.6%) in death from any cause (P < .001).

CANVAS. The Canagliflozin Cardiovascular Assessment Study (CANVAS) integrated 2 multicenter, placebo-controlled, randomized trials with 10,142 participants and a mean follow-up of 3.6 years.²³ Patients were randomized to receive canagliflozin (100-300 mg/d) or placebo. Approximately two-thirds of patients had a history of CV disease (therefore representing secondary prevention); one-third had CV risk factors only (primary prevention).

In CANVAS, patients receiving canagliflozin had a risk reduction in MACE-3, establishing superiority compared with placebo (P < .001). There was also a significant reduction in progression of albuminuria (P < .05). Superiority was not shown for the secondary outcome of death from any cause. Canagliflozin had no effect on the primary endpoint (MACE-3) in the subgroup of participants who did not have a history of CV disease. Similar to what was found with empagliflozin in EMPA-REG OUTCOME, CANVAS participants had a reduced risk of HHF.

Continue to: Patients on canagliflozin...

Patients on canagliflozin unexpectedly had an increased incidence of amputations (6.3 participants, compared with 3.4 participants, for every 1000 patient–years). This finding led to a black box warning for canagliflozin about the risk of lower-limb amputation.

DECLARE-TIMI 58. The Dapagliflozin Effect of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 trial (DECLARETIMI 58) was the largest SGLT-2 inhibitor outcomes trial to date, enrolling 17,160 patients with T2D who also had established CV disease or multiple risk factors for atherosclerotic CV disease. The trial compared dapagliflozin, 10 mg/d, and placebo, following patients for a median 4.2 years.²⁴ Unlike CANVAS and EMPA-REG OUTCOME, DECLARE-TIMI 58 included CV death and HHF as primary outcomes, in addition to MACE-3.

Dapagliflozin was noninferior to placebo with regard to MACE-3. However, its use did result in a lower rate of CV death and HHF by an RRR of 17% (ARR, 1.9%). Risk reduction was greatest in patients with HF who had a reduced ejection fraction (ARR = 9.2%).²⁵

In October, the FDA approved dapagliflozin to reduce the risk of HHF in adults with T2D and established CV disease or multiple CV risk factors. Before initiating the drug, physicians should evaluate the patient's renal function and monitor periodically.

Meta-analyses of SGLT-2 inhibitors

Systematic review. Usman et al released a meta-analysis in 2018 that included 35 randomized, placebo-controlled trials (including EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58) that had assessed the use of SGLT-2 inhibitors in nearly 35,000 patients with T2D.²⁶ This review concluded that, as a class, SGLT-2 inhibitors reduce all-cause mortality, major adverse cardiac events, nonfatal MI, and HF and HHF, compared with placebo.

Continue to: CVD-REAL

CVD-REAL. A separate study, Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL), of 154,528 patients who were treated with canagliflozin, dapagliflozin, or empagliflozin, showed that initiation of SGLT-2 inhibitors, compared with other glucose- lowering therapies, was associated with a 39% reduction in HHF; a 51% reduction in death from any cause; and a 46% reduction in the composite of HHF or death (P < .001).²⁷

CVD-REAL was unique because it was the largest real-world study to assess the effectiveness of SGLT-2 inhibitors on HHF and mortality. The study utilized data from patients in the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom, based on information obtained from medical claims, primary care and hospital records, and national registries that compared patients who were either newly started on an SGLT-2 inhibitor or another glucose-lowering drug. The drug used by most patients in the trial was canagliflozin (53%), followed by dapagliflozin (42%), and empagliflozin (5%).

In this meta-analysis, similar therapeutic effects were seen across countries, regardless of geographic differences, in the use of specific SGLT-2 inhibitors, suggesting a class effect. Of particular significance was that most (87%) patients enrolled in CVD-REAL did not have prior CV disease. Despite this, results for examined outcomes in CVD-REAL were similar to what was seen in other SGLT-2 inhibitor trials that were designed to study patients with established CV disease.

Risk of adverse effects of newer antidiabetic agents

DPP-4 inhibitors. Alogliptin and sitagliptin carry a black-box warning about potential risk of HF. In SAVOR-TIMI, a 27% increase was detected in the rate of HHF after approximately 2 years of saxagliptin therapy.⁶ Although HF should not be considered a class effect for DPP-4 inhibitors, patients who have risk factors for HF should be monitored for signs and symptoms of HF.

Continue to: Cases of acute pancreatitis...

Cases of acute pancreatitis have been reported in association with all DPP-4 inhibitors available in the United States. A combined analysis of DDP-4 inhibitor trials suggested an increased relative risk of 79% and an absolute risk of 0.13%, which translates to 1 or 2 additional cases of acute pancreatitis for every 1000 patients treated for 2 years.²⁸

There have been numerous postmarketing reports of severe joint pain in patients taking a DPP-4 inhibitor. Most recently, cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.²⁹

GLP-1 receptor agonists carry a black box warning for medullary thyroid (C-cell) tumor risk. GLP-1 receptor agonists are contraindicated in patients with a personal or family history of this cancer, although this FDA warning is based solely on observations from animal models.

In addition, GLP-1 receptor agonists can increase the risk of cholecystitis and pancreatitis. Not uncommonly, they cause gastrointestinal symptoms when first started and when the dosage is titrated upward. Most GLP-1 receptor agonists can be used in patients with renal impairment, although data regarding their use in Stages 4 and 5 chronic kidney disease are limited.³⁰ Semaglutide was found, in the SUSTAIN-6 trial, to be associated with an increased rate of complications of retinopathy, including vitreous hemorrhage and blindness (P = .02)³¹

SGLT-2 inhibitors are associated with an increased incidence of genitourinary infection, bone fracture (canagliflozin), amputation (canagliflozin), and euglycemic diabetic ketoacidosis. Agents in this class should be avoided in patients with moderate or severe renal impairment, primarily due to a lack of efficacy. They are contraindicated in patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. (Dapagliflozin is not recommended when eGFR is < 45 mL/min/ 1.73 m2.) These agents carry an FDA warning about the risk of acute kidney injury.³⁰

Continue to: Summing up

Summing up

All glucose-lowering medications used to treat T2D are not equally effective in reducing CV complications. Recent CVOTs have uncovered evidence that certain antidiabetic agents might confer CV and all-cause mortality benefits (TABLE 2^{6,7,9,11,14-17,19-24}).

Discussion of proposed mechanisms for CV outcome superiority of these agents is beyond the scope of this review. It is generally believed that benefits result from mechanisms other than a reduction in the serum glucose level, given the relatively short time frame of the studies and the magnitude of the CV benefit. It is almost certain that mechanisms of CV benefit in the 2 landmark studies—LEADER and EMPA-REG OUTCOME—are distinct from each other.³²

See “When planning T2D pharmacotherapy, include newer agents that offer CV benefit,” ^33-38 for a stepwise approach to treating T2D, including the role of agents that have efficacy in modifying the risk of CV disease.

ACKNOWLEDGMENTS
Linda Speer, MD, Kevin Phelps, DO, and Jay Shubrook, DO, provided support and editorial assistance.

CORRESPONDENCE
Robert Gotfried, DO, FAAFP, Department of Family Medicine, University of Toledo College of Medicine, 3333 Glendale Avenue, Toledo, OH 43614; Robert.gotfried@utoledo.edu.

The association between type 2 diabetes (T2D) and cardiovascular (CV) disease is well-established:

• Type 2 diabetes approximately doubles the risk of coronary artery disease, stroke, and peripheral arterial disease, independent of conventional risk factors¹
• CV disease is the leading cause of morbidity and mortality in patients with T2D
• CV disease is the largest contributor to direct and indirect costs of the health care of patients who have T2D.²

In recent years, new classes of agents for treating T2D have been introduced (TABLE 1). Prior to 2008, the US Food and Drug Administration (FDA) approved drugs in those new classes based simply on their effectiveness in reducing the blood glucose level. Concerns about the CV safety of specific drugs (eg, rosiglitazone, muraglitazar) emerged from a number of trials, suggesting that these agents might increase the risk of CV events.^3,4

All glucose-lowering medications used to treat type 2 diabetes are not equally effective in reducing CV complications.

Consequently, in 2008, the FDA issued guidance to the pharmaceutical industry: Preapproval and postapproval trials of all new antidiabetic drugs must now assess potential excess CV risk.⁵ CV outcomes trials (CVOTs), performed in accordance with FDA guidelines, have therefore become the focus of evaluating novel treatment options. In most CVOTs, combined primary CV endpoints have included CV mortality, nonfatal myocardial infarction (MI), and nonfatal stroke—taken together, what is known as the composite of these 3 major adverse CV events, or MACE-3.

To date, 15 CVOTs have been completed, assessing 3 novel classes of antihyperglycemic agents:

• dipeptidyl peptidase-4 (DPP-4) inhibitors
• glucagon-like peptide-1 (GLP-1) receptor agonists
• sodium–glucose cotransporter-2 (SGLT-2) inhibitors.

None of these trials identified any increased incidence of MACE; 7 found CV benefit. This review summarizes what the CVOTs revealed about these antihyperglycemic agents and their ability to yield a reduction in MACE and a decrease in all-cause mortality in patients with T2D and elevated CV disease risk. Armed with this information, you will have the tools you need to offer patients with T2D CV benefit while managing their primary disease.

Cardiovascular outcomes trials: DPP-4 inhibitors

Four trials. Trials of DPP-4 inhibitors that have been completed and reported are of saxagliptin (SAVOR-TIMI 53⁶), alogliptin (EXAMINE⁷), sitagliptin (TECOS⁸), and linagliptin (CARMELINA⁹); others are in progress. In general, researchers enrolled patients at high risk of CV events, although inclusion criteria varied substantially. Consistently, these studies demonstrated that DPP-4 inhibition neither increased nor decreased (ie, were noninferior) the 3-point MACE (SAVOR-TIMI 53 noninferiority, P < .001; EXAMINE, P < .001; TECOS, P < .001).

Continue to: Rather than improve...

Rather than improve CV outcomes, there was some evidence that DPP-4 inhibitors might be associated with an increased risk of hospitalization for heart failure (HHF). In the SAVOR-TIMI 53 trial, patients randomized to saxagliptin had a 0.7% absolute increase in risk of HHF (P = .98).⁶ In the EXAMINE trial, patients treated with alogliptin showed a nonsignificant trend for HHF.¹⁰ In both the TECOS and CARMELINA trials, no difference was recorded in the rate of HHF.^8,9,11 Subsequent meta-analysis that summarized the risk of HHF in CVOTs with DPP-4 inhibitors indicated a nonsignificant trend to increased risk.¹²

It’s likely that the CV benefits result from mechanisms other than a reduction in the serum glucose level, given the short time frame of the studies and the magnitude of the CV benefit.

From these trials alone, it appears that DPP-4 inhibitors are unlikely to provide CV benefit. Data from additional trials are needed to evaluate the possible association between these medications and heart failure (HF). However, largely as a result of the findings from SAVOR-TIMI 53 and EXAMINE, the FDA issued a Drug Safety Communication in April 2016, adding warnings about HF to the labeling of saxagliptin and alogliptin.¹³

CARMELINA was designed to also evaluate kidney outcomes in patients with T2D. As with other DPP-4 inhibitor trials, the primary aim was to establish noninferiority, compared with placebo, for time to MACE-3 (P < .001). Secondary outcomes were defined as time to first occurrence of end-stage renal disease, death due to renal failure, and sustained decrease from baseline of ≥ 40% in the estimated glomerular filtration rate. The incidence of the secondary kidney composite results was not significantly different between groups randomized to linagliptin or placebo.⁹

Cardiovascular outcomes trials: GLP-1 receptor agonists

ELIXA. The CV safety of GLP-1 receptor agonists has been evaluated in several randomized clinical trials. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial was the first¹⁴: Lixisenatide was studied in 6068 patients with recent hospitalization for acute coronary syndrome. Lixisenatide therapy was neutral with regard to CV outcomes, which met the primary endpoint: noninferiority to placebo (P < .001). There was no increase in either HF or HHF.

Continue to: LEADER

LEADER. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial (LEADER) evaluated long-term effects of liraglutide, compared to placebo, on CV events in patients with T2D.¹⁵ It was a multicenter, double-blind, placebocontrolled study that followed 9340 participants, most (81%) of whom had established CV disease, over 5 years. LEADER is considered a landmark study because it was the first large CVOT to show significant benefit for a GLP-1 receptor agonist.

Liraglutide demonstrated reductions in first occurrence of death from CV causes, nonfatal MI or nonfatal stroke, overall CV mortality, and all-cause mortality. The composite MACE-3 showed a relative risk reduction (RRR) of 13%, equivalent to an absolute risk reduction (ARR) of 1.9% (noninferiority, P < .001; superiority, P < .01). The RRR was 22% for death from CV causes, with an ARR of 1.3% (P = .007); the RRR for death from any cause was 15%, with an ARR of 1.4% (P = .02).

In addition, there was a lower rate of nephropathy (1.5 events for every 100 patient–years in the liraglutide group [P = .003], compared with 1.9 events every 100 patient–years in the placebo group).¹⁵

Results clearly demonstrated benefit. No significant difference was seen in the liraglutide rate of HHF, compared to the rate in the placebo group.

SUSTAIN-6. Evidence for the CV benefit of GLP-1 receptor agonists was also demonstrated in the phase 3 Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6).¹⁶ This was a study of 3297 patients with T2D at high risk of CV disease and with a mean hemoglobin A_1c (HbA_1c) value of 8.7%, 83% of whom had established CV disease. Patients were randomized to semaglutide or placebo. Note: SUSTAIN-6 was a noninferiority safety study; as such, it was not actually designed to assess or establish superiority.

Continue to: The incidence of MACE-3...

The incidence of MACE-3 was significantly reduced among patients treated with semaglutide (P = .02) after median followup of 2.1 years. The expanded composite outcome (death from CV causes, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina or HF), also showed a significant reduction with semaglutide (P = .002), compared with placebo. There was no difference in the overall hospitalization rate or rate of death from any cause.

EXSCEL. The Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL)^17,18 was a phase III/IV, double-blind, pragmatic placebo-controlled study of 14,752 patients at any level of CV risk, for a median 3.2 years. The study population was intentionally more diverse than in earlier GLP-1 receptor agonist studies. The researchers hypothesized that patients at increased risk of MACE would experience a comparatively greater relative treatment benefit with exenatide than those at lower risk. That did not prove to be the case.

EXSCEL did confirm noninferiority compared with placebo (P < .001), but once-weekly exenatide resulted in a nonsignificant reduction in major adverse CV events, and a trend for RRR in all-cause mortality (RRR = 14%; ARR = 1% [P = .06]).

HARMONY OUTCOMES. The Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease study (HARMONY OUTCOMES)¹⁹ was a double-blind, randomized, placebocontrolled trial conducted at 610 sites across 28 countries. The study investigated albiglutide, 30 to 50 mg once weekly, compared with placebo. It included 9463 patients ages ≥ 40 years with T2D who had an HbA_1c > 7% (median value, 8.7%) and established CV disease. Patients were evaluated for a median 1.6 years.

Albiglutide reduced the risk of CV causes of death, nonfatal MI, and nonfatal stroke by an RRR of 22%, (ARR, 2%) (noninferiority, P < .0001; superiority, P < .0006).

Continue to: REWIND

REWIND. The Researching Cardiovascular Events with a Weekly INcretin in Diabetes trial (REWIND),²⁰ the most recently completed GLP-1 receptor agonist CVOT (presented at the 2019 American Diabetes Association [ADA] Conference in June and published simultaneously in The Lancet), was a multicenter, randomized, double-blind placebo-controlled trial designed to assess the effect of weekly dulaglutide, 1.5 mg, compared with placebo, in 9901 participants enrolled at 371 sites in 24 countries. Mean patient age was 66.2 years, with women constituting 4589 (46.3%) of participants.

REWIND was distinct from other CVOTs in several ways:

• Other CVOTs were designed to show noninferiority compared with placebo regarding CV events; REWIND was designed to establish superiority
• In contrast to trials of other GLP-1 receptor agonists, in which most patients had established CV disease, only 31% of REWIND participants had a history of CV disease or a prior CV event (although 69% did have CV risk factors without underlying disease)
• REWIND was much longer (median follow-up, 5.4 years) than other GLP-1 receptor agonist trials (median follow-up, 1.5 to 3.8 years).

In REWIND, the primary composite outcome of MACE-3 occurred in 12% of participants assigned to dulaglutide, compared with 13.1% assigned to placebo (P = .026). This equated to 2.4 events for every 100 person– years on dulaglutide, compared with 2.7 events for every 100 person–years on placebo. There was a consistent effect on all MACE-3 components, although the greatest reductions were observed in nonfatal stroke (P = .017). Overall risk reduction was the same for primary and secondary prevention cohorts (P = .97), as well as in patients with either an HbA_1c value < 7.2% or ≥ 7.2% (P = .75). Risk reduction was consistent across age, sex, duration of T2D, and body mass index.

Dulaglutide did not significantly affect the incidence of all-cause mortality, heart failure, revascularization, or hospital admission. Forty-seven percent of patients taking dulaglutide reported gastrointestinal adverse effects (P = .0001).

Cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.

In a separate analysis of secondary outcomes, ²¹ dulaglutide reduced the composite renal outcomes of new-onset macroalbuminuria (P = .0001); decline of ≥ 30% in the estimated glomerular filtration rate (P = .066); and chronic renal replacement therapy (P = .39). Investigators estimated that 1 composite renal outcome event would be prevented for every 31 patients treated with dulaglutide for a median 5.4 years.

Continue to: Cardiovascular outcomes trials...

Cardiovascular outcomes trials: SGLT-2 inhibitors

EMPA-REG OUTCOME. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) was also a landmark study because it was the first dedicated CVOT to show that an antihyperglycemic agent 1) decreased CV mortality and all-cause mortality, and 2) reduced HHF in patients with T2D and established CV disease.22 In this trial, 7020 patients with T2D who were at high risk of CV events were randomized and treated with empagliflozin, 10 or 25 mg, or placebo, in addition to standard care, and were followed for a median 2.6 years.

In October, the FDA approved dapaglifozin to reduce the risk of hospitalization for heart failure in adults with T2D and established CV disease.

Compared with placebo, empagliflozin resulted in an RRR of 14% (ARR, 1.6%) in the primary endpoint of CV death, nonfatal MI, and stroke, confirming study drug superiority (P = .04). When compared with placebo, the empagliflozin group had an RRR of 38% in CV mortality, (ARR < 2.2%) (P < .001); an RRR of 35% in HHF (ARR, 1.4%) (P = .002); and an RRR of 32% (ARR, 2.6%) in death from any cause (P < .001).

CANVAS. The Canagliflozin Cardiovascular Assessment Study (CANVAS) integrated 2 multicenter, placebo-controlled, randomized trials with 10,142 participants and a mean follow-up of 3.6 years.²³ Patients were randomized to receive canagliflozin (100-300 mg/d) or placebo. Approximately two-thirds of patients had a history of CV disease (therefore representing secondary prevention); one-third had CV risk factors only (primary prevention).

In CANVAS, patients receiving canagliflozin had a risk reduction in MACE-3, establishing superiority compared with placebo (P < .001). There was also a significant reduction in progression of albuminuria (P < .05). Superiority was not shown for the secondary outcome of death from any cause. Canagliflozin had no effect on the primary endpoint (MACE-3) in the subgroup of participants who did not have a history of CV disease. Similar to what was found with empagliflozin in EMPA-REG OUTCOME, CANVAS participants had a reduced risk of HHF.

Continue to: Patients on canagliflozin...

Patients on canagliflozin unexpectedly had an increased incidence of amputations (6.3 participants, compared with 3.4 participants, for every 1000 patient–years). This finding led to a black box warning for canagliflozin about the risk of lower-limb amputation.

DECLARE-TIMI 58. The Dapagliflozin Effect of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 trial (DECLARETIMI 58) was the largest SGLT-2 inhibitor outcomes trial to date, enrolling 17,160 patients with T2D who also had established CV disease or multiple risk factors for atherosclerotic CV disease. The trial compared dapagliflozin, 10 mg/d, and placebo, following patients for a median 4.2 years.²⁴ Unlike CANVAS and EMPA-REG OUTCOME, DECLARE-TIMI 58 included CV death and HHF as primary outcomes, in addition to MACE-3.

Dapagliflozin was noninferior to placebo with regard to MACE-3. However, its use did result in a lower rate of CV death and HHF by an RRR of 17% (ARR, 1.9%). Risk reduction was greatest in patients with HF who had a reduced ejection fraction (ARR = 9.2%).²⁵

In October, the FDA approved dapagliflozin to reduce the risk of HHF in adults with T2D and established CV disease or multiple CV risk factors. Before initiating the drug, physicians should evaluate the patient's renal function and monitor periodically.

Meta-analyses of SGLT-2 inhibitors

Systematic review. Usman et al released a meta-analysis in 2018 that included 35 randomized, placebo-controlled trials (including EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58) that had assessed the use of SGLT-2 inhibitors in nearly 35,000 patients with T2D.²⁶ This review concluded that, as a class, SGLT-2 inhibitors reduce all-cause mortality, major adverse cardiac events, nonfatal MI, and HF and HHF, compared with placebo.

Continue to: CVD-REAL

CVD-REAL. A separate study, Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL), of 154,528 patients who were treated with canagliflozin, dapagliflozin, or empagliflozin, showed that initiation of SGLT-2 inhibitors, compared with other glucose- lowering therapies, was associated with a 39% reduction in HHF; a 51% reduction in death from any cause; and a 46% reduction in the composite of HHF or death (P < .001).²⁷

CVD-REAL was unique because it was the largest real-world study to assess the effectiveness of SGLT-2 inhibitors on HHF and mortality. The study utilized data from patients in the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom, based on information obtained from medical claims, primary care and hospital records, and national registries that compared patients who were either newly started on an SGLT-2 inhibitor or another glucose-lowering drug. The drug used by most patients in the trial was canagliflozin (53%), followed by dapagliflozin (42%), and empagliflozin (5%).

In this meta-analysis, similar therapeutic effects were seen across countries, regardless of geographic differences, in the use of specific SGLT-2 inhibitors, suggesting a class effect. Of particular significance was that most (87%) patients enrolled in CVD-REAL did not have prior CV disease. Despite this, results for examined outcomes in CVD-REAL were similar to what was seen in other SGLT-2 inhibitor trials that were designed to study patients with established CV disease.

Risk of adverse effects of newer antidiabetic agents

DPP-4 inhibitors. Alogliptin and sitagliptin carry a black-box warning about potential risk of HF. In SAVOR-TIMI, a 27% increase was detected in the rate of HHF after approximately 2 years of saxagliptin therapy.⁶ Although HF should not be considered a class effect for DPP-4 inhibitors, patients who have risk factors for HF should be monitored for signs and symptoms of HF.

Continue to: Cases of acute pancreatitis...

Cases of acute pancreatitis have been reported in association with all DPP-4 inhibitors available in the United States. A combined analysis of DDP-4 inhibitor trials suggested an increased relative risk of 79% and an absolute risk of 0.13%, which translates to 1 or 2 additional cases of acute pancreatitis for every 1000 patients treated for 2 years.²⁸

There have been numerous postmarketing reports of severe joint pain in patients taking a DPP-4 inhibitor. Most recently, cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.²⁹

GLP-1 receptor agonists carry a black box warning for medullary thyroid (C-cell) tumor risk. GLP-1 receptor agonists are contraindicated in patients with a personal or family history of this cancer, although this FDA warning is based solely on observations from animal models.

In addition, GLP-1 receptor agonists can increase the risk of cholecystitis and pancreatitis. Not uncommonly, they cause gastrointestinal symptoms when first started and when the dosage is titrated upward. Most GLP-1 receptor agonists can be used in patients with renal impairment, although data regarding their use in Stages 4 and 5 chronic kidney disease are limited.³⁰ Semaglutide was found, in the SUSTAIN-6 trial, to be associated with an increased rate of complications of retinopathy, including vitreous hemorrhage and blindness (P = .02)³¹

SGLT-2 inhibitors are associated with an increased incidence of genitourinary infection, bone fracture (canagliflozin), amputation (canagliflozin), and euglycemic diabetic ketoacidosis. Agents in this class should be avoided in patients with moderate or severe renal impairment, primarily due to a lack of efficacy. They are contraindicated in patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. (Dapagliflozin is not recommended when eGFR is < 45 mL/min/ 1.73 m2.) These agents carry an FDA warning about the risk of acute kidney injury.³⁰

Continue to: Summing up

Summing up

All glucose-lowering medications used to treat T2D are not equally effective in reducing CV complications. Recent CVOTs have uncovered evidence that certain antidiabetic agents might confer CV and all-cause mortality benefits (TABLE 2^{6,7,9,11,14-17,19-24}).

Discussion of proposed mechanisms for CV outcome superiority of these agents is beyond the scope of this review. It is generally believed that benefits result from mechanisms other than a reduction in the serum glucose level, given the relatively short time frame of the studies and the magnitude of the CV benefit. It is almost certain that mechanisms of CV benefit in the 2 landmark studies—LEADER and EMPA-REG OUTCOME—are distinct from each other.³²

See “When planning T2D pharmacotherapy, include newer agents that offer CV benefit,” ^33-38 for a stepwise approach to treating T2D, including the role of agents that have efficacy in modifying the risk of CV disease.

ACKNOWLEDGMENTS
Linda Speer, MD, Kevin Phelps, DO, and Jay Shubrook, DO, provided support and editorial assistance.

CORRESPONDENCE
Robert Gotfried, DO, FAAFP, Department of Family Medicine, University of Toledo College of Medicine, 3333 Glendale Avenue, Toledo, OH 43614; Robert.gotfried@utoledo.edu.

The association between type 2 diabetes (T2D) and cardiovascular (CV) disease is well-established:

• Type 2 diabetes approximately doubles the risk of coronary artery disease, stroke, and peripheral arterial disease, independent of conventional risk factors¹
• CV disease is the leading cause of morbidity and mortality in patients with T2D
• CV disease is the largest contributor to direct and indirect costs of the health care of patients who have T2D.²

In recent years, new classes of agents for treating T2D have been introduced (TABLE 1). Prior to 2008, the US Food and Drug Administration (FDA) approved drugs in those new classes based simply on their effectiveness in reducing the blood glucose level. Concerns about the CV safety of specific drugs (eg, rosiglitazone, muraglitazar) emerged from a number of trials, suggesting that these agents might increase the risk of CV events.^3,4

All glucose-lowering medications used to treat type 2 diabetes are not equally effective in reducing CV complications.

Consequently, in 2008, the FDA issued guidance to the pharmaceutical industry: Preapproval and postapproval trials of all new antidiabetic drugs must now assess potential excess CV risk.⁵ CV outcomes trials (CVOTs), performed in accordance with FDA guidelines, have therefore become the focus of evaluating novel treatment options. In most CVOTs, combined primary CV endpoints have included CV mortality, nonfatal myocardial infarction (MI), and nonfatal stroke—taken together, what is known as the composite of these 3 major adverse CV events, or MACE-3.

To date, 15 CVOTs have been completed, assessing 3 novel classes of antihyperglycemic agents:

• dipeptidyl peptidase-4 (DPP-4) inhibitors
• glucagon-like peptide-1 (GLP-1) receptor agonists
• sodium–glucose cotransporter-2 (SGLT-2) inhibitors.

None of these trials identified any increased incidence of MACE; 7 found CV benefit. This review summarizes what the CVOTs revealed about these antihyperglycemic agents and their ability to yield a reduction in MACE and a decrease in all-cause mortality in patients with T2D and elevated CV disease risk. Armed with this information, you will have the tools you need to offer patients with T2D CV benefit while managing their primary disease.

Cardiovascular outcomes trials: DPP-4 inhibitors

Four trials. Trials of DPP-4 inhibitors that have been completed and reported are of saxagliptin (SAVOR-TIMI 53⁶), alogliptin (EXAMINE⁷), sitagliptin (TECOS⁸), and linagliptin (CARMELINA⁹); others are in progress. In general, researchers enrolled patients at high risk of CV events, although inclusion criteria varied substantially. Consistently, these studies demonstrated that DPP-4 inhibition neither increased nor decreased (ie, were noninferior) the 3-point MACE (SAVOR-TIMI 53 noninferiority, P < .001; EXAMINE, P < .001; TECOS, P < .001).

Continue to: Rather than improve...

Rather than improve CV outcomes, there was some evidence that DPP-4 inhibitors might be associated with an increased risk of hospitalization for heart failure (HHF). In the SAVOR-TIMI 53 trial, patients randomized to saxagliptin had a 0.7% absolute increase in risk of HHF (P = .98).⁶ In the EXAMINE trial, patients treated with alogliptin showed a nonsignificant trend for HHF.¹⁰ In both the TECOS and CARMELINA trials, no difference was recorded in the rate of HHF.^8,9,11 Subsequent meta-analysis that summarized the risk of HHF in CVOTs with DPP-4 inhibitors indicated a nonsignificant trend to increased risk.¹²

It’s likely that the CV benefits result from mechanisms other than a reduction in the serum glucose level, given the short time frame of the studies and the magnitude of the CV benefit.

From these trials alone, it appears that DPP-4 inhibitors are unlikely to provide CV benefit. Data from additional trials are needed to evaluate the possible association between these medications and heart failure (HF). However, largely as a result of the findings from SAVOR-TIMI 53 and EXAMINE, the FDA issued a Drug Safety Communication in April 2016, adding warnings about HF to the labeling of saxagliptin and alogliptin.¹³

CARMELINA was designed to also evaluate kidney outcomes in patients with T2D. As with other DPP-4 inhibitor trials, the primary aim was to establish noninferiority, compared with placebo, for time to MACE-3 (P < .001). Secondary outcomes were defined as time to first occurrence of end-stage renal disease, death due to renal failure, and sustained decrease from baseline of ≥ 40% in the estimated glomerular filtration rate. The incidence of the secondary kidney composite results was not significantly different between groups randomized to linagliptin or placebo.⁹

Cardiovascular outcomes trials: GLP-1 receptor agonists

ELIXA. The CV safety of GLP-1 receptor agonists has been evaluated in several randomized clinical trials. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial was the first¹⁴: Lixisenatide was studied in 6068 patients with recent hospitalization for acute coronary syndrome. Lixisenatide therapy was neutral with regard to CV outcomes, which met the primary endpoint: noninferiority to placebo (P < .001). There was no increase in either HF or HHF.

Continue to: LEADER

LEADER. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial (LEADER) evaluated long-term effects of liraglutide, compared to placebo, on CV events in patients with T2D.¹⁵ It was a multicenter, double-blind, placebocontrolled study that followed 9340 participants, most (81%) of whom had established CV disease, over 5 years. LEADER is considered a landmark study because it was the first large CVOT to show significant benefit for a GLP-1 receptor agonist.

Liraglutide demonstrated reductions in first occurrence of death from CV causes, nonfatal MI or nonfatal stroke, overall CV mortality, and all-cause mortality. The composite MACE-3 showed a relative risk reduction (RRR) of 13%, equivalent to an absolute risk reduction (ARR) of 1.9% (noninferiority, P < .001; superiority, P < .01). The RRR was 22% for death from CV causes, with an ARR of 1.3% (P = .007); the RRR for death from any cause was 15%, with an ARR of 1.4% (P = .02).

In addition, there was a lower rate of nephropathy (1.5 events for every 100 patient–years in the liraglutide group [P = .003], compared with 1.9 events every 100 patient–years in the placebo group).¹⁵

Results clearly demonstrated benefit. No significant difference was seen in the liraglutide rate of HHF, compared to the rate in the placebo group.

SUSTAIN-6. Evidence for the CV benefit of GLP-1 receptor agonists was also demonstrated in the phase 3 Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6).¹⁶ This was a study of 3297 patients with T2D at high risk of CV disease and with a mean hemoglobin A_1c (HbA_1c) value of 8.7%, 83% of whom had established CV disease. Patients were randomized to semaglutide or placebo. Note: SUSTAIN-6 was a noninferiority safety study; as such, it was not actually designed to assess or establish superiority.

Continue to: The incidence of MACE-3...

The incidence of MACE-3 was significantly reduced among patients treated with semaglutide (P = .02) after median followup of 2.1 years. The expanded composite outcome (death from CV causes, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina or HF), also showed a significant reduction with semaglutide (P = .002), compared with placebo. There was no difference in the overall hospitalization rate or rate of death from any cause.

EXSCEL. The Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL)^17,18 was a phase III/IV, double-blind, pragmatic placebo-controlled study of 14,752 patients at any level of CV risk, for a median 3.2 years. The study population was intentionally more diverse than in earlier GLP-1 receptor agonist studies. The researchers hypothesized that patients at increased risk of MACE would experience a comparatively greater relative treatment benefit with exenatide than those at lower risk. That did not prove to be the case.

EXSCEL did confirm noninferiority compared with placebo (P < .001), but once-weekly exenatide resulted in a nonsignificant reduction in major adverse CV events, and a trend for RRR in all-cause mortality (RRR = 14%; ARR = 1% [P = .06]).

HARMONY OUTCOMES. The Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease study (HARMONY OUTCOMES)¹⁹ was a double-blind, randomized, placebocontrolled trial conducted at 610 sites across 28 countries. The study investigated albiglutide, 30 to 50 mg once weekly, compared with placebo. It included 9463 patients ages ≥ 40 years with T2D who had an HbA_1c > 7% (median value, 8.7%) and established CV disease. Patients were evaluated for a median 1.6 years.

Albiglutide reduced the risk of CV causes of death, nonfatal MI, and nonfatal stroke by an RRR of 22%, (ARR, 2%) (noninferiority, P < .0001; superiority, P < .0006).

Continue to: REWIND

REWIND. The Researching Cardiovascular Events with a Weekly INcretin in Diabetes trial (REWIND),²⁰ the most recently completed GLP-1 receptor agonist CVOT (presented at the 2019 American Diabetes Association [ADA] Conference in June and published simultaneously in The Lancet), was a multicenter, randomized, double-blind placebo-controlled trial designed to assess the effect of weekly dulaglutide, 1.5 mg, compared with placebo, in 9901 participants enrolled at 371 sites in 24 countries. Mean patient age was 66.2 years, with women constituting 4589 (46.3%) of participants.

REWIND was distinct from other CVOTs in several ways:

• Other CVOTs were designed to show noninferiority compared with placebo regarding CV events; REWIND was designed to establish superiority
• In contrast to trials of other GLP-1 receptor agonists, in which most patients had established CV disease, only 31% of REWIND participants had a history of CV disease or a prior CV event (although 69% did have CV risk factors without underlying disease)
• REWIND was much longer (median follow-up, 5.4 years) than other GLP-1 receptor agonist trials (median follow-up, 1.5 to 3.8 years).

In REWIND, the primary composite outcome of MACE-3 occurred in 12% of participants assigned to dulaglutide, compared with 13.1% assigned to placebo (P = .026). This equated to 2.4 events for every 100 person– years on dulaglutide, compared with 2.7 events for every 100 person–years on placebo. There was a consistent effect on all MACE-3 components, although the greatest reductions were observed in nonfatal stroke (P = .017). Overall risk reduction was the same for primary and secondary prevention cohorts (P = .97), as well as in patients with either an HbA_1c value < 7.2% or ≥ 7.2% (P = .75). Risk reduction was consistent across age, sex, duration of T2D, and body mass index.

Dulaglutide did not significantly affect the incidence of all-cause mortality, heart failure, revascularization, or hospital admission. Forty-seven percent of patients taking dulaglutide reported gastrointestinal adverse effects (P = .0001).

Cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.

In a separate analysis of secondary outcomes, ²¹ dulaglutide reduced the composite renal outcomes of new-onset macroalbuminuria (P = .0001); decline of ≥ 30% in the estimated glomerular filtration rate (P = .066); and chronic renal replacement therapy (P = .39). Investigators estimated that 1 composite renal outcome event would be prevented for every 31 patients treated with dulaglutide for a median 5.4 years.

Continue to: Cardiovascular outcomes trials...

Cardiovascular outcomes trials: SGLT-2 inhibitors

EMPA-REG OUTCOME. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) was also a landmark study because it was the first dedicated CVOT to show that an antihyperglycemic agent 1) decreased CV mortality and all-cause mortality, and 2) reduced HHF in patients with T2D and established CV disease.22 In this trial, 7020 patients with T2D who were at high risk of CV events were randomized and treated with empagliflozin, 10 or 25 mg, or placebo, in addition to standard care, and were followed for a median 2.6 years.

In October, the FDA approved dapaglifozin to reduce the risk of hospitalization for heart failure in adults with T2D and established CV disease.

Compared with placebo, empagliflozin resulted in an RRR of 14% (ARR, 1.6%) in the primary endpoint of CV death, nonfatal MI, and stroke, confirming study drug superiority (P = .04). When compared with placebo, the empagliflozin group had an RRR of 38% in CV mortality, (ARR < 2.2%) (P < .001); an RRR of 35% in HHF (ARR, 1.4%) (P = .002); and an RRR of 32% (ARR, 2.6%) in death from any cause (P < .001).

CANVAS. The Canagliflozin Cardiovascular Assessment Study (CANVAS) integrated 2 multicenter, placebo-controlled, randomized trials with 10,142 participants and a mean follow-up of 3.6 years.²³ Patients were randomized to receive canagliflozin (100-300 mg/d) or placebo. Approximately two-thirds of patients had a history of CV disease (therefore representing secondary prevention); one-third had CV risk factors only (primary prevention).

In CANVAS, patients receiving canagliflozin had a risk reduction in MACE-3, establishing superiority compared with placebo (P < .001). There was also a significant reduction in progression of albuminuria (P < .05). Superiority was not shown for the secondary outcome of death from any cause. Canagliflozin had no effect on the primary endpoint (MACE-3) in the subgroup of participants who did not have a history of CV disease. Similar to what was found with empagliflozin in EMPA-REG OUTCOME, CANVAS participants had a reduced risk of HHF.

Continue to: Patients on canagliflozin...

Patients on canagliflozin unexpectedly had an increased incidence of amputations (6.3 participants, compared with 3.4 participants, for every 1000 patient–years). This finding led to a black box warning for canagliflozin about the risk of lower-limb amputation.

DECLARE-TIMI 58. The Dapagliflozin Effect of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 trial (DECLARETIMI 58) was the largest SGLT-2 inhibitor outcomes trial to date, enrolling 17,160 patients with T2D who also had established CV disease or multiple risk factors for atherosclerotic CV disease. The trial compared dapagliflozin, 10 mg/d, and placebo, following patients for a median 4.2 years.²⁴ Unlike CANVAS and EMPA-REG OUTCOME, DECLARE-TIMI 58 included CV death and HHF as primary outcomes, in addition to MACE-3.

Dapagliflozin was noninferior to placebo with regard to MACE-3. However, its use did result in a lower rate of CV death and HHF by an RRR of 17% (ARR, 1.9%). Risk reduction was greatest in patients with HF who had a reduced ejection fraction (ARR = 9.2%).²⁵

In October, the FDA approved dapagliflozin to reduce the risk of HHF in adults with T2D and established CV disease or multiple CV risk factors. Before initiating the drug, physicians should evaluate the patient's renal function and monitor periodically.

Meta-analyses of SGLT-2 inhibitors

Systematic review. Usman et al released a meta-analysis in 2018 that included 35 randomized, placebo-controlled trials (including EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58) that had assessed the use of SGLT-2 inhibitors in nearly 35,000 patients with T2D.²⁶ This review concluded that, as a class, SGLT-2 inhibitors reduce all-cause mortality, major adverse cardiac events, nonfatal MI, and HF and HHF, compared with placebo.

Continue to: CVD-REAL

CVD-REAL. A separate study, Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL), of 154,528 patients who were treated with canagliflozin, dapagliflozin, or empagliflozin, showed that initiation of SGLT-2 inhibitors, compared with other glucose- lowering therapies, was associated with a 39% reduction in HHF; a 51% reduction in death from any cause; and a 46% reduction in the composite of HHF or death (P < .001).²⁷

CVD-REAL was unique because it was the largest real-world study to assess the effectiveness of SGLT-2 inhibitors on HHF and mortality. The study utilized data from patients in the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom, based on information obtained from medical claims, primary care and hospital records, and national registries that compared patients who were either newly started on an SGLT-2 inhibitor or another glucose-lowering drug. The drug used by most patients in the trial was canagliflozin (53%), followed by dapagliflozin (42%), and empagliflozin (5%).

In this meta-analysis, similar therapeutic effects were seen across countries, regardless of geographic differences, in the use of specific SGLT-2 inhibitors, suggesting a class effect. Of particular significance was that most (87%) patients enrolled in CVD-REAL did not have prior CV disease. Despite this, results for examined outcomes in CVD-REAL were similar to what was seen in other SGLT-2 inhibitor trials that were designed to study patients with established CV disease.

Risk of adverse effects of newer antidiabetic agents

DPP-4 inhibitors. Alogliptin and sitagliptin carry a black-box warning about potential risk of HF. In SAVOR-TIMI, a 27% increase was detected in the rate of HHF after approximately 2 years of saxagliptin therapy.⁶ Although HF should not be considered a class effect for DPP-4 inhibitors, patients who have risk factors for HF should be monitored for signs and symptoms of HF.

Continue to: Cases of acute pancreatitis...

Cases of acute pancreatitis have been reported in association with all DPP-4 inhibitors available in the United States. A combined analysis of DDP-4 inhibitor trials suggested an increased relative risk of 79% and an absolute risk of 0.13%, which translates to 1 or 2 additional cases of acute pancreatitis for every 1000 patients treated for 2 years.²⁸

There have been numerous postmarketing reports of severe joint pain in patients taking a DPP-4 inhibitor. Most recently, cases of bullous pemphigoid have been reported after initiation of DPP-4 inhibitor therapy.²⁹

GLP-1 receptor agonists carry a black box warning for medullary thyroid (C-cell) tumor risk. GLP-1 receptor agonists are contraindicated in patients with a personal or family history of this cancer, although this FDA warning is based solely on observations from animal models.

In addition, GLP-1 receptor agonists can increase the risk of cholecystitis and pancreatitis. Not uncommonly, they cause gastrointestinal symptoms when first started and when the dosage is titrated upward. Most GLP-1 receptor agonists can be used in patients with renal impairment, although data regarding their use in Stages 4 and 5 chronic kidney disease are limited.³⁰ Semaglutide was found, in the SUSTAIN-6 trial, to be associated with an increased rate of complications of retinopathy, including vitreous hemorrhage and blindness (P = .02)³¹

SGLT-2 inhibitors are associated with an increased incidence of genitourinary infection, bone fracture (canagliflozin), amputation (canagliflozin), and euglycemic diabetic ketoacidosis. Agents in this class should be avoided in patients with moderate or severe renal impairment, primarily due to a lack of efficacy. They are contraindicated in patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. (Dapagliflozin is not recommended when eGFR is < 45 mL/min/ 1.73 m2.) These agents carry an FDA warning about the risk of acute kidney injury.³⁰

Continue to: Summing up

Summing up

All glucose-lowering medications used to treat T2D are not equally effective in reducing CV complications. Recent CVOTs have uncovered evidence that certain antidiabetic agents might confer CV and all-cause mortality benefits (TABLE 2^{6,7,9,11,14-17,19-24}).

Discussion of proposed mechanisms for CV outcome superiority of these agents is beyond the scope of this review. It is generally believed that benefits result from mechanisms other than a reduction in the serum glucose level, given the relatively short time frame of the studies and the magnitude of the CV benefit. It is almost certain that mechanisms of CV benefit in the 2 landmark studies—LEADER and EMPA-REG OUTCOME—are distinct from each other.³²

See “When planning T2D pharmacotherapy, include newer agents that offer CV benefit,” ^33-38 for a stepwise approach to treating T2D, including the role of agents that have efficacy in modifying the risk of CV disease.

ACKNOWLEDGMENTS
Linda Speer, MD, Kevin Phelps, DO, and Jay Shubrook, DO, provided support and editorial assistance.

CORRESPONDENCE
Robert Gotfried, DO, FAAFP, Department of Family Medicine, University of Toledo College of Medicine, 3333 Glendale Avenue, Toledo, OH 43614; Robert.gotfried@utoledo.edu.

Cardiovascular disease (CVD) remains the leading cause of global mortality. In 2015, 41.5% of the US population had at least 1 form of CVD and CVD accounted for nearly 18 million deaths worldwide.1,2 The major disease categories represented include myocardial infarction (MI), sudden death, strokes, calcific aortic valve stenosis (CAVS), and peripheral vascular disease.^1,2 In terms of health care costs, quality of life, and caregiver burden, the overall impact of disease prevalence continues to rise.^1,3-6 There is an urgent need for more precise and earlier CVD risk assessment to guide lifestyle and therapeutic interventions for prevention of disease progression as well as potential reversal of preclinical disease. Even at a young age, visible coronary atherosclerosis has been found in up to 11% of “healthy” active individuals during autopsies for trauma fatalities.^7,8

The impact of CVD on the US and global populations is profound. In 2011, CVD prevalence was predicted to reach 40% by 2030.9 That estimate was exceeded in 2015, and it is now predicted that by 2035, 45% of the US population will suffer from some form of clinical or preclinical CVD. In 2015, the decadeslong decline in CVD mortality was reversed for the first time since 1969, showing a 1% increase in deaths from CVD.¹ Nearly 300,000 of those using US Department of Veterans Affairs (VA) services were hospitalized for CVD between 2010 and 2014.¹⁰ The annual direct and indirect costs related to CVD in the US are estimated at $329.7 billion, and these costs are predicted to top $1 trillion by 2035.¹ Heart attack, coronary atherosclerosis, and stroke accounted for 3 of the 10 most expensive conditions treated in US hospitals in 2013.¹¹ Globally, the estimate for CVD-related direct and indirect costs was $863 billion in 2010 and may exceed $1 trillion by 2030.¹²

The nature of military service adds additional risk factors, such as posttraumatic stress disorder, depression, sleep disorders and physical trauma which increase CVD morbidity/ mortality in service members, veterans, and their families.^13-16 In addition, living in lowerincome areas (countries or neighborhoods) can increase the risk of both CVD incidence and fatalities, particularly in younger individuals.^17-20 The Military Health System (MHS) and VA are responsible for the care of those individuals who have voluntarily taken on these additional risks through their time in service. This responsibility calls for rapid translation to practice tools and resources that can support interventions to minimize as many modifiable risk factors as possible and improve longterm health. This strategy aligns with the World Health Organization’s (WHO) focus on prevention of disease progression through interventions targeting modifiable risk.^3-6,21-23 The driving force behind the launch of the US Department of Health and Human Services (HHS) Million Hearts program was the goal of preventing 1 million heart attacks and strokes by 2017 with risk reduction through aspirin, blood pressure control, cholesterol management, smoking cessation, sodium reduction, and physical activity.^24,25 While some reductions in CVD events have been documented, the outcomes fell short of the goals set, highlighting both the need and value of continued and expanded efforts for CVD risk reduction.²⁶

More precise assessment of risk factors during preventative care, as well as after a diagnosis of CVD, may improve the timeliness and precision of earlier interventions (both lifestyle and therapeutic) that reduce CVD morbidity and mortality^.27 Personalized or precision medicine approaches take into account differences in socioeconomic, environmental, and lifestyle factors that are potentially reversible, as well as gender, race, and ethnicity.^28-31 Current methods of predicting CVD risk have considerable room for improvement.²⁷ About 40% of patients with newly diagnosed CVD have normal traditional cholesterol profiles, including those whose first cardiac event proves fatal.^29-33 Currently available risk scores (hundreds have been described in the literature) mischaracterize risk in minority populations and women, and have shown deficiencies in identifying preclinical atherosclerosis.^34,35 The failure to recognize preclinical CVD in military personnel during their active duty life cycle results in missed opportunities for improved health and readiness sustainment.

Most CVD risk prediction models incorporate some form of blood lipids. Total cholesterol (TC) is most commonly used in clinical practice, along with high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglycerides (TG).^23,27,36 High LDLC and/or TC are well established as lipid-related CVD risk factors and are incorporated into many CVD risk scoring systems/models described in the literature.²⁷ LDLC reduction is commonly recommended as CVD prevention, but even with optimal statin treatment, there is still considerable residual risk for new and recurrent CVD events.^{28,32,34,35,37-42}

Incorporating novel biomarkers and alternative lipid measurements may improve risk prediction and aid targeted treatment, ultimately reducing CVD events.²⁷ Apolipoprotein B (ApoB) is a major atherogenic component embedded in LDL and VLDL correlating to non-HDLC and may be useful in the setting of triglycerides ≥ 200 mg/d as levels > 130 mg/ dL appear to be risk-enhancing, but measurements may be unreliable.⁴³ According to the 2018 Cholesterol Guidelines, lipoprotein(a) [Lp(a)] elevation also is recognized as a risk-enhancing factor that is particularly implicated when there is a strong family history of premature atherosclerotic CVD or personal history of CVD not explained by major risk factors.⁴³

Lp(a) elevation is a largely underrecognized category of lipid disorder that impacts up to 20% to 30% of the population globally and within the US, although there is considerable variability by geographic location and ethnicity.⁴⁴ Globally, Lp(a) elevation places > 1 billion people at moderate to high risk for CVD.44 Lp(a) has a strong genetic component and is recognized as a distinct and independent risk factor for MI, sudden death, strokes and CAVS. Lp(a) has an extensive body of evidence to support its distinct role both as a causal factor in CVD and as an augmentation to traditional risk factors.^44-48

Lipoproteni(a) Elevation Use For Diagnosis

The importance of Lp(a) elevation as a clinical diagnosis rather than a laboratory abnormality alone was brought forward by the Lipoprotein(a) Foundation. Its founder, Sandra Tremulis, is a survivor of an acute coronary event that occurred when she was 39-years old, despite running marathons and having none of the traditional CVD lifestyle risk factors.⁴⁹ This experience inspired her to create the Lipoprotein(a) Foundation to give a voice to families living with or at risk for CVD due to Lp(a) elevation.

As often happens in the progress of medicine, patients and their families drive change based on their personal experiences with the gaps in standard clinical practice. It was this foundation—not a member of the medical establishment—that submitted the formal request for the addition of new ICD-10-CM diagnostic and family history codes for Lp(a) elevation during the Centers for Disease Control and Prevention (CDC) September 2017 ICD-10-CM Coordination and Maintenance Committee meeting.⁵⁰ In June 2018, the final ICD-10-CM code addenda for 2019 was released and included the new codes E78.⁴¹ (Elevated Lp[a]) and Z83.430 (Family history of elevated Lp[a]).⁵² After the new codes were approved, both the American Heart Association and the National Lipid Association added recommendations regarding Lp(a) testing to their clinical practice guidelines.^43,52

Practically, these codes standardize billing and payment for legitimate clinical work and laboratory testing. Prior to the addition of Lp(a) elevation as a clinical diagnosis, testing and treatment of Lp(a) elevation was considered experimental and not medically necessary until after a cardiovascular event had already occurred. Services for Lp(a) elevation were therefore not reimbursed by many healthcare organizations and insurance companies. The new ICD-10-CM codes encourage the assessment of Lp(a) both in individuals with early onset major CVD events and in presumably fit, healthy individuals, particularly when there is a family history of Lp(a) elevation. Given that Lp(a) levels do not change significantly over time, the current understanding is that only a single measurement is needed to define the individual risk over a lifetime.^41,42,44,45 As therapies targeting Lp(a) levels evolve, repeated measurements may be indicated to monitor response and direct changes in management. “Elevated Lipoprotein(a)” is the first laboratory testing abnormality that has achieved the status of a clinical diagnosis.

Lp(a) Measurements

There is considerable complexity to the measurement of lipoproteins in blood samples due to heterogeneity in both density and size of particles as illustrated in the Figure.⁵³

For traditional lipids measured in clinical practice, the size and density ranges from small high-density lipoprotein (HDL) through LDLC and intermediate- density lipoprotein (IDL) to the largest least dense particles in the very low-density lipoprotein (VLDL) and chylomicron remnant fractions. Standard lipid profiles consist of mass concentration measurements (mg/dL) of TC, TG, HDLC, and LDLC.⁵³ Non-HDLC (calculated as: TC−HDLC) consists of all cholesterol found in atherogenic lipoproteins, including remnant-C and Lp(a). Until recently, the cholesterol content of Lp(a), corresponding to about 30% of Lp(a) total mass, was included in the TC, non-HDLC and LDLC measurements with no separate reporting by the majority of clinical laboratories.

After > 50 years of research on the structure and biochemistry of Lp(a), the physiology and biological functions of these complex and polymorphic lipoprotein particles are not fully understood. Lp(a) is composed of a lipoprotein particle similar in composition to LDL (protein and lipid), containing 1 molecule of ApoB wrapped around a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface.⁴⁸ The presence of a unique hydrophilic, highly glycosylated protein referred to as apolopoprotienA (apo[a]), covalently attached to ApoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL.⁴⁸ Cholesterol rich ApoB is an important component within many lipoproteins pathogenic for atherosclerosis and CVD.^45,47,53

The apo(a) contributes to the increased density of Lp(a) compared to LDLC with associated reduced binding affinity to the LDL receptor. This reduced receptor binding affinity is a presumed mechanism for the lack of Lp(a) plasma level response to statin therapies, which increase hepatic LDL receptor activity.⁴⁷ Apo(a) evolved from the plasminogen gene through duplication and remodeling and demonstrates extensive heterogeneity in protein size, with > 40 different apo(a) isoforms resulting in > 40 different Lp(a) particle sizes. Size of the apo(a) particle is determined by the number of pleated structures known as kringles. Most people (> 80%) carry 2 different-sized apo(a) isoforms. Plasma Lp(a) level is determined by the net production of apo(a) in each isoform, and the smaller apo(a) isoforms are associated with higher plasma levels of Lp(a).⁴⁵

Given the heterogeneity in Lp(a) molecular weight, which can vary even within individuals, recommendations have been made for reporting results as particle numbers or concentrations (nmol/L or mmol/L) rather than as mass concentration (mg/dL).⁵⁵ However, the majority of the large CVD morbidity and mortality outcomes studies used Lp(a) mass concentration levels in mg/ dL to characterize risk levels.^56,57 There is no standardized method to convert Lp(a) measurements from mg/dL to nmol/L.⁵⁵ Current assays using WHO standardized reagents and controls are reliable for categorizing risk levels.⁵⁸

The European Atherosclerosis Society consensus panel recommended that desirable Lp(a) levels should be below the 80th percentile (< 50 mg/dL or < 125 nmol/L) in patients with intermediate or high CVD risk.⁵⁹ Subsequent epidemiological and Mendelian randomization studies have been performed in general populations with no history of CVD and demonstrated that increased CVD risk can be detected with Lp(a) levels as low as 25 to 30 mg/dL.^56,60-63 In secondary prevention populations with prior CVD and optimal treatment (statins, antiplatelet drugs), recurrent event risk was also increased with elevated Lp(a).^63-66

Using immunoturbidometric assays, Varvel and colleagues reported the prevalence of elevated Lp(a) mass concentration levels (mg/dL) in > 500,000 US patients undergoing clinical evaluations based on data from a referral laboratory of patients.⁵⁸ The mean Lp(a) levels were 34.0 mg/dL with median (interquartile range [IQR]) levels at 17 (7-47) mg/dL and overall range of 0 to 907 mg/dL.⁵⁸ Females had higher Lp(a) levels compared to males but no ethnic or racial breakdown was provided. Lp(a) levels > 30 mg/dL and > 50 mg/dL were present in 35% and 24% of subjects, respectively. Table 1 displays the relationship between various Lp(a) level cut-offs to mean levels of LDLC, estimated LDLC corrected for Lp(a), TC, HDLC, and TG.⁵⁸ The data demonstrate that Lp(a) elevation cannot be inferred from LDLC levels nor from any of the other traditional lipoprotein measures. Patients with high risk Lp(a) levels may have normal LDLC. While Lp(a) thresholds have been identified for stratification of CVD risk, the target levels for risk reduction have not been specifically defined, particularly since therapies are not widely available for reduction of Lp(a). Table 2 provides an overview of clinical lipoprotein measurements that may be reasonable targets for therapeutic interventions and reduction of CVD risk.^44,53,55 In general, existing studies suggest that radical reduction (> 80%) is required to impact long-term outcomes, particularly in individuals with severe disease.^68,69

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk.^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis.^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD.^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction.⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system.⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses.^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events.^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD.⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis.^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210).⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD).⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls.^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL.⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a).⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy.^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a).^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients.⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes.⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a).⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation.⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a).⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a).⁹⁴

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries.⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL).^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations.¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a).^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD.^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years.¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events.^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men.^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a).⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold.¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups.^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans.¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels.^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity.^78,113,115

Lifestyle and Cardiovascular Health

It is noteworthy that the Lp(a) genetic risks can also be modified by lifestyle risk reduction even in the absence of significant blood level reductions. For example, Khera and colleagues constructed a genetic risk profile for CVD that included genes related to Lp(a).¹¹⁶ Subjects with high genetic risk were more likely to experience CVD events compared with subjects with low genetic risk. However, risks for CVD were attenuated by 4 healthy lifestyle factors: current nonsmoker, body mass index < 30, at least weekly physical activity, and a healthy diet. Subjects with high genetic risk and an unhealthy lifestyle (0 or 1 of the 4 healthy lifestyle factors) were the most likely to develop CVD (Hazard ratio [HR], 3.5), but that risk was lower for subjects with healthy (3 or 4 of the 4 healthy lifestyle factors) and intermediate lifestyles (2 of the 4 healthy lifestyle factors) (HR, 1.9 and 2.2, respectively), despite despite high genetic risk for CVD.

While the independent CVD risk associated with elevated Lp(a) does not appear to be responsive to lifestyle risk reduction alone, certainly elevated LDLC and traditional risk factors can increase the overall CVD risk and are worthy of preventive interventions. In particular, inflammation from any source exacerbates CVD risk. Proatherogenic diet, insufficient sleep, lack of exercise, and maladaptive stress responses are other targets for personalized CVD risk reduction. ^28,117 Studies of dietary modifications and other lifestyle factors have shown reduced risk of CVD events, despite lack of reduction in Lp(a) levels.^119,120 It is noteworthy that statin therapy (with or without ezetimibe) fails to impact CAVS progression, likely because statins either raise or have no effect on Lp(a) levels.^92,119

Until recently, there has been no evidence supporting any therapeutic intervention causing clinically meaningful reductions in Lp(a). Table 4 lists major drug classes and their effects on Lp(a) and CVD outcomes; however, a detailed discussion of each of these therapies is beyond the scope of this review. Drugs that reduce Lp(a) by 20-30% have varying effects on CVD outcomes, from no effect^122,123 to a 10% to 20% decrease in CVD events when compared with a placebo.^124,125 Because these drugs also produce substantial reductions in LDLC, it is not possible to determine how much of the beneficial effects are due to reductions in Lp(a).

Lipoprotein apheresis produces profound reductions in Lp(a) of 60 to 80% in very highrisk populations.^69,126 Within-subjects comparisons show up to 80% reductions in CVD events, relative to event rates prior to treatment initiation.^69,127 Early trials of antisense oligonucleotide against apo(a) therapies show potential to produce similar outcomes.^128,129 These treatments may be particularly effective in patients with isolated Lp(a) elevations.

Summary

Lp(a) elevation is a major contributor to cardiovascular disease risk and has been recognized as an ICD-10-CM coded clinical diagnosis, the first laboratory abnormality to be defined a clinical disease in the asymptomatic healthy young individuals. This change addresses currently under- diagnosed CVD risk independent of LDLC reduction strategies. A brief overview of recent guidelines for the clinical use of Lp(a) testing from the American Heart Association^43,151 and the National Lipid Association52 can be found in Table 5. Although drug therapies for lowering Lp(a) levels remain limited, new treatment options are actively being developed.

Many Americans with high Lp(a) have not yet been identified. Expanded one-time screening can inform these patients of their cardiovascular risk and increase their access to early, aggressive lifestyle modification and optimal lipid-lowering therapy. Given the further increased CVD risk factors for military service members and veterans, a case can be made for broader screening and enhanced surveillance of elevated Lp(a) in these presumably healthy and fit individuals as well as management focused on modifiable risk factors.

Acknowledgements

This program initiative was conducted by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. as part of the Integrative Cardiac Health Project at Walter Reed National Military Medical Center (WRNMMC), and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick under Contract Number: W81XWH-16-2-0007. It reflects literature review preparatory work for a research protocol but does not involve an actual research project. The work in this manuscript was supported by the staff of the Integrative Cardiac Health Project (ICHP) with special thanks to Claire Fuller, Elaine Walizer, Dr. Mariam Kashani and the entire health coaching team.

Cardiovascular disease (CVD) remains the leading cause of global mortality. In 2015, 41.5% of the US population had at least 1 form of CVD and CVD accounted for nearly 18 million deaths worldwide.1,2 The major disease categories represented include myocardial infarction (MI), sudden death, strokes, calcific aortic valve stenosis (CAVS), and peripheral vascular disease.^1,2 In terms of health care costs, quality of life, and caregiver burden, the overall impact of disease prevalence continues to rise.^1,3-6 There is an urgent need for more precise and earlier CVD risk assessment to guide lifestyle and therapeutic interventions for prevention of disease progression as well as potential reversal of preclinical disease. Even at a young age, visible coronary atherosclerosis has been found in up to 11% of “healthy” active individuals during autopsies for trauma fatalities.^7,8

The impact of CVD on the US and global populations is profound. In 2011, CVD prevalence was predicted to reach 40% by 2030.9 That estimate was exceeded in 2015, and it is now predicted that by 2035, 45% of the US population will suffer from some form of clinical or preclinical CVD. In 2015, the decadeslong decline in CVD mortality was reversed for the first time since 1969, showing a 1% increase in deaths from CVD.¹ Nearly 300,000 of those using US Department of Veterans Affairs (VA) services were hospitalized for CVD between 2010 and 2014.¹⁰ The annual direct and indirect costs related to CVD in the US are estimated at $329.7 billion, and these costs are predicted to top $1 trillion by 2035.¹ Heart attack, coronary atherosclerosis, and stroke accounted for 3 of the 10 most expensive conditions treated in US hospitals in 2013.¹¹ Globally, the estimate for CVD-related direct and indirect costs was $863 billion in 2010 and may exceed $1 trillion by 2030.¹²

The nature of military service adds additional risk factors, such as posttraumatic stress disorder, depression, sleep disorders and physical trauma which increase CVD morbidity/ mortality in service members, veterans, and their families.^13-16 In addition, living in lowerincome areas (countries or neighborhoods) can increase the risk of both CVD incidence and fatalities, particularly in younger individuals.^17-20 The Military Health System (MHS) and VA are responsible for the care of those individuals who have voluntarily taken on these additional risks through their time in service. This responsibility calls for rapid translation to practice tools and resources that can support interventions to minimize as many modifiable risk factors as possible and improve longterm health. This strategy aligns with the World Health Organization’s (WHO) focus on prevention of disease progression through interventions targeting modifiable risk.^3-6,21-23 The driving force behind the launch of the US Department of Health and Human Services (HHS) Million Hearts program was the goal of preventing 1 million heart attacks and strokes by 2017 with risk reduction through aspirin, blood pressure control, cholesterol management, smoking cessation, sodium reduction, and physical activity.^24,25 While some reductions in CVD events have been documented, the outcomes fell short of the goals set, highlighting both the need and value of continued and expanded efforts for CVD risk reduction.²⁶

More precise assessment of risk factors during preventative care, as well as after a diagnosis of CVD, may improve the timeliness and precision of earlier interventions (both lifestyle and therapeutic) that reduce CVD morbidity and mortality^.27 Personalized or precision medicine approaches take into account differences in socioeconomic, environmental, and lifestyle factors that are potentially reversible, as well as gender, race, and ethnicity.^28-31 Current methods of predicting CVD risk have considerable room for improvement.²⁷ About 40% of patients with newly diagnosed CVD have normal traditional cholesterol profiles, including those whose first cardiac event proves fatal.^29-33 Currently available risk scores (hundreds have been described in the literature) mischaracterize risk in minority populations and women, and have shown deficiencies in identifying preclinical atherosclerosis.^34,35 The failure to recognize preclinical CVD in military personnel during their active duty life cycle results in missed opportunities for improved health and readiness sustainment.

Most CVD risk prediction models incorporate some form of blood lipids. Total cholesterol (TC) is most commonly used in clinical practice, along with high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglycerides (TG).^23,27,36 High LDLC and/or TC are well established as lipid-related CVD risk factors and are incorporated into many CVD risk scoring systems/models described in the literature.²⁷ LDLC reduction is commonly recommended as CVD prevention, but even with optimal statin treatment, there is still considerable residual risk for new and recurrent CVD events.^{28,32,34,35,37-42}

Incorporating novel biomarkers and alternative lipid measurements may improve risk prediction and aid targeted treatment, ultimately reducing CVD events.²⁷ Apolipoprotein B (ApoB) is a major atherogenic component embedded in LDL and VLDL correlating to non-HDLC and may be useful in the setting of triglycerides ≥ 200 mg/d as levels > 130 mg/ dL appear to be risk-enhancing, but measurements may be unreliable.⁴³ According to the 2018 Cholesterol Guidelines, lipoprotein(a) [Lp(a)] elevation also is recognized as a risk-enhancing factor that is particularly implicated when there is a strong family history of premature atherosclerotic CVD or personal history of CVD not explained by major risk factors.⁴³

Lp(a) elevation is a largely underrecognized category of lipid disorder that impacts up to 20% to 30% of the population globally and within the US, although there is considerable variability by geographic location and ethnicity.⁴⁴ Globally, Lp(a) elevation places > 1 billion people at moderate to high risk for CVD.44 Lp(a) has a strong genetic component and is recognized as a distinct and independent risk factor for MI, sudden death, strokes and CAVS. Lp(a) has an extensive body of evidence to support its distinct role both as a causal factor in CVD and as an augmentation to traditional risk factors.^44-48

Lipoproteni(a) Elevation Use For Diagnosis

The importance of Lp(a) elevation as a clinical diagnosis rather than a laboratory abnormality alone was brought forward by the Lipoprotein(a) Foundation. Its founder, Sandra Tremulis, is a survivor of an acute coronary event that occurred when she was 39-years old, despite running marathons and having none of the traditional CVD lifestyle risk factors.⁴⁹ This experience inspired her to create the Lipoprotein(a) Foundation to give a voice to families living with or at risk for CVD due to Lp(a) elevation.

As often happens in the progress of medicine, patients and their families drive change based on their personal experiences with the gaps in standard clinical practice. It was this foundation—not a member of the medical establishment—that submitted the formal request for the addition of new ICD-10-CM diagnostic and family history codes for Lp(a) elevation during the Centers for Disease Control and Prevention (CDC) September 2017 ICD-10-CM Coordination and Maintenance Committee meeting.⁵⁰ In June 2018, the final ICD-10-CM code addenda for 2019 was released and included the new codes E78.⁴¹ (Elevated Lp[a]) and Z83.430 (Family history of elevated Lp[a]).⁵² After the new codes were approved, both the American Heart Association and the National Lipid Association added recommendations regarding Lp(a) testing to their clinical practice guidelines.^43,52

Practically, these codes standardize billing and payment for legitimate clinical work and laboratory testing. Prior to the addition of Lp(a) elevation as a clinical diagnosis, testing and treatment of Lp(a) elevation was considered experimental and not medically necessary until after a cardiovascular event had already occurred. Services for Lp(a) elevation were therefore not reimbursed by many healthcare organizations and insurance companies. The new ICD-10-CM codes encourage the assessment of Lp(a) both in individuals with early onset major CVD events and in presumably fit, healthy individuals, particularly when there is a family history of Lp(a) elevation. Given that Lp(a) levels do not change significantly over time, the current understanding is that only a single measurement is needed to define the individual risk over a lifetime.^41,42,44,45 As therapies targeting Lp(a) levels evolve, repeated measurements may be indicated to monitor response and direct changes in management. “Elevated Lipoprotein(a)” is the first laboratory testing abnormality that has achieved the status of a clinical diagnosis.

Lp(a) Measurements

There is considerable complexity to the measurement of lipoproteins in blood samples due to heterogeneity in both density and size of particles as illustrated in the Figure.⁵³

For traditional lipids measured in clinical practice, the size and density ranges from small high-density lipoprotein (HDL) through LDLC and intermediate- density lipoprotein (IDL) to the largest least dense particles in the very low-density lipoprotein (VLDL) and chylomicron remnant fractions. Standard lipid profiles consist of mass concentration measurements (mg/dL) of TC, TG, HDLC, and LDLC.⁵³ Non-HDLC (calculated as: TC−HDLC) consists of all cholesterol found in atherogenic lipoproteins, including remnant-C and Lp(a). Until recently, the cholesterol content of Lp(a), corresponding to about 30% of Lp(a) total mass, was included in the TC, non-HDLC and LDLC measurements with no separate reporting by the majority of clinical laboratories.

After > 50 years of research on the structure and biochemistry of Lp(a), the physiology and biological functions of these complex and polymorphic lipoprotein particles are not fully understood. Lp(a) is composed of a lipoprotein particle similar in composition to LDL (protein and lipid), containing 1 molecule of ApoB wrapped around a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface.⁴⁸ The presence of a unique hydrophilic, highly glycosylated protein referred to as apolopoprotienA (apo[a]), covalently attached to ApoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL.⁴⁸ Cholesterol rich ApoB is an important component within many lipoproteins pathogenic for atherosclerosis and CVD.^45,47,53

The apo(a) contributes to the increased density of Lp(a) compared to LDLC with associated reduced binding affinity to the LDL receptor. This reduced receptor binding affinity is a presumed mechanism for the lack of Lp(a) plasma level response to statin therapies, which increase hepatic LDL receptor activity.⁴⁷ Apo(a) evolved from the plasminogen gene through duplication and remodeling and demonstrates extensive heterogeneity in protein size, with > 40 different apo(a) isoforms resulting in > 40 different Lp(a) particle sizes. Size of the apo(a) particle is determined by the number of pleated structures known as kringles. Most people (> 80%) carry 2 different-sized apo(a) isoforms. Plasma Lp(a) level is determined by the net production of apo(a) in each isoform, and the smaller apo(a) isoforms are associated with higher plasma levels of Lp(a).⁴⁵

Given the heterogeneity in Lp(a) molecular weight, which can vary even within individuals, recommendations have been made for reporting results as particle numbers or concentrations (nmol/L or mmol/L) rather than as mass concentration (mg/dL).⁵⁵ However, the majority of the large CVD morbidity and mortality outcomes studies used Lp(a) mass concentration levels in mg/ dL to characterize risk levels.^56,57 There is no standardized method to convert Lp(a) measurements from mg/dL to nmol/L.⁵⁵ Current assays using WHO standardized reagents and controls are reliable for categorizing risk levels.⁵⁸

The European Atherosclerosis Society consensus panel recommended that desirable Lp(a) levels should be below the 80th percentile (< 50 mg/dL or < 125 nmol/L) in patients with intermediate or high CVD risk.⁵⁹ Subsequent epidemiological and Mendelian randomization studies have been performed in general populations with no history of CVD and demonstrated that increased CVD risk can be detected with Lp(a) levels as low as 25 to 30 mg/dL.^56,60-63 In secondary prevention populations with prior CVD and optimal treatment (statins, antiplatelet drugs), recurrent event risk was also increased with elevated Lp(a).^63-66

Using immunoturbidometric assays, Varvel and colleagues reported the prevalence of elevated Lp(a) mass concentration levels (mg/dL) in > 500,000 US patients undergoing clinical evaluations based on data from a referral laboratory of patients.⁵⁸ The mean Lp(a) levels were 34.0 mg/dL with median (interquartile range [IQR]) levels at 17 (7-47) mg/dL and overall range of 0 to 907 mg/dL.⁵⁸ Females had higher Lp(a) levels compared to males but no ethnic or racial breakdown was provided. Lp(a) levels > 30 mg/dL and > 50 mg/dL were present in 35% and 24% of subjects, respectively. Table 1 displays the relationship between various Lp(a) level cut-offs to mean levels of LDLC, estimated LDLC corrected for Lp(a), TC, HDLC, and TG.⁵⁸ The data demonstrate that Lp(a) elevation cannot be inferred from LDLC levels nor from any of the other traditional lipoprotein measures. Patients with high risk Lp(a) levels may have normal LDLC. While Lp(a) thresholds have been identified for stratification of CVD risk, the target levels for risk reduction have not been specifically defined, particularly since therapies are not widely available for reduction of Lp(a). Table 2 provides an overview of clinical lipoprotein measurements that may be reasonable targets for therapeutic interventions and reduction of CVD risk.^44,53,55 In general, existing studies suggest that radical reduction (> 80%) is required to impact long-term outcomes, particularly in individuals with severe disease.^68,69

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk.^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis.^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD.^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction.⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system.⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses.^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events.^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD.⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis.^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210).⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD).⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls.^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL.⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a).⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy.^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a).^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients.⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes.⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a).⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation.⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a).⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a).⁹⁴

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries.⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL).^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations.¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a).^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD.^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years.¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events.^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men.^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a).⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold.¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups.^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans.¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels.^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity.^78,113,115

Lifestyle and Cardiovascular Health

It is noteworthy that the Lp(a) genetic risks can also be modified by lifestyle risk reduction even in the absence of significant blood level reductions. For example, Khera and colleagues constructed a genetic risk profile for CVD that included genes related to Lp(a).¹¹⁶ Subjects with high genetic risk were more likely to experience CVD events compared with subjects with low genetic risk. However, risks for CVD were attenuated by 4 healthy lifestyle factors: current nonsmoker, body mass index < 30, at least weekly physical activity, and a healthy diet. Subjects with high genetic risk and an unhealthy lifestyle (0 or 1 of the 4 healthy lifestyle factors) were the most likely to develop CVD (Hazard ratio [HR], 3.5), but that risk was lower for subjects with healthy (3 or 4 of the 4 healthy lifestyle factors) and intermediate lifestyles (2 of the 4 healthy lifestyle factors) (HR, 1.9 and 2.2, respectively), despite despite high genetic risk for CVD.

While the independent CVD risk associated with elevated Lp(a) does not appear to be responsive to lifestyle risk reduction alone, certainly elevated LDLC and traditional risk factors can increase the overall CVD risk and are worthy of preventive interventions. In particular, inflammation from any source exacerbates CVD risk. Proatherogenic diet, insufficient sleep, lack of exercise, and maladaptive stress responses are other targets for personalized CVD risk reduction. ^28,117 Studies of dietary modifications and other lifestyle factors have shown reduced risk of CVD events, despite lack of reduction in Lp(a) levels.^119,120 It is noteworthy that statin therapy (with or without ezetimibe) fails to impact CAVS progression, likely because statins either raise or have no effect on Lp(a) levels.^92,119

Until recently, there has been no evidence supporting any therapeutic intervention causing clinically meaningful reductions in Lp(a). Table 4 lists major drug classes and their effects on Lp(a) and CVD outcomes; however, a detailed discussion of each of these therapies is beyond the scope of this review. Drugs that reduce Lp(a) by 20-30% have varying effects on CVD outcomes, from no effect^122,123 to a 10% to 20% decrease in CVD events when compared with a placebo.^124,125 Because these drugs also produce substantial reductions in LDLC, it is not possible to determine how much of the beneficial effects are due to reductions in Lp(a).

Lipoprotein apheresis produces profound reductions in Lp(a) of 60 to 80% in very highrisk populations.^69,126 Within-subjects comparisons show up to 80% reductions in CVD events, relative to event rates prior to treatment initiation.^69,127 Early trials of antisense oligonucleotide against apo(a) therapies show potential to produce similar outcomes.^128,129 These treatments may be particularly effective in patients with isolated Lp(a) elevations.

Summary

Lp(a) elevation is a major contributor to cardiovascular disease risk and has been recognized as an ICD-10-CM coded clinical diagnosis, the first laboratory abnormality to be defined a clinical disease in the asymptomatic healthy young individuals. This change addresses currently under- diagnosed CVD risk independent of LDLC reduction strategies. A brief overview of recent guidelines for the clinical use of Lp(a) testing from the American Heart Association^43,151 and the National Lipid Association52 can be found in Table 5. Although drug therapies for lowering Lp(a) levels remain limited, new treatment options are actively being developed.

Many Americans with high Lp(a) have not yet been identified. Expanded one-time screening can inform these patients of their cardiovascular risk and increase their access to early, aggressive lifestyle modification and optimal lipid-lowering therapy. Given the further increased CVD risk factors for military service members and veterans, a case can be made for broader screening and enhanced surveillance of elevated Lp(a) in these presumably healthy and fit individuals as well as management focused on modifiable risk factors.

Acknowledgements

This program initiative was conducted by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. as part of the Integrative Cardiac Health Project at Walter Reed National Military Medical Center (WRNMMC), and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick under Contract Number: W81XWH-16-2-0007. It reflects literature review preparatory work for a research protocol but does not involve an actual research project. The work in this manuscript was supported by the staff of the Integrative Cardiac Health Project (ICHP) with special thanks to Claire Fuller, Elaine Walizer, Dr. Mariam Kashani and the entire health coaching team.

Cardiovascular disease (CVD) remains the leading cause of global mortality. In 2015, 41.5% of the US population had at least 1 form of CVD and CVD accounted for nearly 18 million deaths worldwide.1,2 The major disease categories represented include myocardial infarction (MI), sudden death, strokes, calcific aortic valve stenosis (CAVS), and peripheral vascular disease.^1,2 In terms of health care costs, quality of life, and caregiver burden, the overall impact of disease prevalence continues to rise.^1,3-6 There is an urgent need for more precise and earlier CVD risk assessment to guide lifestyle and therapeutic interventions for prevention of disease progression as well as potential reversal of preclinical disease. Even at a young age, visible coronary atherosclerosis has been found in up to 11% of “healthy” active individuals during autopsies for trauma fatalities.^7,8

The impact of CVD on the US and global populations is profound. In 2011, CVD prevalence was predicted to reach 40% by 2030.9 That estimate was exceeded in 2015, and it is now predicted that by 2035, 45% of the US population will suffer from some form of clinical or preclinical CVD. In 2015, the decadeslong decline in CVD mortality was reversed for the first time since 1969, showing a 1% increase in deaths from CVD.¹ Nearly 300,000 of those using US Department of Veterans Affairs (VA) services were hospitalized for CVD between 2010 and 2014.¹⁰ The annual direct and indirect costs related to CVD in the US are estimated at $329.7 billion, and these costs are predicted to top $1 trillion by 2035.¹ Heart attack, coronary atherosclerosis, and stroke accounted for 3 of the 10 most expensive conditions treated in US hospitals in 2013.¹¹ Globally, the estimate for CVD-related direct and indirect costs was $863 billion in 2010 and may exceed $1 trillion by 2030.¹²

The nature of military service adds additional risk factors, such as posttraumatic stress disorder, depression, sleep disorders and physical trauma which increase CVD morbidity/ mortality in service members, veterans, and their families.^13-16 In addition, living in lowerincome areas (countries or neighborhoods) can increase the risk of both CVD incidence and fatalities, particularly in younger individuals.^17-20 The Military Health System (MHS) and VA are responsible for the care of those individuals who have voluntarily taken on these additional risks through their time in service. This responsibility calls for rapid translation to practice tools and resources that can support interventions to minimize as many modifiable risk factors as possible and improve longterm health. This strategy aligns with the World Health Organization’s (WHO) focus on prevention of disease progression through interventions targeting modifiable risk.^3-6,21-23 The driving force behind the launch of the US Department of Health and Human Services (HHS) Million Hearts program was the goal of preventing 1 million heart attacks and strokes by 2017 with risk reduction through aspirin, blood pressure control, cholesterol management, smoking cessation, sodium reduction, and physical activity.^24,25 While some reductions in CVD events have been documented, the outcomes fell short of the goals set, highlighting both the need and value of continued and expanded efforts for CVD risk reduction.²⁶

More precise assessment of risk factors during preventative care, as well as after a diagnosis of CVD, may improve the timeliness and precision of earlier interventions (both lifestyle and therapeutic) that reduce CVD morbidity and mortality^.27 Personalized or precision medicine approaches take into account differences in socioeconomic, environmental, and lifestyle factors that are potentially reversible, as well as gender, race, and ethnicity.^28-31 Current methods of predicting CVD risk have considerable room for improvement.²⁷ About 40% of patients with newly diagnosed CVD have normal traditional cholesterol profiles, including those whose first cardiac event proves fatal.^29-33 Currently available risk scores (hundreds have been described in the literature) mischaracterize risk in minority populations and women, and have shown deficiencies in identifying preclinical atherosclerosis.^34,35 The failure to recognize preclinical CVD in military personnel during their active duty life cycle results in missed opportunities for improved health and readiness sustainment.

Most CVD risk prediction models incorporate some form of blood lipids. Total cholesterol (TC) is most commonly used in clinical practice, along with high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglycerides (TG).^23,27,36 High LDLC and/or TC are well established as lipid-related CVD risk factors and are incorporated into many CVD risk scoring systems/models described in the literature.²⁷ LDLC reduction is commonly recommended as CVD prevention, but even with optimal statin treatment, there is still considerable residual risk for new and recurrent CVD events.^{28,32,34,35,37-42}

Incorporating novel biomarkers and alternative lipid measurements may improve risk prediction and aid targeted treatment, ultimately reducing CVD events.²⁷ Apolipoprotein B (ApoB) is a major atherogenic component embedded in LDL and VLDL correlating to non-HDLC and may be useful in the setting of triglycerides ≥ 200 mg/d as levels > 130 mg/ dL appear to be risk-enhancing, but measurements may be unreliable.⁴³ According to the 2018 Cholesterol Guidelines, lipoprotein(a) [Lp(a)] elevation also is recognized as a risk-enhancing factor that is particularly implicated when there is a strong family history of premature atherosclerotic CVD or personal history of CVD not explained by major risk factors.⁴³

Lp(a) elevation is a largely underrecognized category of lipid disorder that impacts up to 20% to 30% of the population globally and within the US, although there is considerable variability by geographic location and ethnicity.⁴⁴ Globally, Lp(a) elevation places > 1 billion people at moderate to high risk for CVD.44 Lp(a) has a strong genetic component and is recognized as a distinct and independent risk factor for MI, sudden death, strokes and CAVS. Lp(a) has an extensive body of evidence to support its distinct role both as a causal factor in CVD and as an augmentation to traditional risk factors.^44-48

Lipoproteni(a) Elevation Use For Diagnosis

The importance of Lp(a) elevation as a clinical diagnosis rather than a laboratory abnormality alone was brought forward by the Lipoprotein(a) Foundation. Its founder, Sandra Tremulis, is a survivor of an acute coronary event that occurred when she was 39-years old, despite running marathons and having none of the traditional CVD lifestyle risk factors.⁴⁹ This experience inspired her to create the Lipoprotein(a) Foundation to give a voice to families living with or at risk for CVD due to Lp(a) elevation.

As often happens in the progress of medicine, patients and their families drive change based on their personal experiences with the gaps in standard clinical practice. It was this foundation—not a member of the medical establishment—that submitted the formal request for the addition of new ICD-10-CM diagnostic and family history codes for Lp(a) elevation during the Centers for Disease Control and Prevention (CDC) September 2017 ICD-10-CM Coordination and Maintenance Committee meeting.⁵⁰ In June 2018, the final ICD-10-CM code addenda for 2019 was released and included the new codes E78.⁴¹ (Elevated Lp[a]) and Z83.430 (Family history of elevated Lp[a]).⁵² After the new codes were approved, both the American Heart Association and the National Lipid Association added recommendations regarding Lp(a) testing to their clinical practice guidelines.^43,52

Practically, these codes standardize billing and payment for legitimate clinical work and laboratory testing. Prior to the addition of Lp(a) elevation as a clinical diagnosis, testing and treatment of Lp(a) elevation was considered experimental and not medically necessary until after a cardiovascular event had already occurred. Services for Lp(a) elevation were therefore not reimbursed by many healthcare organizations and insurance companies. The new ICD-10-CM codes encourage the assessment of Lp(a) both in individuals with early onset major CVD events and in presumably fit, healthy individuals, particularly when there is a family history of Lp(a) elevation. Given that Lp(a) levels do not change significantly over time, the current understanding is that only a single measurement is needed to define the individual risk over a lifetime.^41,42,44,45 As therapies targeting Lp(a) levels evolve, repeated measurements may be indicated to monitor response and direct changes in management. “Elevated Lipoprotein(a)” is the first laboratory testing abnormality that has achieved the status of a clinical diagnosis.

Lp(a) Measurements

There is considerable complexity to the measurement of lipoproteins in blood samples due to heterogeneity in both density and size of particles as illustrated in the Figure.⁵³

For traditional lipids measured in clinical practice, the size and density ranges from small high-density lipoprotein (HDL) through LDLC and intermediate- density lipoprotein (IDL) to the largest least dense particles in the very low-density lipoprotein (VLDL) and chylomicron remnant fractions. Standard lipid profiles consist of mass concentration measurements (mg/dL) of TC, TG, HDLC, and LDLC.⁵³ Non-HDLC (calculated as: TC−HDLC) consists of all cholesterol found in atherogenic lipoproteins, including remnant-C and Lp(a). Until recently, the cholesterol content of Lp(a), corresponding to about 30% of Lp(a) total mass, was included in the TC, non-HDLC and LDLC measurements with no separate reporting by the majority of clinical laboratories.

After > 50 years of research on the structure and biochemistry of Lp(a), the physiology and biological functions of these complex and polymorphic lipoprotein particles are not fully understood. Lp(a) is composed of a lipoprotein particle similar in composition to LDL (protein and lipid), containing 1 molecule of ApoB wrapped around a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface.⁴⁸ The presence of a unique hydrophilic, highly glycosylated protein referred to as apolopoprotienA (apo[a]), covalently attached to ApoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL.⁴⁸ Cholesterol rich ApoB is an important component within many lipoproteins pathogenic for atherosclerosis and CVD.^45,47,53

The apo(a) contributes to the increased density of Lp(a) compared to LDLC with associated reduced binding affinity to the LDL receptor. This reduced receptor binding affinity is a presumed mechanism for the lack of Lp(a) plasma level response to statin therapies, which increase hepatic LDL receptor activity.⁴⁷ Apo(a) evolved from the plasminogen gene through duplication and remodeling and demonstrates extensive heterogeneity in protein size, with > 40 different apo(a) isoforms resulting in > 40 different Lp(a) particle sizes. Size of the apo(a) particle is determined by the number of pleated structures known as kringles. Most people (> 80%) carry 2 different-sized apo(a) isoforms. Plasma Lp(a) level is determined by the net production of apo(a) in each isoform, and the smaller apo(a) isoforms are associated with higher plasma levels of Lp(a).⁴⁵

Given the heterogeneity in Lp(a) molecular weight, which can vary even within individuals, recommendations have been made for reporting results as particle numbers or concentrations (nmol/L or mmol/L) rather than as mass concentration (mg/dL).⁵⁵ However, the majority of the large CVD morbidity and mortality outcomes studies used Lp(a) mass concentration levels in mg/ dL to characterize risk levels.^56,57 There is no standardized method to convert Lp(a) measurements from mg/dL to nmol/L.⁵⁵ Current assays using WHO standardized reagents and controls are reliable for categorizing risk levels.⁵⁸

The European Atherosclerosis Society consensus panel recommended that desirable Lp(a) levels should be below the 80th percentile (< 50 mg/dL or < 125 nmol/L) in patients with intermediate or high CVD risk.⁵⁹ Subsequent epidemiological and Mendelian randomization studies have been performed in general populations with no history of CVD and demonstrated that increased CVD risk can be detected with Lp(a) levels as low as 25 to 30 mg/dL.^56,60-63 In secondary prevention populations with prior CVD and optimal treatment (statins, antiplatelet drugs), recurrent event risk was also increased with elevated Lp(a).^63-66

Using immunoturbidometric assays, Varvel and colleagues reported the prevalence of elevated Lp(a) mass concentration levels (mg/dL) in > 500,000 US patients undergoing clinical evaluations based on data from a referral laboratory of patients.⁵⁸ The mean Lp(a) levels were 34.0 mg/dL with median (interquartile range [IQR]) levels at 17 (7-47) mg/dL and overall range of 0 to 907 mg/dL.⁵⁸ Females had higher Lp(a) levels compared to males but no ethnic or racial breakdown was provided. Lp(a) levels > 30 mg/dL and > 50 mg/dL were present in 35% and 24% of subjects, respectively. Table 1 displays the relationship between various Lp(a) level cut-offs to mean levels of LDLC, estimated LDLC corrected for Lp(a), TC, HDLC, and TG.⁵⁸ The data demonstrate that Lp(a) elevation cannot be inferred from LDLC levels nor from any of the other traditional lipoprotein measures. Patients with high risk Lp(a) levels may have normal LDLC. While Lp(a) thresholds have been identified for stratification of CVD risk, the target levels for risk reduction have not been specifically defined, particularly since therapies are not widely available for reduction of Lp(a). Table 2 provides an overview of clinical lipoprotein measurements that may be reasonable targets for therapeutic interventions and reduction of CVD risk.^44,53,55 In general, existing studies suggest that radical reduction (> 80%) is required to impact long-term outcomes, particularly in individuals with severe disease.^68,69

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk.^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis.^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD.^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction.⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system.⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses.^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events.^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD.⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis.^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210).⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD).⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls.^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL.⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a).⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy.^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a).^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients.⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes.⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a).⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation.⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a).⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a).⁹⁴

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries.⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL).^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations.¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a).^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD.^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years.¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events.^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men.^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a).⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold.¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups.^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans.¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels.^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity.^78,113,115

Lifestyle and Cardiovascular Health

It is noteworthy that the Lp(a) genetic risks can also be modified by lifestyle risk reduction even in the absence of significant blood level reductions. For example, Khera and colleagues constructed a genetic risk profile for CVD that included genes related to Lp(a).¹¹⁶ Subjects with high genetic risk were more likely to experience CVD events compared with subjects with low genetic risk. However, risks for CVD were attenuated by 4 healthy lifestyle factors: current nonsmoker, body mass index < 30, at least weekly physical activity, and a healthy diet. Subjects with high genetic risk and an unhealthy lifestyle (0 or 1 of the 4 healthy lifestyle factors) were the most likely to develop CVD (Hazard ratio [HR], 3.5), but that risk was lower for subjects with healthy (3 or 4 of the 4 healthy lifestyle factors) and intermediate lifestyles (2 of the 4 healthy lifestyle factors) (HR, 1.9 and 2.2, respectively), despite despite high genetic risk for CVD.

While the independent CVD risk associated with elevated Lp(a) does not appear to be responsive to lifestyle risk reduction alone, certainly elevated LDLC and traditional risk factors can increase the overall CVD risk and are worthy of preventive interventions. In particular, inflammation from any source exacerbates CVD risk. Proatherogenic diet, insufficient sleep, lack of exercise, and maladaptive stress responses are other targets for personalized CVD risk reduction. ^28,117 Studies of dietary modifications and other lifestyle factors have shown reduced risk of CVD events, despite lack of reduction in Lp(a) levels.^119,120 It is noteworthy that statin therapy (with or without ezetimibe) fails to impact CAVS progression, likely because statins either raise or have no effect on Lp(a) levels.^92,119

Until recently, there has been no evidence supporting any therapeutic intervention causing clinically meaningful reductions in Lp(a). Table 4 lists major drug classes and their effects on Lp(a) and CVD outcomes; however, a detailed discussion of each of these therapies is beyond the scope of this review. Drugs that reduce Lp(a) by 20-30% have varying effects on CVD outcomes, from no effect^122,123 to a 10% to 20% decrease in CVD events when compared with a placebo.^124,125 Because these drugs also produce substantial reductions in LDLC, it is not possible to determine how much of the beneficial effects are due to reductions in Lp(a).

Lipoprotein apheresis produces profound reductions in Lp(a) of 60 to 80% in very highrisk populations.^69,126 Within-subjects comparisons show up to 80% reductions in CVD events, relative to event rates prior to treatment initiation.^69,127 Early trials of antisense oligonucleotide against apo(a) therapies show potential to produce similar outcomes.^128,129 These treatments may be particularly effective in patients with isolated Lp(a) elevations.

Summary

Lp(a) elevation is a major contributor to cardiovascular disease risk and has been recognized as an ICD-10-CM coded clinical diagnosis, the first laboratory abnormality to be defined a clinical disease in the asymptomatic healthy young individuals. This change addresses currently under- diagnosed CVD risk independent of LDLC reduction strategies. A brief overview of recent guidelines for the clinical use of Lp(a) testing from the American Heart Association^43,151 and the National Lipid Association52 can be found in Table 5. Although drug therapies for lowering Lp(a) levels remain limited, new treatment options are actively being developed.

Many Americans with high Lp(a) have not yet been identified. Expanded one-time screening can inform these patients of their cardiovascular risk and increase their access to early, aggressive lifestyle modification and optimal lipid-lowering therapy. Given the further increased CVD risk factors for military service members and veterans, a case can be made for broader screening and enhanced surveillance of elevated Lp(a) in these presumably healthy and fit individuals as well as management focused on modifiable risk factors.

Acknowledgements

This program initiative was conducted by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. as part of the Integrative Cardiac Health Project at Walter Reed National Military Medical Center (WRNMMC), and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick under Contract Number: W81XWH-16-2-0007. It reflects literature review preparatory work for a research protocol but does not involve an actual research project. The work in this manuscript was supported by the staff of the Integrative Cardiac Health Project (ICHP) with special thanks to Claire Fuller, Elaine Walizer, Dr. Mariam Kashani and the entire health coaching team.

The US Department of Veterans Affairs (VA) remains the largest integrated health care system in the US serving 9 million veterans. Two recent studies that compared 30-day mortality and readmission rates between VA and non-VA hospitals among older men with acute myocardial infarction (AMI), and heart failure (HF). The studies found that hospitalization at VA hospitals was associated with lower risk-standardized 30-day all-cause mortality rates for MI and HF when compared with hospitalization at non-VA hospitals.^1,2

However, it is unknown whether the delivery of cardiovascular care is optimized in the VA system. For example, in comparisons between generalist-led hospitalized care for MI and HF, several studies have demonstrated that cardiology-led care has been associated with lower rates of mortality.^3-5 Although data on the types of cardiac technology and use of cardiac procedures were described previously, we have not found detailed information on the types of inpatient cardiology services provided at VA medical centers nationwide.^1,6,7 To develop further improvements in delivery of cardiovascular care within the VA, a better understanding of the types of resources that are currently available within the VA system must be made available. In this article, we present results of a national survey of cardiology services at VA facilities.

Methods

From February to March of 2017, we conducted a comprehensive nation-wide survey of all VA facilities to quantify the availability of cardiology services, excluding cardiothoracic surgical services. The survey questions are listed in the Appendix. The chief of medicine and the chief of cardiology were each e-mailed 3 times at every facility. If no response was received from a facility, we e-mailed the chief of staff 3 times. If there still was no response, the remaining facilities were contacted by phone and study authors (PE and WB) spoke to individuals directly regarding the structure of cardiology services at a facility. Responses were categorized by facility level of complexity. Complexity designation was determined by the VA Central Office (VACO)—level 1 facilities represent the most complex and level 3 facilities are the least complex. VACO also divides facility complexity into sublevels, for example level 1A facilities generally are associated with academic medical centers and provide the highest levels (tertiary or quaternary) of care.⁸

Results were coded according to a predetermined rubric for how cardiology services are structured (admitting service, consult service, inpatient, outpatient, other) and for how they were staffed (attending only, house staff, or advanced practice providers (APPs). After the first wave of surveys, 2 additional questions were added to the survey tool; these asked about employed vs contracted cardiologist and use of APPs. The results were tabulated and simple percentages calculated to express the prevalence of each structure and staffing model.

The study was reviewed and approved by the University of Utah/Salt Lake City VA Medical Center joint institutional review board and all authors completed human subjects research training.

Results

Study authors initially identified all 168 VA medical center facilities operating in 2017. Initial polling revealed that multiple facilities either were substations or had agreements for cardiology services from larger facilities, with 1 facility having 2 campuses with different levels of service at each. After adjusting for these nuances, the total number of potential respondents was 139. We obtained a response from 122 of the 139 facilities for an overall survey completion rate of 88%. Response rates varied by complexity level (Table 1). The survey received responses from all Level 1A and 1B facilities, 96% from Level 1C facilities; 83% (20/24) from level 2 facilities, and 62% (18/30) from level 3 facilities. (Please note that in the reference document providing detailed descriptions of the VA level of complexity has different numbers for each facility type given that there has been reassignments of the levels since our survey was completed.)⁸

We were specifically interested in inpatient cardiology services and whether facilities provided only consult services or inpatient services led by a cardiology attending. Having inpatient services does not exclude the availability of consult-liaison services (Table 2).

Higher complexity facilities (1A and 1B) were more likely to have dedicated, cardiology-led inpatient services, while lower complexity facilities relied on a cardiology consult service. Two-thirds of Level 3 facilities did not have inpatient cardiology services available.

Dedicated cardiovascular care unit (CCU) teams were the most common inpatient service provided, present in more than half of all Level 1 facilities and 83% of Level 1A facilities (Table 3). Cardiology-led floor teams were available in 45% and 33% of level 1A and 1B facilities, respectively, but were much less common in Level 1C and Levels 2 and 3 facilities (4%, 10%, 0%, respectively). Only 31% of Level 1 facilities had both a CCU team and a cardiology-led inpatient floor team. Inpatient consulting cardiologists were commonly available at Levels 1 and 2 facilities; however, only 33% of Level 3 facilities had inpatient consulting cardiologists.

Housestaff-managed inpatient services, teams consisting of, but not limited to, medical residents in training, led by a cardiology attending were present in 73% of Level 1 facilities. Interestingly, Level 1B facilities were more likely to have housestaff-led services than were Level 1A facilities (90% and 80% respectively). Inpatient advanced heart failure services were less common and available only in Level 1 facilities. We did not survey the specific details of the other (eg, led by a noncardiology attending physician) models of inpatient cardiology care provided.

Cardiac catheterization (including interventional cardiology and electrophysiology [EP]) services, varied considerably. Ninety percent of Level 1A facilities offered interventional services, compared with only 52% of Level 1C facilities offered interventions. EP services were divided into simple (device only) and complex (ablations). As noted, complex EP services were more common in more complex facilities; for example, 10% of Level 2 facilities offered device placement but none had advanced EP services.

Outpatient services were widely available. Most facilities offered outpatient consultative cardiology services, ranging from 95% (Level 1) to 89% (Level 3) and outpatient cardiology continuity clinics 99% (Level 1) to 72% (Level 3).

Regardless of level of complexity, > 80% of facilities employed cardiologists. Many also used contract cardiologists. No facility utilized only contracted cardiologists. Use of nurse practitioners (NPs) and physician assistants (PAs) to assist with managing inpatient services was relatively common, with 61% of Level 1 facilities using such services.

Discussion

Studies of patient outcomes for various conditions, including cardiac conditions, in the 1990s found that when compared with non-VA health-care systems, patient outcomes in the VA were less favorable.⁹ During the late 1990s, the VA embraced quality and safety initiatives that have continued to the present time.^9,10 Recent studies have found that, in most (but not all) cases, VA patient outcomes are as good as, and in many cases better, than are non-VA patient outcomes.^1,10,11 The exact changes that have improved care are not clear, though studies of other health care systems have considered variation in services and costs in relationship to morbidity and mortality outcomes.^12-14 In the context of better patient outcomes in VA hospitals, the present study provides insight into the cardiology services available at VA facilities throughout the nation.

Limitations

While this study provides background information that may be useful in comparing cardiology services between VA and non-VA systems, drawing causal relationships may not be warranted. For example, while the literature generally supports the concept of inpatient cardiology services led by an attending cardiologist, a substantial numbers of VA inpatient facilities have not yet adopted this model.^4-6 Even among more complex, level 1 facilities, we found that only 31% offered both an inpatient CCU and floor team service led by an attending cardiologist physician. Thus, 69% of Level 1 facilities reported caring for patients with a primary cardiology problem through a noncardiology admitting services (with access to a cardiology consultation service). Additional studies should be conducted that would evaluate patient outcomes in relationship to the types of services available at a given VA medical center. Patient outcomes in relationship to service provision between the VA and non-VA health care systems also are warranted.

This study is limited by its reliance on self-reporting. Although we believe that we reached respondents who were qualified to complete the survey, the accuracy of reporting was not independently validated. Further, we asked questions about the most frequent models of cardiology care but may not have captured more novel methods. In trying to keep the survey time to < 2 minutes, we did not explore other details of cardiology services, such as the availability of a dedicated pharmacist, nor more advanced procedures such as transcatheter aortic valve replacement. Additionally, the present study is a snapshot of cardiology services for a given period, and, as noted above, did not look at patient outcomes. Further research is needed to determine which service provided is most beneficial or feasible in improving patient outcomes, which includes examining the various models of inpatient cardiology-led services for optimal care delivery.

Conclusion

Cardiology services were widely available throughout the VA system. However, the types of services available varied considerably. Predictably, facilities that were more complex generally had more advanced services available. Providing a general overview of how cardiovascular care is being delivered currently across VA systems helps to identify areas for optimization within VA facilities of various complexities with initiatives such as implementation of cardiology-led inpatient services, which may be beneficial in improving patient care outcomes as demonstrated previously in other large healthcare systems.

Acknowledgments
This material is the result of work supported with resources and use of the facilities at the George E. Wahlen Salt Lake City VA Medical Center. We are grateful to all of those who responded to our survey, and the support of the facility leadership. We are thankful for Tasia M. Nash and Tammy Jackson who helped to organize the data, and to Leigh Eleazer for her help in the manuscript preparation and formatting. 

The US Department of Veterans Affairs (VA) remains the largest integrated health care system in the US serving 9 million veterans. Two recent studies that compared 30-day mortality and readmission rates between VA and non-VA hospitals among older men with acute myocardial infarction (AMI), and heart failure (HF). The studies found that hospitalization at VA hospitals was associated with lower risk-standardized 30-day all-cause mortality rates for MI and HF when compared with hospitalization at non-VA hospitals.^1,2

However, it is unknown whether the delivery of cardiovascular care is optimized in the VA system. For example, in comparisons between generalist-led hospitalized care for MI and HF, several studies have demonstrated that cardiology-led care has been associated with lower rates of mortality.^3-5 Although data on the types of cardiac technology and use of cardiac procedures were described previously, we have not found detailed information on the types of inpatient cardiology services provided at VA medical centers nationwide.^1,6,7 To develop further improvements in delivery of cardiovascular care within the VA, a better understanding of the types of resources that are currently available within the VA system must be made available. In this article, we present results of a national survey of cardiology services at VA facilities.

Methods

From February to March of 2017, we conducted a comprehensive nation-wide survey of all VA facilities to quantify the availability of cardiology services, excluding cardiothoracic surgical services. The survey questions are listed in the Appendix. The chief of medicine and the chief of cardiology were each e-mailed 3 times at every facility. If no response was received from a facility, we e-mailed the chief of staff 3 times. If there still was no response, the remaining facilities were contacted by phone and study authors (PE and WB) spoke to individuals directly regarding the structure of cardiology services at a facility. Responses were categorized by facility level of complexity. Complexity designation was determined by the VA Central Office (VACO)—level 1 facilities represent the most complex and level 3 facilities are the least complex. VACO also divides facility complexity into sublevels, for example level 1A facilities generally are associated with academic medical centers and provide the highest levels (tertiary or quaternary) of care.⁸

Results were coded according to a predetermined rubric for how cardiology services are structured (admitting service, consult service, inpatient, outpatient, other) and for how they were staffed (attending only, house staff, or advanced practice providers (APPs). After the first wave of surveys, 2 additional questions were added to the survey tool; these asked about employed vs contracted cardiologist and use of APPs. The results were tabulated and simple percentages calculated to express the prevalence of each structure and staffing model.

The study was reviewed and approved by the University of Utah/Salt Lake City VA Medical Center joint institutional review board and all authors completed human subjects research training.

Results

Study authors initially identified all 168 VA medical center facilities operating in 2017. Initial polling revealed that multiple facilities either were substations or had agreements for cardiology services from larger facilities, with 1 facility having 2 campuses with different levels of service at each. After adjusting for these nuances, the total number of potential respondents was 139. We obtained a response from 122 of the 139 facilities for an overall survey completion rate of 88%. Response rates varied by complexity level (Table 1). The survey received responses from all Level 1A and 1B facilities, 96% from Level 1C facilities; 83% (20/24) from level 2 facilities, and 62% (18/30) from level 3 facilities. (Please note that in the reference document providing detailed descriptions of the VA level of complexity has different numbers for each facility type given that there has been reassignments of the levels since our survey was completed.)⁸

We were specifically interested in inpatient cardiology services and whether facilities provided only consult services or inpatient services led by a cardiology attending. Having inpatient services does not exclude the availability of consult-liaison services (Table 2).

Higher complexity facilities (1A and 1B) were more likely to have dedicated, cardiology-led inpatient services, while lower complexity facilities relied on a cardiology consult service. Two-thirds of Level 3 facilities did not have inpatient cardiology services available.

Dedicated cardiovascular care unit (CCU) teams were the most common inpatient service provided, present in more than half of all Level 1 facilities and 83% of Level 1A facilities (Table 3). Cardiology-led floor teams were available in 45% and 33% of level 1A and 1B facilities, respectively, but were much less common in Level 1C and Levels 2 and 3 facilities (4%, 10%, 0%, respectively). Only 31% of Level 1 facilities had both a CCU team and a cardiology-led inpatient floor team. Inpatient consulting cardiologists were commonly available at Levels 1 and 2 facilities; however, only 33% of Level 3 facilities had inpatient consulting cardiologists.

Housestaff-managed inpatient services, teams consisting of, but not limited to, medical residents in training, led by a cardiology attending were present in 73% of Level 1 facilities. Interestingly, Level 1B facilities were more likely to have housestaff-led services than were Level 1A facilities (90% and 80% respectively). Inpatient advanced heart failure services were less common and available only in Level 1 facilities. We did not survey the specific details of the other (eg, led by a noncardiology attending physician) models of inpatient cardiology care provided.

Cardiac catheterization (including interventional cardiology and electrophysiology [EP]) services, varied considerably. Ninety percent of Level 1A facilities offered interventional services, compared with only 52% of Level 1C facilities offered interventions. EP services were divided into simple (device only) and complex (ablations). As noted, complex EP services were more common in more complex facilities; for example, 10% of Level 2 facilities offered device placement but none had advanced EP services.

Outpatient services were widely available. Most facilities offered outpatient consultative cardiology services, ranging from 95% (Level 1) to 89% (Level 3) and outpatient cardiology continuity clinics 99% (Level 1) to 72% (Level 3).

Regardless of level of complexity, > 80% of facilities employed cardiologists. Many also used contract cardiologists. No facility utilized only contracted cardiologists. Use of nurse practitioners (NPs) and physician assistants (PAs) to assist with managing inpatient services was relatively common, with 61% of Level 1 facilities using such services.

Discussion

Studies of patient outcomes for various conditions, including cardiac conditions, in the 1990s found that when compared with non-VA health-care systems, patient outcomes in the VA were less favorable.⁹ During the late 1990s, the VA embraced quality and safety initiatives that have continued to the present time.^9,10 Recent studies have found that, in most (but not all) cases, VA patient outcomes are as good as, and in many cases better, than are non-VA patient outcomes.^1,10,11 The exact changes that have improved care are not clear, though studies of other health care systems have considered variation in services and costs in relationship to morbidity and mortality outcomes.^12-14 In the context of better patient outcomes in VA hospitals, the present study provides insight into the cardiology services available at VA facilities throughout the nation.

Limitations

While this study provides background information that may be useful in comparing cardiology services between VA and non-VA systems, drawing causal relationships may not be warranted. For example, while the literature generally supports the concept of inpatient cardiology services led by an attending cardiologist, a substantial numbers of VA inpatient facilities have not yet adopted this model.^4-6 Even among more complex, level 1 facilities, we found that only 31% offered both an inpatient CCU and floor team service led by an attending cardiologist physician. Thus, 69% of Level 1 facilities reported caring for patients with a primary cardiology problem through a noncardiology admitting services (with access to a cardiology consultation service). Additional studies should be conducted that would evaluate patient outcomes in relationship to the types of services available at a given VA medical center. Patient outcomes in relationship to service provision between the VA and non-VA health care systems also are warranted.

This study is limited by its reliance on self-reporting. Although we believe that we reached respondents who were qualified to complete the survey, the accuracy of reporting was not independently validated. Further, we asked questions about the most frequent models of cardiology care but may not have captured more novel methods. In trying to keep the survey time to < 2 minutes, we did not explore other details of cardiology services, such as the availability of a dedicated pharmacist, nor more advanced procedures such as transcatheter aortic valve replacement. Additionally, the present study is a snapshot of cardiology services for a given period, and, as noted above, did not look at patient outcomes. Further research is needed to determine which service provided is most beneficial or feasible in improving patient outcomes, which includes examining the various models of inpatient cardiology-led services for optimal care delivery.

Conclusion

Cardiology services were widely available throughout the VA system. However, the types of services available varied considerably. Predictably, facilities that were more complex generally had more advanced services available. Providing a general overview of how cardiovascular care is being delivered currently across VA systems helps to identify areas for optimization within VA facilities of various complexities with initiatives such as implementation of cardiology-led inpatient services, which may be beneficial in improving patient care outcomes as demonstrated previously in other large healthcare systems.

Acknowledgments
This material is the result of work supported with resources and use of the facilities at the George E. Wahlen Salt Lake City VA Medical Center. We are grateful to all of those who responded to our survey, and the support of the facility leadership. We are thankful for Tasia M. Nash and Tammy Jackson who helped to organize the data, and to Leigh Eleazer for her help in the manuscript preparation and formatting. 

The US Department of Veterans Affairs (VA) remains the largest integrated health care system in the US serving 9 million veterans. Two recent studies that compared 30-day mortality and readmission rates between VA and non-VA hospitals among older men with acute myocardial infarction (AMI), and heart failure (HF). The studies found that hospitalization at VA hospitals was associated with lower risk-standardized 30-day all-cause mortality rates for MI and HF when compared with hospitalization at non-VA hospitals.^1,2

However, it is unknown whether the delivery of cardiovascular care is optimized in the VA system. For example, in comparisons between generalist-led hospitalized care for MI and HF, several studies have demonstrated that cardiology-led care has been associated with lower rates of mortality.^3-5 Although data on the types of cardiac technology and use of cardiac procedures were described previously, we have not found detailed information on the types of inpatient cardiology services provided at VA medical centers nationwide.^1,6,7 To develop further improvements in delivery of cardiovascular care within the VA, a better understanding of the types of resources that are currently available within the VA system must be made available. In this article, we present results of a national survey of cardiology services at VA facilities.

Methods

From February to March of 2017, we conducted a comprehensive nation-wide survey of all VA facilities to quantify the availability of cardiology services, excluding cardiothoracic surgical services. The survey questions are listed in the Appendix. The chief of medicine and the chief of cardiology were each e-mailed 3 times at every facility. If no response was received from a facility, we e-mailed the chief of staff 3 times. If there still was no response, the remaining facilities were contacted by phone and study authors (PE and WB) spoke to individuals directly regarding the structure of cardiology services at a facility. Responses were categorized by facility level of complexity. Complexity designation was determined by the VA Central Office (VACO)—level 1 facilities represent the most complex and level 3 facilities are the least complex. VACO also divides facility complexity into sublevels, for example level 1A facilities generally are associated with academic medical centers and provide the highest levels (tertiary or quaternary) of care.⁸

Results were coded according to a predetermined rubric for how cardiology services are structured (admitting service, consult service, inpatient, outpatient, other) and for how they were staffed (attending only, house staff, or advanced practice providers (APPs). After the first wave of surveys, 2 additional questions were added to the survey tool; these asked about employed vs contracted cardiologist and use of APPs. The results were tabulated and simple percentages calculated to express the prevalence of each structure and staffing model.

The study was reviewed and approved by the University of Utah/Salt Lake City VA Medical Center joint institutional review board and all authors completed human subjects research training.

Results

Study authors initially identified all 168 VA medical center facilities operating in 2017. Initial polling revealed that multiple facilities either were substations or had agreements for cardiology services from larger facilities, with 1 facility having 2 campuses with different levels of service at each. After adjusting for these nuances, the total number of potential respondents was 139. We obtained a response from 122 of the 139 facilities for an overall survey completion rate of 88%. Response rates varied by complexity level (Table 1). The survey received responses from all Level 1A and 1B facilities, 96% from Level 1C facilities; 83% (20/24) from level 2 facilities, and 62% (18/30) from level 3 facilities. (Please note that in the reference document providing detailed descriptions of the VA level of complexity has different numbers for each facility type given that there has been reassignments of the levels since our survey was completed.)⁸

We were specifically interested in inpatient cardiology services and whether facilities provided only consult services or inpatient services led by a cardiology attending. Having inpatient services does not exclude the availability of consult-liaison services (Table 2).

Higher complexity facilities (1A and 1B) were more likely to have dedicated, cardiology-led inpatient services, while lower complexity facilities relied on a cardiology consult service. Two-thirds of Level 3 facilities did not have inpatient cardiology services available.

Dedicated cardiovascular care unit (CCU) teams were the most common inpatient service provided, present in more than half of all Level 1 facilities and 83% of Level 1A facilities (Table 3). Cardiology-led floor teams were available in 45% and 33% of level 1A and 1B facilities, respectively, but were much less common in Level 1C and Levels 2 and 3 facilities (4%, 10%, 0%, respectively). Only 31% of Level 1 facilities had both a CCU team and a cardiology-led inpatient floor team. Inpatient consulting cardiologists were commonly available at Levels 1 and 2 facilities; however, only 33% of Level 3 facilities had inpatient consulting cardiologists.

Housestaff-managed inpatient services, teams consisting of, but not limited to, medical residents in training, led by a cardiology attending were present in 73% of Level 1 facilities. Interestingly, Level 1B facilities were more likely to have housestaff-led services than were Level 1A facilities (90% and 80% respectively). Inpatient advanced heart failure services were less common and available only in Level 1 facilities. We did not survey the specific details of the other (eg, led by a noncardiology attending physician) models of inpatient cardiology care provided.

Cardiac catheterization (including interventional cardiology and electrophysiology [EP]) services, varied considerably. Ninety percent of Level 1A facilities offered interventional services, compared with only 52% of Level 1C facilities offered interventions. EP services were divided into simple (device only) and complex (ablations). As noted, complex EP services were more common in more complex facilities; for example, 10% of Level 2 facilities offered device placement but none had advanced EP services.

Outpatient services were widely available. Most facilities offered outpatient consultative cardiology services, ranging from 95% (Level 1) to 89% (Level 3) and outpatient cardiology continuity clinics 99% (Level 1) to 72% (Level 3).

Regardless of level of complexity, > 80% of facilities employed cardiologists. Many also used contract cardiologists. No facility utilized only contracted cardiologists. Use of nurse practitioners (NPs) and physician assistants (PAs) to assist with managing inpatient services was relatively common, with 61% of Level 1 facilities using such services.

Discussion

Studies of patient outcomes for various conditions, including cardiac conditions, in the 1990s found that when compared with non-VA health-care systems, patient outcomes in the VA were less favorable.⁹ During the late 1990s, the VA embraced quality and safety initiatives that have continued to the present time.^9,10 Recent studies have found that, in most (but not all) cases, VA patient outcomes are as good as, and in many cases better, than are non-VA patient outcomes.^1,10,11 The exact changes that have improved care are not clear, though studies of other health care systems have considered variation in services and costs in relationship to morbidity and mortality outcomes.^12-14 In the context of better patient outcomes in VA hospitals, the present study provides insight into the cardiology services available at VA facilities throughout the nation.

Limitations

While this study provides background information that may be useful in comparing cardiology services between VA and non-VA systems, drawing causal relationships may not be warranted. For example, while the literature generally supports the concept of inpatient cardiology services led by an attending cardiologist, a substantial numbers of VA inpatient facilities have not yet adopted this model.^4-6 Even among more complex, level 1 facilities, we found that only 31% offered both an inpatient CCU and floor team service led by an attending cardiologist physician. Thus, 69% of Level 1 facilities reported caring for patients with a primary cardiology problem through a noncardiology admitting services (with access to a cardiology consultation service). Additional studies should be conducted that would evaluate patient outcomes in relationship to the types of services available at a given VA medical center. Patient outcomes in relationship to service provision between the VA and non-VA health care systems also are warranted.

This study is limited by its reliance on self-reporting. Although we believe that we reached respondents who were qualified to complete the survey, the accuracy of reporting was not independently validated. Further, we asked questions about the most frequent models of cardiology care but may not have captured more novel methods. In trying to keep the survey time to < 2 minutes, we did not explore other details of cardiology services, such as the availability of a dedicated pharmacist, nor more advanced procedures such as transcatheter aortic valve replacement. Additionally, the present study is a snapshot of cardiology services for a given period, and, as noted above, did not look at patient outcomes. Further research is needed to determine which service provided is most beneficial or feasible in improving patient outcomes, which includes examining the various models of inpatient cardiology-led services for optimal care delivery.

Conclusion

Cardiology services were widely available throughout the VA system. However, the types of services available varied considerably. Predictably, facilities that were more complex generally had more advanced services available. Providing a general overview of how cardiovascular care is being delivered currently across VA systems helps to identify areas for optimization within VA facilities of various complexities with initiatives such as implementation of cardiology-led inpatient services, which may be beneficial in improving patient care outcomes as demonstrated previously in other large healthcare systems.

Acknowledgments
This material is the result of work supported with resources and use of the facilities at the George E. Wahlen Salt Lake City VA Medical Center. We are grateful to all of those who responded to our survey, and the support of the facility leadership. We are thankful for Tasia M. Nash and Tammy Jackson who helped to organize the data, and to Leigh Eleazer for her help in the manuscript preparation and formatting. 

The decision to perform stress testing in the evaluation of chest pain is often based on the pretest likelihood of coronary artery disease (CAD).^1-7 Cardiac risk scores, which incorporate smoking status, blood pressure, diabetes mellitus, and cholesterol levels, also may provide further risk stratification.^8-11 Assuming that the prevalence of CAD increases with age, young adults could be deemed low risk, not warranting cardiac screening.¹²

Professional society guidelines from the American College of Cardiology/American Heart Association and American College of Physicians^4,5 recommend stress testing as the initial diagnostic test for CAD in symptomatic patients; additionally, the guidelines also suggest that screening stress tests may confer primary prevention benefit in intermediate-risk asymptomatic patients.^9,13 Exercise treadmill testing is considered the initial modality of choice, given its technical ease and lower cost, compared with stress echocardiography.¹⁴

Previously published reports have shown the limited use of stress testing to screen young asymptomatic adults.^15-17 Because this patient demographic typically has a low pretest likelihood of CAD, positive stress tests are often false-positive results.^7,18 The consequence of false-positive testing may be unnecessary additional cardiac testing, potentially leading to more patient harm than benefit.^18,19 For active-duty service members, false-positive testing also has the potential to affect worldwide deployability and/or sea duty status while further risk stratification is performed; as a result, mission readiness may be impacted.Although the number of clinic visits for chest pain has declined, there has been a discordant increase in the rates of stress testing in the US.^20-22 Additionally, the rate of stress testing among young adults, specifically in the 25- to 34-year age group, has increased in recent years. Given the rising use of stress tests in the young patient population, the clinical use of stress testing needs to be reassessed.

Although much of the literature has already demonstrated the low value of stress testing in young asymptomatic adults, no data currently exist regarding its outpatient use in evaluating young symptomatic patients. The military represents a predominantly young cross-section of the general population suitable for exploring this topic. Using a cohort of active-duty service members, we aimed to determine the use of outpatient stress testing in evaluating young patients with atypical chest pain.

Methods

The US Department of Defense (DoD) Military Health System Database Repository (MDR) and Comprehensive Ambulatory Professional Encounter Record (CAPER) were the data sources for this study. The MDR contains continually updated, longitudinal electronic medical records (EMRs) for nearly 1.4 million active-duty service members and is composed of administrative, medical, pharmacy, and clinical data. The Naval Medical Center Portsmouth (NMCP) Institutional Review Board approved this study.

Study Cohort

We performed chart reviews of service members aged 18 to 35 years who received cardiac stress testing at NMCP, an academic tertiary care center, within 30 days after an office visit for atypical chest pain between October 1, 2010, and September 30, 2015. Atypical chest pain was defined as any outpatient claim with ICD-9 code, 786.5x, in the primary diagnosis field (Table 1).⁴  

Demographics and cardiac risk factors (ie, hypertension, hyperlipidemia, diabetes mellitus, and smoking status) were assessed prior to index chest pain evaluations and defined via ICD-9 codes within outpatient records.

Cardiac Testing Outcomes

Patients were initially categorized by the results of baseline electrocardiograms (ECG) and index stress tests (ie, exercise treadmill or stress echocardiography, exercise or Lexiscan myocardial perfusion imaging, dobutamine stress echocardiography). Positive tests were defined as those having electrical or structural ischemic changes. Chronotropic changes were infrequent and nonpathologic and were not counted. Patient endpoints were either additional cardiac testing or negative index stress test without additional testing.

Statistical Analysis

The agreement between both baseline ECG and index stress test as well as index stress test and additional cardiac testing were analyzed using McNemar test and matched-pair odds ratios (ORs) with corresponding 95% CIs. Analyses were stratified by demographics and cardiac risk factors to assess for potential confounding. Analyses were performed using SAS version 9.4 (Cary, NC).

Results

A total of 1,036 patients were evaluated for atypical chest pain and had index stress testing between October 1, 2010 and September 30, 2015. The study cohort was 69% male with a mean (SD) age of 27.3 (4.7) years. More than 60% of the cohort was older than aged > 25 years. 

In the initial testing cohort, exercise treadmill test (59.3%) and exercise echocardiogram (37.1%) were the most common stress testing modalities. The mean (SD) metabolic equivalents (METS) achieved among individuals who performed exercise stress testing was 13.9 (2.8). There were 65 patients who had a positive baseline ECG/negative index stress test, 958 patients had a negative ECG/negative index test, and 8 patients had a negative ECG/positive index test. 

There were 102 patients (10%) who performed additional cardiac testing. Among this subgroup, 13 patients (1.3%) had additional testing for further evaluation of a positive index stress test (Table 4) and 89 patients (8.6%) had testing for continuing atypical chest pain despite a negative index stress test. 

Coronary computed tomography angiography (CCTA) demonstrated nonobstructive CAD in 3 patients (0.3%) within the study cohort. There was no obstructive CAD identified in our cohort. Two patients had negative left heart catheterizations (LHC). One of these patients had a negative LHC and a negative Lexiscan after a CCTA showed CAD; all 3 of these additional tests were performed for evaluation of continued chest pain despite negative index stress testing. The positive predictive value of cardiac stress testing for nonobstructive CAD in this low-risk population was 15.4% (2 of 13). Stratification by demographics, CAD risk factors, and cardiac test results revealed no presence of confounding factors during analyses.

Discussion

In this retrospective, observational study of 1,036 young patients with atypical chest pain who had stress testing, there was relatively strong agreement between baseline ECG and index stress test results. Individuals also were 8 times more likely to have positive baseline ECGs and negative stress testing than having the opposite finding. Additional cardiac testing similarly demonstrated congruency with index stress testing and showed the propensity for false-positive stress tests. Further testing with CCTA demonstrated minimal nonobstructive CAD in < 1% of the study cohort and 2 LHC were negative. Despite the low prevalence of CAD and apparent low diagnostic use of stress testing in our young cohort, symptomatic service members still require stress testing to determine deployment suitability.

The low yield of outpatient stress testing in our young population is rooted in Bayes’ theorem, which highlights the importance of pretest likelihood in the diagnosis of CAD.^7,23 Because our cohort had a low prevalence and low pretest likelihood of CAD, positive index stress tests were often false-positive results and consequently did not increase the posttest likelihood of CAD, resulting in low positive predictive value. Additional cardiac testing had limited clinical value in our cohort. The 3 cases of nonobstructive CAD were unlikely to be pathologic given the minimal degree of observed stenosis and the 2 LHC did not require revascularization. These results are similar to those shown by Christman and colleagues and Mudrick and colleagues, which highlighted the low yield of additional cardiac studies and low rate of revascularization among symptomatic patients without known cardiac disease, respectively.^18,19

This is the first study, to our knowledge, to quantitatively demonstrate the low use of outpatient stress testing for young adults with atypical chest pain. Previous studies that assessed stress testing for young patients with chest pain in acute settings such as emergency departments and chest pain observation units, similarly demonstrated minimal yield of routine diagnostic testing.^23,24 This further highlights the premise that outpatient and even emergent-setting stress testing in low cardiac risk individuals may be of limited value and not always necessary.

Limitations

There were several study limitations. As a single-center, cross-sectional review, we may not be able to extrapolate our findings to the general population. However, given the low prevalence of CAD in young adults, stress testing would likely have limited value regardless of the sample distribution; so it may be possible to extend our findings beyond our cohort. Also, neither baseline ECG nor index stress test (irrespective of modality) could be given a diagnostic value in predicting ischemia alone; doing so would require comparison with the gold standard—heart catheterization. Although referral bias has been associated with diagnostic performance of stress testing, we did not adjust for this phenomenon.²⁵ Given the higher average metabolic equivalents achieved in our cohort, this potential bias likely did not affect diagnostic performance.

Conclusion

There was low diagnostic use of outpatient stress testing and additional cardiac testing for CAD among young patients with atypical chest pain. The limited value of cardiac stress testing is likely a function of the low CAD prevalence within this population, suggesting that younger patients may not necessarily require stress testing for chest pain evaluations as long as pretest likelihood is low. Despite our results, we maintain that the decision to perform stress testing should still be guided by clinical judgment, but perhaps our findings may alleviate physicians’ concerns over the urgency of when to refer low-risk patients for testing. Although we are cautious in inferring our findings to the general population, the similarity it shares with those from other published reports may suggest its applicability beyond our study cohort.

The decision to perform stress testing in the evaluation of chest pain is often based on the pretest likelihood of coronary artery disease (CAD).^1-7 Cardiac risk scores, which incorporate smoking status, blood pressure, diabetes mellitus, and cholesterol levels, also may provide further risk stratification.^8-11 Assuming that the prevalence of CAD increases with age, young adults could be deemed low risk, not warranting cardiac screening.¹²

Professional society guidelines from the American College of Cardiology/American Heart Association and American College of Physicians^4,5 recommend stress testing as the initial diagnostic test for CAD in symptomatic patients; additionally, the guidelines also suggest that screening stress tests may confer primary prevention benefit in intermediate-risk asymptomatic patients.^9,13 Exercise treadmill testing is considered the initial modality of choice, given its technical ease and lower cost, compared with stress echocardiography.¹⁴

Previously published reports have shown the limited use of stress testing to screen young asymptomatic adults.^15-17 Because this patient demographic typically has a low pretest likelihood of CAD, positive stress tests are often false-positive results.^7,18 The consequence of false-positive testing may be unnecessary additional cardiac testing, potentially leading to more patient harm than benefit.^18,19 For active-duty service members, false-positive testing also has the potential to affect worldwide deployability and/or sea duty status while further risk stratification is performed; as a result, mission readiness may be impacted.Although the number of clinic visits for chest pain has declined, there has been a discordant increase in the rates of stress testing in the US.^20-22 Additionally, the rate of stress testing among young adults, specifically in the 25- to 34-year age group, has increased in recent years. Given the rising use of stress tests in the young patient population, the clinical use of stress testing needs to be reassessed.

Although much of the literature has already demonstrated the low value of stress testing in young asymptomatic adults, no data currently exist regarding its outpatient use in evaluating young symptomatic patients. The military represents a predominantly young cross-section of the general population suitable for exploring this topic. Using a cohort of active-duty service members, we aimed to determine the use of outpatient stress testing in evaluating young patients with atypical chest pain.

Methods

The US Department of Defense (DoD) Military Health System Database Repository (MDR) and Comprehensive Ambulatory Professional Encounter Record (CAPER) were the data sources for this study. The MDR contains continually updated, longitudinal electronic medical records (EMRs) for nearly 1.4 million active-duty service members and is composed of administrative, medical, pharmacy, and clinical data. The Naval Medical Center Portsmouth (NMCP) Institutional Review Board approved this study.

Study Cohort

We performed chart reviews of service members aged 18 to 35 years who received cardiac stress testing at NMCP, an academic tertiary care center, within 30 days after an office visit for atypical chest pain between October 1, 2010, and September 30, 2015. Atypical chest pain was defined as any outpatient claim with ICD-9 code, 786.5x, in the primary diagnosis field (Table 1).⁴  

Demographics and cardiac risk factors (ie, hypertension, hyperlipidemia, diabetes mellitus, and smoking status) were assessed prior to index chest pain evaluations and defined via ICD-9 codes within outpatient records.

Cardiac Testing Outcomes

Patients were initially categorized by the results of baseline electrocardiograms (ECG) and index stress tests (ie, exercise treadmill or stress echocardiography, exercise or Lexiscan myocardial perfusion imaging, dobutamine stress echocardiography). Positive tests were defined as those having electrical or structural ischemic changes. Chronotropic changes were infrequent and nonpathologic and were not counted. Patient endpoints were either additional cardiac testing or negative index stress test without additional testing.

Statistical Analysis

The agreement between both baseline ECG and index stress test as well as index stress test and additional cardiac testing were analyzed using McNemar test and matched-pair odds ratios (ORs) with corresponding 95% CIs. Analyses were stratified by demographics and cardiac risk factors to assess for potential confounding. Analyses were performed using SAS version 9.4 (Cary, NC).

Results

A total of 1,036 patients were evaluated for atypical chest pain and had index stress testing between October 1, 2010 and September 30, 2015. The study cohort was 69% male with a mean (SD) age of 27.3 (4.7) years. More than 60% of the cohort was older than aged > 25 years. 

In the initial testing cohort, exercise treadmill test (59.3%) and exercise echocardiogram (37.1%) were the most common stress testing modalities. The mean (SD) metabolic equivalents (METS) achieved among individuals who performed exercise stress testing was 13.9 (2.8). There were 65 patients who had a positive baseline ECG/negative index stress test, 958 patients had a negative ECG/negative index test, and 8 patients had a negative ECG/positive index test. 

There were 102 patients (10%) who performed additional cardiac testing. Among this subgroup, 13 patients (1.3%) had additional testing for further evaluation of a positive index stress test (Table 4) and 89 patients (8.6%) had testing for continuing atypical chest pain despite a negative index stress test. 

Coronary computed tomography angiography (CCTA) demonstrated nonobstructive CAD in 3 patients (0.3%) within the study cohort. There was no obstructive CAD identified in our cohort. Two patients had negative left heart catheterizations (LHC). One of these patients had a negative LHC and a negative Lexiscan after a CCTA showed CAD; all 3 of these additional tests were performed for evaluation of continued chest pain despite negative index stress testing. The positive predictive value of cardiac stress testing for nonobstructive CAD in this low-risk population was 15.4% (2 of 13). Stratification by demographics, CAD risk factors, and cardiac test results revealed no presence of confounding factors during analyses.

Discussion

In this retrospective, observational study of 1,036 young patients with atypical chest pain who had stress testing, there was relatively strong agreement between baseline ECG and index stress test results. Individuals also were 8 times more likely to have positive baseline ECGs and negative stress testing than having the opposite finding. Additional cardiac testing similarly demonstrated congruency with index stress testing and showed the propensity for false-positive stress tests. Further testing with CCTA demonstrated minimal nonobstructive CAD in < 1% of the study cohort and 2 LHC were negative. Despite the low prevalence of CAD and apparent low diagnostic use of stress testing in our young cohort, symptomatic service members still require stress testing to determine deployment suitability.

The low yield of outpatient stress testing in our young population is rooted in Bayes’ theorem, which highlights the importance of pretest likelihood in the diagnosis of CAD.^7,23 Because our cohort had a low prevalence and low pretest likelihood of CAD, positive index stress tests were often false-positive results and consequently did not increase the posttest likelihood of CAD, resulting in low positive predictive value. Additional cardiac testing had limited clinical value in our cohort. The 3 cases of nonobstructive CAD were unlikely to be pathologic given the minimal degree of observed stenosis and the 2 LHC did not require revascularization. These results are similar to those shown by Christman and colleagues and Mudrick and colleagues, which highlighted the low yield of additional cardiac studies and low rate of revascularization among symptomatic patients without known cardiac disease, respectively.^18,19

This is the first study, to our knowledge, to quantitatively demonstrate the low use of outpatient stress testing for young adults with atypical chest pain. Previous studies that assessed stress testing for young patients with chest pain in acute settings such as emergency departments and chest pain observation units, similarly demonstrated minimal yield of routine diagnostic testing.^23,24 This further highlights the premise that outpatient and even emergent-setting stress testing in low cardiac risk individuals may be of limited value and not always necessary.

Limitations

There were several study limitations. As a single-center, cross-sectional review, we may not be able to extrapolate our findings to the general population. However, given the low prevalence of CAD in young adults, stress testing would likely have limited value regardless of the sample distribution; so it may be possible to extend our findings beyond our cohort. Also, neither baseline ECG nor index stress test (irrespective of modality) could be given a diagnostic value in predicting ischemia alone; doing so would require comparison with the gold standard—heart catheterization. Although referral bias has been associated with diagnostic performance of stress testing, we did not adjust for this phenomenon.²⁵ Given the higher average metabolic equivalents achieved in our cohort, this potential bias likely did not affect diagnostic performance.

Conclusion

There was low diagnostic use of outpatient stress testing and additional cardiac testing for CAD among young patients with atypical chest pain. The limited value of cardiac stress testing is likely a function of the low CAD prevalence within this population, suggesting that younger patients may not necessarily require stress testing for chest pain evaluations as long as pretest likelihood is low. Despite our results, we maintain that the decision to perform stress testing should still be guided by clinical judgment, but perhaps our findings may alleviate physicians’ concerns over the urgency of when to refer low-risk patients for testing. Although we are cautious in inferring our findings to the general population, the similarity it shares with those from other published reports may suggest its applicability beyond our study cohort.

The decision to perform stress testing in the evaluation of chest pain is often based on the pretest likelihood of coronary artery disease (CAD).^1-7 Cardiac risk scores, which incorporate smoking status, blood pressure, diabetes mellitus, and cholesterol levels, also may provide further risk stratification.^8-11 Assuming that the prevalence of CAD increases with age, young adults could be deemed low risk, not warranting cardiac screening.¹²

Professional society guidelines from the American College of Cardiology/American Heart Association and American College of Physicians^4,5 recommend stress testing as the initial diagnostic test for CAD in symptomatic patients; additionally, the guidelines also suggest that screening stress tests may confer primary prevention benefit in intermediate-risk asymptomatic patients.^9,13 Exercise treadmill testing is considered the initial modality of choice, given its technical ease and lower cost, compared with stress echocardiography.¹⁴

Previously published reports have shown the limited use of stress testing to screen young asymptomatic adults.^15-17 Because this patient demographic typically has a low pretest likelihood of CAD, positive stress tests are often false-positive results.^7,18 The consequence of false-positive testing may be unnecessary additional cardiac testing, potentially leading to more patient harm than benefit.^18,19 For active-duty service members, false-positive testing also has the potential to affect worldwide deployability and/or sea duty status while further risk stratification is performed; as a result, mission readiness may be impacted.Although the number of clinic visits for chest pain has declined, there has been a discordant increase in the rates of stress testing in the US.^20-22 Additionally, the rate of stress testing among young adults, specifically in the 25- to 34-year age group, has increased in recent years. Given the rising use of stress tests in the young patient population, the clinical use of stress testing needs to be reassessed.

Although much of the literature has already demonstrated the low value of stress testing in young asymptomatic adults, no data currently exist regarding its outpatient use in evaluating young symptomatic patients. The military represents a predominantly young cross-section of the general population suitable for exploring this topic. Using a cohort of active-duty service members, we aimed to determine the use of outpatient stress testing in evaluating young patients with atypical chest pain.

Methods

The US Department of Defense (DoD) Military Health System Database Repository (MDR) and Comprehensive Ambulatory Professional Encounter Record (CAPER) were the data sources for this study. The MDR contains continually updated, longitudinal electronic medical records (EMRs) for nearly 1.4 million active-duty service members and is composed of administrative, medical, pharmacy, and clinical data. The Naval Medical Center Portsmouth (NMCP) Institutional Review Board approved this study.

Study Cohort

We performed chart reviews of service members aged 18 to 35 years who received cardiac stress testing at NMCP, an academic tertiary care center, within 30 days after an office visit for atypical chest pain between October 1, 2010, and September 30, 2015. Atypical chest pain was defined as any outpatient claim with ICD-9 code, 786.5x, in the primary diagnosis field (Table 1).⁴  

Demographics and cardiac risk factors (ie, hypertension, hyperlipidemia, diabetes mellitus, and smoking status) were assessed prior to index chest pain evaluations and defined via ICD-9 codes within outpatient records.

Cardiac Testing Outcomes

Patients were initially categorized by the results of baseline electrocardiograms (ECG) and index stress tests (ie, exercise treadmill or stress echocardiography, exercise or Lexiscan myocardial perfusion imaging, dobutamine stress echocardiography). Positive tests were defined as those having electrical or structural ischemic changes. Chronotropic changes were infrequent and nonpathologic and were not counted. Patient endpoints were either additional cardiac testing or negative index stress test without additional testing.

Statistical Analysis

The agreement between both baseline ECG and index stress test as well as index stress test and additional cardiac testing were analyzed using McNemar test and matched-pair odds ratios (ORs) with corresponding 95% CIs. Analyses were stratified by demographics and cardiac risk factors to assess for potential confounding. Analyses were performed using SAS version 9.4 (Cary, NC).

Results

A total of 1,036 patients were evaluated for atypical chest pain and had index stress testing between October 1, 2010 and September 30, 2015. The study cohort was 69% male with a mean (SD) age of 27.3 (4.7) years. More than 60% of the cohort was older than aged > 25 years. 

In the initial testing cohort, exercise treadmill test (59.3%) and exercise echocardiogram (37.1%) were the most common stress testing modalities. The mean (SD) metabolic equivalents (METS) achieved among individuals who performed exercise stress testing was 13.9 (2.8). There were 65 patients who had a positive baseline ECG/negative index stress test, 958 patients had a negative ECG/negative index test, and 8 patients had a negative ECG/positive index test. 

There were 102 patients (10%) who performed additional cardiac testing. Among this subgroup, 13 patients (1.3%) had additional testing for further evaluation of a positive index stress test (Table 4) and 89 patients (8.6%) had testing for continuing atypical chest pain despite a negative index stress test. 

Coronary computed tomography angiography (CCTA) demonstrated nonobstructive CAD in 3 patients (0.3%) within the study cohort. There was no obstructive CAD identified in our cohort. Two patients had negative left heart catheterizations (LHC). One of these patients had a negative LHC and a negative Lexiscan after a CCTA showed CAD; all 3 of these additional tests were performed for evaluation of continued chest pain despite negative index stress testing. The positive predictive value of cardiac stress testing for nonobstructive CAD in this low-risk population was 15.4% (2 of 13). Stratification by demographics, CAD risk factors, and cardiac test results revealed no presence of confounding factors during analyses.

Discussion

In this retrospective, observational study of 1,036 young patients with atypical chest pain who had stress testing, there was relatively strong agreement between baseline ECG and index stress test results. Individuals also were 8 times more likely to have positive baseline ECGs and negative stress testing than having the opposite finding. Additional cardiac testing similarly demonstrated congruency with index stress testing and showed the propensity for false-positive stress tests. Further testing with CCTA demonstrated minimal nonobstructive CAD in < 1% of the study cohort and 2 LHC were negative. Despite the low prevalence of CAD and apparent low diagnostic use of stress testing in our young cohort, symptomatic service members still require stress testing to determine deployment suitability.

The low yield of outpatient stress testing in our young population is rooted in Bayes’ theorem, which highlights the importance of pretest likelihood in the diagnosis of CAD.^7,23 Because our cohort had a low prevalence and low pretest likelihood of CAD, positive index stress tests were often false-positive results and consequently did not increase the posttest likelihood of CAD, resulting in low positive predictive value. Additional cardiac testing had limited clinical value in our cohort. The 3 cases of nonobstructive CAD were unlikely to be pathologic given the minimal degree of observed stenosis and the 2 LHC did not require revascularization. These results are similar to those shown by Christman and colleagues and Mudrick and colleagues, which highlighted the low yield of additional cardiac studies and low rate of revascularization among symptomatic patients without known cardiac disease, respectively.^18,19

This is the first study, to our knowledge, to quantitatively demonstrate the low use of outpatient stress testing for young adults with atypical chest pain. Previous studies that assessed stress testing for young patients with chest pain in acute settings such as emergency departments and chest pain observation units, similarly demonstrated minimal yield of routine diagnostic testing.^23,24 This further highlights the premise that outpatient and even emergent-setting stress testing in low cardiac risk individuals may be of limited value and not always necessary.

Limitations

There were several study limitations. As a single-center, cross-sectional review, we may not be able to extrapolate our findings to the general population. However, given the low prevalence of CAD in young adults, stress testing would likely have limited value regardless of the sample distribution; so it may be possible to extend our findings beyond our cohort. Also, neither baseline ECG nor index stress test (irrespective of modality) could be given a diagnostic value in predicting ischemia alone; doing so would require comparison with the gold standard—heart catheterization. Although referral bias has been associated with diagnostic performance of stress testing, we did not adjust for this phenomenon.²⁵ Given the higher average metabolic equivalents achieved in our cohort, this potential bias likely did not affect diagnostic performance.

Conclusion

There was low diagnostic use of outpatient stress testing and additional cardiac testing for CAD among young patients with atypical chest pain. The limited value of cardiac stress testing is likely a function of the low CAD prevalence within this population, suggesting that younger patients may not necessarily require stress testing for chest pain evaluations as long as pretest likelihood is low. Despite our results, we maintain that the decision to perform stress testing should still be guided by clinical judgment, but perhaps our findings may alleviate physicians’ concerns over the urgency of when to refer low-risk patients for testing. Although we are cautious in inferring our findings to the general population, the similarity it shares with those from other published reports may suggest its applicability beyond our study cohort.

Background: Identifying paroxysmal atrial fibrillation (AFib) as the etiology of a transient ischemic attack (TIA) or stroke has implications for treatment as well as secondary prevention. Currently, there is not a universal, practical way to help determine which patients would benefit from prolonged cardiac monitoring to establish the diagnosis of AFib.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Background: Identifying paroxysmal atrial fibrillation (AFib) as the etiology of a transient ischemic attack (TIA) or stroke has implications for treatment as well as secondary prevention. Currently, there is not a universal, practical way to help determine which patients would benefit from prolonged cardiac monitoring to establish the diagnosis of AFib.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Background: Identifying paroxysmal atrial fibrillation (AFib) as the etiology of a transient ischemic attack (TIA) or stroke has implications for treatment as well as secondary prevention. Currently, there is not a universal, practical way to help determine which patients would benefit from prolonged cardiac monitoring to establish the diagnosis of AFib.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Click here to access November 2019 Quality Improvement in Cardiovascular and Diabetes Care

Table of Contents

• Research News
• Open Clinical Trials for American Indians With Diabetes Mellitus
• Program Process Change to Improve Completion of Foot Exams and Amputation Risk Assessments for Veterans with Diabetes
• An Intervention to Address Obesity in Patients with Diabetes
• Lipoprotein(a) Elevation: A New Diagnostic Code with Relevance to Service Members and Veterans
• A National Survey of Veterans Affairs Medical Centers’ Cardiology Services

Click here to access November 2019 Quality Improvement in Cardiovascular and Diabetes Care

Table of Contents

• Research News
• Open Clinical Trials for American Indians With Diabetes Mellitus
• Program Process Change to Improve Completion of Foot Exams and Amputation Risk Assessments for Veterans with Diabetes
• An Intervention to Address Obesity in Patients with Diabetes
• Lipoprotein(a) Elevation: A New Diagnostic Code with Relevance to Service Members and Veterans
• A National Survey of Veterans Affairs Medical Centers’ Cardiology Services

Click here to access November 2019 Quality Improvement in Cardiovascular and Diabetes Care

Table of Contents

• Research News
• Open Clinical Trials for American Indians With Diabetes Mellitus
• Program Process Change to Improve Completion of Foot Exams and Amputation Risk Assessments for Veterans with Diabetes
• An Intervention to Address Obesity in Patients with Diabetes
• Lipoprotein(a) Elevation: A New Diagnostic Code with Relevance to Service Members and Veterans
• A National Survey of Veterans Affairs Medical Centers’ Cardiology Services