Higher baseline cardiorespiratory fitness (CRF) is associated with better outcomes after atrial fibrillation (AFib) ablation, according to new research.

In a single-center, retrospective cohort study, patients with the highest level of baseline CRF had significantly lower rates of arrhythmia recurrence and death than did patients with lower levels of CRF.

“It is stunning how just a simple measure, in this case walking on a treadmill, can predict whether atrial fibrillation ablation will be a successful endeavor or if it will fail,” senior author Wael A. Jaber, MD, professor of medicine, Cleveland Clinic, said in an interview.

“We found that ablation was not successful in most patients who had poor functional class and, conversely, that it was successful in most patients who were in tip-top shape when they walked on the treadmill. Our results can help clinicians inform patients about what they can expect after the procedure, depending on the baseline fitness level,” Dr. Jaber said.

The study was published online Aug. 2 in Heart Rhythm.

Several studies have shown a reduction in AFib incidence among individuals who report a physically active lifestyle, but the extent to which baseline CRF influences arrhythmia rates after AFib ablation is unknown, the authors note.

For the study, Dr. Jaber and colleagues analyzed results in 591 consecutive patients (mean age, 66.5 years; 75% male) with symptomatic paroxysmal or persistent AFib who underwent de novo AFib ablation at their institution. Only patients who had undergone an exercise stress test in the 12 months before AFib ablation (average, 4.5 months) were included.

Age- and sex-specific predicted metabolic equivalents (METs) were calculated using the St. James model for women and the Veterans Affairs referral model for men. The number of METs achieved was then divided by the predicted METs, and the patients were categorized into low (<85% predicted; n = 152), adequate (85%-100% predicted; n = 115), and high (>100% predicted; n = 324) CRF groups. Functional capacity was characterized as poor in 56 patients (9.5%), fair in 94 (16.0%), average in 225 (38.1%), good in 169 (28.6%), and high in 47 (8.0%).

During a mean follow-up of 32 months, arrhythmia recurrence was observed in 79% of patients in the low-CRF group, 54% of patients in the adequate-CRF group, and 27.5% of patients in the high-CRF group (P < .0001). Rates of repeat arrhythmia-related hospitalization, repeat rhythm-control procedures, and the need for ongoing antiarrhythmic therapy (ATT) were significantly lower in the high-CRF group. Specifically, ATT was stopped in 56% of patients in the high-CRF group, compared with 24% in the adequate-CRF group and 11% in the low-CRF group (P < .0001). Rehospitalization for arrhythmia was required in 18.5%, 38.0%, and 60.5% of cases, respectively, and repeat direct-current cardioversion or ablation was performed in 26.0%, 49.0%, and 65.0%, respectively (P < .0001 for both).

Death occurred in 11% of the low-CRF group, compared with 4% in the adequate-CRF group and 2.5% in the high-CRF group. Most (70%) of the deaths were caused by cardiovascular events, including heart failure, cardiac arrest, and coronary artery disease. The most common cause of noncardiac death was respiratory failure (13%), followed by sepsis (10%), malignancy (3%), and complications of Parkinson’s disease (3%).

“Although there was a statistically significant association between higher CRF and lower mortality in this cohort, the findings are to be viewed through the prism of a small sample size and relatively low death rate,” the authors wrote.


 

Don’t “overpromise” results

“The important message for clinicians is that when, you are discussing what to expect after atrial fibrillation ablation with your patients, do not overpromise the results. You can inform them that the success of the procedure depends more on how they perform on the baseline exercise test, and less on the ablation itself,” Dr. Jaber said.

Clinicians might want to consider advising their patients to become more active and increase their fitness level before undergoing the procedure, but whether doing so will improve outcomes is still unknown.

“This is what we don’t know. It makes sense. Hopefully, our results will encourage people to be more active before they arrive here for the procedure,” he said. “Our study is retrospective and is hypothesis generating, but we are planning a prospective study where patients will be referred to cardiac rehab prior to having ablation to try to improve their functional class to see if this will improve outcomes.”

Survival of the fittest

In an accompanying editorial commentary, Eric Black-Maier, MD, and Jonathan P. Piccini Sr, MD, from Duke University Medical Center, Durham, N.C., wrote that the findings have “important implications for clinical practice and raise important additional questions.”

They note that catheter ablation as a first-line rhythm-control strategy, per current recommendations, “seems reasonable” in individuals with high baseline cardiorespiratory fitness, but that the benefit is less clear for patients with poor baseline CRF and uncontrolled risk factors.

“Significant limitations in functional status may be at least partially attributable to uncontrolled [AFib], and patients with limited exercise capacity may stand to gain most from successful catheter ablation,” the editorialists wrote.

“Furthermore, because shorter time from [AFib] diagnosis to catheter ablation has been associated with improved outcomes, the decision to postpone ablation in favor of lifestyle modification is not without potential adverse consequences,” they added.

Dr. Black-Maier and Dr. Piccini agree with the need for additional prospective randomized clinical trials to confirm that exercise training to improve cardiorespiratory fitness before AFib ablation is practical and effective for reducing arrhythmia recurrence.

“Over the past 50-plus years, our understanding of cardiorespiratory fitness, exercise capacity, and arrhythmia occurrence in patients with [AFib] continues to evolve,” the editorialists concluded. Data from the study “clearly demonstrate that arrhythmia-free survival is indeed survival of the fittest. Time will tell if exercise training and improvements in cardiorespiratory fitness can change outcomes after ablation.”

The study was sponsored by the Cleveland Clinic. Dr. Jaber and Dr. Black-Maier report no relevant financial relationships. Dr. Piccini receives grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serves as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, MyoKardia, Sanofi, Philips, and UpToDate.
 

A version of this story originally appeared on Medscape.com.

Higher baseline cardiorespiratory fitness (CRF) is associated with better outcomes after atrial fibrillation (AFib) ablation, according to new research.

In a single-center, retrospective cohort study, patients with the highest level of baseline CRF had significantly lower rates of arrhythmia recurrence and death than did patients with lower levels of CRF.

“It is stunning how just a simple measure, in this case walking on a treadmill, can predict whether atrial fibrillation ablation will be a successful endeavor or if it will fail,” senior author Wael A. Jaber, MD, professor of medicine, Cleveland Clinic, said in an interview.

“We found that ablation was not successful in most patients who had poor functional class and, conversely, that it was successful in most patients who were in tip-top shape when they walked on the treadmill. Our results can help clinicians inform patients about what they can expect after the procedure, depending on the baseline fitness level,” Dr. Jaber said.

The study was published online Aug. 2 in Heart Rhythm.

Several studies have shown a reduction in AFib incidence among individuals who report a physically active lifestyle, but the extent to which baseline CRF influences arrhythmia rates after AFib ablation is unknown, the authors note.

For the study, Dr. Jaber and colleagues analyzed results in 591 consecutive patients (mean age, 66.5 years; 75% male) with symptomatic paroxysmal or persistent AFib who underwent de novo AFib ablation at their institution. Only patients who had undergone an exercise stress test in the 12 months before AFib ablation (average, 4.5 months) were included.

Age- and sex-specific predicted metabolic equivalents (METs) were calculated using the St. James model for women and the Veterans Affairs referral model for men. The number of METs achieved was then divided by the predicted METs, and the patients were categorized into low (<85% predicted; n = 152), adequate (85%-100% predicted; n = 115), and high (>100% predicted; n = 324) CRF groups. Functional capacity was characterized as poor in 56 patients (9.5%), fair in 94 (16.0%), average in 225 (38.1%), good in 169 (28.6%), and high in 47 (8.0%).

During a mean follow-up of 32 months, arrhythmia recurrence was observed in 79% of patients in the low-CRF group, 54% of patients in the adequate-CRF group, and 27.5% of patients in the high-CRF group (P < .0001). Rates of repeat arrhythmia-related hospitalization, repeat rhythm-control procedures, and the need for ongoing antiarrhythmic therapy (ATT) were significantly lower in the high-CRF group. Specifically, ATT was stopped in 56% of patients in the high-CRF group, compared with 24% in the adequate-CRF group and 11% in the low-CRF group (P < .0001). Rehospitalization for arrhythmia was required in 18.5%, 38.0%, and 60.5% of cases, respectively, and repeat direct-current cardioversion or ablation was performed in 26.0%, 49.0%, and 65.0%, respectively (P < .0001 for both).

Death occurred in 11% of the low-CRF group, compared with 4% in the adequate-CRF group and 2.5% in the high-CRF group. Most (70%) of the deaths were caused by cardiovascular events, including heart failure, cardiac arrest, and coronary artery disease. The most common cause of noncardiac death was respiratory failure (13%), followed by sepsis (10%), malignancy (3%), and complications of Parkinson’s disease (3%).

“Although there was a statistically significant association between higher CRF and lower mortality in this cohort, the findings are to be viewed through the prism of a small sample size and relatively low death rate,” the authors wrote.


 

Don’t “overpromise” results

“The important message for clinicians is that when, you are discussing what to expect after atrial fibrillation ablation with your patients, do not overpromise the results. You can inform them that the success of the procedure depends more on how they perform on the baseline exercise test, and less on the ablation itself,” Dr. Jaber said.

Clinicians might want to consider advising their patients to become more active and increase their fitness level before undergoing the procedure, but whether doing so will improve outcomes is still unknown.

“This is what we don’t know. It makes sense. Hopefully, our results will encourage people to be more active before they arrive here for the procedure,” he said. “Our study is retrospective and is hypothesis generating, but we are planning a prospective study where patients will be referred to cardiac rehab prior to having ablation to try to improve their functional class to see if this will improve outcomes.”

Survival of the fittest

In an accompanying editorial commentary, Eric Black-Maier, MD, and Jonathan P. Piccini Sr, MD, from Duke University Medical Center, Durham, N.C., wrote that the findings have “important implications for clinical practice and raise important additional questions.”

They note that catheter ablation as a first-line rhythm-control strategy, per current recommendations, “seems reasonable” in individuals with high baseline cardiorespiratory fitness, but that the benefit is less clear for patients with poor baseline CRF and uncontrolled risk factors.

“Significant limitations in functional status may be at least partially attributable to uncontrolled [AFib], and patients with limited exercise capacity may stand to gain most from successful catheter ablation,” the editorialists wrote.

“Furthermore, because shorter time from [AFib] diagnosis to catheter ablation has been associated with improved outcomes, the decision to postpone ablation in favor of lifestyle modification is not without potential adverse consequences,” they added.

Dr. Black-Maier and Dr. Piccini agree with the need for additional prospective randomized clinical trials to confirm that exercise training to improve cardiorespiratory fitness before AFib ablation is practical and effective for reducing arrhythmia recurrence.

“Over the past 50-plus years, our understanding of cardiorespiratory fitness, exercise capacity, and arrhythmia occurrence in patients with [AFib] continues to evolve,” the editorialists concluded. Data from the study “clearly demonstrate that arrhythmia-free survival is indeed survival of the fittest. Time will tell if exercise training and improvements in cardiorespiratory fitness can change outcomes after ablation.”

The study was sponsored by the Cleveland Clinic. Dr. Jaber and Dr. Black-Maier report no relevant financial relationships. Dr. Piccini receives grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serves as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, MyoKardia, Sanofi, Philips, and UpToDate.
 

A version of this story originally appeared on Medscape.com.

Higher baseline cardiorespiratory fitness (CRF) is associated with better outcomes after atrial fibrillation (AFib) ablation, according to new research.

In a single-center, retrospective cohort study, patients with the highest level of baseline CRF had significantly lower rates of arrhythmia recurrence and death than did patients with lower levels of CRF.

“It is stunning how just a simple measure, in this case walking on a treadmill, can predict whether atrial fibrillation ablation will be a successful endeavor or if it will fail,” senior author Wael A. Jaber, MD, professor of medicine, Cleveland Clinic, said in an interview.

“We found that ablation was not successful in most patients who had poor functional class and, conversely, that it was successful in most patients who were in tip-top shape when they walked on the treadmill. Our results can help clinicians inform patients about what they can expect after the procedure, depending on the baseline fitness level,” Dr. Jaber said.

The study was published online Aug. 2 in Heart Rhythm.

Several studies have shown a reduction in AFib incidence among individuals who report a physically active lifestyle, but the extent to which baseline CRF influences arrhythmia rates after AFib ablation is unknown, the authors note.

For the study, Dr. Jaber and colleagues analyzed results in 591 consecutive patients (mean age, 66.5 years; 75% male) with symptomatic paroxysmal or persistent AFib who underwent de novo AFib ablation at their institution. Only patients who had undergone an exercise stress test in the 12 months before AFib ablation (average, 4.5 months) were included.

Age- and sex-specific predicted metabolic equivalents (METs) were calculated using the St. James model for women and the Veterans Affairs referral model for men. The number of METs achieved was then divided by the predicted METs, and the patients were categorized into low (<85% predicted; n = 152), adequate (85%-100% predicted; n = 115), and high (>100% predicted; n = 324) CRF groups. Functional capacity was characterized as poor in 56 patients (9.5%), fair in 94 (16.0%), average in 225 (38.1%), good in 169 (28.6%), and high in 47 (8.0%).

During a mean follow-up of 32 months, arrhythmia recurrence was observed in 79% of patients in the low-CRF group, 54% of patients in the adequate-CRF group, and 27.5% of patients in the high-CRF group (P < .0001). Rates of repeat arrhythmia-related hospitalization, repeat rhythm-control procedures, and the need for ongoing antiarrhythmic therapy (ATT) were significantly lower in the high-CRF group. Specifically, ATT was stopped in 56% of patients in the high-CRF group, compared with 24% in the adequate-CRF group and 11% in the low-CRF group (P < .0001). Rehospitalization for arrhythmia was required in 18.5%, 38.0%, and 60.5% of cases, respectively, and repeat direct-current cardioversion or ablation was performed in 26.0%, 49.0%, and 65.0%, respectively (P < .0001 for both).

Death occurred in 11% of the low-CRF group, compared with 4% in the adequate-CRF group and 2.5% in the high-CRF group. Most (70%) of the deaths were caused by cardiovascular events, including heart failure, cardiac arrest, and coronary artery disease. The most common cause of noncardiac death was respiratory failure (13%), followed by sepsis (10%), malignancy (3%), and complications of Parkinson’s disease (3%).

“Although there was a statistically significant association between higher CRF and lower mortality in this cohort, the findings are to be viewed through the prism of a small sample size and relatively low death rate,” the authors wrote.


 

Don’t “overpromise” results

“The important message for clinicians is that when, you are discussing what to expect after atrial fibrillation ablation with your patients, do not overpromise the results. You can inform them that the success of the procedure depends more on how they perform on the baseline exercise test, and less on the ablation itself,” Dr. Jaber said.

Clinicians might want to consider advising their patients to become more active and increase their fitness level before undergoing the procedure, but whether doing so will improve outcomes is still unknown.

“This is what we don’t know. It makes sense. Hopefully, our results will encourage people to be more active before they arrive here for the procedure,” he said. “Our study is retrospective and is hypothesis generating, but we are planning a prospective study where patients will be referred to cardiac rehab prior to having ablation to try to improve their functional class to see if this will improve outcomes.”

Survival of the fittest

In an accompanying editorial commentary, Eric Black-Maier, MD, and Jonathan P. Piccini Sr, MD, from Duke University Medical Center, Durham, N.C., wrote that the findings have “important implications for clinical practice and raise important additional questions.”

They note that catheter ablation as a first-line rhythm-control strategy, per current recommendations, “seems reasonable” in individuals with high baseline cardiorespiratory fitness, but that the benefit is less clear for patients with poor baseline CRF and uncontrolled risk factors.

“Significant limitations in functional status may be at least partially attributable to uncontrolled [AFib], and patients with limited exercise capacity may stand to gain most from successful catheter ablation,” the editorialists wrote.

“Furthermore, because shorter time from [AFib] diagnosis to catheter ablation has been associated with improved outcomes, the decision to postpone ablation in favor of lifestyle modification is not without potential adverse consequences,” they added.

Dr. Black-Maier and Dr. Piccini agree with the need for additional prospective randomized clinical trials to confirm that exercise training to improve cardiorespiratory fitness before AFib ablation is practical and effective for reducing arrhythmia recurrence.

“Over the past 50-plus years, our understanding of cardiorespiratory fitness, exercise capacity, and arrhythmia occurrence in patients with [AFib] continues to evolve,” the editorialists concluded. Data from the study “clearly demonstrate that arrhythmia-free survival is indeed survival of the fittest. Time will tell if exercise training and improvements in cardiorespiratory fitness can change outcomes after ablation.”

The study was sponsored by the Cleveland Clinic. Dr. Jaber and Dr. Black-Maier report no relevant financial relationships. Dr. Piccini receives grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serves as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, MyoKardia, Sanofi, Philips, and UpToDate.
 

A version of this story originally appeared on Medscape.com.

People living with HIV who put on extra pounds and develop metabolic syndrome or related disorders linked in part to certain antiretroviral agents remain a concern today, even as the drugs used to suppress HIV infection have evolved over the decades.

Linkage of HIV treatment with lipodystrophy and insulin resistance or diabetes began in the 1990s with protease inhibitors (Clin Infect Dis. 2000 Jun;30[suppl 2]:s135-42). Several reports over the years also tied any form of effective antiretroviral therapy to weight gain in HIV patients (Antivir Ther. 2012;17[7]:1281-9). More recently, reports have rattled the HIV-treatment community by associating alarmingly high levels of weight gain with a useful and relatively new drug, tenofovir alafenamide fumarate (TAF) – a nucleoside reverse transcriptase inhibitor (NRTI) approved for use in the United States in late 2016, as well as certain agents from an entirely different antiretroviral therapy (ART) class, the integrase strand transfer inhibitors (INSTIs). Both TAF and the INSTIs have come to play major roles in the HIV-treatment landscape, despite relevant and concerning recent weight gain observations with these drugs, such as in a 2019 meta-analysis of eight trials with 5,680 treatment-naive patients who started ART during 2003-2015 (Clin Infect Dis. 2019 Oct 14;doi: 10.1093/cid/ciz999).

“Weight gain is clearly seen in studies of dolutegravir [DTG] or bictegravir [BTG] with TAF,” wrote W.D. Francois Venter, PhD and Andrew Hill, PhD in a recent published commentary on the topic (Lancet HIV. 2020 Jun 1;7[6]:e389-400). Both DTG and BTG are INSTI class members.

“Excessive weight gain, defined as more than 10% over baseline, has recently been observed among people with HIV initiating or switching to regimens incorporating TAF, an INSTI, or both, particularly DTG,” wrote Jordan E. Lake, MD, an HIV specialist at the University of Texas Health Science Center at Houston, in a recent commentary posted online. Women and Black patients “are at even greater risk for excessive weight gain,” Dr. Lake added.

“In recent times, it has emerged that weight gain is more pronounced with the integrase inhibitor class of agents, especially dolutegravir and bictegravir, the so-called second-generation” INSTIs, said Anna Maria Geretti, MD, a professor of clinical infection, microbiology, and immunology at the University of Liverpool, England. ”The effect is more pronounced in women and people of non-White ethnicity, and is of concern because of the associated potential risk of metabolic syndrome, cardiovascular disease, etc.,” Dr. Geretti said in an interview.

The unprecedented susceptibility to weight gain seen recently in non-White women may in part have resulted from the tendency of many earlier treatment trials to have cohorts comprised predominantly of White men, Dr. Venter noted in an interview.
 

Alarming weight gains reported

Perhaps the most eye-popping example of the potential for weight gain with the combination of TAF with an INSTI came in a recent report from the ADVANCE trial, a randomized, head-to-head comparison of three regimens in 1,053 HIV patients in South Africa. After 144 weeks on a regimen of TAF (Vemlidy), DTG (Tivicay), and FTC (emtricitabine, Emtriva), another NRTI, women gained an averaged of more than 12 kg, compared with their baseline weight, significantly more than in two comparator groups, Simiso Sokhela, MB, reported at the virtual meeting of the International AIDS conference. The women in ADVANCE on the TAF-DTG-FTC regimen also had an 11% rate of incident metabolic syndrome during their first 96 weeks on treatment, compared with rates of 8% among patients on a different form of tenofovir, tenofovir disoproxil fumarate (TDF), along with DTG-FTC, and 5% among those on TDF–EFV (efavirenz, Sustiva)–FTC said Dr. Sokhela, an HIV researcher at Ezintsha, a division of the University of the Witwatersrand in Johannesburg, South Africa.

“We believe that these results support the World Health Organization guidelines that reserve TAF for only patients with osteoporosis or impaired renal function,” Dr. Sokhela said during a press briefing at the conference. The WHO guidelines list the first-line regimen as TDF-DTG-3TC (lamivudine; Epivir) or FTC. “The risk for becoming obese continued to increase after 96 weeks” of chronic use of these drugs, she added.

“All regimens are now brilliant at viral control. Finding the ones that don’t make patients obese or have other long-term side effects is now the priority,” noted Dr. Venter, a professor and HIV researcher at University of the Witwatersrand, head of Ezintsha, and lead investigator of ADVANCE. Clinicians and researchers have recently thought that combining TAF and an INSTI plus FTC or a similar NRTI “would be the ultimate regimen to replace the nonnucleoside reverse transcriptase inhibitors (NNRTIs)” such as EFV, “but now we have a major headache” with unexpectedly high weight gains in some patients, Dr. Venter said.

Weight gains “over 10 kg are unlikely to be acceptable in any circumstances, especially when starting body mass index is already borderline overweight,” wrote Dr. Venter along with Dr. Hill in their commentary. Until recently, many clinicians chalked up weight gain on newly begun ART as a manifestation of the patient’s “return-to-health,” but this interpretation “gives a positive spin to a potentially serious and common side effect,” they added.
 

More from ADVANCE

The primary efficacy endpoint of ADVANCE was suppression of viral load to less than 50 RNA copies/mL after 48 weeks on treatment, and the result showed that the TAF-DTG-FTC regimen and the TDF-DTG-FTC regimen were each noninferior to the control regimen of TDF-EFV-FTC (New Engl J Med. 2019 Aug 29;381[9]:803-15). Virtually all of the enrolled patients were Black, and 59% were women. Planned follow-up of all patients ran for 96 weeks. After 48 weeks, weight gain among the women averaged 6.4 kg, 3.2 kg, and 1.7 kg in the TAF-DTG, TDF-DTG, and TDF-EFV arms respectively. After 96 weeks, the average weight gains among women were 8.2 kg, 4.6 kg, and 3.2 kg, respectively, in new results reported by Dr. Sokhela at the IAC. Follow-up to 144 weeks was partial and included about a quarter of the enrolled women, with gains averaging 12.3 kg, 7.4 kg, and 5.5 kg respectively. The pattern of weight gain among men tracked the pattern in women, but the magnitude of gain was less. Among men followed for 144 weeks, average gain among those on TAF-DTG-FTC was 7.2 kg, the largest gain seen among men on any regimen and at any follow-up time in the study.

Dr. Sokhela also reported data on body composition analyses, which showed that the weight gains were largely in fat rather than lean tissue, fat accumulation was significantly greater in women than men, and that in both sexes fat accumulated roughly equally in the trunk and on limbs.

An additional analysis looked at the incidence of new-onset obesity among the women who had a normal body mass index at baseline. After 96 weeks, incident obesity occurred in 14% of women on the TAG-DTG-FTC regimen, 8% on TDF-DTG-FTC, and in 2% of women maintained on TDF-EFV-FTC, said Dr. Hill in a separate report at the conference.
 

Weight starts to weigh in

“I am very mindful of weight gain potential, and I talk to patients about it. It doesn’t determine what regimen I choose for a patient” right now, “but it’s only a matter of time before it starts influencing what we do, particularly if we can achieve efficacy with fewer drugs,” commented Babafemi O. Taiwo, MD, professor of medicine and chief of infectious diseases at Northwestern University in Chicago. “I’ve had some patients show up with a weight gain of 20 kg, and that shouldn’t happen,” he said during a recent online educational session. Dr. Taiwo said his recent practice has been to warn patients about possible weight gain and to urge them to get back in touch with him quickly if it happens.

“Virologic suppression is the most important goal with ART, and the U.S. Department of Health and Human Services currently recommends INSTI-based ART for most PWH [people with HIV],” wrote Dr. Lake in April 2020. “I counsel all PWH initiating ART about the potential for weight gain, and I discuss their current diet and healthy lifestyle habits. I explain to patients that we will monitor their weight, and if weight gain seems more than either of us are comfortable with then we will reassess. Only a small percentage of patients experience excessive weight gain after starting ART.” Dr. Lake also stressed that she had not yet begun to change the regimen a patient is on solely because of weight gain. “We do not know whether this weight gain is reversible,” she noted.

“I do not anticipate that a risk of weight gain at present will dictate a change in guidelines,” said Dr. Geretti. “Drugs such as dolutegravir and bictegravir are very effective, and they are unlikely to cause drug resistance. Further data on the mechanism of weight gain and the reversibility after a change of treatment will help refine drug selection in the near future,” she predicted.

“I consider weight gain when prescribing because my patients hear about this. It’s a side effect that my patients really care about, and I don’t blame them,” said Lisa Hightow-Weidman, MD, a professor and HIV specialist at the University of North Carolina at Chapel Hill, during an on-line educational session. “If you don’t discuss it with a patient and then weight gain happens and the patient finds out [the known risk from their treatment] they may have an issue,” she noted. But weight gain is not a reason to avoid these drugs. “They are great medications in many ways, with once-daily regimens and few side effects.”
 

Weight gain during pregnancy a special concern

An additional analysis of data from ADVANCE presented at the conference highlighted what the observed weight gain on ART could mean for women who become pregnant while on treatment. Based on a systematic literature review, the ADVANCE investigators calculated the relative risk for six obesity-related pregnancy complications, compared with nonobese women: preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, postpartum hemorrhage, and caesarean delivery. Based on the obesity changes among women on their assigned ART in ADVANCE, the researchers calculated the predicted incidence of these six complications. The analysis showed that for every 1,000 women, those on TAG-DTG-FTC would have an excess of 53 obesity-related pregnancy complications, those on TDF-DTG-FTC would develop 28 excess pregnancy complications, and those on TDG-EFV-FTC would have four excess complications, reported Dr. Hill at the International AIDS conference.

The researchers also ran a similar simulation for the incidence of neonatal complications that could result when mothers are obese because of their ART. The six neonatal complications included in this analysis were small for gestational age, large for gestational age, macrosomia, neonatal death, stillbirth, and neural tube defects. Based on the excess rate of incident obesity, they calculated that for every 1,000 pregnancies women on TAD-DTG-FTC would have 24 additional infants born with one of these complications, women on TDF-DTG-FTC would have an excess of 13 of these events, and women on TDG-EFV-FTC would have an excess of three such obesity-related neonatal complications, Dr. Hill said.
 

Sorting out the drugs

Results from several additional studies reported at the conference have started trying to discern exactly which ART drugs and regimens pose the greatest weight gain risk and which have the least risk while retaining high efficacy and resistance barriers.

Further evidence implicating any type of ART as a driver of increased weight came from a review of 8,256 adults infected with HIV and members of the Kaiser Permanente health system in three U.S. regions during 2000-2016. Researchers matched these cases using several demographic factors with just under 130,000 members without HIV. Those infected by HIV had half the prevalence of obesity as the matched controls at baseline. During 12 years of follow-up, those infected with HIV had a threefold higher rate of weight gain than those who were uninfected. Annual weight gain averaged 0.06 kg/year among the uninfected people and 0.22 kg/year among those infected with HIV, a statistically significant difference that was consistent regardless of whether people started the study at a normal body mass index, overweight, or obese, reported Michael J. Silverberg, PhD, an epidemiologist with Kaiser Permanente in Oakland, Calif.

Another study tried to focus on the weight gain impact when patients on three-drug ART regimens changed from taking TDF to TAF. This analysis used data collected in the OPERA (Observational Pharmaco-Epidemiology Research & Analysis) longitudinal cohort of about 115,000 U.S. PWH. The observational cohort included nearly 7,000 patients who made a TDF-to-TAF switch, including 3,288 patients who maintained treatment during this switch with an INSTI, 1,454 who maintained a background regimen based on a NNRTI, 1,430 patients who also switched from an INSTI to a different drug, and 747 patients maintained on a boosted dose of a protease inhibitor. All patients were well controlled on their baseline regimen, with at least two consecutive measures showing undetectable viral load.

Patients who maintained their background regimens while changing from TDF to TAF had a 2.0-2.6 kg increase in weight during the 9 months immediately following their switch to TAF, reported Patrick Mallon, MB, a professor of microbial diseases at University College Dublin. Among the patients who both switched to TAF and also switched to treatment with an INSTI, weight gain during the 9 months after the switch averaged 2.6-4.5 kg, depending on which INSTI was started. Patients who switched to treatment with elvitegravir/cobicistat (an INSTI plus a boosting agent) averaged a gain of 2.6 kg during 9 months, those who switched to DTG averaged a 3.1-kg gain, and those who switched to BTG averaged a 4.6-kg increase, Dr. Mallon reported at the conference.

These findings “give us a good sense that the weight gain is real. This is not just overeating or not exercising, but weight changes coincidental with a change in HIV treatment,” commented David Wohl, MD, professor of medicine and site leader of the HIV Prevention and Treatment Clinical Trials Unit at the University of North Carolina at Chapel Hill, during an online educational session.

Contrary to this evidence suggesting a consistent uptick in weight when patients start TAF treatment was a recent report on 629 HIV patients randomized to treatment with TAF-BTG-FTC or abacavir (an NRTI, Ziagen)–DTG-3TC, which found similar weight gains between these two regimens after 144 weeks on treatment (Lancet HIV. 2020 Jun;7[6]:e389-400). This finding had the effect of “strengthening the argument that TAF is simply an innocent bystander” and does not play a central role in weight gain, and supporting the notion that the alternative tenofovir formulation, TDF, differs from TAF by promoting weight loss, Dr. Venter and Dr. Hill suggested in their commentary that accompanied this report.

The new findings from Dr. Mallon raise “serious questions about the way we have moved to TAF as a replacement for TDF, especially because the benefits [from TAF] are for a small subgroup – patients with renal disease or osteoporosis,” Dr. Venter said in an interview. “The question is, will we see weight gain like this” if TAF was combined with a non-INSTI drug? he wondered.

While some study results have suggested a mitigating effect from TDF on weight gain, that wasn’t the case in the AFRICOS (African Cohort Study) study of 1,954 PWH who started treatment with TDF-DTG-FTC (742 patients) or a different three-drug regimen. After a median of 225 days on treatment, those who started on TDF-DTG-FTC had an adjusted, 85% higher rate of developing a high body mass index, compared with patients on a different ART regimen, Julie Ake, MD, reported in a talk at the conference. Her conclusion focused on the possible involvement of DTG: “Consistent with previous reports, dolutegravir was significantly associated with an increased risk of developing high body mass index,” said Dr. Ake, director of the U.S. Military HIV Research Program in Bethesda, Md. and leader of AFRICOS.

A potential workaround to some drugs that cause excessive the weight gain is to just not use them. That was part of the rationale for the TANGO study, which took 741 HIV-infected patients with successful viral suppression on a regimen of TAF-FTC plus one or two additional agents and switched half of them to a TAF-less, two-drug regimen of DTG-FTC. This open-label study’s primary endpoint was noninferiority for viral suppression of the DTG-FTC regimen, compared with patients who stayed on their starting regimen, and the results proved that DTG-FTC was just as effective over 48 weeks for this outcome (Clin Infect Dis. 2020 Jan 6. doi: 10.1093/cid/ciz1243).

At the conference, TANGO’s lead investigator, Jean van Wyk, MD, reported the weight and metabolic effects of the switch. The results showed a similar and small weight gain (on average less than 1 kg) during 48 week follow-up regardless of whether patients remained on their baseline, TAF-containing regimen or switched to DTG-FTC, said Dr. van Wyk, global medical lead for HIV treatment at Viiv Healthcare, the company that markets DTG. About three-quarters of patients in both arms received “boosted” dosages of their drugs, and in this subgroup, patients on DTG-FTC showed statistically significant benefits in several lipid levels, fasting glucose level, and in their degree of insulin resistance. Dr. van Wyk said. These between-group differences were not statistically significant among the “unboosted” patients, and the results failed to show a significant between-group difference in the incidence of metabolic syndrome.

Dr. Venter called these results “exciting,” and noted that he already uses the DTG-FTC two-drug combination “a lot” to treat PWH and renal disease.

A second alternative regimen showcased in a talk at the conference used the three-drug regimen of TDF-FTC plus the NNRTI, DOR (doravirine, Pifeltro). The DRIVE-SHIFT trial enrolled 670 HIV patients with successfully suppressed viral load on conventional regimens who were either switched to TDF-DOR-FTC or maintained on their baseline treatment. After 48 weeks, results confirmed the primary efficacy endpoint of noninferiority for maintenance of suppression with the investigational regimen (J Acquir Immune Defic Syndr. 2019 Aug;81[4]:463-72).

A post-hoc analysis looked at weight changes among these patients after as much as 144 weeks of follow-up. The results showed that patients switched to TDF-DOR-FTC had an average weight increase of 1.2-1.4 kg after more than 2 years on the new regimen, with fewer than 10% of patients having a 10% or greater weight gain with DOR, a “next-generation” NNRTI, reported Princy N. Kumar, MD, professor at Georgetown University and chief of infectious diseases at MedStar Georgetown University Hospital in Washington. “Weight gain was minimal, even over the long term,” she noted.

The tested DOR-based regimen also looks “very exciting,” but the populations it’s been tested have also been largely limited to White men, and limited data exist about the regimen’s performance in pregnant women, commented Dr. Venter. The DRIVE-SHIRT patient cohort was about 85% men, and about three-quarters White.

More weight data needed

HIV-treatment researchers and clinicians seem agreed that weight gain and other metabolic effects from HIV treatment need more assessment and evidence because current data, while suggestive, is also inconclusive.

“Clinical trials are desperately needed to understand the mechanisms of and potential therapeutic options for excessive weight gain on ART,” wrote Dr. Lake in her commentary in April. “While more research is needed,” the new data reported at the virtual International AIDS conference “get us closer to understanding the effects of integrase inhibitors and TAF on weight and the potential metabolic consequences,” she commented as chair of the conference session where these reports occurred.

“Further data on the mechanism of weight gain and its reversibility after a change of treatment will help refine drug selection in the near future,” predicted Dr. Geretti.

“It’s hard to understand physiologically how drugs from such different classes all seem to have weight effects; it’s maddening,” said Dr. Venter. “We need decent studies in all patient populations. That will now be the priority,” he declared. “Patients shouldn’t have to choose” between drugs that most effectively control their HIV infection and drugs that don’t pose a risk for weight gain or metabolic derangements. PWH “should not have to face obesity as their new epidemic,” he wrote with Dr. Hill.

ADVANCE was funded in part by Viiv, the company that markets dolutegravir (Tivicay), and received drugs supplied by Gilead and Viiv. TANGO was sponsored by Viiv. DRIVE-SHIFT was funded by Merck, the company that markets doravirine (Pifeltro). Dr. Lake, Dr. Sokhela, Dr. Ake, and Dr. Kumar had no disclosures, Dr. Venter has received personal fees from Adcock Ingraham, Aspen Healthcare, Johnson and Johnson, Merck, Mylan, Roche, and Viiv. Dr. Hill has received payments from Merck. Dr. Geretti has received honoraria and research funding from Gilead, Jansse, Roche, and Viiv. Dr. Taiwo has had financial relationships with Gilead, Janssen, and Viiv. Dr. Hightow-Weidman has received honoraria from Gilead and Jansse. Dr. Wohl has been a consultant to Gilead, Johnson and Johnson, and Merck. Dr. Silverberg received research funding from Gilead. Dr. Mallon has been an advisor to and speaker on behalf of Bristol-Myers Squibb, Cilag, Gilead, Jansse, Merck Sharp & Dohme, and Viiv. Dr. van Wyk is a Viiv employee.

mzoler@mdedge.com

People living with HIV who put on extra pounds and develop metabolic syndrome or related disorders linked in part to certain antiretroviral agents remain a concern today, even as the drugs used to suppress HIV infection have evolved over the decades.

Linkage of HIV treatment with lipodystrophy and insulin resistance or diabetes began in the 1990s with protease inhibitors (Clin Infect Dis. 2000 Jun;30[suppl 2]:s135-42). Several reports over the years also tied any form of effective antiretroviral therapy to weight gain in HIV patients (Antivir Ther. 2012;17[7]:1281-9). More recently, reports have rattled the HIV-treatment community by associating alarmingly high levels of weight gain with a useful and relatively new drug, tenofovir alafenamide fumarate (TAF) – a nucleoside reverse transcriptase inhibitor (NRTI) approved for use in the United States in late 2016, as well as certain agents from an entirely different antiretroviral therapy (ART) class, the integrase strand transfer inhibitors (INSTIs). Both TAF and the INSTIs have come to play major roles in the HIV-treatment landscape, despite relevant and concerning recent weight gain observations with these drugs, such as in a 2019 meta-analysis of eight trials with 5,680 treatment-naive patients who started ART during 2003-2015 (Clin Infect Dis. 2019 Oct 14;doi: 10.1093/cid/ciz999).

“Weight gain is clearly seen in studies of dolutegravir [DTG] or bictegravir [BTG] with TAF,” wrote W.D. Francois Venter, PhD and Andrew Hill, PhD in a recent published commentary on the topic (Lancet HIV. 2020 Jun 1;7[6]:e389-400). Both DTG and BTG are INSTI class members.

“Excessive weight gain, defined as more than 10% over baseline, has recently been observed among people with HIV initiating or switching to regimens incorporating TAF, an INSTI, or both, particularly DTG,” wrote Jordan E. Lake, MD, an HIV specialist at the University of Texas Health Science Center at Houston, in a recent commentary posted online. Women and Black patients “are at even greater risk for excessive weight gain,” Dr. Lake added.

“In recent times, it has emerged that weight gain is more pronounced with the integrase inhibitor class of agents, especially dolutegravir and bictegravir, the so-called second-generation” INSTIs, said Anna Maria Geretti, MD, a professor of clinical infection, microbiology, and immunology at the University of Liverpool, England. ”The effect is more pronounced in women and people of non-White ethnicity, and is of concern because of the associated potential risk of metabolic syndrome, cardiovascular disease, etc.,” Dr. Geretti said in an interview.

The unprecedented susceptibility to weight gain seen recently in non-White women may in part have resulted from the tendency of many earlier treatment trials to have cohorts comprised predominantly of White men, Dr. Venter noted in an interview.
 

Alarming weight gains reported

Perhaps the most eye-popping example of the potential for weight gain with the combination of TAF with an INSTI came in a recent report from the ADVANCE trial, a randomized, head-to-head comparison of three regimens in 1,053 HIV patients in South Africa. After 144 weeks on a regimen of TAF (Vemlidy), DTG (Tivicay), and FTC (emtricitabine, Emtriva), another NRTI, women gained an averaged of more than 12 kg, compared with their baseline weight, significantly more than in two comparator groups, Simiso Sokhela, MB, reported at the virtual meeting of the International AIDS conference. The women in ADVANCE on the TAF-DTG-FTC regimen also had an 11% rate of incident metabolic syndrome during their first 96 weeks on treatment, compared with rates of 8% among patients on a different form of tenofovir, tenofovir disoproxil fumarate (TDF), along with DTG-FTC, and 5% among those on TDF–EFV (efavirenz, Sustiva)–FTC said Dr. Sokhela, an HIV researcher at Ezintsha, a division of the University of the Witwatersrand in Johannesburg, South Africa.

“We believe that these results support the World Health Organization guidelines that reserve TAF for only patients with osteoporosis or impaired renal function,” Dr. Sokhela said during a press briefing at the conference. The WHO guidelines list the first-line regimen as TDF-DTG-3TC (lamivudine; Epivir) or FTC. “The risk for becoming obese continued to increase after 96 weeks” of chronic use of these drugs, she added.

“All regimens are now brilliant at viral control. Finding the ones that don’t make patients obese or have other long-term side effects is now the priority,” noted Dr. Venter, a professor and HIV researcher at University of the Witwatersrand, head of Ezintsha, and lead investigator of ADVANCE. Clinicians and researchers have recently thought that combining TAF and an INSTI plus FTC or a similar NRTI “would be the ultimate regimen to replace the nonnucleoside reverse transcriptase inhibitors (NNRTIs)” such as EFV, “but now we have a major headache” with unexpectedly high weight gains in some patients, Dr. Venter said.

Weight gains “over 10 kg are unlikely to be acceptable in any circumstances, especially when starting body mass index is already borderline overweight,” wrote Dr. Venter along with Dr. Hill in their commentary. Until recently, many clinicians chalked up weight gain on newly begun ART as a manifestation of the patient’s “return-to-health,” but this interpretation “gives a positive spin to a potentially serious and common side effect,” they added.
 

More from ADVANCE

The primary efficacy endpoint of ADVANCE was suppression of viral load to less than 50 RNA copies/mL after 48 weeks on treatment, and the result showed that the TAF-DTG-FTC regimen and the TDF-DTG-FTC regimen were each noninferior to the control regimen of TDF-EFV-FTC (New Engl J Med. 2019 Aug 29;381[9]:803-15). Virtually all of the enrolled patients were Black, and 59% were women. Planned follow-up of all patients ran for 96 weeks. After 48 weeks, weight gain among the women averaged 6.4 kg, 3.2 kg, and 1.7 kg in the TAF-DTG, TDF-DTG, and TDF-EFV arms respectively. After 96 weeks, the average weight gains among women were 8.2 kg, 4.6 kg, and 3.2 kg, respectively, in new results reported by Dr. Sokhela at the IAC. Follow-up to 144 weeks was partial and included about a quarter of the enrolled women, with gains averaging 12.3 kg, 7.4 kg, and 5.5 kg respectively. The pattern of weight gain among men tracked the pattern in women, but the magnitude of gain was less. Among men followed for 144 weeks, average gain among those on TAF-DTG-FTC was 7.2 kg, the largest gain seen among men on any regimen and at any follow-up time in the study.

Dr. Sokhela also reported data on body composition analyses, which showed that the weight gains were largely in fat rather than lean tissue, fat accumulation was significantly greater in women than men, and that in both sexes fat accumulated roughly equally in the trunk and on limbs.

An additional analysis looked at the incidence of new-onset obesity among the women who had a normal body mass index at baseline. After 96 weeks, incident obesity occurred in 14% of women on the TAG-DTG-FTC regimen, 8% on TDF-DTG-FTC, and in 2% of women maintained on TDF-EFV-FTC, said Dr. Hill in a separate report at the conference.
 

Weight starts to weigh in

“I am very mindful of weight gain potential, and I talk to patients about it. It doesn’t determine what regimen I choose for a patient” right now, “but it’s only a matter of time before it starts influencing what we do, particularly if we can achieve efficacy with fewer drugs,” commented Babafemi O. Taiwo, MD, professor of medicine and chief of infectious diseases at Northwestern University in Chicago. “I’ve had some patients show up with a weight gain of 20 kg, and that shouldn’t happen,” he said during a recent online educational session. Dr. Taiwo said his recent practice has been to warn patients about possible weight gain and to urge them to get back in touch with him quickly if it happens.

“Virologic suppression is the most important goal with ART, and the U.S. Department of Health and Human Services currently recommends INSTI-based ART for most PWH [people with HIV],” wrote Dr. Lake in April 2020. “I counsel all PWH initiating ART about the potential for weight gain, and I discuss their current diet and healthy lifestyle habits. I explain to patients that we will monitor their weight, and if weight gain seems more than either of us are comfortable with then we will reassess. Only a small percentage of patients experience excessive weight gain after starting ART.” Dr. Lake also stressed that she had not yet begun to change the regimen a patient is on solely because of weight gain. “We do not know whether this weight gain is reversible,” she noted.

“I do not anticipate that a risk of weight gain at present will dictate a change in guidelines,” said Dr. Geretti. “Drugs such as dolutegravir and bictegravir are very effective, and they are unlikely to cause drug resistance. Further data on the mechanism of weight gain and the reversibility after a change of treatment will help refine drug selection in the near future,” she predicted.

“I consider weight gain when prescribing because my patients hear about this. It’s a side effect that my patients really care about, and I don’t blame them,” said Lisa Hightow-Weidman, MD, a professor and HIV specialist at the University of North Carolina at Chapel Hill, during an on-line educational session. “If you don’t discuss it with a patient and then weight gain happens and the patient finds out [the known risk from their treatment] they may have an issue,” she noted. But weight gain is not a reason to avoid these drugs. “They are great medications in many ways, with once-daily regimens and few side effects.”
 

Weight gain during pregnancy a special concern

An additional analysis of data from ADVANCE presented at the conference highlighted what the observed weight gain on ART could mean for women who become pregnant while on treatment. Based on a systematic literature review, the ADVANCE investigators calculated the relative risk for six obesity-related pregnancy complications, compared with nonobese women: preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, postpartum hemorrhage, and caesarean delivery. Based on the obesity changes among women on their assigned ART in ADVANCE, the researchers calculated the predicted incidence of these six complications. The analysis showed that for every 1,000 women, those on TAG-DTG-FTC would have an excess of 53 obesity-related pregnancy complications, those on TDF-DTG-FTC would develop 28 excess pregnancy complications, and those on TDG-EFV-FTC would have four excess complications, reported Dr. Hill at the International AIDS conference.

The researchers also ran a similar simulation for the incidence of neonatal complications that could result when mothers are obese because of their ART. The six neonatal complications included in this analysis were small for gestational age, large for gestational age, macrosomia, neonatal death, stillbirth, and neural tube defects. Based on the excess rate of incident obesity, they calculated that for every 1,000 pregnancies women on TAD-DTG-FTC would have 24 additional infants born with one of these complications, women on TDF-DTG-FTC would have an excess of 13 of these events, and women on TDG-EFV-FTC would have an excess of three such obesity-related neonatal complications, Dr. Hill said.
 

Sorting out the drugs

Results from several additional studies reported at the conference have started trying to discern exactly which ART drugs and regimens pose the greatest weight gain risk and which have the least risk while retaining high efficacy and resistance barriers.

Further evidence implicating any type of ART as a driver of increased weight came from a review of 8,256 adults infected with HIV and members of the Kaiser Permanente health system in three U.S. regions during 2000-2016. Researchers matched these cases using several demographic factors with just under 130,000 members without HIV. Those infected by HIV had half the prevalence of obesity as the matched controls at baseline. During 12 years of follow-up, those infected with HIV had a threefold higher rate of weight gain than those who were uninfected. Annual weight gain averaged 0.06 kg/year among the uninfected people and 0.22 kg/year among those infected with HIV, a statistically significant difference that was consistent regardless of whether people started the study at a normal body mass index, overweight, or obese, reported Michael J. Silverberg, PhD, an epidemiologist with Kaiser Permanente in Oakland, Calif.

Another study tried to focus on the weight gain impact when patients on three-drug ART regimens changed from taking TDF to TAF. This analysis used data collected in the OPERA (Observational Pharmaco-Epidemiology Research & Analysis) longitudinal cohort of about 115,000 U.S. PWH. The observational cohort included nearly 7,000 patients who made a TDF-to-TAF switch, including 3,288 patients who maintained treatment during this switch with an INSTI, 1,454 who maintained a background regimen based on a NNRTI, 1,430 patients who also switched from an INSTI to a different drug, and 747 patients maintained on a boosted dose of a protease inhibitor. All patients were well controlled on their baseline regimen, with at least two consecutive measures showing undetectable viral load.

Patients who maintained their background regimens while changing from TDF to TAF had a 2.0-2.6 kg increase in weight during the 9 months immediately following their switch to TAF, reported Patrick Mallon, MB, a professor of microbial diseases at University College Dublin. Among the patients who both switched to TAF and also switched to treatment with an INSTI, weight gain during the 9 months after the switch averaged 2.6-4.5 kg, depending on which INSTI was started. Patients who switched to treatment with elvitegravir/cobicistat (an INSTI plus a boosting agent) averaged a gain of 2.6 kg during 9 months, those who switched to DTG averaged a 3.1-kg gain, and those who switched to BTG averaged a 4.6-kg increase, Dr. Mallon reported at the conference.

These findings “give us a good sense that the weight gain is real. This is not just overeating or not exercising, but weight changes coincidental with a change in HIV treatment,” commented David Wohl, MD, professor of medicine and site leader of the HIV Prevention and Treatment Clinical Trials Unit at the University of North Carolina at Chapel Hill, during an online educational session.

Contrary to this evidence suggesting a consistent uptick in weight when patients start TAF treatment was a recent report on 629 HIV patients randomized to treatment with TAF-BTG-FTC or abacavir (an NRTI, Ziagen)–DTG-3TC, which found similar weight gains between these two regimens after 144 weeks on treatment (Lancet HIV. 2020 Jun;7[6]:e389-400). This finding had the effect of “strengthening the argument that TAF is simply an innocent bystander” and does not play a central role in weight gain, and supporting the notion that the alternative tenofovir formulation, TDF, differs from TAF by promoting weight loss, Dr. Venter and Dr. Hill suggested in their commentary that accompanied this report.

The new findings from Dr. Mallon raise “serious questions about the way we have moved to TAF as a replacement for TDF, especially because the benefits [from TAF] are for a small subgroup – patients with renal disease or osteoporosis,” Dr. Venter said in an interview. “The question is, will we see weight gain like this” if TAF was combined with a non-INSTI drug? he wondered.

While some study results have suggested a mitigating effect from TDF on weight gain, that wasn’t the case in the AFRICOS (African Cohort Study) study of 1,954 PWH who started treatment with TDF-DTG-FTC (742 patients) or a different three-drug regimen. After a median of 225 days on treatment, those who started on TDF-DTG-FTC had an adjusted, 85% higher rate of developing a high body mass index, compared with patients on a different ART regimen, Julie Ake, MD, reported in a talk at the conference. Her conclusion focused on the possible involvement of DTG: “Consistent with previous reports, dolutegravir was significantly associated with an increased risk of developing high body mass index,” said Dr. Ake, director of the U.S. Military HIV Research Program in Bethesda, Md. and leader of AFRICOS.

A potential workaround to some drugs that cause excessive the weight gain is to just not use them. That was part of the rationale for the TANGO study, which took 741 HIV-infected patients with successful viral suppression on a regimen of TAF-FTC plus one or two additional agents and switched half of them to a TAF-less, two-drug regimen of DTG-FTC. This open-label study’s primary endpoint was noninferiority for viral suppression of the DTG-FTC regimen, compared with patients who stayed on their starting regimen, and the results proved that DTG-FTC was just as effective over 48 weeks for this outcome (Clin Infect Dis. 2020 Jan 6. doi: 10.1093/cid/ciz1243).

At the conference, TANGO’s lead investigator, Jean van Wyk, MD, reported the weight and metabolic effects of the switch. The results showed a similar and small weight gain (on average less than 1 kg) during 48 week follow-up regardless of whether patients remained on their baseline, TAF-containing regimen or switched to DTG-FTC, said Dr. van Wyk, global medical lead for HIV treatment at Viiv Healthcare, the company that markets DTG. About three-quarters of patients in both arms received “boosted” dosages of their drugs, and in this subgroup, patients on DTG-FTC showed statistically significant benefits in several lipid levels, fasting glucose level, and in their degree of insulin resistance. Dr. van Wyk said. These between-group differences were not statistically significant among the “unboosted” patients, and the results failed to show a significant between-group difference in the incidence of metabolic syndrome.

Dr. Venter called these results “exciting,” and noted that he already uses the DTG-FTC two-drug combination “a lot” to treat PWH and renal disease.

A second alternative regimen showcased in a talk at the conference used the three-drug regimen of TDF-FTC plus the NNRTI, DOR (doravirine, Pifeltro). The DRIVE-SHIFT trial enrolled 670 HIV patients with successfully suppressed viral load on conventional regimens who were either switched to TDF-DOR-FTC or maintained on their baseline treatment. After 48 weeks, results confirmed the primary efficacy endpoint of noninferiority for maintenance of suppression with the investigational regimen (J Acquir Immune Defic Syndr. 2019 Aug;81[4]:463-72).

A post-hoc analysis looked at weight changes among these patients after as much as 144 weeks of follow-up. The results showed that patients switched to TDF-DOR-FTC had an average weight increase of 1.2-1.4 kg after more than 2 years on the new regimen, with fewer than 10% of patients having a 10% or greater weight gain with DOR, a “next-generation” NNRTI, reported Princy N. Kumar, MD, professor at Georgetown University and chief of infectious diseases at MedStar Georgetown University Hospital in Washington. “Weight gain was minimal, even over the long term,” she noted.

The tested DOR-based regimen also looks “very exciting,” but the populations it’s been tested have also been largely limited to White men, and limited data exist about the regimen’s performance in pregnant women, commented Dr. Venter. The DRIVE-SHIRT patient cohort was about 85% men, and about three-quarters White.

More weight data needed

HIV-treatment researchers and clinicians seem agreed that weight gain and other metabolic effects from HIV treatment need more assessment and evidence because current data, while suggestive, is also inconclusive.

“Clinical trials are desperately needed to understand the mechanisms of and potential therapeutic options for excessive weight gain on ART,” wrote Dr. Lake in her commentary in April. “While more research is needed,” the new data reported at the virtual International AIDS conference “get us closer to understanding the effects of integrase inhibitors and TAF on weight and the potential metabolic consequences,” she commented as chair of the conference session where these reports occurred.

“Further data on the mechanism of weight gain and its reversibility after a change of treatment will help refine drug selection in the near future,” predicted Dr. Geretti.

“It’s hard to understand physiologically how drugs from such different classes all seem to have weight effects; it’s maddening,” said Dr. Venter. “We need decent studies in all patient populations. That will now be the priority,” he declared. “Patients shouldn’t have to choose” between drugs that most effectively control their HIV infection and drugs that don’t pose a risk for weight gain or metabolic derangements. PWH “should not have to face obesity as their new epidemic,” he wrote with Dr. Hill.

ADVANCE was funded in part by Viiv, the company that markets dolutegravir (Tivicay), and received drugs supplied by Gilead and Viiv. TANGO was sponsored by Viiv. DRIVE-SHIFT was funded by Merck, the company that markets doravirine (Pifeltro). Dr. Lake, Dr. Sokhela, Dr. Ake, and Dr. Kumar had no disclosures, Dr. Venter has received personal fees from Adcock Ingraham, Aspen Healthcare, Johnson and Johnson, Merck, Mylan, Roche, and Viiv. Dr. Hill has received payments from Merck. Dr. Geretti has received honoraria and research funding from Gilead, Jansse, Roche, and Viiv. Dr. Taiwo has had financial relationships with Gilead, Janssen, and Viiv. Dr. Hightow-Weidman has received honoraria from Gilead and Jansse. Dr. Wohl has been a consultant to Gilead, Johnson and Johnson, and Merck. Dr. Silverberg received research funding from Gilead. Dr. Mallon has been an advisor to and speaker on behalf of Bristol-Myers Squibb, Cilag, Gilead, Jansse, Merck Sharp & Dohme, and Viiv. Dr. van Wyk is a Viiv employee.

mzoler@mdedge.com

People living with HIV who put on extra pounds and develop metabolic syndrome or related disorders linked in part to certain antiretroviral agents remain a concern today, even as the drugs used to suppress HIV infection have evolved over the decades.

Linkage of HIV treatment with lipodystrophy and insulin resistance or diabetes began in the 1990s with protease inhibitors (Clin Infect Dis. 2000 Jun;30[suppl 2]:s135-42). Several reports over the years also tied any form of effective antiretroviral therapy to weight gain in HIV patients (Antivir Ther. 2012;17[7]:1281-9). More recently, reports have rattled the HIV-treatment community by associating alarmingly high levels of weight gain with a useful and relatively new drug, tenofovir alafenamide fumarate (TAF) – a nucleoside reverse transcriptase inhibitor (NRTI) approved for use in the United States in late 2016, as well as certain agents from an entirely different antiretroviral therapy (ART) class, the integrase strand transfer inhibitors (INSTIs). Both TAF and the INSTIs have come to play major roles in the HIV-treatment landscape, despite relevant and concerning recent weight gain observations with these drugs, such as in a 2019 meta-analysis of eight trials with 5,680 treatment-naive patients who started ART during 2003-2015 (Clin Infect Dis. 2019 Oct 14;doi: 10.1093/cid/ciz999).

“Weight gain is clearly seen in studies of dolutegravir [DTG] or bictegravir [BTG] with TAF,” wrote W.D. Francois Venter, PhD and Andrew Hill, PhD in a recent published commentary on the topic (Lancet HIV. 2020 Jun 1;7[6]:e389-400). Both DTG and BTG are INSTI class members.

“Excessive weight gain, defined as more than 10% over baseline, has recently been observed among people with HIV initiating or switching to regimens incorporating TAF, an INSTI, or both, particularly DTG,” wrote Jordan E. Lake, MD, an HIV specialist at the University of Texas Health Science Center at Houston, in a recent commentary posted online. Women and Black patients “are at even greater risk for excessive weight gain,” Dr. Lake added.

“In recent times, it has emerged that weight gain is more pronounced with the integrase inhibitor class of agents, especially dolutegravir and bictegravir, the so-called second-generation” INSTIs, said Anna Maria Geretti, MD, a professor of clinical infection, microbiology, and immunology at the University of Liverpool, England. ”The effect is more pronounced in women and people of non-White ethnicity, and is of concern because of the associated potential risk of metabolic syndrome, cardiovascular disease, etc.,” Dr. Geretti said in an interview.

The unprecedented susceptibility to weight gain seen recently in non-White women may in part have resulted from the tendency of many earlier treatment trials to have cohorts comprised predominantly of White men, Dr. Venter noted in an interview.
 

Alarming weight gains reported

Perhaps the most eye-popping example of the potential for weight gain with the combination of TAF with an INSTI came in a recent report from the ADVANCE trial, a randomized, head-to-head comparison of three regimens in 1,053 HIV patients in South Africa. After 144 weeks on a regimen of TAF (Vemlidy), DTG (Tivicay), and FTC (emtricitabine, Emtriva), another NRTI, women gained an averaged of more than 12 kg, compared with their baseline weight, significantly more than in two comparator groups, Simiso Sokhela, MB, reported at the virtual meeting of the International AIDS conference. The women in ADVANCE on the TAF-DTG-FTC regimen also had an 11% rate of incident metabolic syndrome during their first 96 weeks on treatment, compared with rates of 8% among patients on a different form of tenofovir, tenofovir disoproxil fumarate (TDF), along with DTG-FTC, and 5% among those on TDF–EFV (efavirenz, Sustiva)–FTC said Dr. Sokhela, an HIV researcher at Ezintsha, a division of the University of the Witwatersrand in Johannesburg, South Africa.

“We believe that these results support the World Health Organization guidelines that reserve TAF for only patients with osteoporosis or impaired renal function,” Dr. Sokhela said during a press briefing at the conference. The WHO guidelines list the first-line regimen as TDF-DTG-3TC (lamivudine; Epivir) or FTC. “The risk for becoming obese continued to increase after 96 weeks” of chronic use of these drugs, she added.

“All regimens are now brilliant at viral control. Finding the ones that don’t make patients obese or have other long-term side effects is now the priority,” noted Dr. Venter, a professor and HIV researcher at University of the Witwatersrand, head of Ezintsha, and lead investigator of ADVANCE. Clinicians and researchers have recently thought that combining TAF and an INSTI plus FTC or a similar NRTI “would be the ultimate regimen to replace the nonnucleoside reverse transcriptase inhibitors (NNRTIs)” such as EFV, “but now we have a major headache” with unexpectedly high weight gains in some patients, Dr. Venter said.

Weight gains “over 10 kg are unlikely to be acceptable in any circumstances, especially when starting body mass index is already borderline overweight,” wrote Dr. Venter along with Dr. Hill in their commentary. Until recently, many clinicians chalked up weight gain on newly begun ART as a manifestation of the patient’s “return-to-health,” but this interpretation “gives a positive spin to a potentially serious and common side effect,” they added.
 

More from ADVANCE

The primary efficacy endpoint of ADVANCE was suppression of viral load to less than 50 RNA copies/mL after 48 weeks on treatment, and the result showed that the TAF-DTG-FTC regimen and the TDF-DTG-FTC regimen were each noninferior to the control regimen of TDF-EFV-FTC (New Engl J Med. 2019 Aug 29;381[9]:803-15). Virtually all of the enrolled patients were Black, and 59% were women. Planned follow-up of all patients ran for 96 weeks. After 48 weeks, weight gain among the women averaged 6.4 kg, 3.2 kg, and 1.7 kg in the TAF-DTG, TDF-DTG, and TDF-EFV arms respectively. After 96 weeks, the average weight gains among women were 8.2 kg, 4.6 kg, and 3.2 kg, respectively, in new results reported by Dr. Sokhela at the IAC. Follow-up to 144 weeks was partial and included about a quarter of the enrolled women, with gains averaging 12.3 kg, 7.4 kg, and 5.5 kg respectively. The pattern of weight gain among men tracked the pattern in women, but the magnitude of gain was less. Among men followed for 144 weeks, average gain among those on TAF-DTG-FTC was 7.2 kg, the largest gain seen among men on any regimen and at any follow-up time in the study.

Dr. Sokhela also reported data on body composition analyses, which showed that the weight gains were largely in fat rather than lean tissue, fat accumulation was significantly greater in women than men, and that in both sexes fat accumulated roughly equally in the trunk and on limbs.

An additional analysis looked at the incidence of new-onset obesity among the women who had a normal body mass index at baseline. After 96 weeks, incident obesity occurred in 14% of women on the TAG-DTG-FTC regimen, 8% on TDF-DTG-FTC, and in 2% of women maintained on TDF-EFV-FTC, said Dr. Hill in a separate report at the conference.
 

Weight starts to weigh in

“I am very mindful of weight gain potential, and I talk to patients about it. It doesn’t determine what regimen I choose for a patient” right now, “but it’s only a matter of time before it starts influencing what we do, particularly if we can achieve efficacy with fewer drugs,” commented Babafemi O. Taiwo, MD, professor of medicine and chief of infectious diseases at Northwestern University in Chicago. “I’ve had some patients show up with a weight gain of 20 kg, and that shouldn’t happen,” he said during a recent online educational session. Dr. Taiwo said his recent practice has been to warn patients about possible weight gain and to urge them to get back in touch with him quickly if it happens.

“Virologic suppression is the most important goal with ART, and the U.S. Department of Health and Human Services currently recommends INSTI-based ART for most PWH [people with HIV],” wrote Dr. Lake in April 2020. “I counsel all PWH initiating ART about the potential for weight gain, and I discuss their current diet and healthy lifestyle habits. I explain to patients that we will monitor their weight, and if weight gain seems more than either of us are comfortable with then we will reassess. Only a small percentage of patients experience excessive weight gain after starting ART.” Dr. Lake also stressed that she had not yet begun to change the regimen a patient is on solely because of weight gain. “We do not know whether this weight gain is reversible,” she noted.

“I do not anticipate that a risk of weight gain at present will dictate a change in guidelines,” said Dr. Geretti. “Drugs such as dolutegravir and bictegravir are very effective, and they are unlikely to cause drug resistance. Further data on the mechanism of weight gain and the reversibility after a change of treatment will help refine drug selection in the near future,” she predicted.

“I consider weight gain when prescribing because my patients hear about this. It’s a side effect that my patients really care about, and I don’t blame them,” said Lisa Hightow-Weidman, MD, a professor and HIV specialist at the University of North Carolina at Chapel Hill, during an on-line educational session. “If you don’t discuss it with a patient and then weight gain happens and the patient finds out [the known risk from their treatment] they may have an issue,” she noted. But weight gain is not a reason to avoid these drugs. “They are great medications in many ways, with once-daily regimens and few side effects.”
 

Weight gain during pregnancy a special concern

An additional analysis of data from ADVANCE presented at the conference highlighted what the observed weight gain on ART could mean for women who become pregnant while on treatment. Based on a systematic literature review, the ADVANCE investigators calculated the relative risk for six obesity-related pregnancy complications, compared with nonobese women: preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, postpartum hemorrhage, and caesarean delivery. Based on the obesity changes among women on their assigned ART in ADVANCE, the researchers calculated the predicted incidence of these six complications. The analysis showed that for every 1,000 women, those on TAG-DTG-FTC would have an excess of 53 obesity-related pregnancy complications, those on TDF-DTG-FTC would develop 28 excess pregnancy complications, and those on TDG-EFV-FTC would have four excess complications, reported Dr. Hill at the International AIDS conference.

The researchers also ran a similar simulation for the incidence of neonatal complications that could result when mothers are obese because of their ART. The six neonatal complications included in this analysis were small for gestational age, large for gestational age, macrosomia, neonatal death, stillbirth, and neural tube defects. Based on the excess rate of incident obesity, they calculated that for every 1,000 pregnancies women on TAD-DTG-FTC would have 24 additional infants born with one of these complications, women on TDF-DTG-FTC would have an excess of 13 of these events, and women on TDG-EFV-FTC would have an excess of three such obesity-related neonatal complications, Dr. Hill said.
 

Sorting out the drugs

Results from several additional studies reported at the conference have started trying to discern exactly which ART drugs and regimens pose the greatest weight gain risk and which have the least risk while retaining high efficacy and resistance barriers.

Further evidence implicating any type of ART as a driver of increased weight came from a review of 8,256 adults infected with HIV and members of the Kaiser Permanente health system in three U.S. regions during 2000-2016. Researchers matched these cases using several demographic factors with just under 130,000 members without HIV. Those infected by HIV had half the prevalence of obesity as the matched controls at baseline. During 12 years of follow-up, those infected with HIV had a threefold higher rate of weight gain than those who were uninfected. Annual weight gain averaged 0.06 kg/year among the uninfected people and 0.22 kg/year among those infected with HIV, a statistically significant difference that was consistent regardless of whether people started the study at a normal body mass index, overweight, or obese, reported Michael J. Silverberg, PhD, an epidemiologist with Kaiser Permanente in Oakland, Calif.

Another study tried to focus on the weight gain impact when patients on three-drug ART regimens changed from taking TDF to TAF. This analysis used data collected in the OPERA (Observational Pharmaco-Epidemiology Research & Analysis) longitudinal cohort of about 115,000 U.S. PWH. The observational cohort included nearly 7,000 patients who made a TDF-to-TAF switch, including 3,288 patients who maintained treatment during this switch with an INSTI, 1,454 who maintained a background regimen based on a NNRTI, 1,430 patients who also switched from an INSTI to a different drug, and 747 patients maintained on a boosted dose of a protease inhibitor. All patients were well controlled on their baseline regimen, with at least two consecutive measures showing undetectable viral load.

Patients who maintained their background regimens while changing from TDF to TAF had a 2.0-2.6 kg increase in weight during the 9 months immediately following their switch to TAF, reported Patrick Mallon, MB, a professor of microbial diseases at University College Dublin. Among the patients who both switched to TAF and also switched to treatment with an INSTI, weight gain during the 9 months after the switch averaged 2.6-4.5 kg, depending on which INSTI was started. Patients who switched to treatment with elvitegravir/cobicistat (an INSTI plus a boosting agent) averaged a gain of 2.6 kg during 9 months, those who switched to DTG averaged a 3.1-kg gain, and those who switched to BTG averaged a 4.6-kg increase, Dr. Mallon reported at the conference.

These findings “give us a good sense that the weight gain is real. This is not just overeating or not exercising, but weight changes coincidental with a change in HIV treatment,” commented David Wohl, MD, professor of medicine and site leader of the HIV Prevention and Treatment Clinical Trials Unit at the University of North Carolina at Chapel Hill, during an online educational session.

Contrary to this evidence suggesting a consistent uptick in weight when patients start TAF treatment was a recent report on 629 HIV patients randomized to treatment with TAF-BTG-FTC or abacavir (an NRTI, Ziagen)–DTG-3TC, which found similar weight gains between these two regimens after 144 weeks on treatment (Lancet HIV. 2020 Jun;7[6]:e389-400). This finding had the effect of “strengthening the argument that TAF is simply an innocent bystander” and does not play a central role in weight gain, and supporting the notion that the alternative tenofovir formulation, TDF, differs from TAF by promoting weight loss, Dr. Venter and Dr. Hill suggested in their commentary that accompanied this report.

The new findings from Dr. Mallon raise “serious questions about the way we have moved to TAF as a replacement for TDF, especially because the benefits [from TAF] are for a small subgroup – patients with renal disease or osteoporosis,” Dr. Venter said in an interview. “The question is, will we see weight gain like this” if TAF was combined with a non-INSTI drug? he wondered.

While some study results have suggested a mitigating effect from TDF on weight gain, that wasn’t the case in the AFRICOS (African Cohort Study) study of 1,954 PWH who started treatment with TDF-DTG-FTC (742 patients) or a different three-drug regimen. After a median of 225 days on treatment, those who started on TDF-DTG-FTC had an adjusted, 85% higher rate of developing a high body mass index, compared with patients on a different ART regimen, Julie Ake, MD, reported in a talk at the conference. Her conclusion focused on the possible involvement of DTG: “Consistent with previous reports, dolutegravir was significantly associated with an increased risk of developing high body mass index,” said Dr. Ake, director of the U.S. Military HIV Research Program in Bethesda, Md. and leader of AFRICOS.

A potential workaround to some drugs that cause excessive the weight gain is to just not use them. That was part of the rationale for the TANGO study, which took 741 HIV-infected patients with successful viral suppression on a regimen of TAF-FTC plus one or two additional agents and switched half of them to a TAF-less, two-drug regimen of DTG-FTC. This open-label study’s primary endpoint was noninferiority for viral suppression of the DTG-FTC regimen, compared with patients who stayed on their starting regimen, and the results proved that DTG-FTC was just as effective over 48 weeks for this outcome (Clin Infect Dis. 2020 Jan 6. doi: 10.1093/cid/ciz1243).

At the conference, TANGO’s lead investigator, Jean van Wyk, MD, reported the weight and metabolic effects of the switch. The results showed a similar and small weight gain (on average less than 1 kg) during 48 week follow-up regardless of whether patients remained on their baseline, TAF-containing regimen or switched to DTG-FTC, said Dr. van Wyk, global medical lead for HIV treatment at Viiv Healthcare, the company that markets DTG. About three-quarters of patients in both arms received “boosted” dosages of their drugs, and in this subgroup, patients on DTG-FTC showed statistically significant benefits in several lipid levels, fasting glucose level, and in their degree of insulin resistance. Dr. van Wyk said. These between-group differences were not statistically significant among the “unboosted” patients, and the results failed to show a significant between-group difference in the incidence of metabolic syndrome.

Dr. Venter called these results “exciting,” and noted that he already uses the DTG-FTC two-drug combination “a lot” to treat PWH and renal disease.

A second alternative regimen showcased in a talk at the conference used the three-drug regimen of TDF-FTC plus the NNRTI, DOR (doravirine, Pifeltro). The DRIVE-SHIFT trial enrolled 670 HIV patients with successfully suppressed viral load on conventional regimens who were either switched to TDF-DOR-FTC or maintained on their baseline treatment. After 48 weeks, results confirmed the primary efficacy endpoint of noninferiority for maintenance of suppression with the investigational regimen (J Acquir Immune Defic Syndr. 2019 Aug;81[4]:463-72).

A post-hoc analysis looked at weight changes among these patients after as much as 144 weeks of follow-up. The results showed that patients switched to TDF-DOR-FTC had an average weight increase of 1.2-1.4 kg after more than 2 years on the new regimen, with fewer than 10% of patients having a 10% or greater weight gain with DOR, a “next-generation” NNRTI, reported Princy N. Kumar, MD, professor at Georgetown University and chief of infectious diseases at MedStar Georgetown University Hospital in Washington. “Weight gain was minimal, even over the long term,” she noted.

The tested DOR-based regimen also looks “very exciting,” but the populations it’s been tested have also been largely limited to White men, and limited data exist about the regimen’s performance in pregnant women, commented Dr. Venter. The DRIVE-SHIRT patient cohort was about 85% men, and about three-quarters White.

More weight data needed

HIV-treatment researchers and clinicians seem agreed that weight gain and other metabolic effects from HIV treatment need more assessment and evidence because current data, while suggestive, is also inconclusive.

“Clinical trials are desperately needed to understand the mechanisms of and potential therapeutic options for excessive weight gain on ART,” wrote Dr. Lake in her commentary in April. “While more research is needed,” the new data reported at the virtual International AIDS conference “get us closer to understanding the effects of integrase inhibitors and TAF on weight and the potential metabolic consequences,” she commented as chair of the conference session where these reports occurred.

“Further data on the mechanism of weight gain and its reversibility after a change of treatment will help refine drug selection in the near future,” predicted Dr. Geretti.

“It’s hard to understand physiologically how drugs from such different classes all seem to have weight effects; it’s maddening,” said Dr. Venter. “We need decent studies in all patient populations. That will now be the priority,” he declared. “Patients shouldn’t have to choose” between drugs that most effectively control their HIV infection and drugs that don’t pose a risk for weight gain or metabolic derangements. PWH “should not have to face obesity as their new epidemic,” he wrote with Dr. Hill.

ADVANCE was funded in part by Viiv, the company that markets dolutegravir (Tivicay), and received drugs supplied by Gilead and Viiv. TANGO was sponsored by Viiv. DRIVE-SHIFT was funded by Merck, the company that markets doravirine (Pifeltro). Dr. Lake, Dr. Sokhela, Dr. Ake, and Dr. Kumar had no disclosures, Dr. Venter has received personal fees from Adcock Ingraham, Aspen Healthcare, Johnson and Johnson, Merck, Mylan, Roche, and Viiv. Dr. Hill has received payments from Merck. Dr. Geretti has received honoraria and research funding from Gilead, Jansse, Roche, and Viiv. Dr. Taiwo has had financial relationships with Gilead, Janssen, and Viiv. Dr. Hightow-Weidman has received honoraria from Gilead and Jansse. Dr. Wohl has been a consultant to Gilead, Johnson and Johnson, and Merck. Dr. Silverberg received research funding from Gilead. Dr. Mallon has been an advisor to and speaker on behalf of Bristol-Myers Squibb, Cilag, Gilead, Jansse, Merck Sharp & Dohme, and Viiv. Dr. van Wyk is a Viiv employee.

mzoler@mdedge.com

The abrupt onset of painful, violaceous coalescing papules, pustules, cysts, and nodules exclusively involving the centrofacial area with an overlying red-cyanotic erythema are the hallmarks of pyoderma faciale.

Pyoderma faciale is a rare disease that affects females in the second and third decades of life; 50% of these patients have a history of acne. The etiology of the condition remains unclear. Hormonal imbalance, inflammatory bowel disease, liver disease, and thyroid disease have been associated with the disorder. Ribavirin and interferon therapies for the treatment of hepatitis C along with high levels of vitamins (B₆ and B₁₂) have been identified as triggers. Culture of purulent drainage typically is sterile or may reveal commensal organisms.

The differential diagnosis includes acne fulminans and acne conglobata. Acne fulminans is not restricted to the face, as is pyoderma faciale, and it involves constitutional symptoms. Acne conglobata is a chronic process that affects males and females. It also involves purulent sinus tracts.

Prompt treatment of pyoderma faciale is essential to prevent widespread eruption, minimize the distress associated with the disfiguring nature of the disorder, and ultimately reduce scarring. Standard therapy consists of oral steroids (prednisone 1 mg/kg/d) for 1 week followed by a slow taper in combination with oral isotretinoin at a low dosage (0.2–0.5 mg/kg). The systemic retinoid is continued until all inflammatory lesions are healed.

In this case, a culture swab taken from the patient’s left cheek did not reveal any unexpected pathogens. The patient was started on oral doxycycline 100 mg bid and prednisone 50 mg/d tapered to 10 mg/d. She was counseled about the risks and benefits of isotretinoin and registered in the iPLEDGE system in anticipation of starting oral isotretinoin at 20 mg/d after negative pregnancy tests, 2 forms of contraception, and the 1-month qualification period.

‌

Photo courtesy of Catherine N. Tchanque-Fossuo, MD, MS, and text courtesy of Catherine N. Tchanque-Fossuo, MD, MS, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The abrupt onset of painful, violaceous coalescing papules, pustules, cysts, and nodules exclusively involving the centrofacial area with an overlying red-cyanotic erythema are the hallmarks of pyoderma faciale.

Pyoderma faciale is a rare disease that affects females in the second and third decades of life; 50% of these patients have a history of acne. The etiology of the condition remains unclear. Hormonal imbalance, inflammatory bowel disease, liver disease, and thyroid disease have been associated with the disorder. Ribavirin and interferon therapies for the treatment of hepatitis C along with high levels of vitamins (B₆ and B₁₂) have been identified as triggers. Culture of purulent drainage typically is sterile or may reveal commensal organisms.

The differential diagnosis includes acne fulminans and acne conglobata. Acne fulminans is not restricted to the face, as is pyoderma faciale, and it involves constitutional symptoms. Acne conglobata is a chronic process that affects males and females. It also involves purulent sinus tracts.

Prompt treatment of pyoderma faciale is essential to prevent widespread eruption, minimize the distress associated with the disfiguring nature of the disorder, and ultimately reduce scarring. Standard therapy consists of oral steroids (prednisone 1 mg/kg/d) for 1 week followed by a slow taper in combination with oral isotretinoin at a low dosage (0.2–0.5 mg/kg). The systemic retinoid is continued until all inflammatory lesions are healed.

In this case, a culture swab taken from the patient’s left cheek did not reveal any unexpected pathogens. The patient was started on oral doxycycline 100 mg bid and prednisone 50 mg/d tapered to 10 mg/d. She was counseled about the risks and benefits of isotretinoin and registered in the iPLEDGE system in anticipation of starting oral isotretinoin at 20 mg/d after negative pregnancy tests, 2 forms of contraception, and the 1-month qualification period.

‌

Photo courtesy of Catherine N. Tchanque-Fossuo, MD, MS, and text courtesy of Catherine N. Tchanque-Fossuo, MD, MS, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The abrupt onset of painful, violaceous coalescing papules, pustules, cysts, and nodules exclusively involving the centrofacial area with an overlying red-cyanotic erythema are the hallmarks of pyoderma faciale.

Pyoderma faciale is a rare disease that affects females in the second and third decades of life; 50% of these patients have a history of acne. The etiology of the condition remains unclear. Hormonal imbalance, inflammatory bowel disease, liver disease, and thyroid disease have been associated with the disorder. Ribavirin and interferon therapies for the treatment of hepatitis C along with high levels of vitamins (B₆ and B₁₂) have been identified as triggers. Culture of purulent drainage typically is sterile or may reveal commensal organisms.

The differential diagnosis includes acne fulminans and acne conglobata. Acne fulminans is not restricted to the face, as is pyoderma faciale, and it involves constitutional symptoms. Acne conglobata is a chronic process that affects males and females. It also involves purulent sinus tracts.

Prompt treatment of pyoderma faciale is essential to prevent widespread eruption, minimize the distress associated with the disfiguring nature of the disorder, and ultimately reduce scarring. Standard therapy consists of oral steroids (prednisone 1 mg/kg/d) for 1 week followed by a slow taper in combination with oral isotretinoin at a low dosage (0.2–0.5 mg/kg). The systemic retinoid is continued until all inflammatory lesions are healed.

In this case, a culture swab taken from the patient’s left cheek did not reveal any unexpected pathogens. The patient was started on oral doxycycline 100 mg bid and prednisone 50 mg/d tapered to 10 mg/d. She was counseled about the risks and benefits of isotretinoin and registered in the iPLEDGE system in anticipation of starting oral isotretinoin at 20 mg/d after negative pregnancy tests, 2 forms of contraception, and the 1-month qualification period.

‌

Photo courtesy of Catherine N. Tchanque-Fossuo, MD, MS, and text courtesy of Catherine N. Tchanque-Fossuo, MD, MS, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

mzoler@mdedge.com

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

mzoler@mdedge.com

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

mzoler@mdedge.com

Evidence for a link between cannabis use and cardiovascular health remains unsupported, and the potential risks outweigh any potential benefits, according to a scientific statement from the American Heart Association.

American Heart Association

The increased legalization of cannabis and cannabis products in the United States has driven medical professionals to evaluate the safety and efficacy of cannabis in relation to health conditions, wrote Robert L. Page II, PharmD, of the University of Colorado, Aurora, and colleagues.

In a statement published in Circulation, the researchers noted that although cannabis has been shown to relieve pain and other symptoms in certain conditions, clinicians in the United States have been limited from studying its health effects because of federal law restrictions. “Cannabis remains a schedule I controlled substance, deeming no accepted medical use, a high potential for abuse, and an unacceptable safety profile,” the researchers wrote.

The statement addresses issues with the use of cannabis by individuals with cardiovascular disease or those at increased risk. Observational studies have shown no cardiovascular benefits associated with cannabis, the writers noted. The most common chemicals in cannabis include THC (tetrahydrocannabinolic acid) and CBD (cannabidiol).

Some research has shown associations between CBD cardiovascular features including lower blood pressure and reduced inflammation, the writers noted. However, THC, the component of cannabis associated with a “high” or intoxication, has been associated with heart rhythm abnormalities. The writers cited data suggesting an increased risk of heart attacks, atrial fibrillation and heart failure, although more research is needed.

The statement outlines common cannabis formulations including plant-based, extracts, crystalline forms, edible products, and tinctures. In addition, the statement notes that synthetic cannabis products are marketed and used in the United States without subject to regulation.

“Over the past 5 years, we have seen a surge in cannabis use, particularly during the COVID-19 pandemic here in Colorado, especially among adolescents and young adults,” Dr. Page said in an interview. Because of the surge, health care practitioners need to familiarize themselves with not only the benefits, but risks associated with cannabis use regardless of the formulation,” he said. As heart disease remains a leading cause of death in the United States, understanding the cardiovascular risks associated with cannabis is crucial at this time.

Dr. Page noted that popular attitudes about cannabis could pose risks to users’ cardiovascular health. “One leading misconception about cannabis is because it is ‘natural’ it must be safe,” Dr. Page said. “As with all medications, cannabis has side effects, some of which can be cardiovascular in nature,” he said. “Significant drug-drug interactions can occur as CBD and THC, both found in cannabis, inhibit CYP3A4, which metabolizes a large number of medications used to treat many cardiovascular conditions,” he noted.

“Unfortunately, much of the published data is observational in nature due to the federal restrictions on cannabis as a schedule I drug,” said Dr. Page. “Nonetheless, safety signals have emerged regarding cannabis use and adverse cardiovascular outcomes, including myocardial infarction, heart failure, and atrial fibrillation. Carefully designed prospective short- and long-term studies regarding cannabis use and cardiovascular safety are needed,” he emphasized.

Areas in particular need of additional research include the cardiovascular effects of cannabis in several vulnerable populations such as adolescents, older adults, pregnant women, transplant recipients, and those with underlying cardiovascular disease, said Dr. Page.

“Nonetheless, based on the safety signals described within this Clinical Science Statement, an open discussion regarding the risks of using cannabis needs to occur between patient and health care providers,” he said. “Furthermore, patients must be transparent regarding their cannabis use with their cardiologist and primary care provider. The cannabis story will continue to evolve and is a rapidly moving/changing target,” he said.

“Whether cannabis use is a definitive risk factor for cardiovascular disease as with tobacco use is still unknown, and both acute and long-term studies are desperately needed to address this issue,” he said.

Dr. Page had no relevant financial conflicts to disclose.

SOURCE: Page et al. Circulation. 2020 Aug 5. doi: 10.1161/CIR.0000000000000883.

Evidence for a link between cannabis use and cardiovascular health remains unsupported, and the potential risks outweigh any potential benefits, according to a scientific statement from the American Heart Association.

American Heart Association

The increased legalization of cannabis and cannabis products in the United States has driven medical professionals to evaluate the safety and efficacy of cannabis in relation to health conditions, wrote Robert L. Page II, PharmD, of the University of Colorado, Aurora, and colleagues.

In a statement published in Circulation, the researchers noted that although cannabis has been shown to relieve pain and other symptoms in certain conditions, clinicians in the United States have been limited from studying its health effects because of federal law restrictions. “Cannabis remains a schedule I controlled substance, deeming no accepted medical use, a high potential for abuse, and an unacceptable safety profile,” the researchers wrote.

The statement addresses issues with the use of cannabis by individuals with cardiovascular disease or those at increased risk. Observational studies have shown no cardiovascular benefits associated with cannabis, the writers noted. The most common chemicals in cannabis include THC (tetrahydrocannabinolic acid) and CBD (cannabidiol).

Some research has shown associations between CBD cardiovascular features including lower blood pressure and reduced inflammation, the writers noted. However, THC, the component of cannabis associated with a “high” or intoxication, has been associated with heart rhythm abnormalities. The writers cited data suggesting an increased risk of heart attacks, atrial fibrillation and heart failure, although more research is needed.

The statement outlines common cannabis formulations including plant-based, extracts, crystalline forms, edible products, and tinctures. In addition, the statement notes that synthetic cannabis products are marketed and used in the United States without subject to regulation.

“Over the past 5 years, we have seen a surge in cannabis use, particularly during the COVID-19 pandemic here in Colorado, especially among adolescents and young adults,” Dr. Page said in an interview. Because of the surge, health care practitioners need to familiarize themselves with not only the benefits, but risks associated with cannabis use regardless of the formulation,” he said. As heart disease remains a leading cause of death in the United States, understanding the cardiovascular risks associated with cannabis is crucial at this time.

Dr. Page noted that popular attitudes about cannabis could pose risks to users’ cardiovascular health. “One leading misconception about cannabis is because it is ‘natural’ it must be safe,” Dr. Page said. “As with all medications, cannabis has side effects, some of which can be cardiovascular in nature,” he said. “Significant drug-drug interactions can occur as CBD and THC, both found in cannabis, inhibit CYP3A4, which metabolizes a large number of medications used to treat many cardiovascular conditions,” he noted.

“Unfortunately, much of the published data is observational in nature due to the federal restrictions on cannabis as a schedule I drug,” said Dr. Page. “Nonetheless, safety signals have emerged regarding cannabis use and adverse cardiovascular outcomes, including myocardial infarction, heart failure, and atrial fibrillation. Carefully designed prospective short- and long-term studies regarding cannabis use and cardiovascular safety are needed,” he emphasized.

Areas in particular need of additional research include the cardiovascular effects of cannabis in several vulnerable populations such as adolescents, older adults, pregnant women, transplant recipients, and those with underlying cardiovascular disease, said Dr. Page.

“Nonetheless, based on the safety signals described within this Clinical Science Statement, an open discussion regarding the risks of using cannabis needs to occur between patient and health care providers,” he said. “Furthermore, patients must be transparent regarding their cannabis use with their cardiologist and primary care provider. The cannabis story will continue to evolve and is a rapidly moving/changing target,” he said.

“Whether cannabis use is a definitive risk factor for cardiovascular disease as with tobacco use is still unknown, and both acute and long-term studies are desperately needed to address this issue,” he said.

Dr. Page had no relevant financial conflicts to disclose.

SOURCE: Page et al. Circulation. 2020 Aug 5. doi: 10.1161/CIR.0000000000000883.

Evidence for a link between cannabis use and cardiovascular health remains unsupported, and the potential risks outweigh any potential benefits, according to a scientific statement from the American Heart Association.

American Heart Association

The increased legalization of cannabis and cannabis products in the United States has driven medical professionals to evaluate the safety and efficacy of cannabis in relation to health conditions, wrote Robert L. Page II, PharmD, of the University of Colorado, Aurora, and colleagues.

In a statement published in Circulation, the researchers noted that although cannabis has been shown to relieve pain and other symptoms in certain conditions, clinicians in the United States have been limited from studying its health effects because of federal law restrictions. “Cannabis remains a schedule I controlled substance, deeming no accepted medical use, a high potential for abuse, and an unacceptable safety profile,” the researchers wrote.

The statement addresses issues with the use of cannabis by individuals with cardiovascular disease or those at increased risk. Observational studies have shown no cardiovascular benefits associated with cannabis, the writers noted. The most common chemicals in cannabis include THC (tetrahydrocannabinolic acid) and CBD (cannabidiol).

Some research has shown associations between CBD cardiovascular features including lower blood pressure and reduced inflammation, the writers noted. However, THC, the component of cannabis associated with a “high” or intoxication, has been associated with heart rhythm abnormalities. The writers cited data suggesting an increased risk of heart attacks, atrial fibrillation and heart failure, although more research is needed.

The statement outlines common cannabis formulations including plant-based, extracts, crystalline forms, edible products, and tinctures. In addition, the statement notes that synthetic cannabis products are marketed and used in the United States without subject to regulation.

“Over the past 5 years, we have seen a surge in cannabis use, particularly during the COVID-19 pandemic here in Colorado, especially among adolescents and young adults,” Dr. Page said in an interview. Because of the surge, health care practitioners need to familiarize themselves with not only the benefits, but risks associated with cannabis use regardless of the formulation,” he said. As heart disease remains a leading cause of death in the United States, understanding the cardiovascular risks associated with cannabis is crucial at this time.

Dr. Page noted that popular attitudes about cannabis could pose risks to users’ cardiovascular health. “One leading misconception about cannabis is because it is ‘natural’ it must be safe,” Dr. Page said. “As with all medications, cannabis has side effects, some of which can be cardiovascular in nature,” he said. “Significant drug-drug interactions can occur as CBD and THC, both found in cannabis, inhibit CYP3A4, which metabolizes a large number of medications used to treat many cardiovascular conditions,” he noted.

“Unfortunately, much of the published data is observational in nature due to the federal restrictions on cannabis as a schedule I drug,” said Dr. Page. “Nonetheless, safety signals have emerged regarding cannabis use and adverse cardiovascular outcomes, including myocardial infarction, heart failure, and atrial fibrillation. Carefully designed prospective short- and long-term studies regarding cannabis use and cardiovascular safety are needed,” he emphasized.

Areas in particular need of additional research include the cardiovascular effects of cannabis in several vulnerable populations such as adolescents, older adults, pregnant women, transplant recipients, and those with underlying cardiovascular disease, said Dr. Page.

“Nonetheless, based on the safety signals described within this Clinical Science Statement, an open discussion regarding the risks of using cannabis needs to occur between patient and health care providers,” he said. “Furthermore, patients must be transparent regarding their cannabis use with their cardiologist and primary care provider. The cannabis story will continue to evolve and is a rapidly moving/changing target,” he said.

“Whether cannabis use is a definitive risk factor for cardiovascular disease as with tobacco use is still unknown, and both acute and long-term studies are desperately needed to address this issue,” he said.

Dr. Page had no relevant financial conflicts to disclose.

SOURCE: Page et al. Circulation. 2020 Aug 5. doi: 10.1161/CIR.0000000000000883.

Women undergoing vaginal surgery have better physical function after 6 weeks when they are positioned in boot stirrups rather than candy cane stirrups, according to the first randomized controlled trial comparing both types of lithotomy stirrups.

“Participants positioned in candy cane stirrups had greater hip abduction than those positioned in boot stirrups, which could provide a rationale for our findings,” suggested Ankita Gupta, MD, MPH, of the University of Louisville (Ky.), and colleagues. Their report is in Obstetrics & Gynecology.

But one expert questions this interpretation, calling it a major limitation of the study.

“The only difference between the two arms of the study is associated with the angles between the femurs,” said Rosanne M. Kho, MD, a gynecologic surgeon at Cleveland Clinic, who was not involved in the study. “The difference of the angles at the femur is not inherent to the type of stirrup but in the method in which the patients were positioned using the two different types of stirrups,” she said. “The same wide angle between the femurs can be attained with the boot stirrups if the patient is not positioned properly. To determine if the same benefit in physical function is achieved with a lesser angle between the femur, the investigators should use only one type of stirrup (whether the candy cane or the boot stirrups) and change only the angles of the femur.”

The study was a single-masked, randomized controlled trial of women undergoing vaginal surgery at the University of Louisville’s division of urogynecology between March 2018 and Oct. 2019. Surgeries included any combination of vaginal hysterectomy, vaginal vault suspension (uterosacral or sacrospinous ligament fixation), vaginectomy (partial or total), mid-urethral slings, or other surgeries such as urethral diverticulectomy, fistula repair, or mesh excision.

Among the 138 women included in the intention-to-treat analysis, 72 were randomized to candy cane, and 66 to boot (Yellofin) stirrups. They were positioned in the assigned stirrup by the attending surgeon, with assistance from the surgical team, after administration of anesthesia and were not informed of their allocation until the end of the study at 6 weeks post surgery.

On day 1 post surgery, a 100-point visual analog scale (VAS) questionnaire was administered for pain in the lower back, hips, buttocks, thighs, knees, calves, and feet, followed by a series of questionnaires at 6 weeks post surgery, including the PROMIS (Patient-Reported Outcomes Measurement Information System) forms on physical function, pain intensity, and pain interference, as well as the Pelvic Floor Disability Index (PFDI-20) and the Patient Global Impression of Improvement forms.

While the authors acknowledged that neurologic injuries following vaginal surgery are rare, and therefore difficult to measure, physical function is a “prudent” alternative measurement.

Although the study was designed to compare lithotomy stirrups, patient positioning also was measured. Once the patient was anesthetized, the surgeon used a goniometer to measure flexion at the hip and knee joints, the angle of abduction and external rotation at the hip. The “angle between the femurs” was measured by placing the fulcrum of the goniometer at the anal opening.

While the angles of flexion at the hips and knees were similar between groups, the study found a significant difference between groups in the angle between the femurs (mean ± standard deviation, 88.7 ± 13.4 candy cane vs. 77.2 ± 13.3 boot, P < .01).

In addition, the primary outcome, change in physical function based on the PROMIS physical function shortform-20a, was significantly different between the two groups: While subjects in the candy cane group demonstrated a decline of 1.9 in mean physical function score at 6 weeks compared to baseline, those in the boot stirrup group showed an increase of 1.9 from baseline. The mean 6-week postoperative scores were 45.8 versus 49.8 for the candy cane and boot stirrup groups respectively (P < .01).

Although it was “well executed by a well-respected group of vaginal surgeons at a major academic institution,” the study has other limitations, noted Dr. Kho.

“Though the measurements were obtained with the goniometer at the beginning of the surgery, it does not appear that a repeat measurement was performed at the end of the case. Is it possible that positioning could have shifted and resulted in further change in the angle of the femur/hip/knees compared to the beginning of the surgery?” she asked.

In addition, “compared to the candy canes, the boot stirrup has bulky boots that could limit opportunities for bedside assistants who were standing next to the primary surgeon to lean against the patient’s thighs during the surgery. Were there measures done to ensure that assistants were not leaning against the [candy cane] patients?”

In terms of the 6-week outcome measure, Dr. Kho suggested PROMIS outcomes measured at 2 weeks and at 4 or 6 weeks “would have provided greater insight to the study question.

“The authors acknowledge that neuropathies due to patient positioning manifest soon after surgery and tend to be transient. Incidence of neuropathy is extremely low in both groups and is equivalent. Factors that could impair quick return to normal activity as a result of the neuromuscular effects due to patient positioning should have been measured earlier,” she suggested.

Finally, Dr. Kho noted that the authors “fail to provide any likely rationale for the impaired physical function measured at 6 weeks that can be attributed to the difference in the angles at the femur. The findings of decreased physical function at 6 weeks in the candy cane group may be incidental, and may be different if measured at an earlier time (which would be more pertinent for this study) or at a later time such as 3 months.”

Individual authors acknowledged personal funds from Society of Gynecologic Surgeons, Elsevier publishing, RBI Medical, and AMAG Pharmaceuticals. Dr. Kho had no relevant financial disclosures.

SOURCE: Gupta A et al. Obstet Gynecol. 2020 July 8. doi: 10.1097/AOG.0000000000003954.

Women undergoing vaginal surgery have better physical function after 6 weeks when they are positioned in boot stirrups rather than candy cane stirrups, according to the first randomized controlled trial comparing both types of lithotomy stirrups.

“Participants positioned in candy cane stirrups had greater hip abduction than those positioned in boot stirrups, which could provide a rationale for our findings,” suggested Ankita Gupta, MD, MPH, of the University of Louisville (Ky.), and colleagues. Their report is in Obstetrics & Gynecology.

But one expert questions this interpretation, calling it a major limitation of the study.

“The only difference between the two arms of the study is associated with the angles between the femurs,” said Rosanne M. Kho, MD, a gynecologic surgeon at Cleveland Clinic, who was not involved in the study. “The difference of the angles at the femur is not inherent to the type of stirrup but in the method in which the patients were positioned using the two different types of stirrups,” she said. “The same wide angle between the femurs can be attained with the boot stirrups if the patient is not positioned properly. To determine if the same benefit in physical function is achieved with a lesser angle between the femur, the investigators should use only one type of stirrup (whether the candy cane or the boot stirrups) and change only the angles of the femur.”

The study was a single-masked, randomized controlled trial of women undergoing vaginal surgery at the University of Louisville’s division of urogynecology between March 2018 and Oct. 2019. Surgeries included any combination of vaginal hysterectomy, vaginal vault suspension (uterosacral or sacrospinous ligament fixation), vaginectomy (partial or total), mid-urethral slings, or other surgeries such as urethral diverticulectomy, fistula repair, or mesh excision.

Among the 138 women included in the intention-to-treat analysis, 72 were randomized to candy cane, and 66 to boot (Yellofin) stirrups. They were positioned in the assigned stirrup by the attending surgeon, with assistance from the surgical team, after administration of anesthesia and were not informed of their allocation until the end of the study at 6 weeks post surgery.

On day 1 post surgery, a 100-point visual analog scale (VAS) questionnaire was administered for pain in the lower back, hips, buttocks, thighs, knees, calves, and feet, followed by a series of questionnaires at 6 weeks post surgery, including the PROMIS (Patient-Reported Outcomes Measurement Information System) forms on physical function, pain intensity, and pain interference, as well as the Pelvic Floor Disability Index (PFDI-20) and the Patient Global Impression of Improvement forms.

While the authors acknowledged that neurologic injuries following vaginal surgery are rare, and therefore difficult to measure, physical function is a “prudent” alternative measurement.

Although the study was designed to compare lithotomy stirrups, patient positioning also was measured. Once the patient was anesthetized, the surgeon used a goniometer to measure flexion at the hip and knee joints, the angle of abduction and external rotation at the hip. The “angle between the femurs” was measured by placing the fulcrum of the goniometer at the anal opening.

While the angles of flexion at the hips and knees were similar between groups, the study found a significant difference between groups in the angle between the femurs (mean ± standard deviation, 88.7 ± 13.4 candy cane vs. 77.2 ± 13.3 boot, P < .01).

In addition, the primary outcome, change in physical function based on the PROMIS physical function shortform-20a, was significantly different between the two groups: While subjects in the candy cane group demonstrated a decline of 1.9 in mean physical function score at 6 weeks compared to baseline, those in the boot stirrup group showed an increase of 1.9 from baseline. The mean 6-week postoperative scores were 45.8 versus 49.8 for the candy cane and boot stirrup groups respectively (P < .01).

Although it was “well executed by a well-respected group of vaginal surgeons at a major academic institution,” the study has other limitations, noted Dr. Kho.

“Though the measurements were obtained with the goniometer at the beginning of the surgery, it does not appear that a repeat measurement was performed at the end of the case. Is it possible that positioning could have shifted and resulted in further change in the angle of the femur/hip/knees compared to the beginning of the surgery?” she asked.

In addition, “compared to the candy canes, the boot stirrup has bulky boots that could limit opportunities for bedside assistants who were standing next to the primary surgeon to lean against the patient’s thighs during the surgery. Were there measures done to ensure that assistants were not leaning against the [candy cane] patients?”

In terms of the 6-week outcome measure, Dr. Kho suggested PROMIS outcomes measured at 2 weeks and at 4 or 6 weeks “would have provided greater insight to the study question.

“The authors acknowledge that neuropathies due to patient positioning manifest soon after surgery and tend to be transient. Incidence of neuropathy is extremely low in both groups and is equivalent. Factors that could impair quick return to normal activity as a result of the neuromuscular effects due to patient positioning should have been measured earlier,” she suggested.

Finally, Dr. Kho noted that the authors “fail to provide any likely rationale for the impaired physical function measured at 6 weeks that can be attributed to the difference in the angles at the femur. The findings of decreased physical function at 6 weeks in the candy cane group may be incidental, and may be different if measured at an earlier time (which would be more pertinent for this study) or at a later time such as 3 months.”

Individual authors acknowledged personal funds from Society of Gynecologic Surgeons, Elsevier publishing, RBI Medical, and AMAG Pharmaceuticals. Dr. Kho had no relevant financial disclosures.

SOURCE: Gupta A et al. Obstet Gynecol. 2020 July 8. doi: 10.1097/AOG.0000000000003954.

Women undergoing vaginal surgery have better physical function after 6 weeks when they are positioned in boot stirrups rather than candy cane stirrups, according to the first randomized controlled trial comparing both types of lithotomy stirrups.

“Participants positioned in candy cane stirrups had greater hip abduction than those positioned in boot stirrups, which could provide a rationale for our findings,” suggested Ankita Gupta, MD, MPH, of the University of Louisville (Ky.), and colleagues. Their report is in Obstetrics & Gynecology.

But one expert questions this interpretation, calling it a major limitation of the study.

“The only difference between the two arms of the study is associated with the angles between the femurs,” said Rosanne M. Kho, MD, a gynecologic surgeon at Cleveland Clinic, who was not involved in the study. “The difference of the angles at the femur is not inherent to the type of stirrup but in the method in which the patients were positioned using the two different types of stirrups,” she said. “The same wide angle between the femurs can be attained with the boot stirrups if the patient is not positioned properly. To determine if the same benefit in physical function is achieved with a lesser angle between the femur, the investigators should use only one type of stirrup (whether the candy cane or the boot stirrups) and change only the angles of the femur.”

The study was a single-masked, randomized controlled trial of women undergoing vaginal surgery at the University of Louisville’s division of urogynecology between March 2018 and Oct. 2019. Surgeries included any combination of vaginal hysterectomy, vaginal vault suspension (uterosacral or sacrospinous ligament fixation), vaginectomy (partial or total), mid-urethral slings, or other surgeries such as urethral diverticulectomy, fistula repair, or mesh excision.

Among the 138 women included in the intention-to-treat analysis, 72 were randomized to candy cane, and 66 to boot (Yellofin) stirrups. They were positioned in the assigned stirrup by the attending surgeon, with assistance from the surgical team, after administration of anesthesia and were not informed of their allocation until the end of the study at 6 weeks post surgery.

On day 1 post surgery, a 100-point visual analog scale (VAS) questionnaire was administered for pain in the lower back, hips, buttocks, thighs, knees, calves, and feet, followed by a series of questionnaires at 6 weeks post surgery, including the PROMIS (Patient-Reported Outcomes Measurement Information System) forms on physical function, pain intensity, and pain interference, as well as the Pelvic Floor Disability Index (PFDI-20) and the Patient Global Impression of Improvement forms.

While the authors acknowledged that neurologic injuries following vaginal surgery are rare, and therefore difficult to measure, physical function is a “prudent” alternative measurement.

Although the study was designed to compare lithotomy stirrups, patient positioning also was measured. Once the patient was anesthetized, the surgeon used a goniometer to measure flexion at the hip and knee joints, the angle of abduction and external rotation at the hip. The “angle between the femurs” was measured by placing the fulcrum of the goniometer at the anal opening.

While the angles of flexion at the hips and knees were similar between groups, the study found a significant difference between groups in the angle between the femurs (mean ± standard deviation, 88.7 ± 13.4 candy cane vs. 77.2 ± 13.3 boot, P < .01).

In addition, the primary outcome, change in physical function based on the PROMIS physical function shortform-20a, was significantly different between the two groups: While subjects in the candy cane group demonstrated a decline of 1.9 in mean physical function score at 6 weeks compared to baseline, those in the boot stirrup group showed an increase of 1.9 from baseline. The mean 6-week postoperative scores were 45.8 versus 49.8 for the candy cane and boot stirrup groups respectively (P < .01).

Although it was “well executed by a well-respected group of vaginal surgeons at a major academic institution,” the study has other limitations, noted Dr. Kho.

“Though the measurements were obtained with the goniometer at the beginning of the surgery, it does not appear that a repeat measurement was performed at the end of the case. Is it possible that positioning could have shifted and resulted in further change in the angle of the femur/hip/knees compared to the beginning of the surgery?” she asked.

In addition, “compared to the candy canes, the boot stirrup has bulky boots that could limit opportunities for bedside assistants who were standing next to the primary surgeon to lean against the patient’s thighs during the surgery. Were there measures done to ensure that assistants were not leaning against the [candy cane] patients?”

In terms of the 6-week outcome measure, Dr. Kho suggested PROMIS outcomes measured at 2 weeks and at 4 or 6 weeks “would have provided greater insight to the study question.

“The authors acknowledge that neuropathies due to patient positioning manifest soon after surgery and tend to be transient. Incidence of neuropathy is extremely low in both groups and is equivalent. Factors that could impair quick return to normal activity as a result of the neuromuscular effects due to patient positioning should have been measured earlier,” she suggested.

Finally, Dr. Kho noted that the authors “fail to provide any likely rationale for the impaired physical function measured at 6 weeks that can be attributed to the difference in the angles at the femur. The findings of decreased physical function at 6 weeks in the candy cane group may be incidental, and may be different if measured at an earlier time (which would be more pertinent for this study) or at a later time such as 3 months.”

Individual authors acknowledged personal funds from Society of Gynecologic Surgeons, Elsevier publishing, RBI Medical, and AMAG Pharmaceuticals. Dr. Kho had no relevant financial disclosures.

SOURCE: Gupta A et al. Obstet Gynecol. 2020 July 8. doi: 10.1097/AOG.0000000000003954.

Prostate cancer treatments have significant detrimental effects on patients’ quality of life, and these effects may have been downplayed or not fully appreciated, according to a presentation at the virtual annual congress of the European Association of Urology (EAU).

Results of EUPROMS – the first patient-driven, international, prostate cancer quality of life study – showed that fatigue, insomnia, urinary incontinence, and sexual function were worse with certain types of treatments.

“Quality of life is negatively impacted by any treatment for prostate cancer other than active surveillance,” said André Deschamps, the chairman of the patient advocacy movement Europa Uomo, which conducted the study with support from Erasmus University Medical Center in Rotterdam, the Netherlands.

Active surveillance “should be promoted as the first option for treatment for those men where it can be offered safely,” Mr. Deschamps said when presenting the study at the EAU congress.

The study showed that quality of life related to urinary incontinence was lowest in patients who had undergone radical prostatectomy, and sexual function was greatly affected by radiotherapy. Radiotherapy and chemotherapy had the greatest impact on patients’ levels of fatigue, and chemotherapy was associated with “the worst possible outcomes in quality of life,” Mr. Deschamps said.

Conversely, “reported quality of life scores are the best in patients where the cancer is discovered in an early, curable stage. Hence, efforts toward early detection and awareness are essential to avoid unnecessary deterioration in quality of life,” Mr. Deschamps said.
 

About the survey and respondents

Between August and November 2019, 2,943 prostate cancer patients from 24 European countries completed a web-based survey made available via the Europa Uomo website. The survey took around 20 minutes to complete and used three validated quality of life questionnaires, the EORTC-QLQ-C30, the EQ-5D-5L, and EPIC-26.

“The questionnaires were available in 19 languages, so every patient could answer in their mother tongue,” Mr. Deschamps pointed out, highlighting that this was a Europe-wide survey and was estimated to account for 0.1% of the patient population in Europe.

Countries with the highest number of respondents were Norway (n = 506), Sweden (n = 386), Belgium (n = 339), Germany (n = 253), Netherlands (n = 244), France (n = 234), Denmark (n = 188), the United Kingdom (n = 187), and Poland (n = 109).

The average age of respondents was 70 years at the time of the survey and 64 years at the time of diagnosis. Most patients (82%) were living with a partner.

Two-thirds of patients had received only one treatment for prostate cancer. This was most often radical prostatectomy, external beam radiotherapy, or active surveillance. Among the 22% of patients who had received two treatments, the therapies were most often a combination of surgery and radiotherapy, androgen deprivation therapy (ADT) and radiotherapy or chemotherapy, and active surveillance and surgery.
 

Fatigue and insomnia

According to the EORTC-QLQ-C30 symptoms questionnaire, fatigue and insomnia were particular problems for men with prostate cancer, as denoted by scores of 25 and 24, respectively, out of a possible 100. Low scores are associated with worse fatigue and insomnia.

The researchers focused their attention on how specific cancer treatments might influence fatigue. They found that radiotherapy doubled and chemotherapy tripled the number of patients reporting fatigue, when compared with active surveillance. The incidence of fatigue was 22% (n = 304), 33% (n = 246), and 11% (n = 179), respectively.

As for insomnia, “it’s bit of a mixed view,” Mr. Deschamps said. “We believe that the progression of disease is more important for insomnia. The only thing you can say is that chemotherapy leads to an increase in reported insomnia.”
 

Urinary continence and sexual function

The EPIC-26 questionnaire was used to look at the health-related quality of life domains of urinary and sexual function. Sexual function was the most impacted area.

“We often hear that decline in sexual functioning is a relatively small problem for prostate cancer patients, and the effect on their quality of life should not be exaggerated,” Mr. Deschamps said in a press statement.

“We also hear that prostate cancer is typically a disease of ‘old men,’ implying that the loss of sexual function is less relevant. This survey paints a different picture,” he added.

Higher EPIC-26 scores signify better function. For urinary incontinence, the score was 100/100 for active surveillance but 65/100 when active surveillance was combined with surgery and 71/100 for surgery alone. The combination of surgery and radiotherapy carried a score of 73/100 for urinary incontinence. Radiotherapy on its own had a score of 92/100, suggesting it was the addition of the surgery that was having a significant effect. The score for radiotherapy plus ADT was 100/100, and the score for chemotherapy was 86/100.

Chemotherapy appeared to have the worst effect on sexual function, with a score of just 12/100. Radiotherapy was not far behind at 17/100, and surgery alone was 21/100. When radiotherapy and surgery were combined, the score was 15/100.

Sexual function scores were also low for all the other treatments considered – 18/100 for radiotherapy and ADT, 26/100 for active surveillance and surgery, and 57/100 for active surveillance alone.
 

Implications for practice

“The data collected and the analysis done provide patients and healthcare professionals with a ‘snapshot’ on the impact of treatments based on the experience of fellow patients,” Mr. Deschamps said. “We hope these results will be used to establish and disseminate realistic expectations on the effects of different treatments for prostate cancer on [quality of life].”

“This study is important because it was initiated by patients and meant for patients,” noted Monique Roobol, PhD, professor of decision-making in urology at the Erasmus University Medical Center in Rotterdam, the Netherlands, where the survey data were analyzed.

“The questionnaires were completed unrelated to a hospital visit, which means respondents had more freedom to answer and provide insight into the effect of treatment on quality of life over a longer period,” she added.

“For me, the key point is that, as health care professionals, we have underestimated the impact on the quality of life for patients treated for prostate cancer,” said Hein van Poppel, MD, PhD, of University Hospitals Leuven (Belgium), who chaired the session in which the data were presented.

Arnulf Stenzl, MD, of Tübingen (Germany) University said in a statement that the survey provided valuable information. “It uses the same questionnaires used in standard clinical settings, but it is both qualitatively and quantitatively different to the kind of study usually undertaken, so it needs to be read alongside these previous studies,” Dr. Stenzl said.

There were several strong points, he said, such as the fact that EUPROMS was the largest study of its kind and thus would “reflect the impact of treatment on a wide range of patients, with different health systems.”

As an official EAU spokesperson, Dr. Stenzl added, “We completely agree that early detection and treatment is essential if we are to avoid problems with quality of life later on. It shows that, for many men, quality of life can be poor after most prostate cancer treatment, especially in advanced disease. This message is clear, and we need to listen to the voices of these patients.”

EUPROMS was conducted by Europa Uomo in conjunction with the Erasmus University Medical Centre in Rotterdam, the Netherlands. Funding was received from Bayer, Ipsen, and Janssen. The companies had no influence over any aspect of the study. The commentators did not have conflicts of interest to disclose.

Prostate cancer treatments have significant detrimental effects on patients’ quality of life, and these effects may have been downplayed or not fully appreciated, according to a presentation at the virtual annual congress of the European Association of Urology (EAU).

Results of EUPROMS – the first patient-driven, international, prostate cancer quality of life study – showed that fatigue, insomnia, urinary incontinence, and sexual function were worse with certain types of treatments.

“Quality of life is negatively impacted by any treatment for prostate cancer other than active surveillance,” said André Deschamps, the chairman of the patient advocacy movement Europa Uomo, which conducted the study with support from Erasmus University Medical Center in Rotterdam, the Netherlands.

Active surveillance “should be promoted as the first option for treatment for those men where it can be offered safely,” Mr. Deschamps said when presenting the study at the EAU congress.

The study showed that quality of life related to urinary incontinence was lowest in patients who had undergone radical prostatectomy, and sexual function was greatly affected by radiotherapy. Radiotherapy and chemotherapy had the greatest impact on patients’ levels of fatigue, and chemotherapy was associated with “the worst possible outcomes in quality of life,” Mr. Deschamps said.

Conversely, “reported quality of life scores are the best in patients where the cancer is discovered in an early, curable stage. Hence, efforts toward early detection and awareness are essential to avoid unnecessary deterioration in quality of life,” Mr. Deschamps said.
 

About the survey and respondents

Between August and November 2019, 2,943 prostate cancer patients from 24 European countries completed a web-based survey made available via the Europa Uomo website. The survey took around 20 minutes to complete and used three validated quality of life questionnaires, the EORTC-QLQ-C30, the EQ-5D-5L, and EPIC-26.

“The questionnaires were available in 19 languages, so every patient could answer in their mother tongue,” Mr. Deschamps pointed out, highlighting that this was a Europe-wide survey and was estimated to account for 0.1% of the patient population in Europe.

Countries with the highest number of respondents were Norway (n = 506), Sweden (n = 386), Belgium (n = 339), Germany (n = 253), Netherlands (n = 244), France (n = 234), Denmark (n = 188), the United Kingdom (n = 187), and Poland (n = 109).

The average age of respondents was 70 years at the time of the survey and 64 years at the time of diagnosis. Most patients (82%) were living with a partner.

Two-thirds of patients had received only one treatment for prostate cancer. This was most often radical prostatectomy, external beam radiotherapy, or active surveillance. Among the 22% of patients who had received two treatments, the therapies were most often a combination of surgery and radiotherapy, androgen deprivation therapy (ADT) and radiotherapy or chemotherapy, and active surveillance and surgery.
 

Fatigue and insomnia

According to the EORTC-QLQ-C30 symptoms questionnaire, fatigue and insomnia were particular problems for men with prostate cancer, as denoted by scores of 25 and 24, respectively, out of a possible 100. Low scores are associated with worse fatigue and insomnia.

The researchers focused their attention on how specific cancer treatments might influence fatigue. They found that radiotherapy doubled and chemotherapy tripled the number of patients reporting fatigue, when compared with active surveillance. The incidence of fatigue was 22% (n = 304), 33% (n = 246), and 11% (n = 179), respectively.

As for insomnia, “it’s bit of a mixed view,” Mr. Deschamps said. “We believe that the progression of disease is more important for insomnia. The only thing you can say is that chemotherapy leads to an increase in reported insomnia.”
 

Urinary continence and sexual function

The EPIC-26 questionnaire was used to look at the health-related quality of life domains of urinary and sexual function. Sexual function was the most impacted area.

“We often hear that decline in sexual functioning is a relatively small problem for prostate cancer patients, and the effect on their quality of life should not be exaggerated,” Mr. Deschamps said in a press statement.

“We also hear that prostate cancer is typically a disease of ‘old men,’ implying that the loss of sexual function is less relevant. This survey paints a different picture,” he added.

Higher EPIC-26 scores signify better function. For urinary incontinence, the score was 100/100 for active surveillance but 65/100 when active surveillance was combined with surgery and 71/100 for surgery alone. The combination of surgery and radiotherapy carried a score of 73/100 for urinary incontinence. Radiotherapy on its own had a score of 92/100, suggesting it was the addition of the surgery that was having a significant effect. The score for radiotherapy plus ADT was 100/100, and the score for chemotherapy was 86/100.

Chemotherapy appeared to have the worst effect on sexual function, with a score of just 12/100. Radiotherapy was not far behind at 17/100, and surgery alone was 21/100. When radiotherapy and surgery were combined, the score was 15/100.

Sexual function scores were also low for all the other treatments considered – 18/100 for radiotherapy and ADT, 26/100 for active surveillance and surgery, and 57/100 for active surveillance alone.
 

Implications for practice

“The data collected and the analysis done provide patients and healthcare professionals with a ‘snapshot’ on the impact of treatments based on the experience of fellow patients,” Mr. Deschamps said. “We hope these results will be used to establish and disseminate realistic expectations on the effects of different treatments for prostate cancer on [quality of life].”

“This study is important because it was initiated by patients and meant for patients,” noted Monique Roobol, PhD, professor of decision-making in urology at the Erasmus University Medical Center in Rotterdam, the Netherlands, where the survey data were analyzed.

“The questionnaires were completed unrelated to a hospital visit, which means respondents had more freedom to answer and provide insight into the effect of treatment on quality of life over a longer period,” she added.

“For me, the key point is that, as health care professionals, we have underestimated the impact on the quality of life for patients treated for prostate cancer,” said Hein van Poppel, MD, PhD, of University Hospitals Leuven (Belgium), who chaired the session in which the data were presented.

Arnulf Stenzl, MD, of Tübingen (Germany) University said in a statement that the survey provided valuable information. “It uses the same questionnaires used in standard clinical settings, but it is both qualitatively and quantitatively different to the kind of study usually undertaken, so it needs to be read alongside these previous studies,” Dr. Stenzl said.

There were several strong points, he said, such as the fact that EUPROMS was the largest study of its kind and thus would “reflect the impact of treatment on a wide range of patients, with different health systems.”

As an official EAU spokesperson, Dr. Stenzl added, “We completely agree that early detection and treatment is essential if we are to avoid problems with quality of life later on. It shows that, for many men, quality of life can be poor after most prostate cancer treatment, especially in advanced disease. This message is clear, and we need to listen to the voices of these patients.”

EUPROMS was conducted by Europa Uomo in conjunction with the Erasmus University Medical Centre in Rotterdam, the Netherlands. Funding was received from Bayer, Ipsen, and Janssen. The companies had no influence over any aspect of the study. The commentators did not have conflicts of interest to disclose.

Prostate cancer treatments have significant detrimental effects on patients’ quality of life, and these effects may have been downplayed or not fully appreciated, according to a presentation at the virtual annual congress of the European Association of Urology (EAU).

Results of EUPROMS – the first patient-driven, international, prostate cancer quality of life study – showed that fatigue, insomnia, urinary incontinence, and sexual function were worse with certain types of treatments.

“Quality of life is negatively impacted by any treatment for prostate cancer other than active surveillance,” said André Deschamps, the chairman of the patient advocacy movement Europa Uomo, which conducted the study with support from Erasmus University Medical Center in Rotterdam, the Netherlands.

Active surveillance “should be promoted as the first option for treatment for those men where it can be offered safely,” Mr. Deschamps said when presenting the study at the EAU congress.

The study showed that quality of life related to urinary incontinence was lowest in patients who had undergone radical prostatectomy, and sexual function was greatly affected by radiotherapy. Radiotherapy and chemotherapy had the greatest impact on patients’ levels of fatigue, and chemotherapy was associated with “the worst possible outcomes in quality of life,” Mr. Deschamps said.

Conversely, “reported quality of life scores are the best in patients where the cancer is discovered in an early, curable stage. Hence, efforts toward early detection and awareness are essential to avoid unnecessary deterioration in quality of life,” Mr. Deschamps said.
 

About the survey and respondents

Between August and November 2019, 2,943 prostate cancer patients from 24 European countries completed a web-based survey made available via the Europa Uomo website. The survey took around 20 minutes to complete and used three validated quality of life questionnaires, the EORTC-QLQ-C30, the EQ-5D-5L, and EPIC-26.

“The questionnaires were available in 19 languages, so every patient could answer in their mother tongue,” Mr. Deschamps pointed out, highlighting that this was a Europe-wide survey and was estimated to account for 0.1% of the patient population in Europe.

Countries with the highest number of respondents were Norway (n = 506), Sweden (n = 386), Belgium (n = 339), Germany (n = 253), Netherlands (n = 244), France (n = 234), Denmark (n = 188), the United Kingdom (n = 187), and Poland (n = 109).

The average age of respondents was 70 years at the time of the survey and 64 years at the time of diagnosis. Most patients (82%) were living with a partner.

Two-thirds of patients had received only one treatment for prostate cancer. This was most often radical prostatectomy, external beam radiotherapy, or active surveillance. Among the 22% of patients who had received two treatments, the therapies were most often a combination of surgery and radiotherapy, androgen deprivation therapy (ADT) and radiotherapy or chemotherapy, and active surveillance and surgery.
 

Fatigue and insomnia

According to the EORTC-QLQ-C30 symptoms questionnaire, fatigue and insomnia were particular problems for men with prostate cancer, as denoted by scores of 25 and 24, respectively, out of a possible 100. Low scores are associated with worse fatigue and insomnia.

The researchers focused their attention on how specific cancer treatments might influence fatigue. They found that radiotherapy doubled and chemotherapy tripled the number of patients reporting fatigue, when compared with active surveillance. The incidence of fatigue was 22% (n = 304), 33% (n = 246), and 11% (n = 179), respectively.

As for insomnia, “it’s bit of a mixed view,” Mr. Deschamps said. “We believe that the progression of disease is more important for insomnia. The only thing you can say is that chemotherapy leads to an increase in reported insomnia.”
 

Urinary continence and sexual function

The EPIC-26 questionnaire was used to look at the health-related quality of life domains of urinary and sexual function. Sexual function was the most impacted area.

“We often hear that decline in sexual functioning is a relatively small problem for prostate cancer patients, and the effect on their quality of life should not be exaggerated,” Mr. Deschamps said in a press statement.

“We also hear that prostate cancer is typically a disease of ‘old men,’ implying that the loss of sexual function is less relevant. This survey paints a different picture,” he added.

Higher EPIC-26 scores signify better function. For urinary incontinence, the score was 100/100 for active surveillance but 65/100 when active surveillance was combined with surgery and 71/100 for surgery alone. The combination of surgery and radiotherapy carried a score of 73/100 for urinary incontinence. Radiotherapy on its own had a score of 92/100, suggesting it was the addition of the surgery that was having a significant effect. The score for radiotherapy plus ADT was 100/100, and the score for chemotherapy was 86/100.

Chemotherapy appeared to have the worst effect on sexual function, with a score of just 12/100. Radiotherapy was not far behind at 17/100, and surgery alone was 21/100. When radiotherapy and surgery were combined, the score was 15/100.

Sexual function scores were also low for all the other treatments considered – 18/100 for radiotherapy and ADT, 26/100 for active surveillance and surgery, and 57/100 for active surveillance alone.
 

Implications for practice

“The data collected and the analysis done provide patients and healthcare professionals with a ‘snapshot’ on the impact of treatments based on the experience of fellow patients,” Mr. Deschamps said. “We hope these results will be used to establish and disseminate realistic expectations on the effects of different treatments for prostate cancer on [quality of life].”

“This study is important because it was initiated by patients and meant for patients,” noted Monique Roobol, PhD, professor of decision-making in urology at the Erasmus University Medical Center in Rotterdam, the Netherlands, where the survey data were analyzed.

“The questionnaires were completed unrelated to a hospital visit, which means respondents had more freedom to answer and provide insight into the effect of treatment on quality of life over a longer period,” she added.

“For me, the key point is that, as health care professionals, we have underestimated the impact on the quality of life for patients treated for prostate cancer,” said Hein van Poppel, MD, PhD, of University Hospitals Leuven (Belgium), who chaired the session in which the data were presented.

Arnulf Stenzl, MD, of Tübingen (Germany) University said in a statement that the survey provided valuable information. “It uses the same questionnaires used in standard clinical settings, but it is both qualitatively and quantitatively different to the kind of study usually undertaken, so it needs to be read alongside these previous studies,” Dr. Stenzl said.

There were several strong points, he said, such as the fact that EUPROMS was the largest study of its kind and thus would “reflect the impact of treatment on a wide range of patients, with different health systems.”

As an official EAU spokesperson, Dr. Stenzl added, “We completely agree that early detection and treatment is essential if we are to avoid problems with quality of life later on. It shows that, for many men, quality of life can be poor after most prostate cancer treatment, especially in advanced disease. This message is clear, and we need to listen to the voices of these patients.”

EUPROMS was conducted by Europa Uomo in conjunction with the Erasmus University Medical Centre in Rotterdam, the Netherlands. Funding was received from Bayer, Ipsen, and Janssen. The companies had no influence over any aspect of the study. The commentators did not have conflicts of interest to disclose.

Background: An estimated 600,000 patients in U.S. hospitals had an order placed in their record that was meant for another patient in 2016. The Office of the National Coordinator for Health Information Technology and the Joint Commission recommend that EHRs limit the number of open records to one at a time based on expert opinion only. There is wide variation in the number of open records allowed among EHRs across the United States currently.

Despite the ability to have up to four open records at one time in the unrestricted group, 66% of the order sessions were completed with only one record open in that group. This limited the power of the study to detect a difference in risk of order errors between the restricted and unrestricted groups.

Bottom line: Limiting clinicians to only one open record did not reduce the proportion of wrong-patient orders, compared with allowing up to four open records concurrently.

Citation: Adelman JS et al. Effect of restriction of the number of concurrently open records in an electronic health record on wrong-patient order errors: A randomized clinical trial. JAMA. 2019;32(18):1780-7.

Dr. Field is a hospitalist at Ochsner Health System, New Orleans.

Background: An estimated 600,000 patients in U.S. hospitals had an order placed in their record that was meant for another patient in 2016. The Office of the National Coordinator for Health Information Technology and the Joint Commission recommend that EHRs limit the number of open records to one at a time based on expert opinion only. There is wide variation in the number of open records allowed among EHRs across the United States currently.

Despite the ability to have up to four open records at one time in the unrestricted group, 66% of the order sessions were completed with only one record open in that group. This limited the power of the study to detect a difference in risk of order errors between the restricted and unrestricted groups.

Bottom line: Limiting clinicians to only one open record did not reduce the proportion of wrong-patient orders, compared with allowing up to four open records concurrently.

Citation: Adelman JS et al. Effect of restriction of the number of concurrently open records in an electronic health record on wrong-patient order errors: A randomized clinical trial. JAMA. 2019;32(18):1780-7.

Dr. Field is a hospitalist at Ochsner Health System, New Orleans.

Background: An estimated 600,000 patients in U.S. hospitals had an order placed in their record that was meant for another patient in 2016. The Office of the National Coordinator for Health Information Technology and the Joint Commission recommend that EHRs limit the number of open records to one at a time based on expert opinion only. There is wide variation in the number of open records allowed among EHRs across the United States currently.

Despite the ability to have up to four open records at one time in the unrestricted group, 66% of the order sessions were completed with only one record open in that group. This limited the power of the study to detect a difference in risk of order errors between the restricted and unrestricted groups.

Bottom line: Limiting clinicians to only one open record did not reduce the proportion of wrong-patient orders, compared with allowing up to four open records concurrently.

Citation: Adelman JS et al. Effect of restriction of the number of concurrently open records in an electronic health record on wrong-patient order errors: A randomized clinical trial. JAMA. 2019;32(18):1780-7.

Dr. Field is a hospitalist at Ochsner Health System, New Orleans.

An observational cohort study of a prospective international database of patients with multiple sclerosis has reported that medical therapy can reduce disability progression in patients with active secondary progressive MS (SPMS) who are prone to inflammatory relapses.

Brian Hoyle/MDedge News

The international researchers, led by Nathanial Lizak, MMBS, of the University of Melbourne, conducted the cohort study of 1,621 patients with SPMS from the MSBase international registry, which prospectively collected the information from 1995 to 2018. Their findings were published in JAMA Neurology.

“Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent,” wrote Dr. Lizak and colleagues of the MSBase Study Group.
 

Therapy’s impact on disease progression

To ensure that they had timely data on the early disease course of all study patients, they researchers only included patients whose diagnosis and first documented Expanded Disability Status Scale (EDSS) score were no more than 24 months apart. At SPMS conversion, 1,494 patients had an EDSS score of less than 7 (on a scale of 0-10); during the follow-up period, 267 of them (17.9%) crossed over the threshold of 7.

Dr. Lizak and colleagues noted that early treatment during relapsing remitting MS didn’t impact outcomes after SPMS conversion.

For evaluating the MS Severity Score (MSSS), the study split the cohort into three groups depending on the efficacy of therapy: low-efficacy treatments, mostly consisting of interferon-beta and glatiramer acetate; medium-efficacy treatments, mostly fingolimod and dimethyl fumarate; and high-efficacy treatments, predominately natalizumab and mitoxantrone.

The MSSS progression slope in the cohort had an average reduction of 0.02 points per year. “For patients who experienced superimposed relapses during SPMS, a reduced MSSS progression slope during SPMS was observed among those who received disease-modifying therapies for a greater proportion of time during SPMS,” Dr. Lizak and colleagues wrote.

MSSS progression slope reduction was more pronounced in the medium- and high-efficacy groups, with a reduction of beta 0.22 (P = .06) and 0.034 (P = .002), respectively.

“Based on our models, the level of disability in patients with active SPMS who are continuously treated with high-efficacy immunotherapies would progress more slowly in comparison with the general population with MS by a mean (standard deviation) of 1.56 (4.60) deciles over 10 years,” Dr. Lizak and colleagues wrote.

While the researchers cited a number of studies that didn’t support immunotherapy for SPMS, they also did cite the EXPAND trial to support treatment with siponimod in SPMS patients (Lancet. 2018;391:1263-73). The ASCEND trial of natalizumab enrolled a largely relapse-free cohort and found no link between treatment and disability progression in SPMS (Lancet Neurol. 2018;17:405-15), and a previous report by the MSBase Study Group found no benefit of therapy when adjusted for SPMS relapse rates (Neurology. 2017;89:1050-9).

“Together with the present study, the existing data converge on the suggestion that relapses during SPMS provide a therapeutic target and a marker of future response to immunotherapy during SPMS,” Dr. Lizak and colleagues wrote.
 

Challenging dogma

Commenting on the research, Mark Freedman, HBSc, MSc, MD, said that the MSBase study makes an important contribution to the literature on management of SPMS. “Up until this point we’ve been basing our assumptions on secondary progressive MS on natural history studies, which are actually quite old, dating back 20-30 years.” Dr. Freedman is senior scientist in the Neuroscience Program at the Ottawa Hospital Research Institute and professor of medicine in neurology at the University of Ottawa.

He said “the most damaging” of those studies was by the late Christian Confavreaux, MD, and colleagues in Lyon, France (N Engl J Med. 2000;343:1430-8), that reported relapses didn’t alter the progression of disability. “In other words, once you’re in EDSS of 4, it’s a runaway train; it doesn’t matter what you do,” Dr. Freedman said.

“That was kind of dogma for years,” he said. “The reason this publication is important is because it’s suggesting that’s not the case.” In other words, the MSBase cohort study is validating what neurologists have been doing in the real world for years: treating patients with SPMS who have relapses.

Dr Lizak reported receiving travel compensation from Merck outside the scope of the study. His coauthors reported numerous financial relationships.

SOURCE: Lizak N et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2453

An observational cohort study of a prospective international database of patients with multiple sclerosis has reported that medical therapy can reduce disability progression in patients with active secondary progressive MS (SPMS) who are prone to inflammatory relapses.

Brian Hoyle/MDedge News

The international researchers, led by Nathanial Lizak, MMBS, of the University of Melbourne, conducted the cohort study of 1,621 patients with SPMS from the MSBase international registry, which prospectively collected the information from 1995 to 2018. Their findings were published in JAMA Neurology.

“Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent,” wrote Dr. Lizak and colleagues of the MSBase Study Group.
 

Therapy’s impact on disease progression

To ensure that they had timely data on the early disease course of all study patients, they researchers only included patients whose diagnosis and first documented Expanded Disability Status Scale (EDSS) score were no more than 24 months apart. At SPMS conversion, 1,494 patients had an EDSS score of less than 7 (on a scale of 0-10); during the follow-up period, 267 of them (17.9%) crossed over the threshold of 7.

Dr. Lizak and colleagues noted that early treatment during relapsing remitting MS didn’t impact outcomes after SPMS conversion.

For evaluating the MS Severity Score (MSSS), the study split the cohort into three groups depending on the efficacy of therapy: low-efficacy treatments, mostly consisting of interferon-beta and glatiramer acetate; medium-efficacy treatments, mostly fingolimod and dimethyl fumarate; and high-efficacy treatments, predominately natalizumab and mitoxantrone.

The MSSS progression slope in the cohort had an average reduction of 0.02 points per year. “For patients who experienced superimposed relapses during SPMS, a reduced MSSS progression slope during SPMS was observed among those who received disease-modifying therapies for a greater proportion of time during SPMS,” Dr. Lizak and colleagues wrote.

MSSS progression slope reduction was more pronounced in the medium- and high-efficacy groups, with a reduction of beta 0.22 (P = .06) and 0.034 (P = .002), respectively.

“Based on our models, the level of disability in patients with active SPMS who are continuously treated with high-efficacy immunotherapies would progress more slowly in comparison with the general population with MS by a mean (standard deviation) of 1.56 (4.60) deciles over 10 years,” Dr. Lizak and colleagues wrote.

While the researchers cited a number of studies that didn’t support immunotherapy for SPMS, they also did cite the EXPAND trial to support treatment with siponimod in SPMS patients (Lancet. 2018;391:1263-73). The ASCEND trial of natalizumab enrolled a largely relapse-free cohort and found no link between treatment and disability progression in SPMS (Lancet Neurol. 2018;17:405-15), and a previous report by the MSBase Study Group found no benefit of therapy when adjusted for SPMS relapse rates (Neurology. 2017;89:1050-9).

“Together with the present study, the existing data converge on the suggestion that relapses during SPMS provide a therapeutic target and a marker of future response to immunotherapy during SPMS,” Dr. Lizak and colleagues wrote.
 

Challenging dogma

Commenting on the research, Mark Freedman, HBSc, MSc, MD, said that the MSBase study makes an important contribution to the literature on management of SPMS. “Up until this point we’ve been basing our assumptions on secondary progressive MS on natural history studies, which are actually quite old, dating back 20-30 years.” Dr. Freedman is senior scientist in the Neuroscience Program at the Ottawa Hospital Research Institute and professor of medicine in neurology at the University of Ottawa.

He said “the most damaging” of those studies was by the late Christian Confavreaux, MD, and colleagues in Lyon, France (N Engl J Med. 2000;343:1430-8), that reported relapses didn’t alter the progression of disability. “In other words, once you’re in EDSS of 4, it’s a runaway train; it doesn’t matter what you do,” Dr. Freedman said.

“That was kind of dogma for years,” he said. “The reason this publication is important is because it’s suggesting that’s not the case.” In other words, the MSBase cohort study is validating what neurologists have been doing in the real world for years: treating patients with SPMS who have relapses.

Dr Lizak reported receiving travel compensation from Merck outside the scope of the study. His coauthors reported numerous financial relationships.

SOURCE: Lizak N et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2453

An observational cohort study of a prospective international database of patients with multiple sclerosis has reported that medical therapy can reduce disability progression in patients with active secondary progressive MS (SPMS) who are prone to inflammatory relapses.

Brian Hoyle/MDedge News

The international researchers, led by Nathanial Lizak, MMBS, of the University of Melbourne, conducted the cohort study of 1,621 patients with SPMS from the MSBase international registry, which prospectively collected the information from 1995 to 2018. Their findings were published in JAMA Neurology.

“Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent,” wrote Dr. Lizak and colleagues of the MSBase Study Group.
 

Therapy’s impact on disease progression

To ensure that they had timely data on the early disease course of all study patients, they researchers only included patients whose diagnosis and first documented Expanded Disability Status Scale (EDSS) score were no more than 24 months apart. At SPMS conversion, 1,494 patients had an EDSS score of less than 7 (on a scale of 0-10); during the follow-up period, 267 of them (17.9%) crossed over the threshold of 7.

Dr. Lizak and colleagues noted that early treatment during relapsing remitting MS didn’t impact outcomes after SPMS conversion.

For evaluating the MS Severity Score (MSSS), the study split the cohort into three groups depending on the efficacy of therapy: low-efficacy treatments, mostly consisting of interferon-beta and glatiramer acetate; medium-efficacy treatments, mostly fingolimod and dimethyl fumarate; and high-efficacy treatments, predominately natalizumab and mitoxantrone.

The MSSS progression slope in the cohort had an average reduction of 0.02 points per year. “For patients who experienced superimposed relapses during SPMS, a reduced MSSS progression slope during SPMS was observed among those who received disease-modifying therapies for a greater proportion of time during SPMS,” Dr. Lizak and colleagues wrote.

MSSS progression slope reduction was more pronounced in the medium- and high-efficacy groups, with a reduction of beta 0.22 (P = .06) and 0.034 (P = .002), respectively.

“Based on our models, the level of disability in patients with active SPMS who are continuously treated with high-efficacy immunotherapies would progress more slowly in comparison with the general population with MS by a mean (standard deviation) of 1.56 (4.60) deciles over 10 years,” Dr. Lizak and colleagues wrote.

While the researchers cited a number of studies that didn’t support immunotherapy for SPMS, they also did cite the EXPAND trial to support treatment with siponimod in SPMS patients (Lancet. 2018;391:1263-73). The ASCEND trial of natalizumab enrolled a largely relapse-free cohort and found no link between treatment and disability progression in SPMS (Lancet Neurol. 2018;17:405-15), and a previous report by the MSBase Study Group found no benefit of therapy when adjusted for SPMS relapse rates (Neurology. 2017;89:1050-9).

“Together with the present study, the existing data converge on the suggestion that relapses during SPMS provide a therapeutic target and a marker of future response to immunotherapy during SPMS,” Dr. Lizak and colleagues wrote.
 

Challenging dogma

Commenting on the research, Mark Freedman, HBSc, MSc, MD, said that the MSBase study makes an important contribution to the literature on management of SPMS. “Up until this point we’ve been basing our assumptions on secondary progressive MS on natural history studies, which are actually quite old, dating back 20-30 years.” Dr. Freedman is senior scientist in the Neuroscience Program at the Ottawa Hospital Research Institute and professor of medicine in neurology at the University of Ottawa.

He said “the most damaging” of those studies was by the late Christian Confavreaux, MD, and colleagues in Lyon, France (N Engl J Med. 2000;343:1430-8), that reported relapses didn’t alter the progression of disability. “In other words, once you’re in EDSS of 4, it’s a runaway train; it doesn’t matter what you do,” Dr. Freedman said.

“That was kind of dogma for years,” he said. “The reason this publication is important is because it’s suggesting that’s not the case.” In other words, the MSBase cohort study is validating what neurologists have been doing in the real world for years: treating patients with SPMS who have relapses.

Dr Lizak reported receiving travel compensation from Merck outside the scope of the study. His coauthors reported numerous financial relationships.

SOURCE: Lizak N et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2453

Patients on antithrombotics after an acute MI will face a greater risk for bleeding and secondary cardiovascular (CV) events if they start taking any nonaspirin NSAID, confirms a large observational study.

Like other research before it, the new study suggests those risks will be much lower for some nonaspirin NSAIDs than others. But it may also challenge at least some conventional thinking about the safety of these drugs, and is based solely on a large cohort in South Korea, a group for which such NSAID data has been in short supply.

“It was intriguing that our study presented better safety profiles with celecoxib and meloxicam versus other subtypes of NSAIDs,” noted the report, published online July 27 in the Journal of the American College of Cardiology.

Most of the NSAIDs included in the analysis, “including naproxen, conferred a significantly higher risk for cardiovascular and bleeding events, compared with celecoxib and meloxicam,” wrote the authors, led by Dong Oh Kang, MD, Korea University Guro Hospital, Seoul, South Korea.

A main contribution of the study “is the thorough and comprehensive evaluation of the Korean population by use of the nationwide prescription claims database that reflects real-world clinical practice,” senior author Cheol Ung Choi, MD, PhD, of the same institution, said in an interview.

“Because we included the largest number of patients of any comparable clinical studies on NSAID treatment after MI thus far, our study may allow the generalizability of the adverse events of NSAIDs to all patients by constituting global evidence encompassing different population groups,” Dr. Choi said.

The analysis has limitations along with its strengths, the authors acknowledged, including its observational design and potential for confounding not addressed in statistical adjustments.

Observers of the study concurred, but some cited evidence pointing to such confounding that is serious enough to question the entire study’s validity.

Among the cohort of more than 100,000 patients followed for an average of about 2.3 years after their MI, the adjusted risk of thromboembolic CV events went up almost 7 times for those who took any NSAID for at least 4 consecutive weeks, compared with those who didn’t take NSAIDs, based on prescription records.

Their adjusted risk of bleeding events – which included gastrointestinal, intracranial, respiratory, or urinary tract bleeding or posthemorrhagic anemia, the group writes – was increased 300%.

There was wide variance in the adjusted hazard ratios for outcomes by type of NSAID. The risk of CV events climbed from a low of about 3 with meloxicam and almost 5 for celecoxib to more than 10 and 12 for naproxen and dexibuprofen, respectively.

The hazard ratios for bleeding ranged from about 3 for both meloxicam and celecoxib to more than 6 for naproxen.

Of note, celecoxib and meloxicam both preferentially target the cyclooxygenase type 2 (COX-2) pathway, and naproxen among NSAIDs once had a reputation for relative cardiac safety, although subsequent studies have challenged that notion.

“On the basis of the contemporary guidelines, NSAID treatment should be limited as much as possible after MI; however, our data suggest that celecoxib and meloxicam could be considered possible alternative choices in patients with MI when NSAID prescription is unavoidable,” the group wrote.

They acknowledged some limitations of the analysis, including an observational design and the possibility of unidentified confounders; that mortality outcomes were not available from the National Health Insurance Service database used in the study; and that the 2009-2013 span for the data didn’t allow consideration of more contemporary antiplatelet agents and direct oral anticoagulants.

Also, NSAID use was based on prescriptions without regard to over-the-counter usage. Although use of over-the-counter NSAIDs is common in Korea, “most MI patients in Korea are prescribed most medications, including NSAIDs, in the hospital. So I think that usage of over-the-counter NSAIDs did not change the results,” Dr. Choi said.

“This study breaks new ground by demonstrating cardiovascular safety of meloxicam (and not only of celecoxib), probably because of its higher COX-2 selectivity,” wrote the authors of an accompanying editorial, Juan J. Badimon, PhD, and Carlos G. Santos-Gallego, MD, both of the Icahn School of Medicine at Mount Sinai, New York.

Notably, “this paper rejects the cardiovascular safety of naproxen, which had been suggested classically and in the previous Danish data, but that was not evident in this study.” The finding is consistent with the PRECISION trial, in which both bleeding and CV risk were increased with naproxen versus other NSAIDs, observed Dr. Badimon and Dr. Santos-Gallego.

They agreed with the authors in recommending that, “although NSAID treatment should be avoided in patients with MI, if the use of NSAIDs is inevitable due to comorbidities, the prescription of celecoxib and meloxicam could be considered as alternative options.”

But, “as no study is perfect, this article also presents some limitations,” the editorial agreed, citing some of the same issues noted by Dr. Kang and associates, along with potential confounding by indication and the lack of “clinical information to adjust (e.g., angiographic features, left ventricular function).”

“There’s undoubtedly residual confounding,” James M. Brophy, MD, PhD, a pharmacoepidemiologist at McGill University, Montreal, said in an interview.

The 400%-900% relative risks for CV events “are just too far in left field, compared to everything else we know,” he said. “There has never been a class of drugs that have shown this sort of magnitude of effect for adverse events.”

Even in PRECISION with its more than 24,000 high-coronary-risk patients randomized and followed for 5 years, Dr. Brophy observed, relative risks for the different NSAIDs varied by an order of magnitude of only 1-2.

“You should be interpreting things in the context of what is already known,” Dr. Brophy said. “The only conclusion I would draw is the paper is fatally flawed.”

The registry included 108,232 primarily male patients followed from their first diagnosed MI for CV and bleeding events. About 1.9% were prescribed at least one NSAID for 4 or more consecutive weeks during the follow-up period averaging 2.3 years, the group reported.

The most frequently prescribed NSAID was diclofenac, at about 72% of prescribed NSAIDs in the analysis for CV events and about 69% in the bleeding-event analysis.

Adding any NSAID to post-MI antithrombotic therapy led to an adjusted HR of 6.96 (P < .001) for CV events and 4.08 (P < .001) for bleeding events, compared with no NSAID treatment.

The 88% of the cohort who were on dual-antiplatelet therapy with aspirin and clopidogrel showed very nearly the same risk increases for both endpoints.

Further studies are needed to confirm the results “and ensure their generalizability to other populations,” Dr. Choi said. They should be validated especially using the claims data bases of countries near Korea, “such as Japan and Taiwan, to examine the reproducibility of the results in similar ethnic populations.”

That the study focused on a cohort in Korea is a strength, contended the authors as well as Dr. Badimon and Dr. Santos-Gallego, given “that most data about NSAIDs were extracted from Western populations, but the risk of thrombosis/bleeding post-MI varies according to ethnicity,” according to the editorial

Dr. Brophy agreed, but doubted that ethnic differences are responsible for variation in relative risks between the current results and other studies. “There are pharmacogenomic differences between different ethnicities as to how they activate these drugs. But I suspect that sort of difference is really minor. Maybe it leads to a 2% or a 5% difference in risks.”

Dr. Kang and associates, Dr. Badimon, Dr. Santos-Gallego, and Dr. Brophy disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients on antithrombotics after an acute MI will face a greater risk for bleeding and secondary cardiovascular (CV) events if they start taking any nonaspirin NSAID, confirms a large observational study.

Like other research before it, the new study suggests those risks will be much lower for some nonaspirin NSAIDs than others. But it may also challenge at least some conventional thinking about the safety of these drugs, and is based solely on a large cohort in South Korea, a group for which such NSAID data has been in short supply.

“It was intriguing that our study presented better safety profiles with celecoxib and meloxicam versus other subtypes of NSAIDs,” noted the report, published online July 27 in the Journal of the American College of Cardiology.

Most of the NSAIDs included in the analysis, “including naproxen, conferred a significantly higher risk for cardiovascular and bleeding events, compared with celecoxib and meloxicam,” wrote the authors, led by Dong Oh Kang, MD, Korea University Guro Hospital, Seoul, South Korea.

A main contribution of the study “is the thorough and comprehensive evaluation of the Korean population by use of the nationwide prescription claims database that reflects real-world clinical practice,” senior author Cheol Ung Choi, MD, PhD, of the same institution, said in an interview.

“Because we included the largest number of patients of any comparable clinical studies on NSAID treatment after MI thus far, our study may allow the generalizability of the adverse events of NSAIDs to all patients by constituting global evidence encompassing different population groups,” Dr. Choi said.

The analysis has limitations along with its strengths, the authors acknowledged, including its observational design and potential for confounding not addressed in statistical adjustments.

Observers of the study concurred, but some cited evidence pointing to such confounding that is serious enough to question the entire study’s validity.

Among the cohort of more than 100,000 patients followed for an average of about 2.3 years after their MI, the adjusted risk of thromboembolic CV events went up almost 7 times for those who took any NSAID for at least 4 consecutive weeks, compared with those who didn’t take NSAIDs, based on prescription records.

Their adjusted risk of bleeding events – which included gastrointestinal, intracranial, respiratory, or urinary tract bleeding or posthemorrhagic anemia, the group writes – was increased 300%.

There was wide variance in the adjusted hazard ratios for outcomes by type of NSAID. The risk of CV events climbed from a low of about 3 with meloxicam and almost 5 for celecoxib to more than 10 and 12 for naproxen and dexibuprofen, respectively.

The hazard ratios for bleeding ranged from about 3 for both meloxicam and celecoxib to more than 6 for naproxen.

Of note, celecoxib and meloxicam both preferentially target the cyclooxygenase type 2 (COX-2) pathway, and naproxen among NSAIDs once had a reputation for relative cardiac safety, although subsequent studies have challenged that notion.

“On the basis of the contemporary guidelines, NSAID treatment should be limited as much as possible after MI; however, our data suggest that celecoxib and meloxicam could be considered possible alternative choices in patients with MI when NSAID prescription is unavoidable,” the group wrote.

They acknowledged some limitations of the analysis, including an observational design and the possibility of unidentified confounders; that mortality outcomes were not available from the National Health Insurance Service database used in the study; and that the 2009-2013 span for the data didn’t allow consideration of more contemporary antiplatelet agents and direct oral anticoagulants.

Also, NSAID use was based on prescriptions without regard to over-the-counter usage. Although use of over-the-counter NSAIDs is common in Korea, “most MI patients in Korea are prescribed most medications, including NSAIDs, in the hospital. So I think that usage of over-the-counter NSAIDs did not change the results,” Dr. Choi said.

“This study breaks new ground by demonstrating cardiovascular safety of meloxicam (and not only of celecoxib), probably because of its higher COX-2 selectivity,” wrote the authors of an accompanying editorial, Juan J. Badimon, PhD, and Carlos G. Santos-Gallego, MD, both of the Icahn School of Medicine at Mount Sinai, New York.

Notably, “this paper rejects the cardiovascular safety of naproxen, which had been suggested classically and in the previous Danish data, but that was not evident in this study.” The finding is consistent with the PRECISION trial, in which both bleeding and CV risk were increased with naproxen versus other NSAIDs, observed Dr. Badimon and Dr. Santos-Gallego.

They agreed with the authors in recommending that, “although NSAID treatment should be avoided in patients with MI, if the use of NSAIDs is inevitable due to comorbidities, the prescription of celecoxib and meloxicam could be considered as alternative options.”

But, “as no study is perfect, this article also presents some limitations,” the editorial agreed, citing some of the same issues noted by Dr. Kang and associates, along with potential confounding by indication and the lack of “clinical information to adjust (e.g., angiographic features, left ventricular function).”

“There’s undoubtedly residual confounding,” James M. Brophy, MD, PhD, a pharmacoepidemiologist at McGill University, Montreal, said in an interview.

The 400%-900% relative risks for CV events “are just too far in left field, compared to everything else we know,” he said. “There has never been a class of drugs that have shown this sort of magnitude of effect for adverse events.”

Even in PRECISION with its more than 24,000 high-coronary-risk patients randomized and followed for 5 years, Dr. Brophy observed, relative risks for the different NSAIDs varied by an order of magnitude of only 1-2.

“You should be interpreting things in the context of what is already known,” Dr. Brophy said. “The only conclusion I would draw is the paper is fatally flawed.”

The registry included 108,232 primarily male patients followed from their first diagnosed MI for CV and bleeding events. About 1.9% were prescribed at least one NSAID for 4 or more consecutive weeks during the follow-up period averaging 2.3 years, the group reported.

The most frequently prescribed NSAID was diclofenac, at about 72% of prescribed NSAIDs in the analysis for CV events and about 69% in the bleeding-event analysis.

Adding any NSAID to post-MI antithrombotic therapy led to an adjusted HR of 6.96 (P < .001) for CV events and 4.08 (P < .001) for bleeding events, compared with no NSAID treatment.

The 88% of the cohort who were on dual-antiplatelet therapy with aspirin and clopidogrel showed very nearly the same risk increases for both endpoints.

Further studies are needed to confirm the results “and ensure their generalizability to other populations,” Dr. Choi said. They should be validated especially using the claims data bases of countries near Korea, “such as Japan and Taiwan, to examine the reproducibility of the results in similar ethnic populations.”

That the study focused on a cohort in Korea is a strength, contended the authors as well as Dr. Badimon and Dr. Santos-Gallego, given “that most data about NSAIDs were extracted from Western populations, but the risk of thrombosis/bleeding post-MI varies according to ethnicity,” according to the editorial

Dr. Brophy agreed, but doubted that ethnic differences are responsible for variation in relative risks between the current results and other studies. “There are pharmacogenomic differences between different ethnicities as to how they activate these drugs. But I suspect that sort of difference is really minor. Maybe it leads to a 2% or a 5% difference in risks.”

Dr. Kang and associates, Dr. Badimon, Dr. Santos-Gallego, and Dr. Brophy disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients on antithrombotics after an acute MI will face a greater risk for bleeding and secondary cardiovascular (CV) events if they start taking any nonaspirin NSAID, confirms a large observational study.

Like other research before it, the new study suggests those risks will be much lower for some nonaspirin NSAIDs than others. But it may also challenge at least some conventional thinking about the safety of these drugs, and is based solely on a large cohort in South Korea, a group for which such NSAID data has been in short supply.

“It was intriguing that our study presented better safety profiles with celecoxib and meloxicam versus other subtypes of NSAIDs,” noted the report, published online July 27 in the Journal of the American College of Cardiology.

Most of the NSAIDs included in the analysis, “including naproxen, conferred a significantly higher risk for cardiovascular and bleeding events, compared with celecoxib and meloxicam,” wrote the authors, led by Dong Oh Kang, MD, Korea University Guro Hospital, Seoul, South Korea.

A main contribution of the study “is the thorough and comprehensive evaluation of the Korean population by use of the nationwide prescription claims database that reflects real-world clinical practice,” senior author Cheol Ung Choi, MD, PhD, of the same institution, said in an interview.

“Because we included the largest number of patients of any comparable clinical studies on NSAID treatment after MI thus far, our study may allow the generalizability of the adverse events of NSAIDs to all patients by constituting global evidence encompassing different population groups,” Dr. Choi said.

The analysis has limitations along with its strengths, the authors acknowledged, including its observational design and potential for confounding not addressed in statistical adjustments.

Observers of the study concurred, but some cited evidence pointing to such confounding that is serious enough to question the entire study’s validity.

Among the cohort of more than 100,000 patients followed for an average of about 2.3 years after their MI, the adjusted risk of thromboembolic CV events went up almost 7 times for those who took any NSAID for at least 4 consecutive weeks, compared with those who didn’t take NSAIDs, based on prescription records.

Their adjusted risk of bleeding events – which included gastrointestinal, intracranial, respiratory, or urinary tract bleeding or posthemorrhagic anemia, the group writes – was increased 300%.

There was wide variance in the adjusted hazard ratios for outcomes by type of NSAID. The risk of CV events climbed from a low of about 3 with meloxicam and almost 5 for celecoxib to more than 10 and 12 for naproxen and dexibuprofen, respectively.

The hazard ratios for bleeding ranged from about 3 for both meloxicam and celecoxib to more than 6 for naproxen.

Of note, celecoxib and meloxicam both preferentially target the cyclooxygenase type 2 (COX-2) pathway, and naproxen among NSAIDs once had a reputation for relative cardiac safety, although subsequent studies have challenged that notion.

“On the basis of the contemporary guidelines, NSAID treatment should be limited as much as possible after MI; however, our data suggest that celecoxib and meloxicam could be considered possible alternative choices in patients with MI when NSAID prescription is unavoidable,” the group wrote.

They acknowledged some limitations of the analysis, including an observational design and the possibility of unidentified confounders; that mortality outcomes were not available from the National Health Insurance Service database used in the study; and that the 2009-2013 span for the data didn’t allow consideration of more contemporary antiplatelet agents and direct oral anticoagulants.

Also, NSAID use was based on prescriptions without regard to over-the-counter usage. Although use of over-the-counter NSAIDs is common in Korea, “most MI patients in Korea are prescribed most medications, including NSAIDs, in the hospital. So I think that usage of over-the-counter NSAIDs did not change the results,” Dr. Choi said.

“This study breaks new ground by demonstrating cardiovascular safety of meloxicam (and not only of celecoxib), probably because of its higher COX-2 selectivity,” wrote the authors of an accompanying editorial, Juan J. Badimon, PhD, and Carlos G. Santos-Gallego, MD, both of the Icahn School of Medicine at Mount Sinai, New York.

Notably, “this paper rejects the cardiovascular safety of naproxen, which had been suggested classically and in the previous Danish data, but that was not evident in this study.” The finding is consistent with the PRECISION trial, in which both bleeding and CV risk were increased with naproxen versus other NSAIDs, observed Dr. Badimon and Dr. Santos-Gallego.

They agreed with the authors in recommending that, “although NSAID treatment should be avoided in patients with MI, if the use of NSAIDs is inevitable due to comorbidities, the prescription of celecoxib and meloxicam could be considered as alternative options.”

But, “as no study is perfect, this article also presents some limitations,” the editorial agreed, citing some of the same issues noted by Dr. Kang and associates, along with potential confounding by indication and the lack of “clinical information to adjust (e.g., angiographic features, left ventricular function).”

“There’s undoubtedly residual confounding,” James M. Brophy, MD, PhD, a pharmacoepidemiologist at McGill University, Montreal, said in an interview.

The 400%-900% relative risks for CV events “are just too far in left field, compared to everything else we know,” he said. “There has never been a class of drugs that have shown this sort of magnitude of effect for adverse events.”

Even in PRECISION with its more than 24,000 high-coronary-risk patients randomized and followed for 5 years, Dr. Brophy observed, relative risks for the different NSAIDs varied by an order of magnitude of only 1-2.

“You should be interpreting things in the context of what is already known,” Dr. Brophy said. “The only conclusion I would draw is the paper is fatally flawed.”

The registry included 108,232 primarily male patients followed from their first diagnosed MI for CV and bleeding events. About 1.9% were prescribed at least one NSAID for 4 or more consecutive weeks during the follow-up period averaging 2.3 years, the group reported.

The most frequently prescribed NSAID was diclofenac, at about 72% of prescribed NSAIDs in the analysis for CV events and about 69% in the bleeding-event analysis.

Adding any NSAID to post-MI antithrombotic therapy led to an adjusted HR of 6.96 (P < .001) for CV events and 4.08 (P < .001) for bleeding events, compared with no NSAID treatment.

The 88% of the cohort who were on dual-antiplatelet therapy with aspirin and clopidogrel showed very nearly the same risk increases for both endpoints.

Further studies are needed to confirm the results “and ensure their generalizability to other populations,” Dr. Choi said. They should be validated especially using the claims data bases of countries near Korea, “such as Japan and Taiwan, to examine the reproducibility of the results in similar ethnic populations.”

That the study focused on a cohort in Korea is a strength, contended the authors as well as Dr. Badimon and Dr. Santos-Gallego, given “that most data about NSAIDs were extracted from Western populations, but the risk of thrombosis/bleeding post-MI varies according to ethnicity,” according to the editorial

Dr. Brophy agreed, but doubted that ethnic differences are responsible for variation in relative risks between the current results and other studies. “There are pharmacogenomic differences between different ethnicities as to how they activate these drugs. But I suspect that sort of difference is really minor. Maybe it leads to a 2% or a 5% difference in risks.”

Dr. Kang and associates, Dr. Badimon, Dr. Santos-Gallego, and Dr. Brophy disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.