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Finerenone’s heart benefits hold up in T2D patients without CVD
Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.
“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.
In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.
Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
CVD history produced heterogeneity for the primary endpoint
In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.
In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.
“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.
Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”
Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”
In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.
Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.
Finerenone looks better for safety
Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.
For treating patients with T2D and CKD ,finerenone overall “looks like a major advance,” Dr. Bhatt said in an interview.
In addition to the positive efficacy results, several experts also focused on what they saw as superior safety of finerenone in the trial, compared with the historical safety of the steroidal mineralocorticoid receptor antagonists (MRAs) now in use: spironolactone and eplerenone.
“I’m a big believer in spironolactone, but it has issues with side effects, and eplerenone never seemed to catch on,” said Dr. Bhatt, who is also executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.
“A lot of physicians like these MRAs, but acknowledge that side effects have kept these drugs from being used to the extent they should.” The existing MRAs, especially spironolactone, have become a key drug class for treating heart failure with reduced ejection fraction (and, some claim, for also treating heart failure with preserved ejection fraction), as well as treatment-resistant hypertension and primary aldosteronism. By design, FIDELIO-DKD did not enroll patients with heart failure because treatment with an MRA is indicated for those with heart failure with reduced ejection fraction.
The spironolactone adverse effect that generates the greatest concern is hyperkalemia. During his discussion of FIDELIO-DKD as designated discussant, Christoph Wanner, MD, noted a recent study in which the incidence of hyperkalemia severe enough to cause study discontinuation was 23% among patients treated with spironolactone for heart failure, which contrasts with the 2.3% rate in FIDELIO-DKD among finerenone recipients. This hyperkalemia incidence from finerenone also improved on the historical performance of other drugs, like aliskiren (Tekturna), said Dr. Wanner, professor and head of nephrology at the University of Würzburg (Germany).
The FIDELIO-DKD results place finerenone alongside the RAS- and SGLT2-inhibitor drug classes as appropriate treatments for most patients with T2D and CKD. “We have entered a new era of effective treatment for diabetic kidney disease,” Dr. Wanner declared.
“The overall safety profile of finerenone looked better, including hyperkalemia,” said Dr. Bhatt. “Hyperkalemia with spironolactone is not necessarily as bad as the perception. With careful monitoring of spironolactone, the hyperkalemia is manageable. But the perception is that it’s bad, and along with gynecomastia it’s a real killer.”
While some dismiss gynecomastia as a major concern (for men) with spironolactone treatment, “if medical students learn one thing about spironolactone, it’s that it can cause gynecomastia,” adding to the negative image that the approved MRAs carry, Dr. Bhatt said.
“The hyperkalemia was manageable. This is very important because of past problems with potassium when using spironolactone,” Dr. Filippatos said. Finerenone also looks “more cardiorenal protective” than the steroidal MRAs, exerting renal benefits in FIDELIO-DKD never previously described for a steroidal MRA.
Some of the uncertainty about the efficacy of finerenone in patients with a history of cardiovascular disease will lift when results are available in about another year from the FIGARO-DKD pivotal trial of finerenone, which enrolled more than 7,000 patients with T2D and CKD (entry criteria very similar to FIDELIO-CKD). A big difference is that FIGARO-DKD has a composite CVD event metric as its primary endpoint, and includes hospitalization for heart failure as one facet of the composite.
FIDELIO-DKD was sponsored by Bayer. Dr. Filippatos has been a lecturer on behalf of, served as a researcher for, or both for Bayer and also for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Bayer and also from several other companies, and he also is an adviser to several companies. Dr. Wanner has received honoraria from Bayer, and also from AstraZeneca, Boehringer Ingelheim, FMC, Gilead, GlaxoSmithKline, Lilly, and Merck.
Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.
“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.
In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.
Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
CVD history produced heterogeneity for the primary endpoint
In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.
In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.
“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.
Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”
Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”
In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.
Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.
Finerenone looks better for safety
Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.
For treating patients with T2D and CKD ,finerenone overall “looks like a major advance,” Dr. Bhatt said in an interview.
In addition to the positive efficacy results, several experts also focused on what they saw as superior safety of finerenone in the trial, compared with the historical safety of the steroidal mineralocorticoid receptor antagonists (MRAs) now in use: spironolactone and eplerenone.
“I’m a big believer in spironolactone, but it has issues with side effects, and eplerenone never seemed to catch on,” said Dr. Bhatt, who is also executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.
“A lot of physicians like these MRAs, but acknowledge that side effects have kept these drugs from being used to the extent they should.” The existing MRAs, especially spironolactone, have become a key drug class for treating heart failure with reduced ejection fraction (and, some claim, for also treating heart failure with preserved ejection fraction), as well as treatment-resistant hypertension and primary aldosteronism. By design, FIDELIO-DKD did not enroll patients with heart failure because treatment with an MRA is indicated for those with heart failure with reduced ejection fraction.
The spironolactone adverse effect that generates the greatest concern is hyperkalemia. During his discussion of FIDELIO-DKD as designated discussant, Christoph Wanner, MD, noted a recent study in which the incidence of hyperkalemia severe enough to cause study discontinuation was 23% among patients treated with spironolactone for heart failure, which contrasts with the 2.3% rate in FIDELIO-DKD among finerenone recipients. This hyperkalemia incidence from finerenone also improved on the historical performance of other drugs, like aliskiren (Tekturna), said Dr. Wanner, professor and head of nephrology at the University of Würzburg (Germany).
The FIDELIO-DKD results place finerenone alongside the RAS- and SGLT2-inhibitor drug classes as appropriate treatments for most patients with T2D and CKD. “We have entered a new era of effective treatment for diabetic kidney disease,” Dr. Wanner declared.
“The overall safety profile of finerenone looked better, including hyperkalemia,” said Dr. Bhatt. “Hyperkalemia with spironolactone is not necessarily as bad as the perception. With careful monitoring of spironolactone, the hyperkalemia is manageable. But the perception is that it’s bad, and along with gynecomastia it’s a real killer.”
While some dismiss gynecomastia as a major concern (for men) with spironolactone treatment, “if medical students learn one thing about spironolactone, it’s that it can cause gynecomastia,” adding to the negative image that the approved MRAs carry, Dr. Bhatt said.
“The hyperkalemia was manageable. This is very important because of past problems with potassium when using spironolactone,” Dr. Filippatos said. Finerenone also looks “more cardiorenal protective” than the steroidal MRAs, exerting renal benefits in FIDELIO-DKD never previously described for a steroidal MRA.
Some of the uncertainty about the efficacy of finerenone in patients with a history of cardiovascular disease will lift when results are available in about another year from the FIGARO-DKD pivotal trial of finerenone, which enrolled more than 7,000 patients with T2D and CKD (entry criteria very similar to FIDELIO-CKD). A big difference is that FIGARO-DKD has a composite CVD event metric as its primary endpoint, and includes hospitalization for heart failure as one facet of the composite.
FIDELIO-DKD was sponsored by Bayer. Dr. Filippatos has been a lecturer on behalf of, served as a researcher for, or both for Bayer and also for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Bayer and also from several other companies, and he also is an adviser to several companies. Dr. Wanner has received honoraria from Bayer, and also from AstraZeneca, Boehringer Ingelheim, FMC, Gilead, GlaxoSmithKline, Lilly, and Merck.
Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.
“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.
In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.
Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
CVD history produced heterogeneity for the primary endpoint
In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.
In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.
“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.
Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”
Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”
In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.
Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.
Finerenone looks better for safety
Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.
For treating patients with T2D and CKD ,finerenone overall “looks like a major advance,” Dr. Bhatt said in an interview.
In addition to the positive efficacy results, several experts also focused on what they saw as superior safety of finerenone in the trial, compared with the historical safety of the steroidal mineralocorticoid receptor antagonists (MRAs) now in use: spironolactone and eplerenone.
“I’m a big believer in spironolactone, but it has issues with side effects, and eplerenone never seemed to catch on,” said Dr. Bhatt, who is also executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.
“A lot of physicians like these MRAs, but acknowledge that side effects have kept these drugs from being used to the extent they should.” The existing MRAs, especially spironolactone, have become a key drug class for treating heart failure with reduced ejection fraction (and, some claim, for also treating heart failure with preserved ejection fraction), as well as treatment-resistant hypertension and primary aldosteronism. By design, FIDELIO-DKD did not enroll patients with heart failure because treatment with an MRA is indicated for those with heart failure with reduced ejection fraction.
The spironolactone adverse effect that generates the greatest concern is hyperkalemia. During his discussion of FIDELIO-DKD as designated discussant, Christoph Wanner, MD, noted a recent study in which the incidence of hyperkalemia severe enough to cause study discontinuation was 23% among patients treated with spironolactone for heart failure, which contrasts with the 2.3% rate in FIDELIO-DKD among finerenone recipients. This hyperkalemia incidence from finerenone also improved on the historical performance of other drugs, like aliskiren (Tekturna), said Dr. Wanner, professor and head of nephrology at the University of Würzburg (Germany).
The FIDELIO-DKD results place finerenone alongside the RAS- and SGLT2-inhibitor drug classes as appropriate treatments for most patients with T2D and CKD. “We have entered a new era of effective treatment for diabetic kidney disease,” Dr. Wanner declared.
“The overall safety profile of finerenone looked better, including hyperkalemia,” said Dr. Bhatt. “Hyperkalemia with spironolactone is not necessarily as bad as the perception. With careful monitoring of spironolactone, the hyperkalemia is manageable. But the perception is that it’s bad, and along with gynecomastia it’s a real killer.”
While some dismiss gynecomastia as a major concern (for men) with spironolactone treatment, “if medical students learn one thing about spironolactone, it’s that it can cause gynecomastia,” adding to the negative image that the approved MRAs carry, Dr. Bhatt said.
“The hyperkalemia was manageable. This is very important because of past problems with potassium when using spironolactone,” Dr. Filippatos said. Finerenone also looks “more cardiorenal protective” than the steroidal MRAs, exerting renal benefits in FIDELIO-DKD never previously described for a steroidal MRA.
Some of the uncertainty about the efficacy of finerenone in patients with a history of cardiovascular disease will lift when results are available in about another year from the FIGARO-DKD pivotal trial of finerenone, which enrolled more than 7,000 patients with T2D and CKD (entry criteria very similar to FIDELIO-CKD). A big difference is that FIGARO-DKD has a composite CVD event metric as its primary endpoint, and includes hospitalization for heart failure as one facet of the composite.
FIDELIO-DKD was sponsored by Bayer. Dr. Filippatos has been a lecturer on behalf of, served as a researcher for, or both for Bayer and also for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Bayer and also from several other companies, and he also is an adviser to several companies. Dr. Wanner has received honoraria from Bayer, and also from AstraZeneca, Boehringer Ingelheim, FMC, Gilead, GlaxoSmithKline, Lilly, and Merck.
FROM AHA 2020
Potential new option: 1-month DAPT post DES, then aspirin alone
One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.
This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.
“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”
The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
Patients with stable angina fared best
The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.
Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.
Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
Trial’s shortcomings temper reaction
“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.
That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.
Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.
“Let’s provide these patients with some options,” the cardiologist urged.
He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.
“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.
Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”
“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.
“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”
Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.
One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.
This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.
“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”
The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
Patients with stable angina fared best
The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.
Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.
Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
Trial’s shortcomings temper reaction
“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.
That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.
Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.
“Let’s provide these patients with some options,” the cardiologist urged.
He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.
“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.
Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”
“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.
“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”
Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.
One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.
This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.
“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”
The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
Patients with stable angina fared best
The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.
Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.
Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
Trial’s shortcomings temper reaction
“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.
That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.
Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.
“Let’s provide these patients with some options,” the cardiologist urged.
He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.
“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.
Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”
“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.
“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”
Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.
FROM AHA 2020
Marijuana use tied to repeat MI, stroke after percutaneous coronary intervention
in separate studies.
Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.
Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.
Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
Need for screening and counseling
Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.
She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.
Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.
Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.
That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”
Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”
Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.
“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.
Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.
After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.
However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.
These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
Hospitalized patients with prior MI
Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).
There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.
During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.
Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).
On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.
The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
In-Hospital outcomes after PCI
Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.
In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).
They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).
Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.
Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.
In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.
Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.
The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.
Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
in separate studies.
Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.
Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.
Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
Need for screening and counseling
Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.
She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.
Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.
Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.
That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”
Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”
Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.
“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.
Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.
After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.
However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.
These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
Hospitalized patients with prior MI
Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).
There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.
During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.
Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).
On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.
The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
In-Hospital outcomes after PCI
Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.
In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).
They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).
Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.
Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.
In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.
Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.
The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.
Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
in separate studies.
Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.
Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.
Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
Need for screening and counseling
Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.
She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.
Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.
Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.
That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”
Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”
Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.
“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.
Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.
After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.
However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.
These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
Hospitalized patients with prior MI
Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).
There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.
During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.
Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).
On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.
The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
In-Hospital outcomes after PCI
Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.
In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).
They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).
Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.
Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.
In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.
Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.
The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.
Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
From AHA 2020
Stenotic lesion outcomes better if fractional flow reserve guides PCI
Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.
For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.
“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”
The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.
“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.
In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.
The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.
Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.
In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.
In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.
It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.
“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.
Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.
“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.
“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.
Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.
For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.
“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”
The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.
“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.
In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.
The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.
Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.
In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.
In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.
It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.
“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.
Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.
“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.
“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.
Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.
For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.
“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”
The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.
“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.
In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.
The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.
Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.
In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.
In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.
It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.
“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.
Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.
“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.
“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.
FROM AHA 2020
First SGLT1/2 inhibitor shows ‘spectacular’ phase 3 safety and efficacy in T2D
Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.
Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.
They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m2; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).
These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.
All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m2.
“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.
“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”
The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.
“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
A dual SGLT inhibitor
What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.
The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m2 at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.
“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”
The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.
“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
First-ever HFpEF benefit
In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.
First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m2, excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.
The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.
Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.
“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
Also safe soon after acute heart failure decompensation
The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.
“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.
SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.
Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.
“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.
Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.
The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.
Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.
Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.
They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m2; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).
These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.
All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m2.
“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.
“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”
The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.
“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
A dual SGLT inhibitor
What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.
The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m2 at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.
“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”
The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.
“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
First-ever HFpEF benefit
In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.
First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m2, excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.
The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.
Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.
“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
Also safe soon after acute heart failure decompensation
The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.
“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.
SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.
Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.
“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.
Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.
The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.
Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.
Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.
They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m2; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).
These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.
All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m2.
“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.
“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”
The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.
“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
A dual SGLT inhibitor
What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.
The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m2 at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.
“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”
The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.
“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
First-ever HFpEF benefit
In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.
First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m2, excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.
The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.
Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.
“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
Also safe soon after acute heart failure decompensation
The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.
“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.
SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.
Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.
“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.
Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.
The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.
FROM AHA 2020
Cardiac arrest in COVID-19 pandemic: ‘Survival is possible’
In the early weeks of the COVID-19 pandemic in the United States, rates of sustained return of spontaneous circulation after out-of-hospital cardiac arrest were lower throughout the country, compared with a year earlier, in one study.
A second study of that period showed that patients with COVID-19 had rates that were better than previously reported of surviving in-hospital cardiac arrest.
Paul S. Chan, MD, presented the out-of-hospital cardiac arrest research, and Oscar J. Mitchell, MD, presented the in-hospital cardiac arrest findings in a late-breaking resuscitation science session at the American Heart Association scientific sessions. The former study was also simultaneously published online Nov. 14 in JAMA Cardiology.
Importantly, “the survival rates were not zero in either setting,” said Dr. Chan, commenting on the implications of both studies taken together.
“The survival rates – either return of circulation or survival to discharge – were not futile,” Dr. Chan, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said in an interview.
“And I think that’s an overall important message – that we can’t write off patients who have a cardiac arrest at this point,” he stressed. “They deserve a response. Although the outcomes might not be as good as we had seen in years prior, we are seeing patients making it out of the hospital and surviving.”
Dr. Mitchell, from the University of Pennsylvania in Philadelphia, echoed this message in an interview.
“I think that the key finding here is that survival is possible after patients with COVID-19 suffer an in-hospital cardiac arrest,” Dr. Mitchell said. “We hope that the information from our study will be of use to frontline providers who are treating patients with COVID-19.”
“In coming weeks, there will likely be increased hospital strain and enormous challenges to providing COVID-19 care,” added Benjamin S. Abella, MD, the senior author of the in-hospital study. Dr. Abella is also from the University of Pennsylvania and was cochair of the Resuscitation Science symposium during the AHA meeting.
“It is crucial that hospital leaders prepare now for how they will manage COVID-19 resuscitation efforts,” Dr. Abella said. “Emergency medicine and critical care leaders must be mindful that many COVID-19 patients with arrest could survive to return to their families.”
“It is important to note both studies demonstrated variations in outcome and that those differences were associated with the differential COVID prevalence and mortality,” session comoderator Cindy H. Hsu, MD, PhD, University of Michigan, said in an interview.
“Future studies,” she said, “should address knowledge gaps including associated comorbidities and affected resuscitation process variables during the COVID-19 pandemic.”
Out-of-hospital cardiac arrest, March 2019 vs. March 2020
Compared with 2019, in 2020, the reported rates of return of spontaneous circulation after out-of-hospital cardiac arrest fell from 25% to 10.6% in New York and from 13.5% to 5.0% in northern Italy – two areas that were severely affected, Dr. Chan noted.
In this study, the researchers aimed to examine whether out-of-hospital cardiac arrest outcomes would be similar throughout the United States, including areas that were less severely affected, in the first weeks of the pandemic.
They linked data from the Cardiac Arrest Registry to Enhance Survival (CARES), which covers an area with about 152 million U.S. residents, with COVID-19 disease mortality data.
There were 9,863 out-of-hospital arrests from March 16 to April 30, 2020, compared with 9,440 cases during this time in 2019.
The patients in both years had a similar age (mean, 62 years) and sex (62% male), but there were more Black patients in 2020 (28% vs. 23%).
Overall, in communities with low to high rates of death from COVID-19, the rate of return of spontaneous circulation was 18% lower in that early pandemic period than in the same time in the previous year (23% vs. 29.8%; adjusted rate ratio, 0.82).
The rates of return of spontaneous circulation were also lower in communities with a low rate of COVID-19 mortality, but to a lesser extent (11%-15% lower in 2020 vs. 2019).
In the subset of emergency medical agencies with complete data on hospital survival, overall rates of survival to discharge were 17% lower during the studied pandemic period versus the same time a year earlier (6.6% vs. 9.8%; adjusted RR, 0.83).
This drop in survival was greater in communities with moderate to high COVID-19 mortality.
These outcomes were not explained by differences in emergency medical services arrival or treatment times, rates of bystander CPR, or initial out-of-hospital cardiac arrest rhythm.
Dr. Chan was a coauthor of an interim guidance issued April 9, 2020, by the AHA and several other medical societies for ways to protect frontline workers from contracting COVID-19 while they were performing CPR.
Communities that were not heavily affected by COVID-19 could have also been following the recommendations, which might have affected outcomes, he speculated.
For example, “when we pause chest compressions it can potentially worsen survival even if it’s for a short period of time. That might explain the lower rates of return of circulation.”
“That guidance was really meant for heavily affected communities,” Dr. Chan added. “Of course, as we speak, the pandemic is pretty much everywhere in the United States. It’s not just in the northeast; it’s not just in Arizona, Florida, California, Texas like it was in the summer. You are seeing surges in 46 of the 50 states.
“If your community is heavily affected by COVID-19 in terms of deaths at this time, paramedics will need to take caution to also help protect themselves, and the guidance may apply at that point,” he said.
In-hospital cardiac arrest, March Through May 2020
The early studies of in-hospital cardiac arrest in patients with COVID-19 showed “concerningly low rates” of return of spontaneous circulation and survival, said Dr. Mitchell.
“The first was a study from Wuhan, which demonstrated a 2.9% 30-day survival and the second was a small cohort from NYC with 0% survival to hospital discharge,” he said. “This raised concerns that offering CPR to patients who had a cardiac arrest from COVID-19 might only hold a low probability of success.”
To investigate this, the researchers formed a COVID study group comprising two hospitals in New York and nine hospitals in the Northeast and West Coast.
They identified 260 hospitalized adult patients with COVID-19 who had in-hospital cardiac arrest between March 1 and May 31, 2020. The patients had a median age of 69 years, and 72% were male. Most had preexisting comorbidities. Most of the cardiac arrests were in the ICU (64%), and almost all were witnessed (91%).
Return of spontaneous circulation occurred in 22% of the patients, and 12% had survived 30 days later. Of the 260 cardiac arrests, most (204) occurred in the New York hospitals.
There was a huge variation in outcomes. The rate of sustained return of spontaneous circulation was much lower in the two hospitals in New York compared with elsewhere (11% vs. 64%), as was 30-day survival (6% vs. 36%).
“Variation in outcomes from [in-hospital cardiac arrest] has been well described prior to the COVID-19 pandemic,” said Dr. Mitchell, “and is felt to be due to a range of factors, including variation in detection and prevention of cardiac arrest, management of patients during the cardiac arrest, and differences in postarrest care – including targeted temperature management and neuroprognostication.”
“We hypothesize that the strains of the COVID-19 pandemic may have amplified these variations (although we were unable to compare hospital performance before and after the pandemic),” he said.
Nevertheless, “in contrast to [earlier] studies, we have found that survival with a good neurological status is possible after in-hospital cardiac arrest in patients with COVID-19, which is certainly reassuring for those of us on the front line.”
Dr. Chan has received research support from the American Heart Association (which helps fund CARES); the National Heart, Lung, and Blood Institute; and Optum Rx. Dr. Abella has received honoraria from NeuroproteXeon, Becton Dickinson, and Physio-Control, and research grants from Medtronic, PCORI, Physio-Control, Stryker, and TerSera. Dr. Mitchell has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
In the early weeks of the COVID-19 pandemic in the United States, rates of sustained return of spontaneous circulation after out-of-hospital cardiac arrest were lower throughout the country, compared with a year earlier, in one study.
A second study of that period showed that patients with COVID-19 had rates that were better than previously reported of surviving in-hospital cardiac arrest.
Paul S. Chan, MD, presented the out-of-hospital cardiac arrest research, and Oscar J. Mitchell, MD, presented the in-hospital cardiac arrest findings in a late-breaking resuscitation science session at the American Heart Association scientific sessions. The former study was also simultaneously published online Nov. 14 in JAMA Cardiology.
Importantly, “the survival rates were not zero in either setting,” said Dr. Chan, commenting on the implications of both studies taken together.
“The survival rates – either return of circulation or survival to discharge – were not futile,” Dr. Chan, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said in an interview.
“And I think that’s an overall important message – that we can’t write off patients who have a cardiac arrest at this point,” he stressed. “They deserve a response. Although the outcomes might not be as good as we had seen in years prior, we are seeing patients making it out of the hospital and surviving.”
Dr. Mitchell, from the University of Pennsylvania in Philadelphia, echoed this message in an interview.
“I think that the key finding here is that survival is possible after patients with COVID-19 suffer an in-hospital cardiac arrest,” Dr. Mitchell said. “We hope that the information from our study will be of use to frontline providers who are treating patients with COVID-19.”
“In coming weeks, there will likely be increased hospital strain and enormous challenges to providing COVID-19 care,” added Benjamin S. Abella, MD, the senior author of the in-hospital study. Dr. Abella is also from the University of Pennsylvania and was cochair of the Resuscitation Science symposium during the AHA meeting.
“It is crucial that hospital leaders prepare now for how they will manage COVID-19 resuscitation efforts,” Dr. Abella said. “Emergency medicine and critical care leaders must be mindful that many COVID-19 patients with arrest could survive to return to their families.”
“It is important to note both studies demonstrated variations in outcome and that those differences were associated with the differential COVID prevalence and mortality,” session comoderator Cindy H. Hsu, MD, PhD, University of Michigan, said in an interview.
“Future studies,” she said, “should address knowledge gaps including associated comorbidities and affected resuscitation process variables during the COVID-19 pandemic.”
Out-of-hospital cardiac arrest, March 2019 vs. March 2020
Compared with 2019, in 2020, the reported rates of return of spontaneous circulation after out-of-hospital cardiac arrest fell from 25% to 10.6% in New York and from 13.5% to 5.0% in northern Italy – two areas that were severely affected, Dr. Chan noted.
In this study, the researchers aimed to examine whether out-of-hospital cardiac arrest outcomes would be similar throughout the United States, including areas that were less severely affected, in the first weeks of the pandemic.
They linked data from the Cardiac Arrest Registry to Enhance Survival (CARES), which covers an area with about 152 million U.S. residents, with COVID-19 disease mortality data.
There were 9,863 out-of-hospital arrests from March 16 to April 30, 2020, compared with 9,440 cases during this time in 2019.
The patients in both years had a similar age (mean, 62 years) and sex (62% male), but there were more Black patients in 2020 (28% vs. 23%).
Overall, in communities with low to high rates of death from COVID-19, the rate of return of spontaneous circulation was 18% lower in that early pandemic period than in the same time in the previous year (23% vs. 29.8%; adjusted rate ratio, 0.82).
The rates of return of spontaneous circulation were also lower in communities with a low rate of COVID-19 mortality, but to a lesser extent (11%-15% lower in 2020 vs. 2019).
In the subset of emergency medical agencies with complete data on hospital survival, overall rates of survival to discharge were 17% lower during the studied pandemic period versus the same time a year earlier (6.6% vs. 9.8%; adjusted RR, 0.83).
This drop in survival was greater in communities with moderate to high COVID-19 mortality.
These outcomes were not explained by differences in emergency medical services arrival or treatment times, rates of bystander CPR, or initial out-of-hospital cardiac arrest rhythm.
Dr. Chan was a coauthor of an interim guidance issued April 9, 2020, by the AHA and several other medical societies for ways to protect frontline workers from contracting COVID-19 while they were performing CPR.
Communities that were not heavily affected by COVID-19 could have also been following the recommendations, which might have affected outcomes, he speculated.
For example, “when we pause chest compressions it can potentially worsen survival even if it’s for a short period of time. That might explain the lower rates of return of circulation.”
“That guidance was really meant for heavily affected communities,” Dr. Chan added. “Of course, as we speak, the pandemic is pretty much everywhere in the United States. It’s not just in the northeast; it’s not just in Arizona, Florida, California, Texas like it was in the summer. You are seeing surges in 46 of the 50 states.
“If your community is heavily affected by COVID-19 in terms of deaths at this time, paramedics will need to take caution to also help protect themselves, and the guidance may apply at that point,” he said.
In-hospital cardiac arrest, March Through May 2020
The early studies of in-hospital cardiac arrest in patients with COVID-19 showed “concerningly low rates” of return of spontaneous circulation and survival, said Dr. Mitchell.
“The first was a study from Wuhan, which demonstrated a 2.9% 30-day survival and the second was a small cohort from NYC with 0% survival to hospital discharge,” he said. “This raised concerns that offering CPR to patients who had a cardiac arrest from COVID-19 might only hold a low probability of success.”
To investigate this, the researchers formed a COVID study group comprising two hospitals in New York and nine hospitals in the Northeast and West Coast.
They identified 260 hospitalized adult patients with COVID-19 who had in-hospital cardiac arrest between March 1 and May 31, 2020. The patients had a median age of 69 years, and 72% were male. Most had preexisting comorbidities. Most of the cardiac arrests were in the ICU (64%), and almost all were witnessed (91%).
Return of spontaneous circulation occurred in 22% of the patients, and 12% had survived 30 days later. Of the 260 cardiac arrests, most (204) occurred in the New York hospitals.
There was a huge variation in outcomes. The rate of sustained return of spontaneous circulation was much lower in the two hospitals in New York compared with elsewhere (11% vs. 64%), as was 30-day survival (6% vs. 36%).
“Variation in outcomes from [in-hospital cardiac arrest] has been well described prior to the COVID-19 pandemic,” said Dr. Mitchell, “and is felt to be due to a range of factors, including variation in detection and prevention of cardiac arrest, management of patients during the cardiac arrest, and differences in postarrest care – including targeted temperature management and neuroprognostication.”
“We hypothesize that the strains of the COVID-19 pandemic may have amplified these variations (although we were unable to compare hospital performance before and after the pandemic),” he said.
Nevertheless, “in contrast to [earlier] studies, we have found that survival with a good neurological status is possible after in-hospital cardiac arrest in patients with COVID-19, which is certainly reassuring for those of us on the front line.”
Dr. Chan has received research support from the American Heart Association (which helps fund CARES); the National Heart, Lung, and Blood Institute; and Optum Rx. Dr. Abella has received honoraria from NeuroproteXeon, Becton Dickinson, and Physio-Control, and research grants from Medtronic, PCORI, Physio-Control, Stryker, and TerSera. Dr. Mitchell has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
In the early weeks of the COVID-19 pandemic in the United States, rates of sustained return of spontaneous circulation after out-of-hospital cardiac arrest were lower throughout the country, compared with a year earlier, in one study.
A second study of that period showed that patients with COVID-19 had rates that were better than previously reported of surviving in-hospital cardiac arrest.
Paul S. Chan, MD, presented the out-of-hospital cardiac arrest research, and Oscar J. Mitchell, MD, presented the in-hospital cardiac arrest findings in a late-breaking resuscitation science session at the American Heart Association scientific sessions. The former study was also simultaneously published online Nov. 14 in JAMA Cardiology.
Importantly, “the survival rates were not zero in either setting,” said Dr. Chan, commenting on the implications of both studies taken together.
“The survival rates – either return of circulation or survival to discharge – were not futile,” Dr. Chan, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said in an interview.
“And I think that’s an overall important message – that we can’t write off patients who have a cardiac arrest at this point,” he stressed. “They deserve a response. Although the outcomes might not be as good as we had seen in years prior, we are seeing patients making it out of the hospital and surviving.”
Dr. Mitchell, from the University of Pennsylvania in Philadelphia, echoed this message in an interview.
“I think that the key finding here is that survival is possible after patients with COVID-19 suffer an in-hospital cardiac arrest,” Dr. Mitchell said. “We hope that the information from our study will be of use to frontline providers who are treating patients with COVID-19.”
“In coming weeks, there will likely be increased hospital strain and enormous challenges to providing COVID-19 care,” added Benjamin S. Abella, MD, the senior author of the in-hospital study. Dr. Abella is also from the University of Pennsylvania and was cochair of the Resuscitation Science symposium during the AHA meeting.
“It is crucial that hospital leaders prepare now for how they will manage COVID-19 resuscitation efforts,” Dr. Abella said. “Emergency medicine and critical care leaders must be mindful that many COVID-19 patients with arrest could survive to return to their families.”
“It is important to note both studies demonstrated variations in outcome and that those differences were associated with the differential COVID prevalence and mortality,” session comoderator Cindy H. Hsu, MD, PhD, University of Michigan, said in an interview.
“Future studies,” she said, “should address knowledge gaps including associated comorbidities and affected resuscitation process variables during the COVID-19 pandemic.”
Out-of-hospital cardiac arrest, March 2019 vs. March 2020
Compared with 2019, in 2020, the reported rates of return of spontaneous circulation after out-of-hospital cardiac arrest fell from 25% to 10.6% in New York and from 13.5% to 5.0% in northern Italy – two areas that were severely affected, Dr. Chan noted.
In this study, the researchers aimed to examine whether out-of-hospital cardiac arrest outcomes would be similar throughout the United States, including areas that were less severely affected, in the first weeks of the pandemic.
They linked data from the Cardiac Arrest Registry to Enhance Survival (CARES), which covers an area with about 152 million U.S. residents, with COVID-19 disease mortality data.
There were 9,863 out-of-hospital arrests from March 16 to April 30, 2020, compared with 9,440 cases during this time in 2019.
The patients in both years had a similar age (mean, 62 years) and sex (62% male), but there were more Black patients in 2020 (28% vs. 23%).
Overall, in communities with low to high rates of death from COVID-19, the rate of return of spontaneous circulation was 18% lower in that early pandemic period than in the same time in the previous year (23% vs. 29.8%; adjusted rate ratio, 0.82).
The rates of return of spontaneous circulation were also lower in communities with a low rate of COVID-19 mortality, but to a lesser extent (11%-15% lower in 2020 vs. 2019).
In the subset of emergency medical agencies with complete data on hospital survival, overall rates of survival to discharge were 17% lower during the studied pandemic period versus the same time a year earlier (6.6% vs. 9.8%; adjusted RR, 0.83).
This drop in survival was greater in communities with moderate to high COVID-19 mortality.
These outcomes were not explained by differences in emergency medical services arrival or treatment times, rates of bystander CPR, or initial out-of-hospital cardiac arrest rhythm.
Dr. Chan was a coauthor of an interim guidance issued April 9, 2020, by the AHA and several other medical societies for ways to protect frontline workers from contracting COVID-19 while they were performing CPR.
Communities that were not heavily affected by COVID-19 could have also been following the recommendations, which might have affected outcomes, he speculated.
For example, “when we pause chest compressions it can potentially worsen survival even if it’s for a short period of time. That might explain the lower rates of return of circulation.”
“That guidance was really meant for heavily affected communities,” Dr. Chan added. “Of course, as we speak, the pandemic is pretty much everywhere in the United States. It’s not just in the northeast; it’s not just in Arizona, Florida, California, Texas like it was in the summer. You are seeing surges in 46 of the 50 states.
“If your community is heavily affected by COVID-19 in terms of deaths at this time, paramedics will need to take caution to also help protect themselves, and the guidance may apply at that point,” he said.
In-hospital cardiac arrest, March Through May 2020
The early studies of in-hospital cardiac arrest in patients with COVID-19 showed “concerningly low rates” of return of spontaneous circulation and survival, said Dr. Mitchell.
“The first was a study from Wuhan, which demonstrated a 2.9% 30-day survival and the second was a small cohort from NYC with 0% survival to hospital discharge,” he said. “This raised concerns that offering CPR to patients who had a cardiac arrest from COVID-19 might only hold a low probability of success.”
To investigate this, the researchers formed a COVID study group comprising two hospitals in New York and nine hospitals in the Northeast and West Coast.
They identified 260 hospitalized adult patients with COVID-19 who had in-hospital cardiac arrest between March 1 and May 31, 2020. The patients had a median age of 69 years, and 72% were male. Most had preexisting comorbidities. Most of the cardiac arrests were in the ICU (64%), and almost all were witnessed (91%).
Return of spontaneous circulation occurred in 22% of the patients, and 12% had survived 30 days later. Of the 260 cardiac arrests, most (204) occurred in the New York hospitals.
There was a huge variation in outcomes. The rate of sustained return of spontaneous circulation was much lower in the two hospitals in New York compared with elsewhere (11% vs. 64%), as was 30-day survival (6% vs. 36%).
“Variation in outcomes from [in-hospital cardiac arrest] has been well described prior to the COVID-19 pandemic,” said Dr. Mitchell, “and is felt to be due to a range of factors, including variation in detection and prevention of cardiac arrest, management of patients during the cardiac arrest, and differences in postarrest care – including targeted temperature management and neuroprognostication.”
“We hypothesize that the strains of the COVID-19 pandemic may have amplified these variations (although we were unable to compare hospital performance before and after the pandemic),” he said.
Nevertheless, “in contrast to [earlier] studies, we have found that survival with a good neurological status is possible after in-hospital cardiac arrest in patients with COVID-19, which is certainly reassuring for those of us on the front line.”
Dr. Chan has received research support from the American Heart Association (which helps fund CARES); the National Heart, Lung, and Blood Institute; and Optum Rx. Dr. Abella has received honoraria from NeuroproteXeon, Becton Dickinson, and Physio-Control, and research grants from Medtronic, PCORI, Physio-Control, Stryker, and TerSera. Dr. Mitchell has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM AHA 2020
New-onset AFib common but unrecognized in the month after cardiac surgery
One in five patients at elevated stroke risk who underwent cardiac surgery with no history of atrial fibrillation preoperatively or at discharge developed postoperative AFib documented on a continuous cardiac rhythm monitoring device within the first 30 days after leaving the hospital in the randomized SEARCH-AF trial.
“Postoperative atrial fibrillation after cardiac surgery is not confined to the hospitalization period per se. We believe that these data should help inform on clinical practice guidelines on monitoring for postoperative atrial fibrillation in such patients,” said Subodh Verma, MD, PhD, reporting the results at the virtual American Heart Association scientific sessions.
“Guidelines provide little or no direction on optimal monitoring post cardiac surgery, particularly if patients are in sinus rhythm at discharge,” the surgeon noted.
SEARCH-AF was an open-label, multicenter study that included 336 patients at elevated stroke risk with an average CHA2DS2-VASc score of 4, no history of preoperative AFib, and none more than briefly with resolution during hospitalization. They were randomized to 30 days of postdischarge continuous cardiac rhythm monitoring with Medtronic’s SEEQ device, to Icentia’s CardioSTAT device, or to usual care, with Holter monitoring at the discretion of the treating physicians.
The primary result was a cumulative duration of AFib or atrial flutter of 6 minutes or longer during that 30-day period. This outcome occurred in 19.6% of the enhanced cardiac monitoring group and 1.7% of usual-care controls. Thus, there is an ongoing persistent occult risk of AFib that typically goes unrecognized. This 10-fold difference in the incidence of postoperative AFib translated into an absolute 17.9% between-group difference and a number-needed-to-treat of 6.
The secondary outcome of a cumulative atrial fib/flutter burden of 6 hours or more during 30 days occurred in 8.6% of the continuously monitored group and none of the controls. A cumulative AFib/flutter burden of 24 hours or greater occurred in 3.1% of the enhanced cardiac monitoring group and zero controls. These are AFib burdens that in other studies have been linked to increased risks of stroke and death, said Dr. Verma, professor of cardiovascular surgery at the University of Toronto.
“From a clinical standpoint, what this trial tells me is for my patients being discharged home tomorrow from the hospital, where they haven’t had AFib and I haven’t initiated anticoagulation, I have a low threshold to monitor these patients and to watch for periods of sustained unrecognized atrial fibrillation,” the surgeon added.
Experts: Results won’t change guidelines
Discussant Ben Freedman, MBBS, PhD, noted that the U.S. Preventive Services Task Force has stated that there are insufficient data available to recommend ECG screening for AFib to prevent stroke. Before the task force can be convinced to recommend it and for payers to cover it, a number of key questions need to be answered. And the SEARCH-AF trial doesn’t provide those answers, said Dr. Freedman, professor of cardiology and deputy director of the Heart Research Institute at the University of Sydney.
First off, it’ll be necessary to know if the risk posed by screen-detected AFib, including postoperative AFib, is similar to that of clinical AFib. Next, it must be shown that this screen-detected postoperative AFib is actionable; that is, that a screening strategy to detect postoperative AFib arising after discharge and then treat with oral anticoagulants will actually prevent more strokes than with usual care. There are large studies underway addressing that question, including HEARTLINE, STROKESTOP, and SAFERGUARD-AF, he observed.
In an interview, Rod S. Passman, MD, who gave a state-of-the-art talk on AFib detection at the meeting and wasn’t involved in SEARCH-AF, said he doesn’t consider the results practice-changing.
“It’s not guideline-changing because you’ve only shown that more intensive monitoring finds more AFib. Guideline-changing would be that finding that AFib and doing something about it impacts hard outcomes, and we don’t have that data yet,” said Dr. Passman, an electrophysiologist who is director of the Center for Arrhythmia Research and professor of medicine and preventive medicine at Northwestern University, Chicago.
The SEARCH-AF trial was funded by the Heart and Stroke Foundation of Canada, Bristol Myers Squibb, Pfizer, and Boehringer Ingelheim. Dr. Verma reported having received speaker’s fees and/or research support from those and other pharmaceutical companies. Dr. Freedman disclosed having no financial conflicts.
One in five patients at elevated stroke risk who underwent cardiac surgery with no history of atrial fibrillation preoperatively or at discharge developed postoperative AFib documented on a continuous cardiac rhythm monitoring device within the first 30 days after leaving the hospital in the randomized SEARCH-AF trial.
“Postoperative atrial fibrillation after cardiac surgery is not confined to the hospitalization period per se. We believe that these data should help inform on clinical practice guidelines on monitoring for postoperative atrial fibrillation in such patients,” said Subodh Verma, MD, PhD, reporting the results at the virtual American Heart Association scientific sessions.
“Guidelines provide little or no direction on optimal monitoring post cardiac surgery, particularly if patients are in sinus rhythm at discharge,” the surgeon noted.
SEARCH-AF was an open-label, multicenter study that included 336 patients at elevated stroke risk with an average CHA2DS2-VASc score of 4, no history of preoperative AFib, and none more than briefly with resolution during hospitalization. They were randomized to 30 days of postdischarge continuous cardiac rhythm monitoring with Medtronic’s SEEQ device, to Icentia’s CardioSTAT device, or to usual care, with Holter monitoring at the discretion of the treating physicians.
The primary result was a cumulative duration of AFib or atrial flutter of 6 minutes or longer during that 30-day period. This outcome occurred in 19.6% of the enhanced cardiac monitoring group and 1.7% of usual-care controls. Thus, there is an ongoing persistent occult risk of AFib that typically goes unrecognized. This 10-fold difference in the incidence of postoperative AFib translated into an absolute 17.9% between-group difference and a number-needed-to-treat of 6.
The secondary outcome of a cumulative atrial fib/flutter burden of 6 hours or more during 30 days occurred in 8.6% of the continuously monitored group and none of the controls. A cumulative AFib/flutter burden of 24 hours or greater occurred in 3.1% of the enhanced cardiac monitoring group and zero controls. These are AFib burdens that in other studies have been linked to increased risks of stroke and death, said Dr. Verma, professor of cardiovascular surgery at the University of Toronto.
“From a clinical standpoint, what this trial tells me is for my patients being discharged home tomorrow from the hospital, where they haven’t had AFib and I haven’t initiated anticoagulation, I have a low threshold to monitor these patients and to watch for periods of sustained unrecognized atrial fibrillation,” the surgeon added.
Experts: Results won’t change guidelines
Discussant Ben Freedman, MBBS, PhD, noted that the U.S. Preventive Services Task Force has stated that there are insufficient data available to recommend ECG screening for AFib to prevent stroke. Before the task force can be convinced to recommend it and for payers to cover it, a number of key questions need to be answered. And the SEARCH-AF trial doesn’t provide those answers, said Dr. Freedman, professor of cardiology and deputy director of the Heart Research Institute at the University of Sydney.
First off, it’ll be necessary to know if the risk posed by screen-detected AFib, including postoperative AFib, is similar to that of clinical AFib. Next, it must be shown that this screen-detected postoperative AFib is actionable; that is, that a screening strategy to detect postoperative AFib arising after discharge and then treat with oral anticoagulants will actually prevent more strokes than with usual care. There are large studies underway addressing that question, including HEARTLINE, STROKESTOP, and SAFERGUARD-AF, he observed.
In an interview, Rod S. Passman, MD, who gave a state-of-the-art talk on AFib detection at the meeting and wasn’t involved in SEARCH-AF, said he doesn’t consider the results practice-changing.
“It’s not guideline-changing because you’ve only shown that more intensive monitoring finds more AFib. Guideline-changing would be that finding that AFib and doing something about it impacts hard outcomes, and we don’t have that data yet,” said Dr. Passman, an electrophysiologist who is director of the Center for Arrhythmia Research and professor of medicine and preventive medicine at Northwestern University, Chicago.
The SEARCH-AF trial was funded by the Heart and Stroke Foundation of Canada, Bristol Myers Squibb, Pfizer, and Boehringer Ingelheim. Dr. Verma reported having received speaker’s fees and/or research support from those and other pharmaceutical companies. Dr. Freedman disclosed having no financial conflicts.
One in five patients at elevated stroke risk who underwent cardiac surgery with no history of atrial fibrillation preoperatively or at discharge developed postoperative AFib documented on a continuous cardiac rhythm monitoring device within the first 30 days after leaving the hospital in the randomized SEARCH-AF trial.
“Postoperative atrial fibrillation after cardiac surgery is not confined to the hospitalization period per se. We believe that these data should help inform on clinical practice guidelines on monitoring for postoperative atrial fibrillation in such patients,” said Subodh Verma, MD, PhD, reporting the results at the virtual American Heart Association scientific sessions.
“Guidelines provide little or no direction on optimal monitoring post cardiac surgery, particularly if patients are in sinus rhythm at discharge,” the surgeon noted.
SEARCH-AF was an open-label, multicenter study that included 336 patients at elevated stroke risk with an average CHA2DS2-VASc score of 4, no history of preoperative AFib, and none more than briefly with resolution during hospitalization. They were randomized to 30 days of postdischarge continuous cardiac rhythm monitoring with Medtronic’s SEEQ device, to Icentia’s CardioSTAT device, or to usual care, with Holter monitoring at the discretion of the treating physicians.
The primary result was a cumulative duration of AFib or atrial flutter of 6 minutes or longer during that 30-day period. This outcome occurred in 19.6% of the enhanced cardiac monitoring group and 1.7% of usual-care controls. Thus, there is an ongoing persistent occult risk of AFib that typically goes unrecognized. This 10-fold difference in the incidence of postoperative AFib translated into an absolute 17.9% between-group difference and a number-needed-to-treat of 6.
The secondary outcome of a cumulative atrial fib/flutter burden of 6 hours or more during 30 days occurred in 8.6% of the continuously monitored group and none of the controls. A cumulative AFib/flutter burden of 24 hours or greater occurred in 3.1% of the enhanced cardiac monitoring group and zero controls. These are AFib burdens that in other studies have been linked to increased risks of stroke and death, said Dr. Verma, professor of cardiovascular surgery at the University of Toronto.
“From a clinical standpoint, what this trial tells me is for my patients being discharged home tomorrow from the hospital, where they haven’t had AFib and I haven’t initiated anticoagulation, I have a low threshold to monitor these patients and to watch for periods of sustained unrecognized atrial fibrillation,” the surgeon added.
Experts: Results won’t change guidelines
Discussant Ben Freedman, MBBS, PhD, noted that the U.S. Preventive Services Task Force has stated that there are insufficient data available to recommend ECG screening for AFib to prevent stroke. Before the task force can be convinced to recommend it and for payers to cover it, a number of key questions need to be answered. And the SEARCH-AF trial doesn’t provide those answers, said Dr. Freedman, professor of cardiology and deputy director of the Heart Research Institute at the University of Sydney.
First off, it’ll be necessary to know if the risk posed by screen-detected AFib, including postoperative AFib, is similar to that of clinical AFib. Next, it must be shown that this screen-detected postoperative AFib is actionable; that is, that a screening strategy to detect postoperative AFib arising after discharge and then treat with oral anticoagulants will actually prevent more strokes than with usual care. There are large studies underway addressing that question, including HEARTLINE, STROKESTOP, and SAFERGUARD-AF, he observed.
In an interview, Rod S. Passman, MD, who gave a state-of-the-art talk on AFib detection at the meeting and wasn’t involved in SEARCH-AF, said he doesn’t consider the results practice-changing.
“It’s not guideline-changing because you’ve only shown that more intensive monitoring finds more AFib. Guideline-changing would be that finding that AFib and doing something about it impacts hard outcomes, and we don’t have that data yet,” said Dr. Passman, an electrophysiologist who is director of the Center for Arrhythmia Research and professor of medicine and preventive medicine at Northwestern University, Chicago.
The SEARCH-AF trial was funded by the Heart and Stroke Foundation of Canada, Bristol Myers Squibb, Pfizer, and Boehringer Ingelheim. Dr. Verma reported having received speaker’s fees and/or research support from those and other pharmaceutical companies. Dr. Freedman disclosed having no financial conflicts.
FROM AHA 2020
VTEs tied to immune checkpoint inhibitor cancer treatment
Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.
The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.
The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.
Hypothesis-generating results
Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.
“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.
“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.
The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.
Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
VTE spikes acutely after ICI treatment
Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.
She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.
Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.
Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.
During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.
The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).
Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.
“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”
The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.
Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.
The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.
The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.
Hypothesis-generating results
Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.
“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.
“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.
The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.
Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
VTE spikes acutely after ICI treatment
Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.
She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.
Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.
Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.
During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.
The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).
Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.
“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”
The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.
Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.
The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.
The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.
Hypothesis-generating results
Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.
“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.
“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.
The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.
Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
VTE spikes acutely after ICI treatment
Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.
She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.
Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.
Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.
During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.
The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).
Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.
“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”
The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.
FROM AHA 2020
SAMSON pins most muscle pain experienced with statins on the nocebo effect
A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.
The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).
“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.
Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.
“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.
Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.
For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.
“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”
Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.
In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.
All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.
So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”
Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”
The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.
Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.
Eleven patients were unable to complete all 12 1-month segments of the trial.
The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.
A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.
In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”
The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”
SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.
The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).
“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.
Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.
“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.
Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.
For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.
“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”
Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.
In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.
All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.
So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”
Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”
The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.
Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.
Eleven patients were unable to complete all 12 1-month segments of the trial.
The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.
A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.
In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”
The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”
SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.
The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).
“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.
Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.
“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.
Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.
For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.
“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”
Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.
In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.
All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.
So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”
Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”
The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.
Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.
Eleven patients were unable to complete all 12 1-month segments of the trial.
The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.
A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.
In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”
The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”
SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
STRENGTH trial questions CV benefit of high-dose omega-3s
Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.
The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).
It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.
Full results were presented Nov. 15 at the virtual American Heart Association scientific sessions and simultaneously published online in JAMA.
These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.
“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, of the Cleveland Clinic, said at the AHA meeting.
The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.
Dr. Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.
The one explanation that Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Dr. Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.
“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Dr. Lincoff said.
Asked whether he used omega-3 fatty acids in his practice, Dr. Lincoff replied, “Aside from patients with triglycerides greater than 500 – for which there is other evidence of benefit – I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”
Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Dr. Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.
“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.
A “manufactured controversy”
The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”
In an interview, he said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”
Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.
Dr. Lincoff outlined other possible explanations for the difference between the two trials.
He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”
There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”
Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.
STRENGTH trial
The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.
They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.
The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment.
At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).
A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69).
Uncertainty prevails
The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.
“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.
Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, noted that DHA may have less biological activity than EPA.
“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Dr. Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”
In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University, Baltimore, said the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.
“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they noted.
“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they concluded. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (i.e., mineral oil vs corn oil) may have affected outcomes remain unresolved.”
The STRENGTH trial was sponsored by AstraZeneca. Dr. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Dr. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Dr. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO, and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Dr. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.
A version of this article originally appeared on Medscape.com.
Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.
The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).
It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.
Full results were presented Nov. 15 at the virtual American Heart Association scientific sessions and simultaneously published online in JAMA.
These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.
“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, of the Cleveland Clinic, said at the AHA meeting.
The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.
Dr. Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.
The one explanation that Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Dr. Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.
“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Dr. Lincoff said.
Asked whether he used omega-3 fatty acids in his practice, Dr. Lincoff replied, “Aside from patients with triglycerides greater than 500 – for which there is other evidence of benefit – I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”
Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Dr. Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.
“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.
A “manufactured controversy”
The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”
In an interview, he said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”
Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.
Dr. Lincoff outlined other possible explanations for the difference between the two trials.
He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”
There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”
Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.
STRENGTH trial
The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.
They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.
The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment.
At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).
A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69).
Uncertainty prevails
The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.
“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.
Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, noted that DHA may have less biological activity than EPA.
“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Dr. Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”
In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University, Baltimore, said the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.
“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they noted.
“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they concluded. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (i.e., mineral oil vs corn oil) may have affected outcomes remain unresolved.”
The STRENGTH trial was sponsored by AstraZeneca. Dr. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Dr. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Dr. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO, and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Dr. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.
A version of this article originally appeared on Medscape.com.
Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.
The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).
It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.
Full results were presented Nov. 15 at the virtual American Heart Association scientific sessions and simultaneously published online in JAMA.
These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.
“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, of the Cleveland Clinic, said at the AHA meeting.
The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.
Dr. Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.
The one explanation that Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Dr. Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.
“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Dr. Lincoff said.
Asked whether he used omega-3 fatty acids in his practice, Dr. Lincoff replied, “Aside from patients with triglycerides greater than 500 – for which there is other evidence of benefit – I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”
Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Dr. Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.
“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.
A “manufactured controversy”
The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”
In an interview, he said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”
Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.
Dr. Lincoff outlined other possible explanations for the difference between the two trials.
He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”
There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”
Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.
STRENGTH trial
The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.
They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.
The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment.
At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).
A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69).
Uncertainty prevails
The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.
“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.
Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, noted that DHA may have less biological activity than EPA.
“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Dr. Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”
In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University, Baltimore, said the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.
“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they noted.
“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they concluded. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (i.e., mineral oil vs corn oil) may have affected outcomes remain unresolved.”
The STRENGTH trial was sponsored by AstraZeneca. Dr. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Dr. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Dr. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO, and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Dr. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.
A version of this article originally appeared on Medscape.com.