Arrhythmias & EP

The American College of Cardiology pulled off an impressive all-virtual meeting in March 2020, less than 3 weeks after canceling its in-person event and just 2 weeks after COVID-19 was declared a national emergency.

Optimistic plans for the annual scientific sessions of the American College of Cardiology (ACC 2021) to be a March hybrid affair in Atlanta pivoted not once, but twice, as the pandemic evolved, with the date pushed back 2 full months, to May 15-17, and the format revised to fully virtual.

“While this meeting is being delivered virtually, I think you’ll see there have been benefits in the time to plan and also the lessons that ACC has learned in virtual education over the past year. This has come together to really create a robust educational and scientific agenda,” ACC 2021 chair Pamela B. Morris, MD, said in a press conference focused on the upcoming meeting.

Over the 3 days, there will be more than 200 education sessions, 10 guideline-specific sessions, and 11 learning pathways that include core areas, but also special topics, such as COVID-19 and the emerging cardio-obstetrics subspecialty.

The meeting will be delivered through a new virtual education program built to optimize real-time interaction between faculty members and attendees, she said. A dedicated portal on the platform will allow attendees to interact virtually, for example, with presenters of the nearly 3,000 ePosters and 420 moderated posters.

For those suffering from Zoom fatigue, the increasingly popular Heart2Heart stage talks have also been converted to podcasts, which cover topics like gender equity in cardiology, the evolving role of advanced practice professionals, and “one of my favorites: art as a tool for healing,” said Dr. Morris, from the Medical University of South Carolina, Charleston. “Those sessions are really not to be missed.”

Reconnecting is an underlying theme of the meeting but the great divider will not be ignored. COVID-19 will be the focus of two 90-minute Intensive Sessions on Saturday, May 15, the first kicking off at 10:30 a.m. ET, with the Bishop Keynote lecture on bringing health equity to the frontline of cardiovascular care, followed by lessons learned during the pandemic, how to conduct clinical trials, and vaccine development.

The second session, set for 12:15 p.m., continues the “silver linings” theme, with case presentations on advances in telehealth, myocardial involvement, and thrombosis in COVID. For those wanting more, 18 abstracts are on tap in a 2-hour Spotlight on Special Topics session beginning at 2:30 p.m.

Asked about the pandemic’s effect on bringing science to fruition this past year, Dr. Morris said there’s no question it’s slowed some of the progress the cardiology community had made but, like clinical practice, “we’ve also surmounted many of those obstacles.”

“I think research has rebounded,” she said. “Just in terms of the number of abstracts and the quality of abstracts that were submitted this year, I don’t think there’s any question that we are right on par with previous years.”

Indeed, 5,258 abstracts from 76 countries were submitted, with more than 3,400 chosen for oral and poster presentation, including 25 late-breaking clinical trials to be presented in five sessions.

The late-breaking presentations and discussions will be prerecorded but speakers and panelists have been invited to be present during the streaming to answer live any questions that may arise in the chat box, ACC 2021 vice chair Douglas Drachman, MD, Massachusetts General Hospital, Boston, said in an interview.
 

Late-breaking clinical trials

The Joint ACC/JACC Late-Breaking Clinical Trials I (Saturday, May 15, 9:00 a.m.–-10:00 a.m.) kicks off with PARADISE-MI, the first head-to-head comparison of an angiotensin receptor neprilysin inhibitor (ARNI) and an ACE inhibitor in patients with reduced ejection fractions (EFs) after MI but no history of heart failure (HF), studying 200 mg sacubitril/valsartan (Entresto) versus 5 mg of ramipril, both twice daily, in 5,669 patients.

Sacubitril/valsartan was initially approved for HF with reduced EF and added a new indication to treat some HF patients with preserved EF. Novartis, however, recently told investors that although numerical trends consistently favored the ARNI over the ACE inhibitor ramipril, the phase 3 study failed to meet the primary endpoint for efficacy superiority of reducing the risk for cardiovascular (CV) death and HF events after an acute MI.

Second up is ADAPTABLE, which looks to close a surprising evidence gap over whether 81 mg or 325 mg daily is the optimal dose of the ubiquitously prescribed aspirin for secondary prevention in high-risk patients with established atherosclerotic CV disease.

The open-label, randomized study will look at efficacy and major bleeding over roughly 4 years in 15,000 patients within PCORnet, the National Patient-centered Clinical Research Network, a partnership of clinical research, health plan research, and patient-powered networks created to streamline patient-reported outcomes research.

“This study will not only give important clinical information for us, practically speaking, whether we should prescribe lower- or higher-dose aspirin, but it may also serve as a template for future pragmatic clinical trial design in the real world,” Dr. Drachman said during the press conference.

Up next is the 4,812-patient Canadian LAAOS III, the largest trial to examine the efficacy of left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation (AFib) already undergoing cardiac surgery. The primary outcome is the first occurrence of stroke or systemic arterial embolism over an average follow-up of 4 years.

Percutaneous closure of the left atrial appendage (LAA) has been shown to reduce stroke in AFib patients at high-risk of bleeding on systemic anticoagulation. But these devices can be expensive and studies haven’t included patients who also have valvular heart disease, a group that actually comprises more than half of patients undergoing cardiac surgery who also have AFib, he noted.

At the same time, surgical LAA closure studies have been small and have had very mixed results. “There isn’t a large-scale rigorous assessment out there for these patients undergoing surgery, so I think this is going to be fascinating to see,” Dr. Drachman said.

The session closes with ATLANTIS, which looks to shed some light on the role of anticoagulation therapy in patients after transcatheter aortic valve replacement (TAVR or TAVI). POPular TAVI, presented at ACC 2020, showed aspirin alone was the preferred antithrombotic therapy over aspirin plus clopidogrel (Plavix) in patients not on oral anticoagulants, but the optimal anticoagulation regimen remains unsettled.

The French open-label, 1,510-patient ATLANTIS trial examined whether the novel oral anticoagulant apixaban (Eliquis) is superior in preventing CV events after TAVR, compared with antiplatelet therapy in patients without an indication for anticoagulation and compared with vitamin K antagonists in those receiving anticoagulants.

An ATLANTIS 4D CT substudy of valve thrombosis is also slated for Saturday’s Featured Clinical Research 1 session at 12:15 p.m. to 1:45 p.m..
 

Sunday LBCTs

Dr. Drachman highlighted a series of other late-breaking studies, including the global DARE-19 trial testing the diabetes and HF drug dapagliflozin (Farxiga) given with local standard-of-care therapy for 30 days in hospitalized COVID-19 patients with CV, metabolic, or renal risk factors.

Although sodium-glucose cotransporter-2 inhibitors have been white-hot of late, top-line results reported last month show dapagliflozin failed to achieve statistical significance for the primary endpoints of reducing organ dysfunction and all-cause mortality and for improving recovery. Details will be presented in the Joint ACC/JAMA Late-Breaking Clinical Trials II (Sunday, May 16, 8:00 a.m.-9:30 a.m.).

Two trials, FLOWER-MI and RADIANCE-HTN TRIO, were singled out in the Joint ACC/New England Journal of Medicine Late-Breaking Clinical Trials III (Sunday, May 16, 10:45 a.m.-12:00 p.m.). FLOWER-MI examines whether fractional flow reserve (FFR) is better than angiography to guide complete multivessel revascularization in ST-elevation MI patients with at least 50% stenosis in at least one nonculprit lesion requiring percutaneous coronary intervention (PCI). Recent studies have shown the superiority of FFR-guided PCI for nonculprit lesions, compared with culprit lesion treatment-only, but this is the first time FFR- and angiography-guided PCI have been compared in STEMI patients.

RADIANCE-HTN TRIO already tipped its hand, with top-line results reported in late 2020 showing that the trial met its primary efficacy endpoint of greater reduction in daytime blood pressure over 2 months with the Paradise endovascular ultrasound renal denervation system, compared with a sham procedure, in 136 patients with resistant hypertension, importantly, after being given a single pill containing a calcium channel blocker, angiotensin II receptor blocker, and diuretic.

Renal denervation for hypertension has been making something of a comeback, with the 2018 RADIANCE-HTN SOLO reporting better ambulatory blood pressure control with the Paradise system than with a sham procedure in the absence of antihypertensive agents. The device has been granted breakthrough device designation from the Food and Drug Administration for the treatment of hypertensive patients who are unable to sufficiently respond to or are intolerant of antihypertensive therapy.
 

Monday LBCTs

In the Late-Breaking Clinical Trials IV session (Monday, May 17, 8 a.m.–9:30 a.m.), Drachman called out a secondary analysis from GALATIC-HF looking at the impact of EF on the therapeutic effect of omecamtiv mecarbil. In last year’s primary analysis, the selective cardiac myosin activator produced a modest but significant reduction in HF events or CV death in 8,232 patients with HF and an EF of 35% or less.

Rounding out the list is the Canadian CAPITAL CHILL study of moderate versus mild therapeutic hypothermia in out-of-hospital cardiac arrest, to be presented in the final Late-Breaking Clinical Trials V session (Monday, May 17, 10:45 a.m.–12:00 p.m.).

The double-blind trial sought to determine whether neurologic outcomes at 6 months are improved by targeting a core temperature of 31 ˚C versus 34 ˚C after the return of spontaneous circulation in comatose survivors of out-of-hospital cardiac arrest.

“For me, I think this could really change practice and has personal relevance from experience with cardiac arrest survivors that I’ve known and care for very deeply,” Dr. Drachman said in an interview. “I think that there’s a lot of opportunity here as well.”

Asked what other trials have the potential to change practice, Dr. Drachman said FLOWER-MI holds particular interest because it looks at how to manage patients with STEMI with multiple lesions at the point of care.

“We’ve gained a lot of clarity from several other prior clinical trials, but this will help to answer the question in a slightly different way of saying: can you eyeball it, can you look at the angiogram and say whether or not that other, nonculprit lesion ought to be treated in the same hospitalization or should you really be using a pressure wire,” he said. “For me as an interventionalist, this is really important because when you finish up doing an intervention on a patient it might be the middle of the night and the patient may be more or less stable, but you’ve already exposed them to the risk of a procedure, should you then move on and do another aspect of the procedure to interrogate with a pressure wire a remaining narrowing? I think that’s very important; that’ll help me make decisions on a day-to-day basis.”

Dr. Drachman also cited RADIANCE-HTN TRIO because it employs an endovascular technique to control blood pressure in patients with hypertension, specifically those resistant to multiple drugs.

During the press conference, Dr. Morris, a preventive cardiologist, put her money on the ADAPTABLE study of aspirin dosing, reiterating that the unique trial design could inform future research, and on Sunday’s 8:45 a.m. late-breaking post hoc analysis from the STRENGTH trial that looks to pick up where the controversy over omega-3 fatty acid preparations left off at last year’s American Heart Association meeting.

A lack of benefit on CV event rates reported with Epanova, a high-dose combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid, led to a contentious debate over how to reconcile STRENGTH with the findings from REDUCE-IT, which showed a 25% relative risk reduction in major CV events with the EPA product icosapent ethyl (Vascepa).

STRENGTH investigator Steven Nissen, MD, Cleveland Clinic, and REDUCE-IT investigator and session panelist Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, will share the virtual stage at ACC 2021, but Dr. Morris said the “good news” is both researchers know one another very well and “will really be focusing on no political issues, just the omega-3 fatty levels in the bloodstream and what does that mean in either trial.

“This is not designed to be a debate, point counterpoint,” she added.

For that, as all cardiologists and journalists know, there will be the wild and woolly #CardioTwitter sphere.

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

The American College of Cardiology pulled off an impressive all-virtual meeting in March 2020, less than 3 weeks after canceling its in-person event and just 2 weeks after COVID-19 was declared a national emergency.

Optimistic plans for the annual scientific sessions of the American College of Cardiology (ACC 2021) to be a March hybrid affair in Atlanta pivoted not once, but twice, as the pandemic evolved, with the date pushed back 2 full months, to May 15-17, and the format revised to fully virtual.

“While this meeting is being delivered virtually, I think you’ll see there have been benefits in the time to plan and also the lessons that ACC has learned in virtual education over the past year. This has come together to really create a robust educational and scientific agenda,” ACC 2021 chair Pamela B. Morris, MD, said in a press conference focused on the upcoming meeting.

Over the 3 days, there will be more than 200 education sessions, 10 guideline-specific sessions, and 11 learning pathways that include core areas, but also special topics, such as COVID-19 and the emerging cardio-obstetrics subspecialty.

The meeting will be delivered through a new virtual education program built to optimize real-time interaction between faculty members and attendees, she said. A dedicated portal on the platform will allow attendees to interact virtually, for example, with presenters of the nearly 3,000 ePosters and 420 moderated posters.

For those suffering from Zoom fatigue, the increasingly popular Heart2Heart stage talks have also been converted to podcasts, which cover topics like gender equity in cardiology, the evolving role of advanced practice professionals, and “one of my favorites: art as a tool for healing,” said Dr. Morris, from the Medical University of South Carolina, Charleston. “Those sessions are really not to be missed.”

Reconnecting is an underlying theme of the meeting but the great divider will not be ignored. COVID-19 will be the focus of two 90-minute Intensive Sessions on Saturday, May 15, the first kicking off at 10:30 a.m. ET, with the Bishop Keynote lecture on bringing health equity to the frontline of cardiovascular care, followed by lessons learned during the pandemic, how to conduct clinical trials, and vaccine development.

The second session, set for 12:15 p.m., continues the “silver linings” theme, with case presentations on advances in telehealth, myocardial involvement, and thrombosis in COVID. For those wanting more, 18 abstracts are on tap in a 2-hour Spotlight on Special Topics session beginning at 2:30 p.m.

Asked about the pandemic’s effect on bringing science to fruition this past year, Dr. Morris said there’s no question it’s slowed some of the progress the cardiology community had made but, like clinical practice, “we’ve also surmounted many of those obstacles.”

“I think research has rebounded,” she said. “Just in terms of the number of abstracts and the quality of abstracts that were submitted this year, I don’t think there’s any question that we are right on par with previous years.”

Indeed, 5,258 abstracts from 76 countries were submitted, with more than 3,400 chosen for oral and poster presentation, including 25 late-breaking clinical trials to be presented in five sessions.

The late-breaking presentations and discussions will be prerecorded but speakers and panelists have been invited to be present during the streaming to answer live any questions that may arise in the chat box, ACC 2021 vice chair Douglas Drachman, MD, Massachusetts General Hospital, Boston, said in an interview.
 

Late-breaking clinical trials

The Joint ACC/JACC Late-Breaking Clinical Trials I (Saturday, May 15, 9:00 a.m.–-10:00 a.m.) kicks off with PARADISE-MI, the first head-to-head comparison of an angiotensin receptor neprilysin inhibitor (ARNI) and an ACE inhibitor in patients with reduced ejection fractions (EFs) after MI but no history of heart failure (HF), studying 200 mg sacubitril/valsartan (Entresto) versus 5 mg of ramipril, both twice daily, in 5,669 patients.

Sacubitril/valsartan was initially approved for HF with reduced EF and added a new indication to treat some HF patients with preserved EF. Novartis, however, recently told investors that although numerical trends consistently favored the ARNI over the ACE inhibitor ramipril, the phase 3 study failed to meet the primary endpoint for efficacy superiority of reducing the risk for cardiovascular (CV) death and HF events after an acute MI.

Second up is ADAPTABLE, which looks to close a surprising evidence gap over whether 81 mg or 325 mg daily is the optimal dose of the ubiquitously prescribed aspirin for secondary prevention in high-risk patients with established atherosclerotic CV disease.

The open-label, randomized study will look at efficacy and major bleeding over roughly 4 years in 15,000 patients within PCORnet, the National Patient-centered Clinical Research Network, a partnership of clinical research, health plan research, and patient-powered networks created to streamline patient-reported outcomes research.

“This study will not only give important clinical information for us, practically speaking, whether we should prescribe lower- or higher-dose aspirin, but it may also serve as a template for future pragmatic clinical trial design in the real world,” Dr. Drachman said during the press conference.

Up next is the 4,812-patient Canadian LAAOS III, the largest trial to examine the efficacy of left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation (AFib) already undergoing cardiac surgery. The primary outcome is the first occurrence of stroke or systemic arterial embolism over an average follow-up of 4 years.

Percutaneous closure of the left atrial appendage (LAA) has been shown to reduce stroke in AFib patients at high-risk of bleeding on systemic anticoagulation. But these devices can be expensive and studies haven’t included patients who also have valvular heart disease, a group that actually comprises more than half of patients undergoing cardiac surgery who also have AFib, he noted.

At the same time, surgical LAA closure studies have been small and have had very mixed results. “There isn’t a large-scale rigorous assessment out there for these patients undergoing surgery, so I think this is going to be fascinating to see,” Dr. Drachman said.

The session closes with ATLANTIS, which looks to shed some light on the role of anticoagulation therapy in patients after transcatheter aortic valve replacement (TAVR or TAVI). POPular TAVI, presented at ACC 2020, showed aspirin alone was the preferred antithrombotic therapy over aspirin plus clopidogrel (Plavix) in patients not on oral anticoagulants, but the optimal anticoagulation regimen remains unsettled.

The French open-label, 1,510-patient ATLANTIS trial examined whether the novel oral anticoagulant apixaban (Eliquis) is superior in preventing CV events after TAVR, compared with antiplatelet therapy in patients without an indication for anticoagulation and compared with vitamin K antagonists in those receiving anticoagulants.

An ATLANTIS 4D CT substudy of valve thrombosis is also slated for Saturday’s Featured Clinical Research 1 session at 12:15 p.m. to 1:45 p.m..
 

Sunday LBCTs

Dr. Drachman highlighted a series of other late-breaking studies, including the global DARE-19 trial testing the diabetes and HF drug dapagliflozin (Farxiga) given with local standard-of-care therapy for 30 days in hospitalized COVID-19 patients with CV, metabolic, or renal risk factors.

Although sodium-glucose cotransporter-2 inhibitors have been white-hot of late, top-line results reported last month show dapagliflozin failed to achieve statistical significance for the primary endpoints of reducing organ dysfunction and all-cause mortality and for improving recovery. Details will be presented in the Joint ACC/JAMA Late-Breaking Clinical Trials II (Sunday, May 16, 8:00 a.m.-9:30 a.m.).

Two trials, FLOWER-MI and RADIANCE-HTN TRIO, were singled out in the Joint ACC/New England Journal of Medicine Late-Breaking Clinical Trials III (Sunday, May 16, 10:45 a.m.-12:00 p.m.). FLOWER-MI examines whether fractional flow reserve (FFR) is better than angiography to guide complete multivessel revascularization in ST-elevation MI patients with at least 50% stenosis in at least one nonculprit lesion requiring percutaneous coronary intervention (PCI). Recent studies have shown the superiority of FFR-guided PCI for nonculprit lesions, compared with culprit lesion treatment-only, but this is the first time FFR- and angiography-guided PCI have been compared in STEMI patients.

RADIANCE-HTN TRIO already tipped its hand, with top-line results reported in late 2020 showing that the trial met its primary efficacy endpoint of greater reduction in daytime blood pressure over 2 months with the Paradise endovascular ultrasound renal denervation system, compared with a sham procedure, in 136 patients with resistant hypertension, importantly, after being given a single pill containing a calcium channel blocker, angiotensin II receptor blocker, and diuretic.

Renal denervation for hypertension has been making something of a comeback, with the 2018 RADIANCE-HTN SOLO reporting better ambulatory blood pressure control with the Paradise system than with a sham procedure in the absence of antihypertensive agents. The device has been granted breakthrough device designation from the Food and Drug Administration for the treatment of hypertensive patients who are unable to sufficiently respond to or are intolerant of antihypertensive therapy.
 

Monday LBCTs

In the Late-Breaking Clinical Trials IV session (Monday, May 17, 8 a.m.–9:30 a.m.), Drachman called out a secondary analysis from GALATIC-HF looking at the impact of EF on the therapeutic effect of omecamtiv mecarbil. In last year’s primary analysis, the selective cardiac myosin activator produced a modest but significant reduction in HF events or CV death in 8,232 patients with HF and an EF of 35% or less.

Rounding out the list is the Canadian CAPITAL CHILL study of moderate versus mild therapeutic hypothermia in out-of-hospital cardiac arrest, to be presented in the final Late-Breaking Clinical Trials V session (Monday, May 17, 10:45 a.m.–12:00 p.m.).

The double-blind trial sought to determine whether neurologic outcomes at 6 months are improved by targeting a core temperature of 31 ˚C versus 34 ˚C after the return of spontaneous circulation in comatose survivors of out-of-hospital cardiac arrest.

“For me, I think this could really change practice and has personal relevance from experience with cardiac arrest survivors that I’ve known and care for very deeply,” Dr. Drachman said in an interview. “I think that there’s a lot of opportunity here as well.”

Asked what other trials have the potential to change practice, Dr. Drachman said FLOWER-MI holds particular interest because it looks at how to manage patients with STEMI with multiple lesions at the point of care.

“We’ve gained a lot of clarity from several other prior clinical trials, but this will help to answer the question in a slightly different way of saying: can you eyeball it, can you look at the angiogram and say whether or not that other, nonculprit lesion ought to be treated in the same hospitalization or should you really be using a pressure wire,” he said. “For me as an interventionalist, this is really important because when you finish up doing an intervention on a patient it might be the middle of the night and the patient may be more or less stable, but you’ve already exposed them to the risk of a procedure, should you then move on and do another aspect of the procedure to interrogate with a pressure wire a remaining narrowing? I think that’s very important; that’ll help me make decisions on a day-to-day basis.”

Dr. Drachman also cited RADIANCE-HTN TRIO because it employs an endovascular technique to control blood pressure in patients with hypertension, specifically those resistant to multiple drugs.

During the press conference, Dr. Morris, a preventive cardiologist, put her money on the ADAPTABLE study of aspirin dosing, reiterating that the unique trial design could inform future research, and on Sunday’s 8:45 a.m. late-breaking post hoc analysis from the STRENGTH trial that looks to pick up where the controversy over omega-3 fatty acid preparations left off at last year’s American Heart Association meeting.

A lack of benefit on CV event rates reported with Epanova, a high-dose combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid, led to a contentious debate over how to reconcile STRENGTH with the findings from REDUCE-IT, which showed a 25% relative risk reduction in major CV events with the EPA product icosapent ethyl (Vascepa).

STRENGTH investigator Steven Nissen, MD, Cleveland Clinic, and REDUCE-IT investigator and session panelist Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, will share the virtual stage at ACC 2021, but Dr. Morris said the “good news” is both researchers know one another very well and “will really be focusing on no political issues, just the omega-3 fatty levels in the bloodstream and what does that mean in either trial.

“This is not designed to be a debate, point counterpoint,” she added.

For that, as all cardiologists and journalists know, there will be the wild and woolly #CardioTwitter sphere.

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

The American College of Cardiology pulled off an impressive all-virtual meeting in March 2020, less than 3 weeks after canceling its in-person event and just 2 weeks after COVID-19 was declared a national emergency.

Optimistic plans for the annual scientific sessions of the American College of Cardiology (ACC 2021) to be a March hybrid affair in Atlanta pivoted not once, but twice, as the pandemic evolved, with the date pushed back 2 full months, to May 15-17, and the format revised to fully virtual.

“While this meeting is being delivered virtually, I think you’ll see there have been benefits in the time to plan and also the lessons that ACC has learned in virtual education over the past year. This has come together to really create a robust educational and scientific agenda,” ACC 2021 chair Pamela B. Morris, MD, said in a press conference focused on the upcoming meeting.

Over the 3 days, there will be more than 200 education sessions, 10 guideline-specific sessions, and 11 learning pathways that include core areas, but also special topics, such as COVID-19 and the emerging cardio-obstetrics subspecialty.

The meeting will be delivered through a new virtual education program built to optimize real-time interaction between faculty members and attendees, she said. A dedicated portal on the platform will allow attendees to interact virtually, for example, with presenters of the nearly 3,000 ePosters and 420 moderated posters.

For those suffering from Zoom fatigue, the increasingly popular Heart2Heart stage talks have also been converted to podcasts, which cover topics like gender equity in cardiology, the evolving role of advanced practice professionals, and “one of my favorites: art as a tool for healing,” said Dr. Morris, from the Medical University of South Carolina, Charleston. “Those sessions are really not to be missed.”

Reconnecting is an underlying theme of the meeting but the great divider will not be ignored. COVID-19 will be the focus of two 90-minute Intensive Sessions on Saturday, May 15, the first kicking off at 10:30 a.m. ET, with the Bishop Keynote lecture on bringing health equity to the frontline of cardiovascular care, followed by lessons learned during the pandemic, how to conduct clinical trials, and vaccine development.

The second session, set for 12:15 p.m., continues the “silver linings” theme, with case presentations on advances in telehealth, myocardial involvement, and thrombosis in COVID. For those wanting more, 18 abstracts are on tap in a 2-hour Spotlight on Special Topics session beginning at 2:30 p.m.

Asked about the pandemic’s effect on bringing science to fruition this past year, Dr. Morris said there’s no question it’s slowed some of the progress the cardiology community had made but, like clinical practice, “we’ve also surmounted many of those obstacles.”

“I think research has rebounded,” she said. “Just in terms of the number of abstracts and the quality of abstracts that were submitted this year, I don’t think there’s any question that we are right on par with previous years.”

Indeed, 5,258 abstracts from 76 countries were submitted, with more than 3,400 chosen for oral and poster presentation, including 25 late-breaking clinical trials to be presented in five sessions.

The late-breaking presentations and discussions will be prerecorded but speakers and panelists have been invited to be present during the streaming to answer live any questions that may arise in the chat box, ACC 2021 vice chair Douglas Drachman, MD, Massachusetts General Hospital, Boston, said in an interview.
 

Late-breaking clinical trials

The Joint ACC/JACC Late-Breaking Clinical Trials I (Saturday, May 15, 9:00 a.m.–-10:00 a.m.) kicks off with PARADISE-MI, the first head-to-head comparison of an angiotensin receptor neprilysin inhibitor (ARNI) and an ACE inhibitor in patients with reduced ejection fractions (EFs) after MI but no history of heart failure (HF), studying 200 mg sacubitril/valsartan (Entresto) versus 5 mg of ramipril, both twice daily, in 5,669 patients.

Sacubitril/valsartan was initially approved for HF with reduced EF and added a new indication to treat some HF patients with preserved EF. Novartis, however, recently told investors that although numerical trends consistently favored the ARNI over the ACE inhibitor ramipril, the phase 3 study failed to meet the primary endpoint for efficacy superiority of reducing the risk for cardiovascular (CV) death and HF events after an acute MI.

Second up is ADAPTABLE, which looks to close a surprising evidence gap over whether 81 mg or 325 mg daily is the optimal dose of the ubiquitously prescribed aspirin for secondary prevention in high-risk patients with established atherosclerotic CV disease.

The open-label, randomized study will look at efficacy and major bleeding over roughly 4 years in 15,000 patients within PCORnet, the National Patient-centered Clinical Research Network, a partnership of clinical research, health plan research, and patient-powered networks created to streamline patient-reported outcomes research.

“This study will not only give important clinical information for us, practically speaking, whether we should prescribe lower- or higher-dose aspirin, but it may also serve as a template for future pragmatic clinical trial design in the real world,” Dr. Drachman said during the press conference.

Up next is the 4,812-patient Canadian LAAOS III, the largest trial to examine the efficacy of left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation (AFib) already undergoing cardiac surgery. The primary outcome is the first occurrence of stroke or systemic arterial embolism over an average follow-up of 4 years.

Percutaneous closure of the left atrial appendage (LAA) has been shown to reduce stroke in AFib patients at high-risk of bleeding on systemic anticoagulation. But these devices can be expensive and studies haven’t included patients who also have valvular heart disease, a group that actually comprises more than half of patients undergoing cardiac surgery who also have AFib, he noted.

At the same time, surgical LAA closure studies have been small and have had very mixed results. “There isn’t a large-scale rigorous assessment out there for these patients undergoing surgery, so I think this is going to be fascinating to see,” Dr. Drachman said.

The session closes with ATLANTIS, which looks to shed some light on the role of anticoagulation therapy in patients after transcatheter aortic valve replacement (TAVR or TAVI). POPular TAVI, presented at ACC 2020, showed aspirin alone was the preferred antithrombotic therapy over aspirin plus clopidogrel (Plavix) in patients not on oral anticoagulants, but the optimal anticoagulation regimen remains unsettled.

The French open-label, 1,510-patient ATLANTIS trial examined whether the novel oral anticoagulant apixaban (Eliquis) is superior in preventing CV events after TAVR, compared with antiplatelet therapy in patients without an indication for anticoagulation and compared with vitamin K antagonists in those receiving anticoagulants.

An ATLANTIS 4D CT substudy of valve thrombosis is also slated for Saturday’s Featured Clinical Research 1 session at 12:15 p.m. to 1:45 p.m..
 

Sunday LBCTs

Dr. Drachman highlighted a series of other late-breaking studies, including the global DARE-19 trial testing the diabetes and HF drug dapagliflozin (Farxiga) given with local standard-of-care therapy for 30 days in hospitalized COVID-19 patients with CV, metabolic, or renal risk factors.

Although sodium-glucose cotransporter-2 inhibitors have been white-hot of late, top-line results reported last month show dapagliflozin failed to achieve statistical significance for the primary endpoints of reducing organ dysfunction and all-cause mortality and for improving recovery. Details will be presented in the Joint ACC/JAMA Late-Breaking Clinical Trials II (Sunday, May 16, 8:00 a.m.-9:30 a.m.).

Two trials, FLOWER-MI and RADIANCE-HTN TRIO, were singled out in the Joint ACC/New England Journal of Medicine Late-Breaking Clinical Trials III (Sunday, May 16, 10:45 a.m.-12:00 p.m.). FLOWER-MI examines whether fractional flow reserve (FFR) is better than angiography to guide complete multivessel revascularization in ST-elevation MI patients with at least 50% stenosis in at least one nonculprit lesion requiring percutaneous coronary intervention (PCI). Recent studies have shown the superiority of FFR-guided PCI for nonculprit lesions, compared with culprit lesion treatment-only, but this is the first time FFR- and angiography-guided PCI have been compared in STEMI patients.

RADIANCE-HTN TRIO already tipped its hand, with top-line results reported in late 2020 showing that the trial met its primary efficacy endpoint of greater reduction in daytime blood pressure over 2 months with the Paradise endovascular ultrasound renal denervation system, compared with a sham procedure, in 136 patients with resistant hypertension, importantly, after being given a single pill containing a calcium channel blocker, angiotensin II receptor blocker, and diuretic.

Renal denervation for hypertension has been making something of a comeback, with the 2018 RADIANCE-HTN SOLO reporting better ambulatory blood pressure control with the Paradise system than with a sham procedure in the absence of antihypertensive agents. The device has been granted breakthrough device designation from the Food and Drug Administration for the treatment of hypertensive patients who are unable to sufficiently respond to or are intolerant of antihypertensive therapy.
 

Monday LBCTs

In the Late-Breaking Clinical Trials IV session (Monday, May 17, 8 a.m.–9:30 a.m.), Drachman called out a secondary analysis from GALATIC-HF looking at the impact of EF on the therapeutic effect of omecamtiv mecarbil. In last year’s primary analysis, the selective cardiac myosin activator produced a modest but significant reduction in HF events or CV death in 8,232 patients with HF and an EF of 35% or less.

Rounding out the list is the Canadian CAPITAL CHILL study of moderate versus mild therapeutic hypothermia in out-of-hospital cardiac arrest, to be presented in the final Late-Breaking Clinical Trials V session (Monday, May 17, 10:45 a.m.–12:00 p.m.).

The double-blind trial sought to determine whether neurologic outcomes at 6 months are improved by targeting a core temperature of 31 ˚C versus 34 ˚C after the return of spontaneous circulation in comatose survivors of out-of-hospital cardiac arrest.

“For me, I think this could really change practice and has personal relevance from experience with cardiac arrest survivors that I’ve known and care for very deeply,” Dr. Drachman said in an interview. “I think that there’s a lot of opportunity here as well.”

Asked what other trials have the potential to change practice, Dr. Drachman said FLOWER-MI holds particular interest because it looks at how to manage patients with STEMI with multiple lesions at the point of care.

“We’ve gained a lot of clarity from several other prior clinical trials, but this will help to answer the question in a slightly different way of saying: can you eyeball it, can you look at the angiogram and say whether or not that other, nonculprit lesion ought to be treated in the same hospitalization or should you really be using a pressure wire,” he said. “For me as an interventionalist, this is really important because when you finish up doing an intervention on a patient it might be the middle of the night and the patient may be more or less stable, but you’ve already exposed them to the risk of a procedure, should you then move on and do another aspect of the procedure to interrogate with a pressure wire a remaining narrowing? I think that’s very important; that’ll help me make decisions on a day-to-day basis.”

Dr. Drachman also cited RADIANCE-HTN TRIO because it employs an endovascular technique to control blood pressure in patients with hypertension, specifically those resistant to multiple drugs.

During the press conference, Dr. Morris, a preventive cardiologist, put her money on the ADAPTABLE study of aspirin dosing, reiterating that the unique trial design could inform future research, and on Sunday’s 8:45 a.m. late-breaking post hoc analysis from the STRENGTH trial that looks to pick up where the controversy over omega-3 fatty acid preparations left off at last year’s American Heart Association meeting.

A lack of benefit on CV event rates reported with Epanova, a high-dose combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid, led to a contentious debate over how to reconcile STRENGTH with the findings from REDUCE-IT, which showed a 25% relative risk reduction in major CV events with the EPA product icosapent ethyl (Vascepa).

STRENGTH investigator Steven Nissen, MD, Cleveland Clinic, and REDUCE-IT investigator and session panelist Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, will share the virtual stage at ACC 2021, but Dr. Morris said the “good news” is both researchers know one another very well and “will really be focusing on no political issues, just the omega-3 fatty levels in the bloodstream and what does that mean in either trial.

“This is not designed to be a debate, point counterpoint,” she added.

For that, as all cardiologists and journalists know, there will be the wild and woolly #CardioTwitter sphere.

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

An examination of coffee consumption habits of almost 400,000 people suggests that those habits are largely driven by a person’s cardiovascular health.

©Elena Moiseeva/fotolia.com

Data from a large population database showed that people with essential hypertension, angina, or cardiac arrhythmias drank less coffee than people who had none of these conditions. When they did drink coffee, it tended to be decaffeinated.

The investigators, led by Elina Hyppönen, PhD, director of the Australian Centre for Precision Health at the University of South Australia, Adelaide, say that this predilection for avoiding coffee, which is known to produce jitteriness and heart palpitations, is based on genetics.

“If your body is telling you not to drink that extra cup of coffee, there’s likely a reason why,” Dr. Hyppönen said in an interview.

The study was published online in the American Journal of Clinical Nutrition.

“People drink coffee as a pick-me-up when they’re feeling tired, or because it tastes good, or simply because it’s part of their daily routine, but what we don’t recognize is that people subconsciously self-regulate safe levels of caffeine based on how high their blood pressure is, and this is likely a result of a protective genetic mechanism, [meaning] that someone who drinks a lot of coffee is likely more genetically tolerant of caffeine, as compared to someone who drinks very little,” Dr. Hyppönen said.

“In addition, we’ve known from past research that when people feel unwell, they tend to drink less coffee. This type of phenomenon, where disease drives behavior, is called reverse causality,” Dr. Hyppönen said.

For this analysis, she and her team used information on 390,435 individuals of European ancestry from the UK Biobank, a large epidemiologic database. Habitual coffee consumption was self-reported, and systolic and diastolic blood pressure and heart rate were measured at baseline. Cardiovascular symptoms at baseline were gleaned from hospital diagnoses, primary care records, and/or self report, the authors note.

To look at the relationship of systolic BP, diastolic BP, and heart rate with coffee consumption, they used a strategy called Mendelian randomization, which allows genetic information such as variants reflecting higher blood pressures and heart rate to be used to provide evidence for a causal association.

Results showed that participants with essential hypertension, angina, or arrhythmia were “all more likely to drink less caffeinated coffee and to be nonhabitual or decaffeinated coffee drinkers compared with those who did not report related symptoms,” the authors write.

Those with higher systolic and diastolic BP based on their genetics tended to drink less caffeinated coffee at baseline, “with consistent genetic evidence to support a causal explanation across all methods,” they noted.

They also found that those people who have a higher resting heart rate due to their genes were more likely to choose decaffeinated coffee.

“These results have two major implications,” Dr. Hyppönen said. “Firstly, they show that our bodies can regulate behavior in ways that we may not realize, and that if something does not feel good to us, there is a likely to be a reason why.”

“Second, our results show that our health status in part regulates the amount of coffee we drink. This is important, because when disease drives behavior, it can lead to misleading health associations in observational studies, and indeed, create a false impression for health benefits if the group of people who do not drink coffee also includes more people who are unwell,” she said.

For now, doctors can tell their patients that this study provides an explanation as to why research on the health effects of habitual coffee consumption has been conflicting, Dr. Hyppönen said.

“Our study also highlights the uncertainty that underlies the claimed health benefits of coffee, but at the same time, it gives a positive message about the ability of our body to regulate our level of coffee consumption in a way that helps us avoid adverse effects.”

“The most common symptoms of excessive coffee consumption are palpitations and rapid heartbeat, also known as tachycardia,” Nieca Goldberg, MD, medical director of the NYU Women’s Heart Program at NYU Langone Health, said in an interview.

“This study was designed to see if cardiac symptoms affect coffee consumption, and it showed that people with hypertension, angina, history of arrhythmias, and poor health tend to be decaffeinated coffee drinkers or no coffee drinkers,” Dr. Goldberg said.

“People naturally alter their coffee intake base on their blood pressure and symptoms of palpitations and/or rapid heart rate,” she said.

The results also suggest that, “we cannot infer health benefit or harm based on the available coffee studies,” Dr. Goldberg added.

The study was funded by the National Health and Medical Research Council, Australia. Dr. Hyppönen and Dr. Goldberg have disclosed no relevant financial relationships.

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

An examination of coffee consumption habits of almost 400,000 people suggests that those habits are largely driven by a person’s cardiovascular health.

©Elena Moiseeva/fotolia.com

Data from a large population database showed that people with essential hypertension, angina, or cardiac arrhythmias drank less coffee than people who had none of these conditions. When they did drink coffee, it tended to be decaffeinated.

The investigators, led by Elina Hyppönen, PhD, director of the Australian Centre for Precision Health at the University of South Australia, Adelaide, say that this predilection for avoiding coffee, which is known to produce jitteriness and heart palpitations, is based on genetics.

“If your body is telling you not to drink that extra cup of coffee, there’s likely a reason why,” Dr. Hyppönen said in an interview.

The study was published online in the American Journal of Clinical Nutrition.

“People drink coffee as a pick-me-up when they’re feeling tired, or because it tastes good, or simply because it’s part of their daily routine, but what we don’t recognize is that people subconsciously self-regulate safe levels of caffeine based on how high their blood pressure is, and this is likely a result of a protective genetic mechanism, [meaning] that someone who drinks a lot of coffee is likely more genetically tolerant of caffeine, as compared to someone who drinks very little,” Dr. Hyppönen said.

“In addition, we’ve known from past research that when people feel unwell, they tend to drink less coffee. This type of phenomenon, where disease drives behavior, is called reverse causality,” Dr. Hyppönen said.

For this analysis, she and her team used information on 390,435 individuals of European ancestry from the UK Biobank, a large epidemiologic database. Habitual coffee consumption was self-reported, and systolic and diastolic blood pressure and heart rate were measured at baseline. Cardiovascular symptoms at baseline were gleaned from hospital diagnoses, primary care records, and/or self report, the authors note.

To look at the relationship of systolic BP, diastolic BP, and heart rate with coffee consumption, they used a strategy called Mendelian randomization, which allows genetic information such as variants reflecting higher blood pressures and heart rate to be used to provide evidence for a causal association.

Results showed that participants with essential hypertension, angina, or arrhythmia were “all more likely to drink less caffeinated coffee and to be nonhabitual or decaffeinated coffee drinkers compared with those who did not report related symptoms,” the authors write.

Those with higher systolic and diastolic BP based on their genetics tended to drink less caffeinated coffee at baseline, “with consistent genetic evidence to support a causal explanation across all methods,” they noted.

They also found that those people who have a higher resting heart rate due to their genes were more likely to choose decaffeinated coffee.

“These results have two major implications,” Dr. Hyppönen said. “Firstly, they show that our bodies can regulate behavior in ways that we may not realize, and that if something does not feel good to us, there is a likely to be a reason why.”

“Second, our results show that our health status in part regulates the amount of coffee we drink. This is important, because when disease drives behavior, it can lead to misleading health associations in observational studies, and indeed, create a false impression for health benefits if the group of people who do not drink coffee also includes more people who are unwell,” she said.

For now, doctors can tell their patients that this study provides an explanation as to why research on the health effects of habitual coffee consumption has been conflicting, Dr. Hyppönen said.

“Our study also highlights the uncertainty that underlies the claimed health benefits of coffee, but at the same time, it gives a positive message about the ability of our body to regulate our level of coffee consumption in a way that helps us avoid adverse effects.”

“The most common symptoms of excessive coffee consumption are palpitations and rapid heartbeat, also known as tachycardia,” Nieca Goldberg, MD, medical director of the NYU Women’s Heart Program at NYU Langone Health, said in an interview.

“This study was designed to see if cardiac symptoms affect coffee consumption, and it showed that people with hypertension, angina, history of arrhythmias, and poor health tend to be decaffeinated coffee drinkers or no coffee drinkers,” Dr. Goldberg said.

“People naturally alter their coffee intake base on their blood pressure and symptoms of palpitations and/or rapid heart rate,” she said.

The results also suggest that, “we cannot infer health benefit or harm based on the available coffee studies,” Dr. Goldberg added.

The study was funded by the National Health and Medical Research Council, Australia. Dr. Hyppönen and Dr. Goldberg have disclosed no relevant financial relationships.

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

An examination of coffee consumption habits of almost 400,000 people suggests that those habits are largely driven by a person’s cardiovascular health.

©Elena Moiseeva/fotolia.com

Data from a large population database showed that people with essential hypertension, angina, or cardiac arrhythmias drank less coffee than people who had none of these conditions. When they did drink coffee, it tended to be decaffeinated.

The investigators, led by Elina Hyppönen, PhD, director of the Australian Centre for Precision Health at the University of South Australia, Adelaide, say that this predilection for avoiding coffee, which is known to produce jitteriness and heart palpitations, is based on genetics.

“If your body is telling you not to drink that extra cup of coffee, there’s likely a reason why,” Dr. Hyppönen said in an interview.

The study was published online in the American Journal of Clinical Nutrition.

“People drink coffee as a pick-me-up when they’re feeling tired, or because it tastes good, or simply because it’s part of their daily routine, but what we don’t recognize is that people subconsciously self-regulate safe levels of caffeine based on how high their blood pressure is, and this is likely a result of a protective genetic mechanism, [meaning] that someone who drinks a lot of coffee is likely more genetically tolerant of caffeine, as compared to someone who drinks very little,” Dr. Hyppönen said.

“In addition, we’ve known from past research that when people feel unwell, they tend to drink less coffee. This type of phenomenon, where disease drives behavior, is called reverse causality,” Dr. Hyppönen said.

For this analysis, she and her team used information on 390,435 individuals of European ancestry from the UK Biobank, a large epidemiologic database. Habitual coffee consumption was self-reported, and systolic and diastolic blood pressure and heart rate were measured at baseline. Cardiovascular symptoms at baseline were gleaned from hospital diagnoses, primary care records, and/or self report, the authors note.

To look at the relationship of systolic BP, diastolic BP, and heart rate with coffee consumption, they used a strategy called Mendelian randomization, which allows genetic information such as variants reflecting higher blood pressures and heart rate to be used to provide evidence for a causal association.

Results showed that participants with essential hypertension, angina, or arrhythmia were “all more likely to drink less caffeinated coffee and to be nonhabitual or decaffeinated coffee drinkers compared with those who did not report related symptoms,” the authors write.

Those with higher systolic and diastolic BP based on their genetics tended to drink less caffeinated coffee at baseline, “with consistent genetic evidence to support a causal explanation across all methods,” they noted.

They also found that those people who have a higher resting heart rate due to their genes were more likely to choose decaffeinated coffee.

“These results have two major implications,” Dr. Hyppönen said. “Firstly, they show that our bodies can regulate behavior in ways that we may not realize, and that if something does not feel good to us, there is a likely to be a reason why.”

“Second, our results show that our health status in part regulates the amount of coffee we drink. This is important, because when disease drives behavior, it can lead to misleading health associations in observational studies, and indeed, create a false impression for health benefits if the group of people who do not drink coffee also includes more people who are unwell,” she said.

For now, doctors can tell their patients that this study provides an explanation as to why research on the health effects of habitual coffee consumption has been conflicting, Dr. Hyppönen said.

“Our study also highlights the uncertainty that underlies the claimed health benefits of coffee, but at the same time, it gives a positive message about the ability of our body to regulate our level of coffee consumption in a way that helps us avoid adverse effects.”

“The most common symptoms of excessive coffee consumption are palpitations and rapid heartbeat, also known as tachycardia,” Nieca Goldberg, MD, medical director of the NYU Women’s Heart Program at NYU Langone Health, said in an interview.

“This study was designed to see if cardiac symptoms affect coffee consumption, and it showed that people with hypertension, angina, history of arrhythmias, and poor health tend to be decaffeinated coffee drinkers or no coffee drinkers,” Dr. Goldberg said.

“People naturally alter their coffee intake base on their blood pressure and symptoms of palpitations and/or rapid heart rate,” she said.

The results also suggest that, “we cannot infer health benefit or harm based on the available coffee studies,” Dr. Goldberg added.

The study was funded by the National Health and Medical Research Council, Australia. Dr. Hyppönen and Dr. Goldberg have disclosed no relevant financial relationships.

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

In 2016, results from the LEADER trial of liraglutide in patients with type 2 diabetes helped jump-start awareness of the potential role of this new class of drugs, the glucagonlike peptide–1 receptor agonists, for reducing cardiovascular events. The randomized, placebo-controlled trial enrolled more than 9000 patients at more than 400 sites in over 30 countries, and took nearly 6 years from the start of patient enrollment to publication of the landmark results.

In December 2020, an independent team of researchers published results from a study with a design identical to LEADER, but used data that came not from a massive, global, years-long trial but from already-existing numbers culled from three large U.S. insurance claim databases. The result of this emulation using real-world data was virtually identical to what the actual trial showed, replicating both the direction and statistical significance of the original finding of the randomized, controlled trial (RCT).

What if research proved that this sort of RCT emulation could reliably be done on a regular basis? What might it mean for regulatory decisions on drugs and devices that historically have been based entirely on efficacy evidence from RCTs?
 

Making the most of a sea of observational data

Medicine in the United States has become increasingly awash in a sea of observational data collected from sources that include electronic health records, insurance claims, and increasingly, personal-health monitoring devices.

The Food and Drug Administration is now in the process of trying to figure out how it can legitimately harness this tsunami of real-world data to make efficacy decisions, essentially creating a new category of evidence to complement traditional data from randomized trials. It’s an opportunity that agency staff and their outside advisors have been keen to seize, especially given the soaring cost of prospective, randomized trials.

Recognition of this untapped resource in part led to a key initiative, among many others, included in the 21st Century Cures Act, passed in December 2016. Among the Act’s mandates was that, by the end of 2021, the FDA would issue guidance on when drug sponsors could use real-world evidence (RWE) to either help support a new indication for an already approved drug or help satisfy postapproval study requirements.

The initiative recognizes that this approach is not appropriate for initial drug approvals, which remain exclusively reliant on evidence from RCTs. Instead, it seems best suited to support expanding indications for already approved drugs.

Although FDA staff have made progress in identifying the challenges and broadening their understanding of how to best handle real-world data that come from observing patients in routine practice, agency leaders stress that this complex issue will likely not be fully resolved by their guidance to be published later this year. The FDA released a draft of the guidance in May 2019.
 

Can RWE be ‘credible and reliable?’

“Whether observational, nonrandomized data can become credible enough to use is what we’re talking about. These are possibilities that need to be explained and better understood,” said Robert Temple, MD, deputy director for clinical science of the FDA Center for Drug Evaluation and Research.

“Since the 1970s, the FDA has recognized historical controls as legitimate, so it’s possible [for RWE] to be credible. The big test is when is it credible and reliable enough [to assess efficacy]?” wondered Dr. Temple during a 2-day workshop on the topic held mid-February and organized by Duke University’s Margolis Center for Health Policy.

“We’re approaching an inflection point regarding how observational studies are generated and used, but our evidentiary standards will not lower, and it will be a case-by-case decision” by the agency as they review future RWE submissions, said John Concato, MD, the FDA’s associate director for real-world evidence, during the workshop.

“We are working toward guidance development, but also looking down the road to what we need to do to enable this,” said Dr. Concato. “It’s a complicated issue. If it was easy, it would have already been fixed.” He added that the agency will likely release a “portfolio” of guidance for submitting real-world data and RWE. Real-world data are raw information that, when analyzed, become RWE.

In short, the FDA seems headed toward guidance that won’t spell out a pathway that guarantees success using RWE but will at least open the door to consideration of this unprecedented application.
 

Not like flipping a switch

The guidance will not activate acceptance of RWE all at once. “It’s not like a light switch,” cautioned Adam Kroetsch, MPP, research director for biomedical innovation and regulatory policy at Duke-Margolis in Washington, D.C. “It’s an evolutionary process,” and the upcoming guidance will provide “just a little more clarity” on what sorts of best practices using RWE the FDA will find persuasive. “It’s hard for the FDA to clearly say what it’s looking for until they see some good examples,” Dr. Kroetsch said in an interview.

What will change is that drug sponsors can submit using RWE, and the FDA “will have a more open-minded view,” predicted Sebastian Schneeweiss, MD, ScD, a workshop participant and chief of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston. “For the first time, a law required [the FDA] to take a serious look” at observational data for efficacy assessment.

“The FDA has had a bias against using RWE for evidence of efficacy but has long used it to understand drug safety. Now the FDA is trying to wrap its arms around how to best use RWE” for efficacy decisions, said Joseph S. Ross, MD, another workshop participant and professor of medicine and public health at Yale University, New Haven, Conn.

The agency’s cautious approach is reassuring, Dr. Ross noted in an interview. “There was worry that the 21st Century Cures Act would open the door to allowing real-world data to be used in ways that weren’t very reliable. Very quickly, the FDA started trying to figure out the best ways to use these data in reasonable ways.”
 

Duplicating RCTs with RWE

To help better understand the potential use of RWE, the FDA sponsored several demonstration projects. Researchers presented results from three of these projects during the workshop in February. All three examined whether RWE, plugged into the design of an actual RCT, can produce roughly similar results when similar patients are used.

A generally consistent finding from the three demonstration projects was that “when the data are fit for purpose” the emulated or duplicated analyses with RWE “can come to similar conclusions” as the actual RCTs, said Dr. Schneeweiss, who leads one of the demonstration projects, RCT DUPLICATE.

At the workshop he reported results from RWE duplications of 20 different RCTs using insurance claims data from U.S. patients. The findings came from 10 duplications already reported in Circulation in December 2020 (including a duplication of the LEADER trial), and an additional 10 as yet unpublished RCT duplications. In the next few months, the researchers intend to assess a final group of 10 more RCT duplications.

Workshop participants also presented results from two other FDA demonstration projects: the OPERAND program run by the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard; and the CERSI program based at Yale and the Mayo Clinic in Rochester, Minn. Both are smaller in scale than RCT DUPLICATE, incorporate lab data in addition to claims data, and in some cases test how well RWE can emulate RCTs that are not yet completed.

Collectively, results from these demonstration projects suggest that RWE can successfully emulate the results of an RCT, said Dr. Ross, a coinvestigator on the CERSI study. But the CERSI findings also highlighted how an RCT can fall short of clinical relevance.

“One of our most important findings was that RCTs don’t always represent real-world practice,” he said. His group attempted to replicate the 5,000-patient GRADE trial of four different drug options added to metformin in patients with type 2 diabetes. One of the four options included insulin glargine (Lantus), and the attempt to emulate the study with RWE hit the bump that no relevant real-world patients in their US claims database actually received the formulation.

That means the GRADE trial “is almost meaningless. It doesn’t reflect real-world practice,” Dr. Ross noted.

Results from the three demonstration projects “highlight the gaps we still have,” summed up Dr. Kroetsch. “They show where we need better data” from observational sources that function as well as data from RCTs.

Still, the demonstration project results are “an important step forward in establishing the validity of real-world evidence,” commented David Kerr, MBChB, an endocrinologist and director of research and innovation at the Sansum Diabetes Research Institute in Santa Barbara, Calif.
 

‘Target trials’ tether RWE

The target trial approach to designing an observational study is a key tool for boosting reliability and applicability of the results. The idea is to create a well-designed trial that could be the basis for a conventional RCT, and then use observational data to flesh out the target trial instead of collecting data from prospectively enrolled patients.

Designing observational studies that emulate target trials allows causal inferences, said Miguel A. Hernán, MD, DrPH, a professor of biostatistics and epidemiology at the Harvard School of Public Health, Boston. Plugging real-world data into the framework of an appropriately designed target trial substantially cuts the risk of a biased analysis, he explained during the workshop.

However, the approach has limitations. The target trial must be a pragmatic trial, and the approach does not work for placebo-controlled trials, although it can accommodate a usual-care control arm. It also usually precludes patient blinding, testing treatments not used in routine practice, and close monitoring of patients in ways that are uncommon in usual care.

The target trial approach received broad endorsement during the workshop as the future for observational studies destined for efficacy consideration by the FDA.

“The idea of prespecifying a target trial is a really fantastic place to start,” commented Robert Ball, MD, deputy director of the FDA Office of Surveillance and Epidemiology. “There is still a whole set of questions once the trial is prespecified, but prespecification would be a fantastic step forward,” he said during the workshop.

Participants also endorsed other important steps to boost the value of observational studies for regulatory reviews, including preregistering the study on a site such as clinicaltrials.gov; being fully transparent about the origins of observational data; using data that match the needs of the target trial; not reviewing the data in advance to avoid cherry picking and gaming the analysis; and reporting neutral or negative results when they occur, something often not currently done for observational analyses.

But although there was clear progress and much agreement among thought leaders at the workshop, FDA representatives stressed caution in moving forward.
 

“No easy answer”

“With more experience, we can learn what works and what doesn’t work in generating valid results from observational studies,” said Dr. Concato. “Although the observational results have upside potential, we need to learn more. There is no easy answer, no checklist for fit-for-use data, no off-the-shelf study design, and no ideal analytic method.”

Dr. Concato acknowledged that the FDA’s goal is clear given the 2016 legislation. “The FDA is embracing our obligations under the 21st Century Cures Act to evaluate use of real-world data and real-world evidence.”

He also suggested that researchers “shy away from a false dichotomy of RCTs or observational studies and instead think about how and when RCTs and observational studies can be designed and conducted to yield trustworthy results.” Dr. Concato’s solution: “a taxonomy of interventional or noninterventional studies.”

“The FDA is under enormous pressure to embrace real-world evidence, both because of the economics of running RCTs and because of the availability of new observational data from electronic health records, wearable devices, claims, etc.,” said Dr. Kerr, who did not participate in the workshop but coauthored an editorial that calls for using real-world data in regulatory decisions for drugs and devices for diabetes. These factors create an “irresistible force” spurring the FDA to consider observational, noninterventional data.

“I think the FDA really wants this to go forward,” Dr. Kerr added in an interview. “The FDA keeps telling us that clinical trials do not have enough women or patients from minority groups. Real-world data is a way to address that. This will not be the death of RCTs, but this work shines a light on the deficiencies of RCTs and how the deficiencies can be dealt with.”

Dr. Kroetsch has reported no relevant financial relationships. Dr. Schneeweiss has reported being a consultant to and holding equity in Aetion and receiving research funding from the FDA. Dr. Ross has reported receiving research funding from the FDA, Johnson & Johnson, and Medtronic. Dr. Hernán has reported being a consultant for Cytel. Dr. Kerr has reported being a consultant for Ascensia, EOFlow, Lifecare, Merck, Novo Nordisk, Roche Diagnostics, and Voluntis. Dr. Temple, Dr. Concato, and Dr. Ball are FDA employees.

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

In 2016, results from the LEADER trial of liraglutide in patients with type 2 diabetes helped jump-start awareness of the potential role of this new class of drugs, the glucagonlike peptide–1 receptor agonists, for reducing cardiovascular events. The randomized, placebo-controlled trial enrolled more than 9000 patients at more than 400 sites in over 30 countries, and took nearly 6 years from the start of patient enrollment to publication of the landmark results.

In December 2020, an independent team of researchers published results from a study with a design identical to LEADER, but used data that came not from a massive, global, years-long trial but from already-existing numbers culled from three large U.S. insurance claim databases. The result of this emulation using real-world data was virtually identical to what the actual trial showed, replicating both the direction and statistical significance of the original finding of the randomized, controlled trial (RCT).

What if research proved that this sort of RCT emulation could reliably be done on a regular basis? What might it mean for regulatory decisions on drugs and devices that historically have been based entirely on efficacy evidence from RCTs?
 

Making the most of a sea of observational data

Medicine in the United States has become increasingly awash in a sea of observational data collected from sources that include electronic health records, insurance claims, and increasingly, personal-health monitoring devices.

The Food and Drug Administration is now in the process of trying to figure out how it can legitimately harness this tsunami of real-world data to make efficacy decisions, essentially creating a new category of evidence to complement traditional data from randomized trials. It’s an opportunity that agency staff and their outside advisors have been keen to seize, especially given the soaring cost of prospective, randomized trials.

Recognition of this untapped resource in part led to a key initiative, among many others, included in the 21st Century Cures Act, passed in December 2016. Among the Act’s mandates was that, by the end of 2021, the FDA would issue guidance on when drug sponsors could use real-world evidence (RWE) to either help support a new indication for an already approved drug or help satisfy postapproval study requirements.

The initiative recognizes that this approach is not appropriate for initial drug approvals, which remain exclusively reliant on evidence from RCTs. Instead, it seems best suited to support expanding indications for already approved drugs.

Although FDA staff have made progress in identifying the challenges and broadening their understanding of how to best handle real-world data that come from observing patients in routine practice, agency leaders stress that this complex issue will likely not be fully resolved by their guidance to be published later this year. The FDA released a draft of the guidance in May 2019.
 

Can RWE be ‘credible and reliable?’

“Whether observational, nonrandomized data can become credible enough to use is what we’re talking about. These are possibilities that need to be explained and better understood,” said Robert Temple, MD, deputy director for clinical science of the FDA Center for Drug Evaluation and Research.

“Since the 1970s, the FDA has recognized historical controls as legitimate, so it’s possible [for RWE] to be credible. The big test is when is it credible and reliable enough [to assess efficacy]?” wondered Dr. Temple during a 2-day workshop on the topic held mid-February and organized by Duke University’s Margolis Center for Health Policy.

“We’re approaching an inflection point regarding how observational studies are generated and used, but our evidentiary standards will not lower, and it will be a case-by-case decision” by the agency as they review future RWE submissions, said John Concato, MD, the FDA’s associate director for real-world evidence, during the workshop.

“We are working toward guidance development, but also looking down the road to what we need to do to enable this,” said Dr. Concato. “It’s a complicated issue. If it was easy, it would have already been fixed.” He added that the agency will likely release a “portfolio” of guidance for submitting real-world data and RWE. Real-world data are raw information that, when analyzed, become RWE.

In short, the FDA seems headed toward guidance that won’t spell out a pathway that guarantees success using RWE but will at least open the door to consideration of this unprecedented application.
 

Not like flipping a switch

The guidance will not activate acceptance of RWE all at once. “It’s not like a light switch,” cautioned Adam Kroetsch, MPP, research director for biomedical innovation and regulatory policy at Duke-Margolis in Washington, D.C. “It’s an evolutionary process,” and the upcoming guidance will provide “just a little more clarity” on what sorts of best practices using RWE the FDA will find persuasive. “It’s hard for the FDA to clearly say what it’s looking for until they see some good examples,” Dr. Kroetsch said in an interview.

What will change is that drug sponsors can submit using RWE, and the FDA “will have a more open-minded view,” predicted Sebastian Schneeweiss, MD, ScD, a workshop participant and chief of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston. “For the first time, a law required [the FDA] to take a serious look” at observational data for efficacy assessment.

“The FDA has had a bias against using RWE for evidence of efficacy but has long used it to understand drug safety. Now the FDA is trying to wrap its arms around how to best use RWE” for efficacy decisions, said Joseph S. Ross, MD, another workshop participant and professor of medicine and public health at Yale University, New Haven, Conn.

The agency’s cautious approach is reassuring, Dr. Ross noted in an interview. “There was worry that the 21st Century Cures Act would open the door to allowing real-world data to be used in ways that weren’t very reliable. Very quickly, the FDA started trying to figure out the best ways to use these data in reasonable ways.”
 

Duplicating RCTs with RWE

To help better understand the potential use of RWE, the FDA sponsored several demonstration projects. Researchers presented results from three of these projects during the workshop in February. All three examined whether RWE, plugged into the design of an actual RCT, can produce roughly similar results when similar patients are used.

A generally consistent finding from the three demonstration projects was that “when the data are fit for purpose” the emulated or duplicated analyses with RWE “can come to similar conclusions” as the actual RCTs, said Dr. Schneeweiss, who leads one of the demonstration projects, RCT DUPLICATE.

At the workshop he reported results from RWE duplications of 20 different RCTs using insurance claims data from U.S. patients. The findings came from 10 duplications already reported in Circulation in December 2020 (including a duplication of the LEADER trial), and an additional 10 as yet unpublished RCT duplications. In the next few months, the researchers intend to assess a final group of 10 more RCT duplications.

Workshop participants also presented results from two other FDA demonstration projects: the OPERAND program run by the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard; and the CERSI program based at Yale and the Mayo Clinic in Rochester, Minn. Both are smaller in scale than RCT DUPLICATE, incorporate lab data in addition to claims data, and in some cases test how well RWE can emulate RCTs that are not yet completed.

Collectively, results from these demonstration projects suggest that RWE can successfully emulate the results of an RCT, said Dr. Ross, a coinvestigator on the CERSI study. But the CERSI findings also highlighted how an RCT can fall short of clinical relevance.

“One of our most important findings was that RCTs don’t always represent real-world practice,” he said. His group attempted to replicate the 5,000-patient GRADE trial of four different drug options added to metformin in patients with type 2 diabetes. One of the four options included insulin glargine (Lantus), and the attempt to emulate the study with RWE hit the bump that no relevant real-world patients in their US claims database actually received the formulation.

That means the GRADE trial “is almost meaningless. It doesn’t reflect real-world practice,” Dr. Ross noted.

Results from the three demonstration projects “highlight the gaps we still have,” summed up Dr. Kroetsch. “They show where we need better data” from observational sources that function as well as data from RCTs.

Still, the demonstration project results are “an important step forward in establishing the validity of real-world evidence,” commented David Kerr, MBChB, an endocrinologist and director of research and innovation at the Sansum Diabetes Research Institute in Santa Barbara, Calif.
 

‘Target trials’ tether RWE

The target trial approach to designing an observational study is a key tool for boosting reliability and applicability of the results. The idea is to create a well-designed trial that could be the basis for a conventional RCT, and then use observational data to flesh out the target trial instead of collecting data from prospectively enrolled patients.

Designing observational studies that emulate target trials allows causal inferences, said Miguel A. Hernán, MD, DrPH, a professor of biostatistics and epidemiology at the Harvard School of Public Health, Boston. Plugging real-world data into the framework of an appropriately designed target trial substantially cuts the risk of a biased analysis, he explained during the workshop.

However, the approach has limitations. The target trial must be a pragmatic trial, and the approach does not work for placebo-controlled trials, although it can accommodate a usual-care control arm. It also usually precludes patient blinding, testing treatments not used in routine practice, and close monitoring of patients in ways that are uncommon in usual care.

The target trial approach received broad endorsement during the workshop as the future for observational studies destined for efficacy consideration by the FDA.

“The idea of prespecifying a target trial is a really fantastic place to start,” commented Robert Ball, MD, deputy director of the FDA Office of Surveillance and Epidemiology. “There is still a whole set of questions once the trial is prespecified, but prespecification would be a fantastic step forward,” he said during the workshop.

Participants also endorsed other important steps to boost the value of observational studies for regulatory reviews, including preregistering the study on a site such as clinicaltrials.gov; being fully transparent about the origins of observational data; using data that match the needs of the target trial; not reviewing the data in advance to avoid cherry picking and gaming the analysis; and reporting neutral or negative results when they occur, something often not currently done for observational analyses.

But although there was clear progress and much agreement among thought leaders at the workshop, FDA representatives stressed caution in moving forward.
 

“No easy answer”

“With more experience, we can learn what works and what doesn’t work in generating valid results from observational studies,” said Dr. Concato. “Although the observational results have upside potential, we need to learn more. There is no easy answer, no checklist for fit-for-use data, no off-the-shelf study design, and no ideal analytic method.”

Dr. Concato acknowledged that the FDA’s goal is clear given the 2016 legislation. “The FDA is embracing our obligations under the 21st Century Cures Act to evaluate use of real-world data and real-world evidence.”

He also suggested that researchers “shy away from a false dichotomy of RCTs or observational studies and instead think about how and when RCTs and observational studies can be designed and conducted to yield trustworthy results.” Dr. Concato’s solution: “a taxonomy of interventional or noninterventional studies.”

“The FDA is under enormous pressure to embrace real-world evidence, both because of the economics of running RCTs and because of the availability of new observational data from electronic health records, wearable devices, claims, etc.,” said Dr. Kerr, who did not participate in the workshop but coauthored an editorial that calls for using real-world data in regulatory decisions for drugs and devices for diabetes. These factors create an “irresistible force” spurring the FDA to consider observational, noninterventional data.

“I think the FDA really wants this to go forward,” Dr. Kerr added in an interview. “The FDA keeps telling us that clinical trials do not have enough women or patients from minority groups. Real-world data is a way to address that. This will not be the death of RCTs, but this work shines a light on the deficiencies of RCTs and how the deficiencies can be dealt with.”

Dr. Kroetsch has reported no relevant financial relationships. Dr. Schneeweiss has reported being a consultant to and holding equity in Aetion and receiving research funding from the FDA. Dr. Ross has reported receiving research funding from the FDA, Johnson & Johnson, and Medtronic. Dr. Hernán has reported being a consultant for Cytel. Dr. Kerr has reported being a consultant for Ascensia, EOFlow, Lifecare, Merck, Novo Nordisk, Roche Diagnostics, and Voluntis. Dr. Temple, Dr. Concato, and Dr. Ball are FDA employees.

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

In 2016, results from the LEADER trial of liraglutide in patients with type 2 diabetes helped jump-start awareness of the potential role of this new class of drugs, the glucagonlike peptide–1 receptor agonists, for reducing cardiovascular events. The randomized, placebo-controlled trial enrolled more than 9000 patients at more than 400 sites in over 30 countries, and took nearly 6 years from the start of patient enrollment to publication of the landmark results.

In December 2020, an independent team of researchers published results from a study with a design identical to LEADER, but used data that came not from a massive, global, years-long trial but from already-existing numbers culled from three large U.S. insurance claim databases. The result of this emulation using real-world data was virtually identical to what the actual trial showed, replicating both the direction and statistical significance of the original finding of the randomized, controlled trial (RCT).

What if research proved that this sort of RCT emulation could reliably be done on a regular basis? What might it mean for regulatory decisions on drugs and devices that historically have been based entirely on efficacy evidence from RCTs?
 

Making the most of a sea of observational data

Medicine in the United States has become increasingly awash in a sea of observational data collected from sources that include electronic health records, insurance claims, and increasingly, personal-health monitoring devices.

The Food and Drug Administration is now in the process of trying to figure out how it can legitimately harness this tsunami of real-world data to make efficacy decisions, essentially creating a new category of evidence to complement traditional data from randomized trials. It’s an opportunity that agency staff and their outside advisors have been keen to seize, especially given the soaring cost of prospective, randomized trials.

Recognition of this untapped resource in part led to a key initiative, among many others, included in the 21st Century Cures Act, passed in December 2016. Among the Act’s mandates was that, by the end of 2021, the FDA would issue guidance on when drug sponsors could use real-world evidence (RWE) to either help support a new indication for an already approved drug or help satisfy postapproval study requirements.

The initiative recognizes that this approach is not appropriate for initial drug approvals, which remain exclusively reliant on evidence from RCTs. Instead, it seems best suited to support expanding indications for already approved drugs.

Although FDA staff have made progress in identifying the challenges and broadening their understanding of how to best handle real-world data that come from observing patients in routine practice, agency leaders stress that this complex issue will likely not be fully resolved by their guidance to be published later this year. The FDA released a draft of the guidance in May 2019.
 

Can RWE be ‘credible and reliable?’

“Whether observational, nonrandomized data can become credible enough to use is what we’re talking about. These are possibilities that need to be explained and better understood,” said Robert Temple, MD, deputy director for clinical science of the FDA Center for Drug Evaluation and Research.

“Since the 1970s, the FDA has recognized historical controls as legitimate, so it’s possible [for RWE] to be credible. The big test is when is it credible and reliable enough [to assess efficacy]?” wondered Dr. Temple during a 2-day workshop on the topic held mid-February and organized by Duke University’s Margolis Center for Health Policy.

“We’re approaching an inflection point regarding how observational studies are generated and used, but our evidentiary standards will not lower, and it will be a case-by-case decision” by the agency as they review future RWE submissions, said John Concato, MD, the FDA’s associate director for real-world evidence, during the workshop.

“We are working toward guidance development, but also looking down the road to what we need to do to enable this,” said Dr. Concato. “It’s a complicated issue. If it was easy, it would have already been fixed.” He added that the agency will likely release a “portfolio” of guidance for submitting real-world data and RWE. Real-world data are raw information that, when analyzed, become RWE.

In short, the FDA seems headed toward guidance that won’t spell out a pathway that guarantees success using RWE but will at least open the door to consideration of this unprecedented application.
 

Not like flipping a switch

The guidance will not activate acceptance of RWE all at once. “It’s not like a light switch,” cautioned Adam Kroetsch, MPP, research director for biomedical innovation and regulatory policy at Duke-Margolis in Washington, D.C. “It’s an evolutionary process,” and the upcoming guidance will provide “just a little more clarity” on what sorts of best practices using RWE the FDA will find persuasive. “It’s hard for the FDA to clearly say what it’s looking for until they see some good examples,” Dr. Kroetsch said in an interview.

What will change is that drug sponsors can submit using RWE, and the FDA “will have a more open-minded view,” predicted Sebastian Schneeweiss, MD, ScD, a workshop participant and chief of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston. “For the first time, a law required [the FDA] to take a serious look” at observational data for efficacy assessment.

“The FDA has had a bias against using RWE for evidence of efficacy but has long used it to understand drug safety. Now the FDA is trying to wrap its arms around how to best use RWE” for efficacy decisions, said Joseph S. Ross, MD, another workshop participant and professor of medicine and public health at Yale University, New Haven, Conn.

The agency’s cautious approach is reassuring, Dr. Ross noted in an interview. “There was worry that the 21st Century Cures Act would open the door to allowing real-world data to be used in ways that weren’t very reliable. Very quickly, the FDA started trying to figure out the best ways to use these data in reasonable ways.”
 

Duplicating RCTs with RWE

To help better understand the potential use of RWE, the FDA sponsored several demonstration projects. Researchers presented results from three of these projects during the workshop in February. All three examined whether RWE, plugged into the design of an actual RCT, can produce roughly similar results when similar patients are used.

A generally consistent finding from the three demonstration projects was that “when the data are fit for purpose” the emulated or duplicated analyses with RWE “can come to similar conclusions” as the actual RCTs, said Dr. Schneeweiss, who leads one of the demonstration projects, RCT DUPLICATE.

At the workshop he reported results from RWE duplications of 20 different RCTs using insurance claims data from U.S. patients. The findings came from 10 duplications already reported in Circulation in December 2020 (including a duplication of the LEADER trial), and an additional 10 as yet unpublished RCT duplications. In the next few months, the researchers intend to assess a final group of 10 more RCT duplications.

Workshop participants also presented results from two other FDA demonstration projects: the OPERAND program run by the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard; and the CERSI program based at Yale and the Mayo Clinic in Rochester, Minn. Both are smaller in scale than RCT DUPLICATE, incorporate lab data in addition to claims data, and in some cases test how well RWE can emulate RCTs that are not yet completed.

Collectively, results from these demonstration projects suggest that RWE can successfully emulate the results of an RCT, said Dr. Ross, a coinvestigator on the CERSI study. But the CERSI findings also highlighted how an RCT can fall short of clinical relevance.

“One of our most important findings was that RCTs don’t always represent real-world practice,” he said. His group attempted to replicate the 5,000-patient GRADE trial of four different drug options added to metformin in patients with type 2 diabetes. One of the four options included insulin glargine (Lantus), and the attempt to emulate the study with RWE hit the bump that no relevant real-world patients in their US claims database actually received the formulation.

That means the GRADE trial “is almost meaningless. It doesn’t reflect real-world practice,” Dr. Ross noted.

Results from the three demonstration projects “highlight the gaps we still have,” summed up Dr. Kroetsch. “They show where we need better data” from observational sources that function as well as data from RCTs.

Still, the demonstration project results are “an important step forward in establishing the validity of real-world evidence,” commented David Kerr, MBChB, an endocrinologist and director of research and innovation at the Sansum Diabetes Research Institute in Santa Barbara, Calif.
 

‘Target trials’ tether RWE

The target trial approach to designing an observational study is a key tool for boosting reliability and applicability of the results. The idea is to create a well-designed trial that could be the basis for a conventional RCT, and then use observational data to flesh out the target trial instead of collecting data from prospectively enrolled patients.

Designing observational studies that emulate target trials allows causal inferences, said Miguel A. Hernán, MD, DrPH, a professor of biostatistics and epidemiology at the Harvard School of Public Health, Boston. Plugging real-world data into the framework of an appropriately designed target trial substantially cuts the risk of a biased analysis, he explained during the workshop.

However, the approach has limitations. The target trial must be a pragmatic trial, and the approach does not work for placebo-controlled trials, although it can accommodate a usual-care control arm. It also usually precludes patient blinding, testing treatments not used in routine practice, and close monitoring of patients in ways that are uncommon in usual care.

The target trial approach received broad endorsement during the workshop as the future for observational studies destined for efficacy consideration by the FDA.

“The idea of prespecifying a target trial is a really fantastic place to start,” commented Robert Ball, MD, deputy director of the FDA Office of Surveillance and Epidemiology. “There is still a whole set of questions once the trial is prespecified, but prespecification would be a fantastic step forward,” he said during the workshop.

Participants also endorsed other important steps to boost the value of observational studies for regulatory reviews, including preregistering the study on a site such as clinicaltrials.gov; being fully transparent about the origins of observational data; using data that match the needs of the target trial; not reviewing the data in advance to avoid cherry picking and gaming the analysis; and reporting neutral or negative results when they occur, something often not currently done for observational analyses.

But although there was clear progress and much agreement among thought leaders at the workshop, FDA representatives stressed caution in moving forward.
 

“No easy answer”

“With more experience, we can learn what works and what doesn’t work in generating valid results from observational studies,” said Dr. Concato. “Although the observational results have upside potential, we need to learn more. There is no easy answer, no checklist for fit-for-use data, no off-the-shelf study design, and no ideal analytic method.”

Dr. Concato acknowledged that the FDA’s goal is clear given the 2016 legislation. “The FDA is embracing our obligations under the 21st Century Cures Act to evaluate use of real-world data and real-world evidence.”

He also suggested that researchers “shy away from a false dichotomy of RCTs or observational studies and instead think about how and when RCTs and observational studies can be designed and conducted to yield trustworthy results.” Dr. Concato’s solution: “a taxonomy of interventional or noninterventional studies.”

“The FDA is under enormous pressure to embrace real-world evidence, both because of the economics of running RCTs and because of the availability of new observational data from electronic health records, wearable devices, claims, etc.,” said Dr. Kerr, who did not participate in the workshop but coauthored an editorial that calls for using real-world data in regulatory decisions for drugs and devices for diabetes. These factors create an “irresistible force” spurring the FDA to consider observational, noninterventional data.

“I think the FDA really wants this to go forward,” Dr. Kerr added in an interview. “The FDA keeps telling us that clinical trials do not have enough women or patients from minority groups. Real-world data is a way to address that. This will not be the death of RCTs, but this work shines a light on the deficiencies of RCTs and how the deficiencies can be dealt with.”

Dr. Kroetsch has reported no relevant financial relationships. Dr. Schneeweiss has reported being a consultant to and holding equity in Aetion and receiving research funding from the FDA. Dr. Ross has reported receiving research funding from the FDA, Johnson & Johnson, and Medtronic. Dr. Hernán has reported being a consultant for Cytel. Dr. Kerr has reported being a consultant for Ascensia, EOFlow, Lifecare, Merck, Novo Nordisk, Roche Diagnostics, and Voluntis. Dr. Temple, Dr. Concato, and Dr. Ball are FDA employees.

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

Survival gains in the management of acute myocardial infarction in recent decades don’t apply to one increasingly common category of MI.

Type 2 MI, triggered by a surge in myocardial oxygen demand or a drop in its supply, is on the rise and might be more prognostically serious than the “classic” atherothrombotic type 1 form, for which there have been such impressive strides in therapy.

Strategies for assessing and treating type 2 MI and another condition it can resemble clinically – nonischemic myocardial injury – have been less rigorously explored and are far less settled.

That could be partly because recent iterations of the consensus-based universal definition of MI define type 1 MI primarily by the atherothrombotic process, whereas “demand” type 2 MI is characterized as secondary to other disorders. The list of potential primary conditions, cardiac and noncardiac, is long.

As a result, patients with type 1 MI are clinically well defined, but those with type 2 MI have so far defied efforts to be clinically characterized in a consistent way. However, recent efforts might change that, given growing appreciation that all-cause and cardiovascular (CV) mortality outcomes are actually worse for patients with type 2 MI.

“That’s because we have lots of treatments for type 1 MI. Type 2 and myocardial injury? We don’t know how to treat them,” David E. Newby, MD, PhD, University of Edinburgh, said in an interview.

Dr. Newby pointed to a widely cited 2018 publication, of which he is a coauthor, documenting 5-year outcomes of 2,122 patients with type 1 MI, type 2 MI, or nonischemic myocardial injury per the newly minted fourth universal definition.

Risk-factor profiles for patients with the latter two conditions contrasted with those of patients with type 1 MI, he observed. They were “a lot older,” were less likely to be smokers, had more hypertension and previous stroke, and a less prominent CV family history.

“So they’re a different beast,” Dr. Newby said. And their prognosis tended to be worse: all-cause mortality was about 62% for patients with type 2 MI and 72% with nonischemic myocardial injury, but only 37% for patients with type 1 MI. The difference between the two types of infarction was driven by an excess of noncardiovascular death after type 2 MI.

Mortality in patients with type 2 MI is “quite high, but it may well be a marker of the fact that you’ve got other serious diseases on board that are associated with poorer outcome,” he said.
 

Risk varies

The degree of risk in type 2 MI seems to vary with the underlying condition, a recent cohort study suggests. In about 3,800 patients with cardiac troponin (cTn) elevations qualifying as MI – a younger group; most were in their 30s and 40s – mortality at 10 years was 12% for those with type 1 MI, but 34% for those with type 2 MI and 46% for the remainder with nonischemic myocardial injury.

Underlying precipitating conditions varied widely among the patients with type 2 MI or nonischemic myocardial injury, and there was broad variation in mortality by etiology among those with type 2 MI. Sepsis and anemia entailed some of the highest risk, and hypertension and arrhythmias some of the lowest.

A prospective, community-based study of 5,460 patients with type 1 MI or type 2 MI reached a similar conclusion, but with a twist. Five-year all-cause mortality contrasted significantly between types of MI at 31% and 52%, respectively, but CV mortality rates were similar in this study.

Mortality in type 2 MI again varied by the precipitating etiology, suggesting that patients can be risk stratified according to pathophysiological mechanism behind their demand infarction, the authors concluded, “underscoring that type 2 MI is not a single entity, rather a group of phenotypic clusters.”

The usually high comorbidity burden and CV risk in patients with type 2 MI, one of those authors said in an interview, suggest there are “opportunities to see whether we can reduce that risk.”

Formal recommendations consistently say that, in patients with type 2 MI, “your first and foremost target should be to treat the underlying trigger and cause,” said Yader Sandoval, MD, Mayo Clinic, Rochester, Minn. That means such opportunities for further CV risk reduction tend to be “underappreciated.”

“In principle, treating the inciting cause of type 2 MI or the injury is important,” said James L. Januzzi, MD, Massachusetts General Hospital, Boston, in an interview, “but I feel quite strongly that there must be more that we can do for these folks.”

Dr. Januzzi is senior author on a recent analysis based on more than 200,000 admissions across the United States that saw a 43% lower risk for in-hospital death and 54% lower risk for 30-day MI readmission for patients with type 2 MI than those with type 1, adjusted for risk factors and comorbidities.

But, “it is important to emphasize that type 2 MI patients had a substantial risk for adverse outcome, nonetheless, and lack a clear management approach,” Dr. Januzzi and colleagues stated in their publication, as reported by this news organization.

“Due to the high rates of long-term cardiovascular events experienced by the frequently encountered type 2 MI patients,” they wrote, “identifying evidence-based therapies represents a major unmet need.”

That such patients tend to be sick with multiple comorbidities and have not yet been clinically well characterized, Dr. Januzzi said, “has stymied our ability to develop a treatment strategy.”
 

Role of the universal definitions

That challenge might in some ways be complicated by the universal definition, especially version 4, in which the definitions for type 1 MI, type 2 MI, and nonischemic myocardial injury are unified biochemically.

This version, published in 2018 in the European Heart Journal and Circulation, introduced a formal definition of myocardial injury, which was hailed as an innovation: cTn elevation to the 99th percentile of the upper limit of normal in a reference population.

It differentiates type 1 MI from type 2 MI by the separate pathophysiology of the ischemia – plaque rupture with intracoronary thrombosis and myocardial oxygen supply–demand mismatch, respectively. In both cases, however, there must be symptoms or objective evidence of ischemia. Absent signs of ischemia, the determination would be nonischemic myocardial injury.

Yet clinically and prognostically, type 2 MI and nonischemic myocardial injury in some ways are more similar to each other than either is to type 1 MI. Both occur secondary to other conditions across diverse clinical settings and can be a challenge to tell apart.

The universal definition’s perspective of the three events – so heavily dependent on cTn levels and myocardial ischemia – fails to account for the myriad complexities of individual patients in practice, some say, and so can muddle the process of risk assessment and therapy.

“Abnormal troponin identifies injury, but it doesn’t identify mechanism. Type 2 MI is highly prevalent, but there are other things that cause abnormal troponins,” Dr. Januzzi said. That’s why it’s important to explore and map out the clinical variables associated with the two conditions, to “understand who has a type 2 MI and who has cardiac injury. And believe it or not, it’s actually harder than it sounds to sort that out.”

“Practically speaking, the differentiation between these events is clinical,” Dr. Sandoval agreed. “There’s not always perfect agreement on what we’re calling what.”

Consequently, the universal definitions might categorize some events in ways that seem inconsistent from a management perspective. For example, they make a sharp distinction between coronary atherothrombotic and coronary nonatherothrombotic MI etiologies. Some clinicians would group MI caused by coronary spasm, coronary embolism, or spontaneous coronary artery dissection along with MI from coronary plaque rupture and thrombosis. But, Dr. Sandoval said, “even though these are coronary issues, they would fall into the type 2 bin.”

Also, about half of cases identified as type 2 MI are caused by tachyarrhythmias, which can elevate troponin and cause ECG changes and possibly symptoms resembling angina, Dr. Newby observed. “But that is completely different from other types of myocardial infarction, which are much more serious.”

So, “it’s a real mess of a diagnosis – acute myocardial injury, type 2 and type 1 MI – and it can be quite difficult to disentangle,” he said. “I think that the definition certainly has let us down.”

The diversity of type 2 MI clinical settings might also be a challenge. Myocardial injury according to cTn, with or without ischemia, occurs widely during critical illnesses and acute conditions, including respiratory distress, sepsis, internal bleeding, stroke, and pulmonary embolism.

Early in the COVID-19 pandemic, much was made of elevated troponin levels and myocarditis as an apparently frequent complication among hospitalized patients. “I raised my hand and said, we’ve been seeing abnormal troponins in people with influenza for 20 years,” Dr. Januzzi said. “Critical illness, infection, toxicity from drugs, from chemotherapy, from alcohol – there are all sorts of potential triggers of myocardial injury.”
 

Troponin ‘overdependence’

With many clinical settings in common and the presence or absence of myocardial ischemia to primarily distinguish them, type 2 MI and nonischemic myocardial injury both can be mistaken for the other. That can send management decisions in inappropriate directions.

A 2019 study looked at 633 cases that had been coded as type 2 MI at a major center and readjudicated them according to the fourth universal definition. Only 57% met all the type 2 criteria, 42% were reclassified as nonischemic myocardial injury, and a few were determined to have unstable angina.

“There’s overdependence on the easiest tool in the universal definition,” said Dr. Januzzi, a coauthor on that study. “Frequently people get seduced by the rise in a troponin value and immediately call it a myocardial infarction, lacking the other components of the universal definition that require evidence for coronary ischemia. That happens every day, where someone with an abnormal troponin is incorrectly branded as having an MI.”

It may not help that the current ICD-10-CM system features a diagnostic code for type 2 MI but not for myocardial injury.

“Instead, the new ICD-10-CM coding includes a proxy called ‘non-MI troponin elevation due to an underlying cause,’ ” wrote Kristian Thygesen, MD, DSc, and Allan S. Jaffe, MD, in a recent editorial. They caution against “using this code for myocardial injury because it is not specific for an elevated cTn value and could represent any abnormal laboratory measurements.” The code could be “misleading,” thereby worsening the potential for miscoding and “misattribution of MI diagnoses.”

That potential suggests there could be a growing population of patients who have been told they had an MI, which then becomes part of their medical record, when, actually, they experienced nonischemic myocardial injury.

“Having seen this occur,” Dr. Januzzi explained, “it affects people emotionally to think they’ve had an MI. Precision in diagnosis is important, which is why the universal definition is so valuable. If people would adhere to it more assiduously, we could reduce the frequency of people getting a misdiagnosis of MI when in fact they had injury.”

Still, he added, “if someone has an illness severe enough to cause myocardial injury, they’re at risk for a bad outcome regardless of whether they did or didn’t have an MI.”
 

The uncertain role of angiography

Angiography isn’t ordered nearly as often for patients ultimately diagnosed with type 2 MI or myocardial injury as for those with type 1 MI. Type 2 MI can hit some patients who have remained symptom free despite possibly unrecognized obstructive coronary artery disease (CAD) when myocardial demand is pushed past supply by a critical illness, tachyarrhythmia, or other acute conditions.

In such cases, “it’s reasonable to hypothesize that revascularization, something that really is not done in the vast majority of patients with type 2 MI, might actually be of benefit,” Dr. Januzzi said.

Whether these patients should routinely have angiography remains an open question. Without intervention, any newly identified obstructive CAD would continue to lurk in the background as a potential threat.

In efforts to differentiate type 2 MI from nonischemic injury, it can be “incredibly hard to know whether or not there’s actual ischemia in the mix. And that’s the only thing that defines the difference before taking an angiogram,” Derek P. Chew, MBBS, MPH, Flinders Medical Centre, Bedford Park, Australia, said in an interview.

Dr. Chew is principal investigator for the ongoing ACT-2 trial that is enrolling hospitalized, hemodynamically stable patients with cTn elevations but no suspicion of type 1 MI and “an unequivocal acute intercurrent diagnosis.” Qualifying diagnoses are prespecified on a list that includes sepsis, pneumonia, septicemia, a systemic inflammatory response, anemia, atrial tachycardia, acute kidney injury, and recent noncardiac surgery.

The patients are randomly assigned to a strategy of routine, usually invasive coronary angiography with discretionary revascularization, or to conservative care with noninvasive functional testing as appropriate. The sicker the patient, the greater the competing risk from other conditions and the less revascularization is likely to improve outcomes, Dr. Chew observed. Importantly, therefore, outcomes in the trial will be stratified by patient risk from comorbidities, measured with baseline GRACE and APACHE III scores.

Dr. Chew said the study aims to determine whether routine angiography is of benefit in patients at some identifiable level of risk, if not the whole range. One possible result, he said, is that there could be a risk-profile “sweet spot” associated with better outcomes in those assigned to angiography.

Enrollment in the trial started about 3 years ago, but “the process has been slow,” he said, because many potentially referring clinicians have a “bias on one side or another,” with about half of them preferring the angiography approach and the other half conservative management.
 

The unsettled role of drug therapy

With their often-complicated clinical profile, patients with type 2 MI or nonischemic myocardial injury tend to be medically undertreated, yet there is observational evidence they can benefit from familiar drug therapies.

In the previously noted cohort study of 3,800 younger patients with one of the three forms of myocardial injury, less than half of patients with type 2 MI received any form of CAD secondary prevention therapy at discharge, the researchers, with first author Avinainder Singh, MD, from Yale University, New Haven, Conn, wrote.

The finding, consistent with Dr. Newby’s study from 2018, suggests that “categorizing the type of MI in young subjects might inform long-term cardiovascular prognosis,” and “emphasizes the need to identify and implement secondary prevention strategies to mitigate the high rate of cardiovascular death in patients with type 2 MI,” they concluded.

Further, outcomes varied with the number of discharge CV meds in an older cohort of patients with myocardial injury. Those with type 2 MI or acute or chronic nonischemic myocardial injury were far less likely than patients with type 1 MI to be prescribed guideline-based drugs. Survival was greater for those on two or three classes of CV medications, compared with one or none, in patients with acute or chronic nonischemic injury.

The investigators urged that patients with nonischemic myocardial injury or type 2 MI “be treated with cardiovascular medication to a larger degree than what is done today.”

When there is documented CAD in patients with type 2 MI, “it would be reasonable to suggest that preventative secondary prevention approaches, such as such lipid-reduction therapy or aspirin, would be beneficial,” Dr. Sandoval said. “But the reality is, there are no randomized trials, there are no prospective studies. ACT-2 is one of the few and early studies that’s really trying to address this.”

“The great majority of these people are not going to the cath lab, but when they do, there seems to be a signal of potential benefit,” Dr. Januzzi said. “For someone with a type 2 MI, it’s quite possible revascularization might help. Then more long-term treatment with medications that are proven in randomized trials to reduce risk would be a very plausible intervention.”

“We’ve actually proposed a number of potential therapeutic interventions to explore, both in people with type 2 MI and in people with injury without MI,” he said. “They might include sodium glucose cotransporter 2 inhibitors. They might include antithrombotic therapy or more aggressive lipid lowering, possibly for the pleiotropic effects rather than the effects on atherosclerosis.”

Any such therapies that prove successful in well-designed trials could well earn both type 2 MI and nonischemic myocardial injury, neglected as disorders in their own right, the kind of respect in clinical care pathways that they likely deserve.

Dr. Newby has disclosed receiving consulting fees or honoraria from Eli Lilly, Roche, Toshiba, Jansen, Reckitt Benckiser Pharmaceuticals, Pfizer, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, CellProthera, and Oncoarendi; and conducting research or receiving grants from Pfizer, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Boehringer Ingelheim, and Inositec. Sandoval reports serving on an advisory board and as a speaker for Abbott Diagnostics and on an advisory board for Roche Diagnostics. Dr. Januzzi has disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on endpoint committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda. Dr. Chew has reported receiving grants from AstraZeneca and Edwards Life Sciences. ACT-2 is sponsored by the National Medical and Health Research Council of Australia.

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

Survival gains in the management of acute myocardial infarction in recent decades don’t apply to one increasingly common category of MI.

Type 2 MI, triggered by a surge in myocardial oxygen demand or a drop in its supply, is on the rise and might be more prognostically serious than the “classic” atherothrombotic type 1 form, for which there have been such impressive strides in therapy.

Strategies for assessing and treating type 2 MI and another condition it can resemble clinically – nonischemic myocardial injury – have been less rigorously explored and are far less settled.

That could be partly because recent iterations of the consensus-based universal definition of MI define type 1 MI primarily by the atherothrombotic process, whereas “demand” type 2 MI is characterized as secondary to other disorders. The list of potential primary conditions, cardiac and noncardiac, is long.

As a result, patients with type 1 MI are clinically well defined, but those with type 2 MI have so far defied efforts to be clinically characterized in a consistent way. However, recent efforts might change that, given growing appreciation that all-cause and cardiovascular (CV) mortality outcomes are actually worse for patients with type 2 MI.

“That’s because we have lots of treatments for type 1 MI. Type 2 and myocardial injury? We don’t know how to treat them,” David E. Newby, MD, PhD, University of Edinburgh, said in an interview.

Dr. Newby pointed to a widely cited 2018 publication, of which he is a coauthor, documenting 5-year outcomes of 2,122 patients with type 1 MI, type 2 MI, or nonischemic myocardial injury per the newly minted fourth universal definition.

Risk-factor profiles for patients with the latter two conditions contrasted with those of patients with type 1 MI, he observed. They were “a lot older,” were less likely to be smokers, had more hypertension and previous stroke, and a less prominent CV family history.

“So they’re a different beast,” Dr. Newby said. And their prognosis tended to be worse: all-cause mortality was about 62% for patients with type 2 MI and 72% with nonischemic myocardial injury, but only 37% for patients with type 1 MI. The difference between the two types of infarction was driven by an excess of noncardiovascular death after type 2 MI.

Mortality in patients with type 2 MI is “quite high, but it may well be a marker of the fact that you’ve got other serious diseases on board that are associated with poorer outcome,” he said.
 

Risk varies

The degree of risk in type 2 MI seems to vary with the underlying condition, a recent cohort study suggests. In about 3,800 patients with cardiac troponin (cTn) elevations qualifying as MI – a younger group; most were in their 30s and 40s – mortality at 10 years was 12% for those with type 1 MI, but 34% for those with type 2 MI and 46% for the remainder with nonischemic myocardial injury.

Underlying precipitating conditions varied widely among the patients with type 2 MI or nonischemic myocardial injury, and there was broad variation in mortality by etiology among those with type 2 MI. Sepsis and anemia entailed some of the highest risk, and hypertension and arrhythmias some of the lowest.

A prospective, community-based study of 5,460 patients with type 1 MI or type 2 MI reached a similar conclusion, but with a twist. Five-year all-cause mortality contrasted significantly between types of MI at 31% and 52%, respectively, but CV mortality rates were similar in this study.

Mortality in type 2 MI again varied by the precipitating etiology, suggesting that patients can be risk stratified according to pathophysiological mechanism behind their demand infarction, the authors concluded, “underscoring that type 2 MI is not a single entity, rather a group of phenotypic clusters.”

The usually high comorbidity burden and CV risk in patients with type 2 MI, one of those authors said in an interview, suggest there are “opportunities to see whether we can reduce that risk.”

Formal recommendations consistently say that, in patients with type 2 MI, “your first and foremost target should be to treat the underlying trigger and cause,” said Yader Sandoval, MD, Mayo Clinic, Rochester, Minn. That means such opportunities for further CV risk reduction tend to be “underappreciated.”

“In principle, treating the inciting cause of type 2 MI or the injury is important,” said James L. Januzzi, MD, Massachusetts General Hospital, Boston, in an interview, “but I feel quite strongly that there must be more that we can do for these folks.”

Dr. Januzzi is senior author on a recent analysis based on more than 200,000 admissions across the United States that saw a 43% lower risk for in-hospital death and 54% lower risk for 30-day MI readmission for patients with type 2 MI than those with type 1, adjusted for risk factors and comorbidities.

But, “it is important to emphasize that type 2 MI patients had a substantial risk for adverse outcome, nonetheless, and lack a clear management approach,” Dr. Januzzi and colleagues stated in their publication, as reported by this news organization.

“Due to the high rates of long-term cardiovascular events experienced by the frequently encountered type 2 MI patients,” they wrote, “identifying evidence-based therapies represents a major unmet need.”

That such patients tend to be sick with multiple comorbidities and have not yet been clinically well characterized, Dr. Januzzi said, “has stymied our ability to develop a treatment strategy.”
 

Role of the universal definitions

That challenge might in some ways be complicated by the universal definition, especially version 4, in which the definitions for type 1 MI, type 2 MI, and nonischemic myocardial injury are unified biochemically.

This version, published in 2018 in the European Heart Journal and Circulation, introduced a formal definition of myocardial injury, which was hailed as an innovation: cTn elevation to the 99th percentile of the upper limit of normal in a reference population.

It differentiates type 1 MI from type 2 MI by the separate pathophysiology of the ischemia – plaque rupture with intracoronary thrombosis and myocardial oxygen supply–demand mismatch, respectively. In both cases, however, there must be symptoms or objective evidence of ischemia. Absent signs of ischemia, the determination would be nonischemic myocardial injury.

Yet clinically and prognostically, type 2 MI and nonischemic myocardial injury in some ways are more similar to each other than either is to type 1 MI. Both occur secondary to other conditions across diverse clinical settings and can be a challenge to tell apart.

The universal definition’s perspective of the three events – so heavily dependent on cTn levels and myocardial ischemia – fails to account for the myriad complexities of individual patients in practice, some say, and so can muddle the process of risk assessment and therapy.

“Abnormal troponin identifies injury, but it doesn’t identify mechanism. Type 2 MI is highly prevalent, but there are other things that cause abnormal troponins,” Dr. Januzzi said. That’s why it’s important to explore and map out the clinical variables associated with the two conditions, to “understand who has a type 2 MI and who has cardiac injury. And believe it or not, it’s actually harder than it sounds to sort that out.”

“Practically speaking, the differentiation between these events is clinical,” Dr. Sandoval agreed. “There’s not always perfect agreement on what we’re calling what.”

Consequently, the universal definitions might categorize some events in ways that seem inconsistent from a management perspective. For example, they make a sharp distinction between coronary atherothrombotic and coronary nonatherothrombotic MI etiologies. Some clinicians would group MI caused by coronary spasm, coronary embolism, or spontaneous coronary artery dissection along with MI from coronary plaque rupture and thrombosis. But, Dr. Sandoval said, “even though these are coronary issues, they would fall into the type 2 bin.”

Also, about half of cases identified as type 2 MI are caused by tachyarrhythmias, which can elevate troponin and cause ECG changes and possibly symptoms resembling angina, Dr. Newby observed. “But that is completely different from other types of myocardial infarction, which are much more serious.”

So, “it’s a real mess of a diagnosis – acute myocardial injury, type 2 and type 1 MI – and it can be quite difficult to disentangle,” he said. “I think that the definition certainly has let us down.”

The diversity of type 2 MI clinical settings might also be a challenge. Myocardial injury according to cTn, with or without ischemia, occurs widely during critical illnesses and acute conditions, including respiratory distress, sepsis, internal bleeding, stroke, and pulmonary embolism.

Early in the COVID-19 pandemic, much was made of elevated troponin levels and myocarditis as an apparently frequent complication among hospitalized patients. “I raised my hand and said, we’ve been seeing abnormal troponins in people with influenza for 20 years,” Dr. Januzzi said. “Critical illness, infection, toxicity from drugs, from chemotherapy, from alcohol – there are all sorts of potential triggers of myocardial injury.”
 

Troponin ‘overdependence’

With many clinical settings in common and the presence or absence of myocardial ischemia to primarily distinguish them, type 2 MI and nonischemic myocardial injury both can be mistaken for the other. That can send management decisions in inappropriate directions.

A 2019 study looked at 633 cases that had been coded as type 2 MI at a major center and readjudicated them according to the fourth universal definition. Only 57% met all the type 2 criteria, 42% were reclassified as nonischemic myocardial injury, and a few were determined to have unstable angina.

“There’s overdependence on the easiest tool in the universal definition,” said Dr. Januzzi, a coauthor on that study. “Frequently people get seduced by the rise in a troponin value and immediately call it a myocardial infarction, lacking the other components of the universal definition that require evidence for coronary ischemia. That happens every day, where someone with an abnormal troponin is incorrectly branded as having an MI.”

It may not help that the current ICD-10-CM system features a diagnostic code for type 2 MI but not for myocardial injury.

“Instead, the new ICD-10-CM coding includes a proxy called ‘non-MI troponin elevation due to an underlying cause,’ ” wrote Kristian Thygesen, MD, DSc, and Allan S. Jaffe, MD, in a recent editorial. They caution against “using this code for myocardial injury because it is not specific for an elevated cTn value and could represent any abnormal laboratory measurements.” The code could be “misleading,” thereby worsening the potential for miscoding and “misattribution of MI diagnoses.”

That potential suggests there could be a growing population of patients who have been told they had an MI, which then becomes part of their medical record, when, actually, they experienced nonischemic myocardial injury.

“Having seen this occur,” Dr. Januzzi explained, “it affects people emotionally to think they’ve had an MI. Precision in diagnosis is important, which is why the universal definition is so valuable. If people would adhere to it more assiduously, we could reduce the frequency of people getting a misdiagnosis of MI when in fact they had injury.”

Still, he added, “if someone has an illness severe enough to cause myocardial injury, they’re at risk for a bad outcome regardless of whether they did or didn’t have an MI.”
 

The uncertain role of angiography

Angiography isn’t ordered nearly as often for patients ultimately diagnosed with type 2 MI or myocardial injury as for those with type 1 MI. Type 2 MI can hit some patients who have remained symptom free despite possibly unrecognized obstructive coronary artery disease (CAD) when myocardial demand is pushed past supply by a critical illness, tachyarrhythmia, or other acute conditions.

In such cases, “it’s reasonable to hypothesize that revascularization, something that really is not done in the vast majority of patients with type 2 MI, might actually be of benefit,” Dr. Januzzi said.

Whether these patients should routinely have angiography remains an open question. Without intervention, any newly identified obstructive CAD would continue to lurk in the background as a potential threat.

In efforts to differentiate type 2 MI from nonischemic injury, it can be “incredibly hard to know whether or not there’s actual ischemia in the mix. And that’s the only thing that defines the difference before taking an angiogram,” Derek P. Chew, MBBS, MPH, Flinders Medical Centre, Bedford Park, Australia, said in an interview.

Dr. Chew is principal investigator for the ongoing ACT-2 trial that is enrolling hospitalized, hemodynamically stable patients with cTn elevations but no suspicion of type 1 MI and “an unequivocal acute intercurrent diagnosis.” Qualifying diagnoses are prespecified on a list that includes sepsis, pneumonia, septicemia, a systemic inflammatory response, anemia, atrial tachycardia, acute kidney injury, and recent noncardiac surgery.

The patients are randomly assigned to a strategy of routine, usually invasive coronary angiography with discretionary revascularization, or to conservative care with noninvasive functional testing as appropriate. The sicker the patient, the greater the competing risk from other conditions and the less revascularization is likely to improve outcomes, Dr. Chew observed. Importantly, therefore, outcomes in the trial will be stratified by patient risk from comorbidities, measured with baseline GRACE and APACHE III scores.

Dr. Chew said the study aims to determine whether routine angiography is of benefit in patients at some identifiable level of risk, if not the whole range. One possible result, he said, is that there could be a risk-profile “sweet spot” associated with better outcomes in those assigned to angiography.

Enrollment in the trial started about 3 years ago, but “the process has been slow,” he said, because many potentially referring clinicians have a “bias on one side or another,” with about half of them preferring the angiography approach and the other half conservative management.
 

The unsettled role of drug therapy

With their often-complicated clinical profile, patients with type 2 MI or nonischemic myocardial injury tend to be medically undertreated, yet there is observational evidence they can benefit from familiar drug therapies.

In the previously noted cohort study of 3,800 younger patients with one of the three forms of myocardial injury, less than half of patients with type 2 MI received any form of CAD secondary prevention therapy at discharge, the researchers, with first author Avinainder Singh, MD, from Yale University, New Haven, Conn, wrote.

The finding, consistent with Dr. Newby’s study from 2018, suggests that “categorizing the type of MI in young subjects might inform long-term cardiovascular prognosis,” and “emphasizes the need to identify and implement secondary prevention strategies to mitigate the high rate of cardiovascular death in patients with type 2 MI,” they concluded.

Further, outcomes varied with the number of discharge CV meds in an older cohort of patients with myocardial injury. Those with type 2 MI or acute or chronic nonischemic myocardial injury were far less likely than patients with type 1 MI to be prescribed guideline-based drugs. Survival was greater for those on two or three classes of CV medications, compared with one or none, in patients with acute or chronic nonischemic injury.

The investigators urged that patients with nonischemic myocardial injury or type 2 MI “be treated with cardiovascular medication to a larger degree than what is done today.”

When there is documented CAD in patients with type 2 MI, “it would be reasonable to suggest that preventative secondary prevention approaches, such as such lipid-reduction therapy or aspirin, would be beneficial,” Dr. Sandoval said. “But the reality is, there are no randomized trials, there are no prospective studies. ACT-2 is one of the few and early studies that’s really trying to address this.”

“The great majority of these people are not going to the cath lab, but when they do, there seems to be a signal of potential benefit,” Dr. Januzzi said. “For someone with a type 2 MI, it’s quite possible revascularization might help. Then more long-term treatment with medications that are proven in randomized trials to reduce risk would be a very plausible intervention.”

“We’ve actually proposed a number of potential therapeutic interventions to explore, both in people with type 2 MI and in people with injury without MI,” he said. “They might include sodium glucose cotransporter 2 inhibitors. They might include antithrombotic therapy or more aggressive lipid lowering, possibly for the pleiotropic effects rather than the effects on atherosclerosis.”

Any such therapies that prove successful in well-designed trials could well earn both type 2 MI and nonischemic myocardial injury, neglected as disorders in their own right, the kind of respect in clinical care pathways that they likely deserve.

Dr. Newby has disclosed receiving consulting fees or honoraria from Eli Lilly, Roche, Toshiba, Jansen, Reckitt Benckiser Pharmaceuticals, Pfizer, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, CellProthera, and Oncoarendi; and conducting research or receiving grants from Pfizer, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Boehringer Ingelheim, and Inositec. Sandoval reports serving on an advisory board and as a speaker for Abbott Diagnostics and on an advisory board for Roche Diagnostics. Dr. Januzzi has disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on endpoint committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda. Dr. Chew has reported receiving grants from AstraZeneca and Edwards Life Sciences. ACT-2 is sponsored by the National Medical and Health Research Council of Australia.

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

Survival gains in the management of acute myocardial infarction in recent decades don’t apply to one increasingly common category of MI.

Type 2 MI, triggered by a surge in myocardial oxygen demand or a drop in its supply, is on the rise and might be more prognostically serious than the “classic” atherothrombotic type 1 form, for which there have been such impressive strides in therapy.

Strategies for assessing and treating type 2 MI and another condition it can resemble clinically – nonischemic myocardial injury – have been less rigorously explored and are far less settled.

That could be partly because recent iterations of the consensus-based universal definition of MI define type 1 MI primarily by the atherothrombotic process, whereas “demand” type 2 MI is characterized as secondary to other disorders. The list of potential primary conditions, cardiac and noncardiac, is long.

As a result, patients with type 1 MI are clinically well defined, but those with type 2 MI have so far defied efforts to be clinically characterized in a consistent way. However, recent efforts might change that, given growing appreciation that all-cause and cardiovascular (CV) mortality outcomes are actually worse for patients with type 2 MI.

“That’s because we have lots of treatments for type 1 MI. Type 2 and myocardial injury? We don’t know how to treat them,” David E. Newby, MD, PhD, University of Edinburgh, said in an interview.

Dr. Newby pointed to a widely cited 2018 publication, of which he is a coauthor, documenting 5-year outcomes of 2,122 patients with type 1 MI, type 2 MI, or nonischemic myocardial injury per the newly minted fourth universal definition.

Risk-factor profiles for patients with the latter two conditions contrasted with those of patients with type 1 MI, he observed. They were “a lot older,” were less likely to be smokers, had more hypertension and previous stroke, and a less prominent CV family history.

“So they’re a different beast,” Dr. Newby said. And their prognosis tended to be worse: all-cause mortality was about 62% for patients with type 2 MI and 72% with nonischemic myocardial injury, but only 37% for patients with type 1 MI. The difference between the two types of infarction was driven by an excess of noncardiovascular death after type 2 MI.

Mortality in patients with type 2 MI is “quite high, but it may well be a marker of the fact that you’ve got other serious diseases on board that are associated with poorer outcome,” he said.
 

Risk varies

The degree of risk in type 2 MI seems to vary with the underlying condition, a recent cohort study suggests. In about 3,800 patients with cardiac troponin (cTn) elevations qualifying as MI – a younger group; most were in their 30s and 40s – mortality at 10 years was 12% for those with type 1 MI, but 34% for those with type 2 MI and 46% for the remainder with nonischemic myocardial injury.

Underlying precipitating conditions varied widely among the patients with type 2 MI or nonischemic myocardial injury, and there was broad variation in mortality by etiology among those with type 2 MI. Sepsis and anemia entailed some of the highest risk, and hypertension and arrhythmias some of the lowest.

A prospective, community-based study of 5,460 patients with type 1 MI or type 2 MI reached a similar conclusion, but with a twist. Five-year all-cause mortality contrasted significantly between types of MI at 31% and 52%, respectively, but CV mortality rates were similar in this study.

Mortality in type 2 MI again varied by the precipitating etiology, suggesting that patients can be risk stratified according to pathophysiological mechanism behind their demand infarction, the authors concluded, “underscoring that type 2 MI is not a single entity, rather a group of phenotypic clusters.”

The usually high comorbidity burden and CV risk in patients with type 2 MI, one of those authors said in an interview, suggest there are “opportunities to see whether we can reduce that risk.”

Formal recommendations consistently say that, in patients with type 2 MI, “your first and foremost target should be to treat the underlying trigger and cause,” said Yader Sandoval, MD, Mayo Clinic, Rochester, Minn. That means such opportunities for further CV risk reduction tend to be “underappreciated.”

“In principle, treating the inciting cause of type 2 MI or the injury is important,” said James L. Januzzi, MD, Massachusetts General Hospital, Boston, in an interview, “but I feel quite strongly that there must be more that we can do for these folks.”

Dr. Januzzi is senior author on a recent analysis based on more than 200,000 admissions across the United States that saw a 43% lower risk for in-hospital death and 54% lower risk for 30-day MI readmission for patients with type 2 MI than those with type 1, adjusted for risk factors and comorbidities.

But, “it is important to emphasize that type 2 MI patients had a substantial risk for adverse outcome, nonetheless, and lack a clear management approach,” Dr. Januzzi and colleagues stated in their publication, as reported by this news organization.

“Due to the high rates of long-term cardiovascular events experienced by the frequently encountered type 2 MI patients,” they wrote, “identifying evidence-based therapies represents a major unmet need.”

That such patients tend to be sick with multiple comorbidities and have not yet been clinically well characterized, Dr. Januzzi said, “has stymied our ability to develop a treatment strategy.”
 

Role of the universal definitions

That challenge might in some ways be complicated by the universal definition, especially version 4, in which the definitions for type 1 MI, type 2 MI, and nonischemic myocardial injury are unified biochemically.

This version, published in 2018 in the European Heart Journal and Circulation, introduced a formal definition of myocardial injury, which was hailed as an innovation: cTn elevation to the 99th percentile of the upper limit of normal in a reference population.

It differentiates type 1 MI from type 2 MI by the separate pathophysiology of the ischemia – plaque rupture with intracoronary thrombosis and myocardial oxygen supply–demand mismatch, respectively. In both cases, however, there must be symptoms or objective evidence of ischemia. Absent signs of ischemia, the determination would be nonischemic myocardial injury.

Yet clinically and prognostically, type 2 MI and nonischemic myocardial injury in some ways are more similar to each other than either is to type 1 MI. Both occur secondary to other conditions across diverse clinical settings and can be a challenge to tell apart.

The universal definition’s perspective of the three events – so heavily dependent on cTn levels and myocardial ischemia – fails to account for the myriad complexities of individual patients in practice, some say, and so can muddle the process of risk assessment and therapy.

“Abnormal troponin identifies injury, but it doesn’t identify mechanism. Type 2 MI is highly prevalent, but there are other things that cause abnormal troponins,” Dr. Januzzi said. That’s why it’s important to explore and map out the clinical variables associated with the two conditions, to “understand who has a type 2 MI and who has cardiac injury. And believe it or not, it’s actually harder than it sounds to sort that out.”

“Practically speaking, the differentiation between these events is clinical,” Dr. Sandoval agreed. “There’s not always perfect agreement on what we’re calling what.”

Consequently, the universal definitions might categorize some events in ways that seem inconsistent from a management perspective. For example, they make a sharp distinction between coronary atherothrombotic and coronary nonatherothrombotic MI etiologies. Some clinicians would group MI caused by coronary spasm, coronary embolism, or spontaneous coronary artery dissection along with MI from coronary plaque rupture and thrombosis. But, Dr. Sandoval said, “even though these are coronary issues, they would fall into the type 2 bin.”

Also, about half of cases identified as type 2 MI are caused by tachyarrhythmias, which can elevate troponin and cause ECG changes and possibly symptoms resembling angina, Dr. Newby observed. “But that is completely different from other types of myocardial infarction, which are much more serious.”

So, “it’s a real mess of a diagnosis – acute myocardial injury, type 2 and type 1 MI – and it can be quite difficult to disentangle,” he said. “I think that the definition certainly has let us down.”

The diversity of type 2 MI clinical settings might also be a challenge. Myocardial injury according to cTn, with or without ischemia, occurs widely during critical illnesses and acute conditions, including respiratory distress, sepsis, internal bleeding, stroke, and pulmonary embolism.

Early in the COVID-19 pandemic, much was made of elevated troponin levels and myocarditis as an apparently frequent complication among hospitalized patients. “I raised my hand and said, we’ve been seeing abnormal troponins in people with influenza for 20 years,” Dr. Januzzi said. “Critical illness, infection, toxicity from drugs, from chemotherapy, from alcohol – there are all sorts of potential triggers of myocardial injury.”
 

Troponin ‘overdependence’

With many clinical settings in common and the presence or absence of myocardial ischemia to primarily distinguish them, type 2 MI and nonischemic myocardial injury both can be mistaken for the other. That can send management decisions in inappropriate directions.

A 2019 study looked at 633 cases that had been coded as type 2 MI at a major center and readjudicated them according to the fourth universal definition. Only 57% met all the type 2 criteria, 42% were reclassified as nonischemic myocardial injury, and a few were determined to have unstable angina.

“There’s overdependence on the easiest tool in the universal definition,” said Dr. Januzzi, a coauthor on that study. “Frequently people get seduced by the rise in a troponin value and immediately call it a myocardial infarction, lacking the other components of the universal definition that require evidence for coronary ischemia. That happens every day, where someone with an abnormal troponin is incorrectly branded as having an MI.”

It may not help that the current ICD-10-CM system features a diagnostic code for type 2 MI but not for myocardial injury.

“Instead, the new ICD-10-CM coding includes a proxy called ‘non-MI troponin elevation due to an underlying cause,’ ” wrote Kristian Thygesen, MD, DSc, and Allan S. Jaffe, MD, in a recent editorial. They caution against “using this code for myocardial injury because it is not specific for an elevated cTn value and could represent any abnormal laboratory measurements.” The code could be “misleading,” thereby worsening the potential for miscoding and “misattribution of MI diagnoses.”

That potential suggests there could be a growing population of patients who have been told they had an MI, which then becomes part of their medical record, when, actually, they experienced nonischemic myocardial injury.

“Having seen this occur,” Dr. Januzzi explained, “it affects people emotionally to think they’ve had an MI. Precision in diagnosis is important, which is why the universal definition is so valuable. If people would adhere to it more assiduously, we could reduce the frequency of people getting a misdiagnosis of MI when in fact they had injury.”

Still, he added, “if someone has an illness severe enough to cause myocardial injury, they’re at risk for a bad outcome regardless of whether they did or didn’t have an MI.”
 

The uncertain role of angiography

Angiography isn’t ordered nearly as often for patients ultimately diagnosed with type 2 MI or myocardial injury as for those with type 1 MI. Type 2 MI can hit some patients who have remained symptom free despite possibly unrecognized obstructive coronary artery disease (CAD) when myocardial demand is pushed past supply by a critical illness, tachyarrhythmia, or other acute conditions.

In such cases, “it’s reasonable to hypothesize that revascularization, something that really is not done in the vast majority of patients with type 2 MI, might actually be of benefit,” Dr. Januzzi said.

Whether these patients should routinely have angiography remains an open question. Without intervention, any newly identified obstructive CAD would continue to lurk in the background as a potential threat.

In efforts to differentiate type 2 MI from nonischemic injury, it can be “incredibly hard to know whether or not there’s actual ischemia in the mix. And that’s the only thing that defines the difference before taking an angiogram,” Derek P. Chew, MBBS, MPH, Flinders Medical Centre, Bedford Park, Australia, said in an interview.

Dr. Chew is principal investigator for the ongoing ACT-2 trial that is enrolling hospitalized, hemodynamically stable patients with cTn elevations but no suspicion of type 1 MI and “an unequivocal acute intercurrent diagnosis.” Qualifying diagnoses are prespecified on a list that includes sepsis, pneumonia, septicemia, a systemic inflammatory response, anemia, atrial tachycardia, acute kidney injury, and recent noncardiac surgery.

The patients are randomly assigned to a strategy of routine, usually invasive coronary angiography with discretionary revascularization, or to conservative care with noninvasive functional testing as appropriate. The sicker the patient, the greater the competing risk from other conditions and the less revascularization is likely to improve outcomes, Dr. Chew observed. Importantly, therefore, outcomes in the trial will be stratified by patient risk from comorbidities, measured with baseline GRACE and APACHE III scores.

Dr. Chew said the study aims to determine whether routine angiography is of benefit in patients at some identifiable level of risk, if not the whole range. One possible result, he said, is that there could be a risk-profile “sweet spot” associated with better outcomes in those assigned to angiography.

Enrollment in the trial started about 3 years ago, but “the process has been slow,” he said, because many potentially referring clinicians have a “bias on one side or another,” with about half of them preferring the angiography approach and the other half conservative management.
 

The unsettled role of drug therapy

With their often-complicated clinical profile, patients with type 2 MI or nonischemic myocardial injury tend to be medically undertreated, yet there is observational evidence they can benefit from familiar drug therapies.

In the previously noted cohort study of 3,800 younger patients with one of the three forms of myocardial injury, less than half of patients with type 2 MI received any form of CAD secondary prevention therapy at discharge, the researchers, with first author Avinainder Singh, MD, from Yale University, New Haven, Conn, wrote.

The finding, consistent with Dr. Newby’s study from 2018, suggests that “categorizing the type of MI in young subjects might inform long-term cardiovascular prognosis,” and “emphasizes the need to identify and implement secondary prevention strategies to mitigate the high rate of cardiovascular death in patients with type 2 MI,” they concluded.

Further, outcomes varied with the number of discharge CV meds in an older cohort of patients with myocardial injury. Those with type 2 MI or acute or chronic nonischemic myocardial injury were far less likely than patients with type 1 MI to be prescribed guideline-based drugs. Survival was greater for those on two or three classes of CV medications, compared with one or none, in patients with acute or chronic nonischemic injury.

The investigators urged that patients with nonischemic myocardial injury or type 2 MI “be treated with cardiovascular medication to a larger degree than what is done today.”

When there is documented CAD in patients with type 2 MI, “it would be reasonable to suggest that preventative secondary prevention approaches, such as such lipid-reduction therapy or aspirin, would be beneficial,” Dr. Sandoval said. “But the reality is, there are no randomized trials, there are no prospective studies. ACT-2 is one of the few and early studies that’s really trying to address this.”

“The great majority of these people are not going to the cath lab, but when they do, there seems to be a signal of potential benefit,” Dr. Januzzi said. “For someone with a type 2 MI, it’s quite possible revascularization might help. Then more long-term treatment with medications that are proven in randomized trials to reduce risk would be a very plausible intervention.”

“We’ve actually proposed a number of potential therapeutic interventions to explore, both in people with type 2 MI and in people with injury without MI,” he said. “They might include sodium glucose cotransporter 2 inhibitors. They might include antithrombotic therapy or more aggressive lipid lowering, possibly for the pleiotropic effects rather than the effects on atherosclerosis.”

Any such therapies that prove successful in well-designed trials could well earn both type 2 MI and nonischemic myocardial injury, neglected as disorders in their own right, the kind of respect in clinical care pathways that they likely deserve.

Dr. Newby has disclosed receiving consulting fees or honoraria from Eli Lilly, Roche, Toshiba, Jansen, Reckitt Benckiser Pharmaceuticals, Pfizer, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, CellProthera, and Oncoarendi; and conducting research or receiving grants from Pfizer, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Boehringer Ingelheim, and Inositec. Sandoval reports serving on an advisory board and as a speaker for Abbott Diagnostics and on an advisory board for Roche Diagnostics. Dr. Januzzi has disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on endpoint committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda. Dr. Chew has reported receiving grants from AstraZeneca and Edwards Life Sciences. ACT-2 is sponsored by the National Medical and Health Research Council of Australia.

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

Some, perhaps many, previously unrecognized cases of atrial fibrillation (AF) will come to light in a screening program aimed at older asymptomatic adults. The key question is whether the challenges of such systematic but age-restricted AF screening in the community, with oral anticoagulation (OAC) offered to those found to have the arrhythmia, is worthwhile in preventing events such as death or stroke.
 

Now there is evidence supporting such a clinical benefit from a large, prospective, randomized trial. A screening program restricted to people 75 or 76 years of age in two Swedish communities, which called on them to use a handheld single-lead ECG system at home intermittently for 2 weeks, was followed by a slight drop in clinical events over about 7 years.

The 4% decline in risk (P = .045) in the STROKESTOP trial’s “intention-to-treat” (ITT) analysis yielded a number needed to treat of 91; that is, that many people had to be targeted by the screening program to prevent one primary-endpoint clinical event.

Those included ischemic stroke, systemic thromboembolism, hospitalization for severe bleeding, and death from any cause, investigators reported April 23 during the virtual European Heart Rhythm Association (EHRA) 2021 Congress.

If that benefit and its significance seem marginal, some secondary findings might be reassuring. Half the population of the target age in the two communities – 13,979 randomly selected people – were invited to join the trial and follow the screening protocol, comprising the ITT cohort. The other half, numbering 13,996, was not invited and served as control subjects.

However, only 51% of the ITT cohort accepted the invitation and participated in the trial; they represented the “as-treated” cohort, observed Emma Svennberg, MD, PhD, Karolinska Institute, Danderyd Hospital, Stockholm, who presented the analysis at the EHRA sessions.

The screening protocol identified untreated AF, whether previously known or unknown, in about 5% of the 7,165 as-treated screening participants; OAC was initiated in about three-fourths of those cases.

The as-treated group, on their own, benefited with a 24% drop in the prospectively defined secondary endpoint of ischemic stroke, compared with the entire control group.

The clinical benefit in the ITT population was “small but significant,” but over the same period in the as-treated cohort, there was a highly significant drop in risk for ischemic stroke, Dr. Svennberg said in an interview.

The trial’s lead message, she said, is that “screening for atrial fibrillation in an elderly population reduces the risk of death and ischemic stroke without increasing the risk of bleeding.”
 

Caveats: As-treated vs. ITT

But there are caveats that complicate interpretation of the trial and, Dr. Svennberg proposed, point to the importance of that interpretation of both the ITT and as-treated analyses.

“We detected significantly more atrial fibrillation in the group that was randomized to screening. A major strength of our study was that we referred all of those individuals for a structured follow-up within the study,” she said. “Although the focus of the follow-up was oral anticoagulant therapy, other risk factors were also assessed and managed, such as hypertension and diabetes.”

It’s possible that increased detection of AF followed by such structured management contributed to the observed benefit, Dr. Svennberg proposed.

However, the exclusion of those in the prespecified ITT population who declined to be screened or otherwise didn’t participate left an as-treated cohort that was healthier than the ITT population or the control group.

Indeed, the nonparticipating invitees were sicker, with significantly more diabetes, vascular disease, hypertension, and heart failure, and higher CHA2DS2VASc stroke risk scores than those who agreed to participate.

“We took a more difficult route in setting up this study, in that we identified all individuals aged 75 to 76 residing in our two regions and excluded no one,” Dr. Svennberg said in an interview. “That means even individuals with end-stage disease, severe dementia, bedridden in nursing homes, et cetera, were also randomized but perhaps not likely or eligible to participate.”

Therefore, some invitees were unable to join the study even as others might have declined “out of low interest” or other personal reasons, she said. “We believe that this mimics how a population-based screening program would be performed if done in our country.”

In the ITT analysis, screening successfully identified previously unknown or untreated cases of AF, which led to expanded OAC use and intensified risk-factor management, “which was key to a successful outcome.”

In the as-treated analysis, Dr. Svennberg said, “I think a combination of the intervention and the population being overall more healthy was driving the secondary endpoint.”
 

Systematic vs. opportunistic screening

Although “opportunistic screening in individuals aged 65 and older” is recommended by current European Society of Cardiology guidelines, systematic screening, such as that used in STROKESTOP, has a much weaker evidence base, observed Renate B. Schnabel, MD, PhD, University Heart & Vascular Center, Hamburg, Germany, as the invited discussant after the STROKESTOP presentation.

STROKESTOP “is one of the first studies, if not the first study,” to show a clinical benefit from screening for AF, Dr. Schnabel said.

Fewer-than-projected primary outcome events were seen during the trial, and event curves for screened and control participants didn’t start to separate until about 4 years into the study, she said. It therefore might take a long time for the screened elderly to realize the clinical benefits of screening.

Studies such as the recent SCREEN-AF and mSTOPS have amply shown that AF screening in the asymptomatic elderly can reveal previously unrecognized AF far more often than would be detected in routine practice, allowing them the opportunity to go on OAC. But the trials weren’t able to show whether the benefits of such management outweigh the risks or costs.

Indeed, on April 20, the U.S. Preventive Services Task Force (USPSTF) released a draft recommendation statement concluding that “the current evidence is insufficient to assess the balance of benefits and harms” associated with AF screening in asymptomatic people at least 50 years of age.

In STROKESTOP, however, benefit for the primary outcome reached significance in the prespecified ITT analysis and “appeared to be driven by the reduction in ischemic stroke incidence,” Dr. Schnabel said.

“The future guidelines have gained strong evidence to judge on systematic atrial fibrillation screening” as it was performed in the trial, she said. “How to implement atrial fibrillation screening, including systematic screening in health care systems across Europe and beyond, remains an open question.”
 

A randomized population

STROKESTOP considered all 75- and 76-year-olds living in Sweden’s Stockholm County (n = 23,888) and the Halland region (n = 4,880) and randomly assigned them to the ITT group or a control group, with stratification by sex, birth year, and geographic region. In both groups, 54.6% were female and the mean CHA2DS2VASc score was 3.5.

People assigned to the ITT cohort were invited to be screened and followed. Those who agreed to participate underwent a baseline ECG assessment to detect or rule out permanent AF. Guideline-based OAC and follow-up was offered to those found with the arrhythmia. Those in sinus rhythm with no history of AF used a handheld single-lead ECG recorder (Zenicor) for 30 seconds twice daily for 14 days.

Structured management, including OAC, was offered to anyone demonstrating sufficient AF, that is, at least one bout without p waves in one 30-second recording or at least two such episodes lasting 10-29 seconds during the 2-week screening period.

In the ITT analysis, the hazard ratio (HR) for the composite clinical primary endpoint was 0.96 (95% confidence interval, 0.920-0.999; P = .045), but in the as-treated analysis, the HR for ischemic stroke was 0.76 (95% CI, 0.68-0.87; P < .001).

“I believe that this will likely be generalizable to most countries’ elderly residents,” Dr. Svennberg said. “I think if we can find a significant difference in our elderly population in Sweden, most countries will be able to do so, or find even more significant results.”

That’s because “baseline detection of AF in Sweden is high,” she said, “so new detection is likely more difficult.” Also, in Sweden, “care can be sought without monetary concern, and prescriptions are provided at low costs to the patients.” Therefore, patients newly identified with AF, whether in studies or not, “would likely be started on therapy.”

It will be important to know whether the screening strategy is cost-effective, Dr. Schnabel said, because “the overall effect, with a hazard ratio of 0.96, is not too big, and costs incurred by systematic screening are comparatively high.”

STROKESTOP “now provides sound information for cost-effectiveness analyses, which to date have largely relied on assumptions.”

STROKESTOP was partially supported by Carl Bennet AB, Boehringer-Ingelheim, Bayer, Bristol-Meyers Squibb, and Pfizer. Dr. Svennberg disclosed receiving fees for lectures or consulting from Bayer, Bristol-Meyers Squibb, Pfizer, Boehringer-Ingelheim, Merck Sharp & Dohme, and Sanofi; and institutional grants from Roche Diagnostics and Carl Bennett Ltd.

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

Some, perhaps many, previously unrecognized cases of atrial fibrillation (AF) will come to light in a screening program aimed at older asymptomatic adults. The key question is whether the challenges of such systematic but age-restricted AF screening in the community, with oral anticoagulation (OAC) offered to those found to have the arrhythmia, is worthwhile in preventing events such as death or stroke.
 

Now there is evidence supporting such a clinical benefit from a large, prospective, randomized trial. A screening program restricted to people 75 or 76 years of age in two Swedish communities, which called on them to use a handheld single-lead ECG system at home intermittently for 2 weeks, was followed by a slight drop in clinical events over about 7 years.

The 4% decline in risk (P = .045) in the STROKESTOP trial’s “intention-to-treat” (ITT) analysis yielded a number needed to treat of 91; that is, that many people had to be targeted by the screening program to prevent one primary-endpoint clinical event.

Those included ischemic stroke, systemic thromboembolism, hospitalization for severe bleeding, and death from any cause, investigators reported April 23 during the virtual European Heart Rhythm Association (EHRA) 2021 Congress.

If that benefit and its significance seem marginal, some secondary findings might be reassuring. Half the population of the target age in the two communities – 13,979 randomly selected people – were invited to join the trial and follow the screening protocol, comprising the ITT cohort. The other half, numbering 13,996, was not invited and served as control subjects.

However, only 51% of the ITT cohort accepted the invitation and participated in the trial; they represented the “as-treated” cohort, observed Emma Svennberg, MD, PhD, Karolinska Institute, Danderyd Hospital, Stockholm, who presented the analysis at the EHRA sessions.

The screening protocol identified untreated AF, whether previously known or unknown, in about 5% of the 7,165 as-treated screening participants; OAC was initiated in about three-fourths of those cases.

The as-treated group, on their own, benefited with a 24% drop in the prospectively defined secondary endpoint of ischemic stroke, compared with the entire control group.

The clinical benefit in the ITT population was “small but significant,” but over the same period in the as-treated cohort, there was a highly significant drop in risk for ischemic stroke, Dr. Svennberg said in an interview.

The trial’s lead message, she said, is that “screening for atrial fibrillation in an elderly population reduces the risk of death and ischemic stroke without increasing the risk of bleeding.”
 

Caveats: As-treated vs. ITT

But there are caveats that complicate interpretation of the trial and, Dr. Svennberg proposed, point to the importance of that interpretation of both the ITT and as-treated analyses.

“We detected significantly more atrial fibrillation in the group that was randomized to screening. A major strength of our study was that we referred all of those individuals for a structured follow-up within the study,” she said. “Although the focus of the follow-up was oral anticoagulant therapy, other risk factors were also assessed and managed, such as hypertension and diabetes.”

It’s possible that increased detection of AF followed by such structured management contributed to the observed benefit, Dr. Svennberg proposed.

However, the exclusion of those in the prespecified ITT population who declined to be screened or otherwise didn’t participate left an as-treated cohort that was healthier than the ITT population or the control group.

Indeed, the nonparticipating invitees were sicker, with significantly more diabetes, vascular disease, hypertension, and heart failure, and higher CHA2DS2VASc stroke risk scores than those who agreed to participate.

“We took a more difficult route in setting up this study, in that we identified all individuals aged 75 to 76 residing in our two regions and excluded no one,” Dr. Svennberg said in an interview. “That means even individuals with end-stage disease, severe dementia, bedridden in nursing homes, et cetera, were also randomized but perhaps not likely or eligible to participate.”

Therefore, some invitees were unable to join the study even as others might have declined “out of low interest” or other personal reasons, she said. “We believe that this mimics how a population-based screening program would be performed if done in our country.”

In the ITT analysis, screening successfully identified previously unknown or untreated cases of AF, which led to expanded OAC use and intensified risk-factor management, “which was key to a successful outcome.”

In the as-treated analysis, Dr. Svennberg said, “I think a combination of the intervention and the population being overall more healthy was driving the secondary endpoint.”
 

Systematic vs. opportunistic screening

Although “opportunistic screening in individuals aged 65 and older” is recommended by current European Society of Cardiology guidelines, systematic screening, such as that used in STROKESTOP, has a much weaker evidence base, observed Renate B. Schnabel, MD, PhD, University Heart & Vascular Center, Hamburg, Germany, as the invited discussant after the STROKESTOP presentation.

STROKESTOP “is one of the first studies, if not the first study,” to show a clinical benefit from screening for AF, Dr. Schnabel said.

Fewer-than-projected primary outcome events were seen during the trial, and event curves for screened and control participants didn’t start to separate until about 4 years into the study, she said. It therefore might take a long time for the screened elderly to realize the clinical benefits of screening.

Studies such as the recent SCREEN-AF and mSTOPS have amply shown that AF screening in the asymptomatic elderly can reveal previously unrecognized AF far more often than would be detected in routine practice, allowing them the opportunity to go on OAC. But the trials weren’t able to show whether the benefits of such management outweigh the risks or costs.

Indeed, on April 20, the U.S. Preventive Services Task Force (USPSTF) released a draft recommendation statement concluding that “the current evidence is insufficient to assess the balance of benefits and harms” associated with AF screening in asymptomatic people at least 50 years of age.

In STROKESTOP, however, benefit for the primary outcome reached significance in the prespecified ITT analysis and “appeared to be driven by the reduction in ischemic stroke incidence,” Dr. Schnabel said.

“The future guidelines have gained strong evidence to judge on systematic atrial fibrillation screening” as it was performed in the trial, she said. “How to implement atrial fibrillation screening, including systematic screening in health care systems across Europe and beyond, remains an open question.”
 

A randomized population

STROKESTOP considered all 75- and 76-year-olds living in Sweden’s Stockholm County (n = 23,888) and the Halland region (n = 4,880) and randomly assigned them to the ITT group or a control group, with stratification by sex, birth year, and geographic region. In both groups, 54.6% were female and the mean CHA2DS2VASc score was 3.5.

People assigned to the ITT cohort were invited to be screened and followed. Those who agreed to participate underwent a baseline ECG assessment to detect or rule out permanent AF. Guideline-based OAC and follow-up was offered to those found with the arrhythmia. Those in sinus rhythm with no history of AF used a handheld single-lead ECG recorder (Zenicor) for 30 seconds twice daily for 14 days.

Structured management, including OAC, was offered to anyone demonstrating sufficient AF, that is, at least one bout without p waves in one 30-second recording or at least two such episodes lasting 10-29 seconds during the 2-week screening period.

In the ITT analysis, the hazard ratio (HR) for the composite clinical primary endpoint was 0.96 (95% confidence interval, 0.920-0.999; P = .045), but in the as-treated analysis, the HR for ischemic stroke was 0.76 (95% CI, 0.68-0.87; P < .001).

“I believe that this will likely be generalizable to most countries’ elderly residents,” Dr. Svennberg said. “I think if we can find a significant difference in our elderly population in Sweden, most countries will be able to do so, or find even more significant results.”

That’s because “baseline detection of AF in Sweden is high,” she said, “so new detection is likely more difficult.” Also, in Sweden, “care can be sought without monetary concern, and prescriptions are provided at low costs to the patients.” Therefore, patients newly identified with AF, whether in studies or not, “would likely be started on therapy.”

It will be important to know whether the screening strategy is cost-effective, Dr. Schnabel said, because “the overall effect, with a hazard ratio of 0.96, is not too big, and costs incurred by systematic screening are comparatively high.”

STROKESTOP “now provides sound information for cost-effectiveness analyses, which to date have largely relied on assumptions.”

STROKESTOP was partially supported by Carl Bennet AB, Boehringer-Ingelheim, Bayer, Bristol-Meyers Squibb, and Pfizer. Dr. Svennberg disclosed receiving fees for lectures or consulting from Bayer, Bristol-Meyers Squibb, Pfizer, Boehringer-Ingelheim, Merck Sharp & Dohme, and Sanofi; and institutional grants from Roche Diagnostics and Carl Bennett Ltd.

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

Some, perhaps many, previously unrecognized cases of atrial fibrillation (AF) will come to light in a screening program aimed at older asymptomatic adults. The key question is whether the challenges of such systematic but age-restricted AF screening in the community, with oral anticoagulation (OAC) offered to those found to have the arrhythmia, is worthwhile in preventing events such as death or stroke.
 

Now there is evidence supporting such a clinical benefit from a large, prospective, randomized trial. A screening program restricted to people 75 or 76 years of age in two Swedish communities, which called on them to use a handheld single-lead ECG system at home intermittently for 2 weeks, was followed by a slight drop in clinical events over about 7 years.

The 4% decline in risk (P = .045) in the STROKESTOP trial’s “intention-to-treat” (ITT) analysis yielded a number needed to treat of 91; that is, that many people had to be targeted by the screening program to prevent one primary-endpoint clinical event.

Those included ischemic stroke, systemic thromboembolism, hospitalization for severe bleeding, and death from any cause, investigators reported April 23 during the virtual European Heart Rhythm Association (EHRA) 2021 Congress.

If that benefit and its significance seem marginal, some secondary findings might be reassuring. Half the population of the target age in the two communities – 13,979 randomly selected people – were invited to join the trial and follow the screening protocol, comprising the ITT cohort. The other half, numbering 13,996, was not invited and served as control subjects.

However, only 51% of the ITT cohort accepted the invitation and participated in the trial; they represented the “as-treated” cohort, observed Emma Svennberg, MD, PhD, Karolinska Institute, Danderyd Hospital, Stockholm, who presented the analysis at the EHRA sessions.

The screening protocol identified untreated AF, whether previously known or unknown, in about 5% of the 7,165 as-treated screening participants; OAC was initiated in about three-fourths of those cases.

The as-treated group, on their own, benefited with a 24% drop in the prospectively defined secondary endpoint of ischemic stroke, compared with the entire control group.

The clinical benefit in the ITT population was “small but significant,” but over the same period in the as-treated cohort, there was a highly significant drop in risk for ischemic stroke, Dr. Svennberg said in an interview.

The trial’s lead message, she said, is that “screening for atrial fibrillation in an elderly population reduces the risk of death and ischemic stroke without increasing the risk of bleeding.”
 

Caveats: As-treated vs. ITT

But there are caveats that complicate interpretation of the trial and, Dr. Svennberg proposed, point to the importance of that interpretation of both the ITT and as-treated analyses.

“We detected significantly more atrial fibrillation in the group that was randomized to screening. A major strength of our study was that we referred all of those individuals for a structured follow-up within the study,” she said. “Although the focus of the follow-up was oral anticoagulant therapy, other risk factors were also assessed and managed, such as hypertension and diabetes.”

It’s possible that increased detection of AF followed by such structured management contributed to the observed benefit, Dr. Svennberg proposed.

However, the exclusion of those in the prespecified ITT population who declined to be screened or otherwise didn’t participate left an as-treated cohort that was healthier than the ITT population or the control group.

Indeed, the nonparticipating invitees were sicker, with significantly more diabetes, vascular disease, hypertension, and heart failure, and higher CHA2DS2VASc stroke risk scores than those who agreed to participate.

“We took a more difficult route in setting up this study, in that we identified all individuals aged 75 to 76 residing in our two regions and excluded no one,” Dr. Svennberg said in an interview. “That means even individuals with end-stage disease, severe dementia, bedridden in nursing homes, et cetera, were also randomized but perhaps not likely or eligible to participate.”

Therefore, some invitees were unable to join the study even as others might have declined “out of low interest” or other personal reasons, she said. “We believe that this mimics how a population-based screening program would be performed if done in our country.”

In the ITT analysis, screening successfully identified previously unknown or untreated cases of AF, which led to expanded OAC use and intensified risk-factor management, “which was key to a successful outcome.”

In the as-treated analysis, Dr. Svennberg said, “I think a combination of the intervention and the population being overall more healthy was driving the secondary endpoint.”
 

Systematic vs. opportunistic screening

Although “opportunistic screening in individuals aged 65 and older” is recommended by current European Society of Cardiology guidelines, systematic screening, such as that used in STROKESTOP, has a much weaker evidence base, observed Renate B. Schnabel, MD, PhD, University Heart & Vascular Center, Hamburg, Germany, as the invited discussant after the STROKESTOP presentation.

STROKESTOP “is one of the first studies, if not the first study,” to show a clinical benefit from screening for AF, Dr. Schnabel said.

Fewer-than-projected primary outcome events were seen during the trial, and event curves for screened and control participants didn’t start to separate until about 4 years into the study, she said. It therefore might take a long time for the screened elderly to realize the clinical benefits of screening.

Studies such as the recent SCREEN-AF and mSTOPS have amply shown that AF screening in the asymptomatic elderly can reveal previously unrecognized AF far more often than would be detected in routine practice, allowing them the opportunity to go on OAC. But the trials weren’t able to show whether the benefits of such management outweigh the risks or costs.

Indeed, on April 20, the U.S. Preventive Services Task Force (USPSTF) released a draft recommendation statement concluding that “the current evidence is insufficient to assess the balance of benefits and harms” associated with AF screening in asymptomatic people at least 50 years of age.

In STROKESTOP, however, benefit for the primary outcome reached significance in the prespecified ITT analysis and “appeared to be driven by the reduction in ischemic stroke incidence,” Dr. Schnabel said.

“The future guidelines have gained strong evidence to judge on systematic atrial fibrillation screening” as it was performed in the trial, she said. “How to implement atrial fibrillation screening, including systematic screening in health care systems across Europe and beyond, remains an open question.”
 

A randomized population

STROKESTOP considered all 75- and 76-year-olds living in Sweden’s Stockholm County (n = 23,888) and the Halland region (n = 4,880) and randomly assigned them to the ITT group or a control group, with stratification by sex, birth year, and geographic region. In both groups, 54.6% were female and the mean CHA2DS2VASc score was 3.5.

People assigned to the ITT cohort were invited to be screened and followed. Those who agreed to participate underwent a baseline ECG assessment to detect or rule out permanent AF. Guideline-based OAC and follow-up was offered to those found with the arrhythmia. Those in sinus rhythm with no history of AF used a handheld single-lead ECG recorder (Zenicor) for 30 seconds twice daily for 14 days.

Structured management, including OAC, was offered to anyone demonstrating sufficient AF, that is, at least one bout without p waves in one 30-second recording or at least two such episodes lasting 10-29 seconds during the 2-week screening period.

In the ITT analysis, the hazard ratio (HR) for the composite clinical primary endpoint was 0.96 (95% confidence interval, 0.920-0.999; P = .045), but in the as-treated analysis, the HR for ischemic stroke was 0.76 (95% CI, 0.68-0.87; P < .001).

“I believe that this will likely be generalizable to most countries’ elderly residents,” Dr. Svennberg said. “I think if we can find a significant difference in our elderly population in Sweden, most countries will be able to do so, or find even more significant results.”

That’s because “baseline detection of AF in Sweden is high,” she said, “so new detection is likely more difficult.” Also, in Sweden, “care can be sought without monetary concern, and prescriptions are provided at low costs to the patients.” Therefore, patients newly identified with AF, whether in studies or not, “would likely be started on therapy.”

It will be important to know whether the screening strategy is cost-effective, Dr. Schnabel said, because “the overall effect, with a hazard ratio of 0.96, is not too big, and costs incurred by systematic screening are comparatively high.”

STROKESTOP “now provides sound information for cost-effectiveness analyses, which to date have largely relied on assumptions.”

STROKESTOP was partially supported by Carl Bennet AB, Boehringer-Ingelheim, Bayer, Bristol-Meyers Squibb, and Pfizer. Dr. Svennberg disclosed receiving fees for lectures or consulting from Bayer, Bristol-Meyers Squibb, Pfizer, Boehringer-Ingelheim, Merck Sharp & Dohme, and Sanofi; and institutional grants from Roche Diagnostics and Carl Bennett Ltd.

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

Young athletes are unlikely to experience ongoing heart problems post–COVID-19 infection.

In a multicenter study conducted during September-December 2020, only 0.7% of 3,018 collegiate athletes who tested positive for SARS-CoV-2 infection were found to have definite, probable, or possible infection-related cardiac involvement.

None experienced an adverse cardiac event and only five (0.2%) required hospitalization for noncardiac complications of COVID-19.

“The take-home message is that cardiac involvement does not happen as much as we had initially feared. It’s in the range of 0.5% to 3%, depending on how you define cardiac involvement, which is not nothing, but it’s not the 30% or 50% that some early studies hinted at,” said Kimberly G. Harmon, MD, of the University of Washington, Seattle.

Nearly 20,000 athletes tested

The researchers prospectively tested 19,378 athletes for SARS-CoV-2 infection from 42 U.S. colleges and universities during the study period. A total of 3,018 (16%; mean age, 20 years; 32% female) tested positive and underwent cardiac evaluation.

“We didn’t prescribe what the schools had to do in terms of cardiac evaluation, but most of these colleges are well resourced, and about 74% of athletes were evaluated using the triad testing strategy of 12-lead electrocardiography, cardiac troponin, and transthoracic echocardiography [TEE], with cardiac magnetic resonance [CMR ]when indicated,” explained Dr. Harmon. Only 198 athletes underwent primary screening with CMR.

Athletes were often tested multiple times for SARS-CoV-2 infection by participating institutions and were included in this study if they had any positive test and underwent postinfection cardiac screening.

The cohort includes athletes representing 26 distinct sporting disciplines, including American-style football (36%), basketball (9%), and cross country/track and field (8%). Most were asymptomatic or had only mild COVID-19 symptoms (33% and 29%, respectively).
 

‘Exercise appears to be protective’

Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG in 0.7% of athletes (21 of 2,999), cardiac troponin elevation in 0.9% (24/2,719), and abnormal TTE findings in 0.9% (24/2,556).

The odds of having cardiac involvement was 3.1 times higher in athletes with cardiopulmonary symptoms.

“One thing we’ve seen in the literature and in this cohort, is that exercise appears to be protective to some extent from COVID-19. We had a lot of cases, but in the whole cohort, only five athletes were hospitalized with COVID and those were for noncardiac reasons,” said Dr. Harmon.

During a median clinical surveillance of 113 days, there was one (0.03%) adverse cardiac event likely unrelated to SARS-CoV-2 infection.

The diagnostic yield for probable or definite cardiac involvement was 6.7 times higher for a CMR obtained for clinical reasons (10.1%) versus a primary screening CMR (1.5%).

“This is data we desperately needed. Small, single-center studies early in the pandemic had indicated a higher prevalence of cardiac involvement, which led us to be very conservative about return-to-play in the early days,” said Jeffrey Lander, MD, who was not involved in the study.

Limit CMR to symptomatic athletes

“I think this data can be extended beyond the college athlete. And it’s fair to say to high school athletes and young recreational athletes who have had asymptomatic or mild infection, you probably don’t need further workup if you’re feeling fine,” suggested Dr. Harmon.

“For those with moderate or severe illness, then the triple screen protocol is a good idea, particularly if they are having any symptoms,” she added.

Dr. Lander agrees that athletes should be screened by appropriate providers before returning to sports, but that CMR should not be used routinely for return-to-play screening.

“We’ve never taken a group of, say, 1,000 college athletes who just recovered from the flu and done cardiac MRIs on them, so it’s a bit like opening Pandora’s box when it’s used too liberally. It’s difficult to assess if the findings are secondary to COVID infection or from something entirely unrelated,” he noted.

ORCCA is a collaboration of the American Heart Association and the American Medical Society for Sports Medicine to track COVID-19 cases among National Collegiate Athletic Association (NCAA) athletes. The current study was supported by a grant from the American Medical Society for Sports Medicine.

Young athletes are unlikely to experience ongoing heart problems post–COVID-19 infection.

In a multicenter study conducted during September-December 2020, only 0.7% of 3,018 collegiate athletes who tested positive for SARS-CoV-2 infection were found to have definite, probable, or possible infection-related cardiac involvement.

None experienced an adverse cardiac event and only five (0.2%) required hospitalization for noncardiac complications of COVID-19.

“The take-home message is that cardiac involvement does not happen as much as we had initially feared. It’s in the range of 0.5% to 3%, depending on how you define cardiac involvement, which is not nothing, but it’s not the 30% or 50% that some early studies hinted at,” said Kimberly G. Harmon, MD, of the University of Washington, Seattle.

Nearly 20,000 athletes tested

The researchers prospectively tested 19,378 athletes for SARS-CoV-2 infection from 42 U.S. colleges and universities during the study period. A total of 3,018 (16%; mean age, 20 years; 32% female) tested positive and underwent cardiac evaluation.

“We didn’t prescribe what the schools had to do in terms of cardiac evaluation, but most of these colleges are well resourced, and about 74% of athletes were evaluated using the triad testing strategy of 12-lead electrocardiography, cardiac troponin, and transthoracic echocardiography [TEE], with cardiac magnetic resonance [CMR ]when indicated,” explained Dr. Harmon. Only 198 athletes underwent primary screening with CMR.

Athletes were often tested multiple times for SARS-CoV-2 infection by participating institutions and were included in this study if they had any positive test and underwent postinfection cardiac screening.

The cohort includes athletes representing 26 distinct sporting disciplines, including American-style football (36%), basketball (9%), and cross country/track and field (8%). Most were asymptomatic or had only mild COVID-19 symptoms (33% and 29%, respectively).
 

‘Exercise appears to be protective’

Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG in 0.7% of athletes (21 of 2,999), cardiac troponin elevation in 0.9% (24/2,719), and abnormal TTE findings in 0.9% (24/2,556).

The odds of having cardiac involvement was 3.1 times higher in athletes with cardiopulmonary symptoms.

“One thing we’ve seen in the literature and in this cohort, is that exercise appears to be protective to some extent from COVID-19. We had a lot of cases, but in the whole cohort, only five athletes were hospitalized with COVID and those were for noncardiac reasons,” said Dr. Harmon.

During a median clinical surveillance of 113 days, there was one (0.03%) adverse cardiac event likely unrelated to SARS-CoV-2 infection.

The diagnostic yield for probable or definite cardiac involvement was 6.7 times higher for a CMR obtained for clinical reasons (10.1%) versus a primary screening CMR (1.5%).

“This is data we desperately needed. Small, single-center studies early in the pandemic had indicated a higher prevalence of cardiac involvement, which led us to be very conservative about return-to-play in the early days,” said Jeffrey Lander, MD, who was not involved in the study.

Limit CMR to symptomatic athletes

“I think this data can be extended beyond the college athlete. And it’s fair to say to high school athletes and young recreational athletes who have had asymptomatic or mild infection, you probably don’t need further workup if you’re feeling fine,” suggested Dr. Harmon.

“For those with moderate or severe illness, then the triple screen protocol is a good idea, particularly if they are having any symptoms,” she added.

Dr. Lander agrees that athletes should be screened by appropriate providers before returning to sports, but that CMR should not be used routinely for return-to-play screening.

“We’ve never taken a group of, say, 1,000 college athletes who just recovered from the flu and done cardiac MRIs on them, so it’s a bit like opening Pandora’s box when it’s used too liberally. It’s difficult to assess if the findings are secondary to COVID infection or from something entirely unrelated,” he noted.

ORCCA is a collaboration of the American Heart Association and the American Medical Society for Sports Medicine to track COVID-19 cases among National Collegiate Athletic Association (NCAA) athletes. The current study was supported by a grant from the American Medical Society for Sports Medicine.

Young athletes are unlikely to experience ongoing heart problems post–COVID-19 infection.

In a multicenter study conducted during September-December 2020, only 0.7% of 3,018 collegiate athletes who tested positive for SARS-CoV-2 infection were found to have definite, probable, or possible infection-related cardiac involvement.

None experienced an adverse cardiac event and only five (0.2%) required hospitalization for noncardiac complications of COVID-19.

“The take-home message is that cardiac involvement does not happen as much as we had initially feared. It’s in the range of 0.5% to 3%, depending on how you define cardiac involvement, which is not nothing, but it’s not the 30% or 50% that some early studies hinted at,” said Kimberly G. Harmon, MD, of the University of Washington, Seattle.

Nearly 20,000 athletes tested

The researchers prospectively tested 19,378 athletes for SARS-CoV-2 infection from 42 U.S. colleges and universities during the study period. A total of 3,018 (16%; mean age, 20 years; 32% female) tested positive and underwent cardiac evaluation.

“We didn’t prescribe what the schools had to do in terms of cardiac evaluation, but most of these colleges are well resourced, and about 74% of athletes were evaluated using the triad testing strategy of 12-lead electrocardiography, cardiac troponin, and transthoracic echocardiography [TEE], with cardiac magnetic resonance [CMR ]when indicated,” explained Dr. Harmon. Only 198 athletes underwent primary screening with CMR.

Athletes were often tested multiple times for SARS-CoV-2 infection by participating institutions and were included in this study if they had any positive test and underwent postinfection cardiac screening.

The cohort includes athletes representing 26 distinct sporting disciplines, including American-style football (36%), basketball (9%), and cross country/track and field (8%). Most were asymptomatic or had only mild COVID-19 symptoms (33% and 29%, respectively).
 

‘Exercise appears to be protective’

Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG in 0.7% of athletes (21 of 2,999), cardiac troponin elevation in 0.9% (24/2,719), and abnormal TTE findings in 0.9% (24/2,556).

The odds of having cardiac involvement was 3.1 times higher in athletes with cardiopulmonary symptoms.

“One thing we’ve seen in the literature and in this cohort, is that exercise appears to be protective to some extent from COVID-19. We had a lot of cases, but in the whole cohort, only five athletes were hospitalized with COVID and those were for noncardiac reasons,” said Dr. Harmon.

During a median clinical surveillance of 113 days, there was one (0.03%) adverse cardiac event likely unrelated to SARS-CoV-2 infection.

The diagnostic yield for probable or definite cardiac involvement was 6.7 times higher for a CMR obtained for clinical reasons (10.1%) versus a primary screening CMR (1.5%).

“This is data we desperately needed. Small, single-center studies early in the pandemic had indicated a higher prevalence of cardiac involvement, which led us to be very conservative about return-to-play in the early days,” said Jeffrey Lander, MD, who was not involved in the study.

Limit CMR to symptomatic athletes

“I think this data can be extended beyond the college athlete. And it’s fair to say to high school athletes and young recreational athletes who have had asymptomatic or mild infection, you probably don’t need further workup if you’re feeling fine,” suggested Dr. Harmon.

“For those with moderate or severe illness, then the triple screen protocol is a good idea, particularly if they are having any symptoms,” she added.

Dr. Lander agrees that athletes should be screened by appropriate providers before returning to sports, but that CMR should not be used routinely for return-to-play screening.

“We’ve never taken a group of, say, 1,000 college athletes who just recovered from the flu and done cardiac MRIs on them, so it’s a bit like opening Pandora’s box when it’s used too liberally. It’s difficult to assess if the findings are secondary to COVID infection or from something entirely unrelated,” he noted.

ORCCA is a collaboration of the American Heart Association and the American Medical Society for Sports Medicine to track COVID-19 cases among National Collegiate Athletic Association (NCAA) athletes. The current study was supported by a grant from the American Medical Society for Sports Medicine.

An updated American Heart Association scientific statement on the role of obesity in cardiovascular disease provides the first new guidance in 15 years, drawing on evidence that’s emerged in that time to clarify the potential of newer drug therapies and interventions like bariatric surgery and lifestyle modifications to curtail cardiovascular disease risks.

“The timing of this information is important because the obesity epidemic contributes significantly to the global burden of cardiovascular disease and numerous chronic health conditions that also impact heart disease,” said Tiffany Powell-Wiley, MD, MPH, chair of the volunteer statement writing group.

“One of the big takeaways that I hope people get from the statement is really making it clear that obesity is a complex disease, and that it is multifactorial,” Dr. Powell-Wiley said in an interview. “There are not just biological reasons why individuals have obesity, but there are environmental, psychosocial, and really multilevel factors that contribute to the development and course of obesity.”

Most significantly, Dr. Powell-Wiley said, “we want to emphasize that we really want to have cardiologists think about and focus on abdominal obesity in particular.”

A metric for cardiovascular risk that seems to gain credibility in the statement is the relationship of waist circumference to height regardless of overall weight. “That is a very important finding that we can now really think of waist circumference as an important measure in our clinical practice,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory in the division of intramural research at the National Heart, Lung, and Blood Institute. “We want to get across to providers that this is something that should be measured and should be followed over time, based on data from the last 15 years that waist circumference and abdominal obesity are associated with higher cardiovascular risk regardless of body mass index.”

The statement provides potentially groundbreaking advice on atrial fibrillation as a consequence of weight, noted Dr. Powell-Wiley. “Up until recently, we haven’t really thought about weight management as a part of managing Afib [atrial fibrillation],” she said. “This statement highlights the need to think about weight management in addition to anticoagulation as part of the pieces for managing Afib.”
 

Evidence on interventions

The statement, published in Circulation, also dives into the evidence surrounding the varied interventions for managing weight.

American Heart Association

“The biggest area where there’s much more data is bariatric surgery,” said Dr. Powell-Wiley. “There’s clear evidence that bariatric surgery lowers cardio mortality and all-cause mortality for patients, but we’ve also seen data around lifestyle interventions, with the Look AHEAD trial, which showed that while there were improvements in CV [cardiovascular] risk factors, we didn’t see the reduction in CV mortality that we wanted to see.”

The statement noted that the Look AHEAD trial (for Action for Health in Diabetes) of people with type 2 diabetes failed to show a significant reduction in major adverse cardiac events or CV mortality after almost 10 years of an intensive weight-loss intervention. Dr. Powell-Wiley added that the result seemed to be related more to the lack of weight loss with lifestyle interventions when compared with bariatric surgery.

The statement also addressed the effectiveness of drug treatments for weight control in managing CV risk, and while the evidence supporting pharmacotherapy specifically for weight loss has been mixed, emerging treatments have shown promise, Dr. Powell-Wiley said. “I think we now have some bright spots with new therapies that have been developed for diabetes and heart failure, such as the SGLT2 inhibitors as well as the GLP-1 agonists, and how they can also appear to improve weight and likely will improve CV mortality in patients with obesity.”

The “obesity paradox,” which Dr. Powell-Wiley noted is “definitely a controversial topic,” is also addressed in the statement. “We try to explain what it is and what we know about it right now,” she said. “We know for instance that patients with obesity, particularly those who have class 1 obesity or patients who are overweight, seem to do better in the short term in relation to coronary artery disease and heart failure, but the reasons for that are not necessarily clear.”

The statement also provides evidence-based insights on the use of diagnostic tools, including stress echocardiography and cardiac MRI as well as coronary angiography, and the clinical significance of specific echocardiographic changes in obese patients.

The writing committee also identified areas that need future research. “It’s really important to emphasize what we learned about the complexity of obesity over this time period,” Dr. Powell-Wiley said. “But again, we don’t have all the answers; there’s a lot more work to be done to understand what type of lifestyle intervention might be most beneficial, especially with addressing abdominal obesity, and how these new therapeutics around heart failure and diabetes may be useful in patients with obesity.

Obesity in adolescents is another area that needs further research, Dr. Powell-Wiley said. “How do we prevent obesity in those populations when we know they’re at risk for so much as they get older? Once you have obesity it’s hard to change that trajectory.”

The scientific statement was prepared by the volunteer writing group on behalf of the AHA’s Council on Lifestyle and Cardiometabolic Health, the Council on Cardiovascular and Stroke Nursing, the Council on Clinical Cardiology, the Council on Epidemiology and Prevention, and the Stroke Council. Committee vice chair Paul Poirier, MD, PhD, reported financial relationships with Abbott, Amgen, AstraZeneca, Bausch Health, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Novo Nordisk, Sanofi, Servier, and HLS Therapeutics. One committee member disclosed a financial relationship with AstraZeneca. Dr. Powell-Wiley and the other committee members have no relationships to disclose.

An updated American Heart Association scientific statement on the role of obesity in cardiovascular disease provides the first new guidance in 15 years, drawing on evidence that’s emerged in that time to clarify the potential of newer drug therapies and interventions like bariatric surgery and lifestyle modifications to curtail cardiovascular disease risks.

“The timing of this information is important because the obesity epidemic contributes significantly to the global burden of cardiovascular disease and numerous chronic health conditions that also impact heart disease,” said Tiffany Powell-Wiley, MD, MPH, chair of the volunteer statement writing group.

“One of the big takeaways that I hope people get from the statement is really making it clear that obesity is a complex disease, and that it is multifactorial,” Dr. Powell-Wiley said in an interview. “There are not just biological reasons why individuals have obesity, but there are environmental, psychosocial, and really multilevel factors that contribute to the development and course of obesity.”

Most significantly, Dr. Powell-Wiley said, “we want to emphasize that we really want to have cardiologists think about and focus on abdominal obesity in particular.”

A metric for cardiovascular risk that seems to gain credibility in the statement is the relationship of waist circumference to height regardless of overall weight. “That is a very important finding that we can now really think of waist circumference as an important measure in our clinical practice,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory in the division of intramural research at the National Heart, Lung, and Blood Institute. “We want to get across to providers that this is something that should be measured and should be followed over time, based on data from the last 15 years that waist circumference and abdominal obesity are associated with higher cardiovascular risk regardless of body mass index.”

The statement provides potentially groundbreaking advice on atrial fibrillation as a consequence of weight, noted Dr. Powell-Wiley. “Up until recently, we haven’t really thought about weight management as a part of managing Afib [atrial fibrillation],” she said. “This statement highlights the need to think about weight management in addition to anticoagulation as part of the pieces for managing Afib.”
 

Evidence on interventions

The statement, published in Circulation, also dives into the evidence surrounding the varied interventions for managing weight.

American Heart Association

“The biggest area where there’s much more data is bariatric surgery,” said Dr. Powell-Wiley. “There’s clear evidence that bariatric surgery lowers cardio mortality and all-cause mortality for patients, but we’ve also seen data around lifestyle interventions, with the Look AHEAD trial, which showed that while there were improvements in CV [cardiovascular] risk factors, we didn’t see the reduction in CV mortality that we wanted to see.”

The statement noted that the Look AHEAD trial (for Action for Health in Diabetes) of people with type 2 diabetes failed to show a significant reduction in major adverse cardiac events or CV mortality after almost 10 years of an intensive weight-loss intervention. Dr. Powell-Wiley added that the result seemed to be related more to the lack of weight loss with lifestyle interventions when compared with bariatric surgery.

The statement also addressed the effectiveness of drug treatments for weight control in managing CV risk, and while the evidence supporting pharmacotherapy specifically for weight loss has been mixed, emerging treatments have shown promise, Dr. Powell-Wiley said. “I think we now have some bright spots with new therapies that have been developed for diabetes and heart failure, such as the SGLT2 inhibitors as well as the GLP-1 agonists, and how they can also appear to improve weight and likely will improve CV mortality in patients with obesity.”

The “obesity paradox,” which Dr. Powell-Wiley noted is “definitely a controversial topic,” is also addressed in the statement. “We try to explain what it is and what we know about it right now,” she said. “We know for instance that patients with obesity, particularly those who have class 1 obesity or patients who are overweight, seem to do better in the short term in relation to coronary artery disease and heart failure, but the reasons for that are not necessarily clear.”

The statement also provides evidence-based insights on the use of diagnostic tools, including stress echocardiography and cardiac MRI as well as coronary angiography, and the clinical significance of specific echocardiographic changes in obese patients.

The writing committee also identified areas that need future research. “It’s really important to emphasize what we learned about the complexity of obesity over this time period,” Dr. Powell-Wiley said. “But again, we don’t have all the answers; there’s a lot more work to be done to understand what type of lifestyle intervention might be most beneficial, especially with addressing abdominal obesity, and how these new therapeutics around heart failure and diabetes may be useful in patients with obesity.

Obesity in adolescents is another area that needs further research, Dr. Powell-Wiley said. “How do we prevent obesity in those populations when we know they’re at risk for so much as they get older? Once you have obesity it’s hard to change that trajectory.”

The scientific statement was prepared by the volunteer writing group on behalf of the AHA’s Council on Lifestyle and Cardiometabolic Health, the Council on Cardiovascular and Stroke Nursing, the Council on Clinical Cardiology, the Council on Epidemiology and Prevention, and the Stroke Council. Committee vice chair Paul Poirier, MD, PhD, reported financial relationships with Abbott, Amgen, AstraZeneca, Bausch Health, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Novo Nordisk, Sanofi, Servier, and HLS Therapeutics. One committee member disclosed a financial relationship with AstraZeneca. Dr. Powell-Wiley and the other committee members have no relationships to disclose.

An updated American Heart Association scientific statement on the role of obesity in cardiovascular disease provides the first new guidance in 15 years, drawing on evidence that’s emerged in that time to clarify the potential of newer drug therapies and interventions like bariatric surgery and lifestyle modifications to curtail cardiovascular disease risks.

“The timing of this information is important because the obesity epidemic contributes significantly to the global burden of cardiovascular disease and numerous chronic health conditions that also impact heart disease,” said Tiffany Powell-Wiley, MD, MPH, chair of the volunteer statement writing group.

“One of the big takeaways that I hope people get from the statement is really making it clear that obesity is a complex disease, and that it is multifactorial,” Dr. Powell-Wiley said in an interview. “There are not just biological reasons why individuals have obesity, but there are environmental, psychosocial, and really multilevel factors that contribute to the development and course of obesity.”

Most significantly, Dr. Powell-Wiley said, “we want to emphasize that we really want to have cardiologists think about and focus on abdominal obesity in particular.”

A metric for cardiovascular risk that seems to gain credibility in the statement is the relationship of waist circumference to height regardless of overall weight. “That is a very important finding that we can now really think of waist circumference as an important measure in our clinical practice,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory in the division of intramural research at the National Heart, Lung, and Blood Institute. “We want to get across to providers that this is something that should be measured and should be followed over time, based on data from the last 15 years that waist circumference and abdominal obesity are associated with higher cardiovascular risk regardless of body mass index.”

The statement provides potentially groundbreaking advice on atrial fibrillation as a consequence of weight, noted Dr. Powell-Wiley. “Up until recently, we haven’t really thought about weight management as a part of managing Afib [atrial fibrillation],” she said. “This statement highlights the need to think about weight management in addition to anticoagulation as part of the pieces for managing Afib.”
 

Evidence on interventions

The statement, published in Circulation, also dives into the evidence surrounding the varied interventions for managing weight.

American Heart Association

“The biggest area where there’s much more data is bariatric surgery,” said Dr. Powell-Wiley. “There’s clear evidence that bariatric surgery lowers cardio mortality and all-cause mortality for patients, but we’ve also seen data around lifestyle interventions, with the Look AHEAD trial, which showed that while there were improvements in CV [cardiovascular] risk factors, we didn’t see the reduction in CV mortality that we wanted to see.”

The statement noted that the Look AHEAD trial (for Action for Health in Diabetes) of people with type 2 diabetes failed to show a significant reduction in major adverse cardiac events or CV mortality after almost 10 years of an intensive weight-loss intervention. Dr. Powell-Wiley added that the result seemed to be related more to the lack of weight loss with lifestyle interventions when compared with bariatric surgery.

The statement also addressed the effectiveness of drug treatments for weight control in managing CV risk, and while the evidence supporting pharmacotherapy specifically for weight loss has been mixed, emerging treatments have shown promise, Dr. Powell-Wiley said. “I think we now have some bright spots with new therapies that have been developed for diabetes and heart failure, such as the SGLT2 inhibitors as well as the GLP-1 agonists, and how they can also appear to improve weight and likely will improve CV mortality in patients with obesity.”

The “obesity paradox,” which Dr. Powell-Wiley noted is “definitely a controversial topic,” is also addressed in the statement. “We try to explain what it is and what we know about it right now,” she said. “We know for instance that patients with obesity, particularly those who have class 1 obesity or patients who are overweight, seem to do better in the short term in relation to coronary artery disease and heart failure, but the reasons for that are not necessarily clear.”

The statement also provides evidence-based insights on the use of diagnostic tools, including stress echocardiography and cardiac MRI as well as coronary angiography, and the clinical significance of specific echocardiographic changes in obese patients.

The writing committee also identified areas that need future research. “It’s really important to emphasize what we learned about the complexity of obesity over this time period,” Dr. Powell-Wiley said. “But again, we don’t have all the answers; there’s a lot more work to be done to understand what type of lifestyle intervention might be most beneficial, especially with addressing abdominal obesity, and how these new therapeutics around heart failure and diabetes may be useful in patients with obesity.

Obesity in adolescents is another area that needs further research, Dr. Powell-Wiley said. “How do we prevent obesity in those populations when we know they’re at risk for so much as they get older? Once you have obesity it’s hard to change that trajectory.”

The scientific statement was prepared by the volunteer writing group on behalf of the AHA’s Council on Lifestyle and Cardiometabolic Health, the Council on Cardiovascular and Stroke Nursing, the Council on Clinical Cardiology, the Council on Epidemiology and Prevention, and the Stroke Council. Committee vice chair Paul Poirier, MD, PhD, reported financial relationships with Abbott, Amgen, AstraZeneca, Bausch Health, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Novo Nordisk, Sanofi, Servier, and HLS Therapeutics. One committee member disclosed a financial relationship with AstraZeneca. Dr. Powell-Wiley and the other committee members have no relationships to disclose.

The Food and Drug Administration has declared Medtronic’s recall of seven models of defibrillating cardiac rhythm devices, caused by a risk for premature battery depletion, as class I, which implies a potential risk for serious injury or death. A total of 444 complaints, but no deaths, have been reported in association with the 239,171 affected devices, the agency said in a statement on April 12, 2021.

Physicians were notified of the company’s recall in early February. It covered implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy–defibrillator (CRT-D) models Evera, Viva, Brava, Claria, Amplia, Compia, and Visia distributed from Aug. 31, 2012 to May 9, 2018.

The devices could be subject to “an unexpected and rapid decrease in battery life” because of a possible short circuit that could lead to a device-replacement alert “earlier than expected.” Some devices may experience full battery depletion “within as little as 1 day” after such an alert.

“If the user does not respond to the first warning, the device may stop functioning. The likelihood that this issue will occur is constant after approximately 3 years after device use,” the announcement said.

Medtronic recommends device replacement no more than 1 week after such an early warning for patients who are not pacing dependent or who have them for primary prevention, but right away for pacing-dependent patients.

A version of this article first appeared on Medscape.com

The Food and Drug Administration has declared Medtronic’s recall of seven models of defibrillating cardiac rhythm devices, caused by a risk for premature battery depletion, as class I, which implies a potential risk for serious injury or death. A total of 444 complaints, but no deaths, have been reported in association with the 239,171 affected devices, the agency said in a statement on April 12, 2021.

Physicians were notified of the company’s recall in early February. It covered implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy–defibrillator (CRT-D) models Evera, Viva, Brava, Claria, Amplia, Compia, and Visia distributed from Aug. 31, 2012 to May 9, 2018.

The devices could be subject to “an unexpected and rapid decrease in battery life” because of a possible short circuit that could lead to a device-replacement alert “earlier than expected.” Some devices may experience full battery depletion “within as little as 1 day” after such an alert.

“If the user does not respond to the first warning, the device may stop functioning. The likelihood that this issue will occur is constant after approximately 3 years after device use,” the announcement said.

Medtronic recommends device replacement no more than 1 week after such an early warning for patients who are not pacing dependent or who have them for primary prevention, but right away for pacing-dependent patients.

A version of this article first appeared on Medscape.com

The Food and Drug Administration has declared Medtronic’s recall of seven models of defibrillating cardiac rhythm devices, caused by a risk for premature battery depletion, as class I, which implies a potential risk for serious injury or death. A total of 444 complaints, but no deaths, have been reported in association with the 239,171 affected devices, the agency said in a statement on April 12, 2021.

Physicians were notified of the company’s recall in early February. It covered implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy–defibrillator (CRT-D) models Evera, Viva, Brava, Claria, Amplia, Compia, and Visia distributed from Aug. 31, 2012 to May 9, 2018.

The devices could be subject to “an unexpected and rapid decrease in battery life” because of a possible short circuit that could lead to a device-replacement alert “earlier than expected.” Some devices may experience full battery depletion “within as little as 1 day” after such an alert.

“If the user does not respond to the first warning, the device may stop functioning. The likelihood that this issue will occur is constant after approximately 3 years after device use,” the announcement said.

Medtronic recommends device replacement no more than 1 week after such an early warning for patients who are not pacing dependent or who have them for primary prevention, but right away for pacing-dependent patients.

A version of this article first appeared on Medscape.com

Remote cardiology clinic visits during COVID-19 were used more often by certain traditionally underserved patient groups, but were also associated with less frequent testing and prescribing, new research shows.

“The COVID-19 pandemic has led to an unprecedented shift in ambulatory cardiovascular care from in-person to remote visits,” lead author Neal Yuan, MD, a cardiology fellow at the Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

Their findings were published online April 5 in JAMA Network Open.

“We wanted to explore whether the transition to remote visits was associated with disparities in how patients accessed care, and also how this transition affected diagnostic test ordering and medication prescribing,” Dr. Yuan said.

The researchers used electronic health records data for all ambulatory cardiology visits at an urban, multisite health system in Los Angeles County during two periods: April 1 to Dec. 31, 2019, the pre-COVID era; and April 1 to Dec. 31, 2020, the COVID era.

The investigators compared patient characteristics and frequencies of medication ordering and cardiology-specific testing across four visit types: pre-COVID in person, used as reference; COVID-era in person; COVID-era video; and COVID-era telephone.

The study looked at 176,781 ambulatory cardiology visits. Of these visits, 87,182 were conducted in person in the pre-COVID period; 74,498 were conducted in person in the COVID era; 4,720 were COVID-era video visits; and 10,381 were COVID-era telephone visits.

In the study cohort, 79,572 patients (45.0%) were female, 127,080 patients (71.9%) were non-Hispanic White, and the mean age was 68.1 years (standard deviation, 17.0).

Patients accessing COVID-era remote visits were more likely to be Asian, Black, or Hispanic, to have private insurance, and to have cardiovascular comorbidities, such as hypertension and heart failure.

Also, patients whose visits were conducted by video were significantly younger than patients whose visits were conducted in person or by telephone (P < .001).

In addition, the study found that clinicians ordered fewer diagnostic tests, such as electrocardiograms and echocardiograms, and were less likely to order any medication, in the pre-COVID era than during the COVID era.

“If you don’t have a patient in front of you, it’s much more difficult to get a physical exam or obtain reliable vital signs,” said Dr. Yuan. Communication can sometimes be difficult, often because of technical issues, like a bad connection. “You might be more reticent to get testing or to prescribe medications if you don’t feel confident knowing what the patient’s vital signs are.”

In addition, he added, “a lot of medications used in the cardiology setting require monitoring patients’ kidney function and electrolytes, and if you can’t do that reliably, you might be more cautious about prescribing those types of medications.”
 

An eye-opening study

Cardiologist Nieca Goldberg, MD, medical director of the New York University Langone womens’ heart program and spokesperson for the American Heart Association, recounted her experience with telemedicine at the height of the pandemic in New York, when everything, including medical outpatient offices, had to close.

“We were experienced with telemedicine because we had started a virtual urgent care program well ahead of the pandemic,” she said. “We started using that to screen people with potential COVID symptoms so that they wouldn’t have to come into the hospital, the medical center, or to the offices and expose people. We learned that it was great to have the telemedicine option from the infectious disease standpoint, and I did visits like that for my own patient population.”

An equally if not more important finding from the study is the fact that telemedicine increased access to care among traditionally underserved demographics, she said.

“This is eye-opening, that you can actually improve access to care by doing telemedicine visits. It was really important to see that telemedicine has added benefit to the way we can see people in the health care system.”

Telemedicine visits had a positive impact at a time when people were isolated at home, Dr. Goldberg said.

“It was a way for them to connect with their doctor and in some ways it was more personal,” she added. “I actually got to meet some of my patients’ family members. It was like making a remote house call.”

Stable cardiology patients can take their blood pressure at home, weigh themselves, and take their own pulse to give an excellent set of vital signs that will indicate how they are doing, said Dr. Goldberg.

“During a remote visit, we can talk to the patient and notice whether or not they are short of breath or coughing, but we can’t listen to their heart or do an EKG or any of the traditional cardiac testing. Still, for someone who is not having symptoms and is able to reliably monitor their blood pressure and weight, a remote visit is sufficient to give you a good sense of how that patient is doing,” she said. “We can talk to them about their medications, any potential side effects, and we can use their blood pressure information to adjust their medications.”

Many patients are becoming more savvy about using tech gadgets and devices to monitor their health.

“Some of my patients were using Apple watches and the Kardia app to address their heart rate. Many had purchased inexpensive pulse oximeters to check their oxygen during the pandemic, and that also reads the pulse,” Dr. Goldberg said.

In-person visits were reserved for symptomatic cardiac patients, she explained.

“Initially during the pandemic, we did mostly telemedicine visits and we organized the office so that each cardiologist would come in 1 day a week to take care of symptomatic cardiac patients. In that way, we were able to socially distance – they provided us with [personal protective equipment]; at NYU there was no problem with that – and nobody waited in the waiting room. To this day, office issues are more efficient and people are not waiting in the waiting room,” she added. “Telemedicine improves access to health care in populations where such access is limited.”

Dr. Yuan’s research is supported by a grant from the National Institutes of Health. Dr. Goldberg reported no relevant financial relationships.

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

Remote cardiology clinic visits during COVID-19 were used more often by certain traditionally underserved patient groups, but were also associated with less frequent testing and prescribing, new research shows.

“The COVID-19 pandemic has led to an unprecedented shift in ambulatory cardiovascular care from in-person to remote visits,” lead author Neal Yuan, MD, a cardiology fellow at the Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

Their findings were published online April 5 in JAMA Network Open.

“We wanted to explore whether the transition to remote visits was associated with disparities in how patients accessed care, and also how this transition affected diagnostic test ordering and medication prescribing,” Dr. Yuan said.

The researchers used electronic health records data for all ambulatory cardiology visits at an urban, multisite health system in Los Angeles County during two periods: April 1 to Dec. 31, 2019, the pre-COVID era; and April 1 to Dec. 31, 2020, the COVID era.

The investigators compared patient characteristics and frequencies of medication ordering and cardiology-specific testing across four visit types: pre-COVID in person, used as reference; COVID-era in person; COVID-era video; and COVID-era telephone.

The study looked at 176,781 ambulatory cardiology visits. Of these visits, 87,182 were conducted in person in the pre-COVID period; 74,498 were conducted in person in the COVID era; 4,720 were COVID-era video visits; and 10,381 were COVID-era telephone visits.

In the study cohort, 79,572 patients (45.0%) were female, 127,080 patients (71.9%) were non-Hispanic White, and the mean age was 68.1 years (standard deviation, 17.0).

Patients accessing COVID-era remote visits were more likely to be Asian, Black, or Hispanic, to have private insurance, and to have cardiovascular comorbidities, such as hypertension and heart failure.

Also, patients whose visits were conducted by video were significantly younger than patients whose visits were conducted in person or by telephone (P < .001).

In addition, the study found that clinicians ordered fewer diagnostic tests, such as electrocardiograms and echocardiograms, and were less likely to order any medication, in the pre-COVID era than during the COVID era.

“If you don’t have a patient in front of you, it’s much more difficult to get a physical exam or obtain reliable vital signs,” said Dr. Yuan. Communication can sometimes be difficult, often because of technical issues, like a bad connection. “You might be more reticent to get testing or to prescribe medications if you don’t feel confident knowing what the patient’s vital signs are.”

In addition, he added, “a lot of medications used in the cardiology setting require monitoring patients’ kidney function and electrolytes, and if you can’t do that reliably, you might be more cautious about prescribing those types of medications.”
 

An eye-opening study

Cardiologist Nieca Goldberg, MD, medical director of the New York University Langone womens’ heart program and spokesperson for the American Heart Association, recounted her experience with telemedicine at the height of the pandemic in New York, when everything, including medical outpatient offices, had to close.

“We were experienced with telemedicine because we had started a virtual urgent care program well ahead of the pandemic,” she said. “We started using that to screen people with potential COVID symptoms so that they wouldn’t have to come into the hospital, the medical center, or to the offices and expose people. We learned that it was great to have the telemedicine option from the infectious disease standpoint, and I did visits like that for my own patient population.”

An equally if not more important finding from the study is the fact that telemedicine increased access to care among traditionally underserved demographics, she said.

“This is eye-opening, that you can actually improve access to care by doing telemedicine visits. It was really important to see that telemedicine has added benefit to the way we can see people in the health care system.”

Telemedicine visits had a positive impact at a time when people were isolated at home, Dr. Goldberg said.

“It was a way for them to connect with their doctor and in some ways it was more personal,” she added. “I actually got to meet some of my patients’ family members. It was like making a remote house call.”

Stable cardiology patients can take their blood pressure at home, weigh themselves, and take their own pulse to give an excellent set of vital signs that will indicate how they are doing, said Dr. Goldberg.

“During a remote visit, we can talk to the patient and notice whether or not they are short of breath or coughing, but we can’t listen to their heart or do an EKG or any of the traditional cardiac testing. Still, for someone who is not having symptoms and is able to reliably monitor their blood pressure and weight, a remote visit is sufficient to give you a good sense of how that patient is doing,” she said. “We can talk to them about their medications, any potential side effects, and we can use their blood pressure information to adjust their medications.”

Many patients are becoming more savvy about using tech gadgets and devices to monitor their health.

“Some of my patients were using Apple watches and the Kardia app to address their heart rate. Many had purchased inexpensive pulse oximeters to check their oxygen during the pandemic, and that also reads the pulse,” Dr. Goldberg said.

In-person visits were reserved for symptomatic cardiac patients, she explained.

“Initially during the pandemic, we did mostly telemedicine visits and we organized the office so that each cardiologist would come in 1 day a week to take care of symptomatic cardiac patients. In that way, we were able to socially distance – they provided us with [personal protective equipment]; at NYU there was no problem with that – and nobody waited in the waiting room. To this day, office issues are more efficient and people are not waiting in the waiting room,” she added. “Telemedicine improves access to health care in populations where such access is limited.”

Dr. Yuan’s research is supported by a grant from the National Institutes of Health. Dr. Goldberg reported no relevant financial relationships.

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

Remote cardiology clinic visits during COVID-19 were used more often by certain traditionally underserved patient groups, but were also associated with less frequent testing and prescribing, new research shows.

“The COVID-19 pandemic has led to an unprecedented shift in ambulatory cardiovascular care from in-person to remote visits,” lead author Neal Yuan, MD, a cardiology fellow at the Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

Their findings were published online April 5 in JAMA Network Open.

“We wanted to explore whether the transition to remote visits was associated with disparities in how patients accessed care, and also how this transition affected diagnostic test ordering and medication prescribing,” Dr. Yuan said.

The researchers used electronic health records data for all ambulatory cardiology visits at an urban, multisite health system in Los Angeles County during two periods: April 1 to Dec. 31, 2019, the pre-COVID era; and April 1 to Dec. 31, 2020, the COVID era.

The investigators compared patient characteristics and frequencies of medication ordering and cardiology-specific testing across four visit types: pre-COVID in person, used as reference; COVID-era in person; COVID-era video; and COVID-era telephone.

The study looked at 176,781 ambulatory cardiology visits. Of these visits, 87,182 were conducted in person in the pre-COVID period; 74,498 were conducted in person in the COVID era; 4,720 were COVID-era video visits; and 10,381 were COVID-era telephone visits.

In the study cohort, 79,572 patients (45.0%) were female, 127,080 patients (71.9%) were non-Hispanic White, and the mean age was 68.1 years (standard deviation, 17.0).

Patients accessing COVID-era remote visits were more likely to be Asian, Black, or Hispanic, to have private insurance, and to have cardiovascular comorbidities, such as hypertension and heart failure.

Also, patients whose visits were conducted by video were significantly younger than patients whose visits were conducted in person or by telephone (P < .001).

In addition, the study found that clinicians ordered fewer diagnostic tests, such as electrocardiograms and echocardiograms, and were less likely to order any medication, in the pre-COVID era than during the COVID era.

“If you don’t have a patient in front of you, it’s much more difficult to get a physical exam or obtain reliable vital signs,” said Dr. Yuan. Communication can sometimes be difficult, often because of technical issues, like a bad connection. “You might be more reticent to get testing or to prescribe medications if you don’t feel confident knowing what the patient’s vital signs are.”

In addition, he added, “a lot of medications used in the cardiology setting require monitoring patients’ kidney function and electrolytes, and if you can’t do that reliably, you might be more cautious about prescribing those types of medications.”
 

An eye-opening study

Cardiologist Nieca Goldberg, MD, medical director of the New York University Langone womens’ heart program and spokesperson for the American Heart Association, recounted her experience with telemedicine at the height of the pandemic in New York, when everything, including medical outpatient offices, had to close.

“We were experienced with telemedicine because we had started a virtual urgent care program well ahead of the pandemic,” she said. “We started using that to screen people with potential COVID symptoms so that they wouldn’t have to come into the hospital, the medical center, or to the offices and expose people. We learned that it was great to have the telemedicine option from the infectious disease standpoint, and I did visits like that for my own patient population.”

An equally if not more important finding from the study is the fact that telemedicine increased access to care among traditionally underserved demographics, she said.

“This is eye-opening, that you can actually improve access to care by doing telemedicine visits. It was really important to see that telemedicine has added benefit to the way we can see people in the health care system.”

Telemedicine visits had a positive impact at a time when people were isolated at home, Dr. Goldberg said.

“It was a way for them to connect with their doctor and in some ways it was more personal,” she added. “I actually got to meet some of my patients’ family members. It was like making a remote house call.”

Stable cardiology patients can take their blood pressure at home, weigh themselves, and take their own pulse to give an excellent set of vital signs that will indicate how they are doing, said Dr. Goldberg.

“During a remote visit, we can talk to the patient and notice whether or not they are short of breath or coughing, but we can’t listen to their heart or do an EKG or any of the traditional cardiac testing. Still, for someone who is not having symptoms and is able to reliably monitor their blood pressure and weight, a remote visit is sufficient to give you a good sense of how that patient is doing,” she said. “We can talk to them about their medications, any potential side effects, and we can use their blood pressure information to adjust their medications.”

Many patients are becoming more savvy about using tech gadgets and devices to monitor their health.

“Some of my patients were using Apple watches and the Kardia app to address their heart rate. Many had purchased inexpensive pulse oximeters to check their oxygen during the pandemic, and that also reads the pulse,” Dr. Goldberg said.

In-person visits were reserved for symptomatic cardiac patients, she explained.

“Initially during the pandemic, we did mostly telemedicine visits and we organized the office so that each cardiologist would come in 1 day a week to take care of symptomatic cardiac patients. In that way, we were able to socially distance – they provided us with [personal protective equipment]; at NYU there was no problem with that – and nobody waited in the waiting room. To this day, office issues are more efficient and people are not waiting in the waiting room,” she added. “Telemedicine improves access to health care in populations where such access is limited.”

Dr. Yuan’s research is supported by a grant from the National Institutes of Health. Dr. Goldberg reported no relevant financial relationships.

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

There may be a dose-related risk for atrial fibrillation (AFib) with omega-3 fatty acid intake, data from four randomized clinical trials suggest.

The latest trial to evaluate the association, the VITAL-RHYTHM study, showed that using a low dose of omega-3 fatty acids or a vitamin D supplement had no significant effect on the risks of developing incident AFib.

The trial, first reported at last year’s American Heart Association meeting, was  published online March 16 in the Journal of the American Medical Association.

Together with three other randomized clinical trials, however, these results suggest a possible dose-related effect of omega-3 fatty acids on the risk for AFib, an accompanying “Editor’s Note” suggests.

The note, by JAMA deputy editor Gregory Curfman, MD, points out that in the past 2 years, four randomized clinical trials have provided data on the risk of AFib with omega-3 fatty acid intake.

In the STRENGTH and REDUCE-IT trials, both of which evaluated high doses (4 g/day) of omega-3 fatty acids in patients with heart disease (or at high risk for it), there was a highly statistically significant increase in risk for AFib in the omega-3 groups vs. controls in both trials.

In the OMEMI trial in elderly patients with a recent myocardial infarction, an intermediate dose (1.8 g/day) of omega-3 fatty acids also showed an increase in AFib risk (hazard ratio, 1.84) but this was not significant. And now, the VITAL-RHYTHM trial shows no significant effect of a low dose (840 mg/day) of omega-3 fatty acids on the risk of developing AFib in a primary prevention population.

“Patients who choose to take omega-3 fatty acids, especially in high doses, should be informed of the risk of AF [AFib] and followed up for the possible development of this common and potentially hazardous arrhythmia,” Dr. Curfman concludes.

The authors of the VITAL-RHYTHM trial, led by Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center, Los Angeles, Calif., explain that the trial was conducted after observational studies had shown that individuals with low blood levels of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D₃ have higher risks of incident AFib, but data on dietary or supplemental intake of these nutrients on AFib risk were mixed.

“To our knowledge, this study is the first randomized, placebo-controlled trial to prospectively test the effect of any intervention on incident AF and is the only trial to test alternative upstream preventive agents for AF in a large enough population over a long enough time period to provide an assessment of the plausible benefits and risks,” they write.

The VITAL-RHYTHM study was an ancillary trial embedded within the Vitamin D and Omega-3 (VITAL) trial, which used a 2 x 2 factorial design to evaluate daily supplementation with 2,000 IU of vitamin D₃ and/or 840 mg of marine omega-3 fatty acids (460 mg EPA and 380 mg DHA), in the primary prevention of cardiovascular disease and cancer in 25,871 men and women age 50 and older in the United States.

Results showed that over a median 5.3 years of treatment and follow-up, the primary endpoint of incident AFib occurred in 3.6% of the study population. For the omega-3 part of the trial, incident AFib events occurred in 3.7% of patients taking EPA/DHA vs. 3.4% of the placebo group, giving a hazard ratio of 1.09, which was not significant (P = .19).

For the vitamin D₃ vs. placebo comparison, results were very similar, with incident AFib events occurring in 3.7% vs. 3.4% of participants, respectively, giving a hazard ratio of 1.09, which was again not significant (P = .19). There was no evidence for interaction between the two study agents.

“Overall, these findings do not support the use of supplemental EPA-DHA or vitamin D₃ for the primary prevention of AFib and provide reassurance regarding lack of a major risk of AFib incidence associated with these commonly used supplements at these doses,” the authors conclude.

Noting that significant increases in AFib have been seen with much higher doses of omega-3 fatty acids in the REDUCE-IT and STRENGTH trials, they add: “Potentially, the adverse effect on AF risk may be dose related, and the higher dosages of EPA used in these other studies might account for the significant adverse effect on AF.”

The researchers say that, to their knowledge, this is the only randomized trial to assess the effect of vitamin D₃ supplementation on AFib risk and results suggest a null effect. They add that subgroup analyses in patients with vitamin D levels considered deficient (<20 ng/mL) did not suggest a benefit; however, the power to detect a benefit in this much smaller subset of the population was limited.

They point out that, while there were no significant differences in incident AFib for either omega-3 fatty acid or vitamin D in the overall study population, an increased risk for incident AFib associated with randomized treatment was observed in selected subgroups.

For omega-3 fatty acids, AFib risk was modestly increased in taller individuals, and for vitamin D₃, elevations in AFib risk were observed in younger individuals and participants who drank less alcohol.

“Although the hazard ratios and tests for interaction were significant, the P values associated with these subgroup analyses have not been adjusted for multiple comparisons. Thus, these findings should be interpreted with caution and considered hypothesis generating,” they warn.

The VITAL Rhythm Study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Albert reported receipt of grants from St Jude Medical, Abbott, and Roche Diagnostics. Dr. Curfman reports no relevant disclosures.

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

There may be a dose-related risk for atrial fibrillation (AFib) with omega-3 fatty acid intake, data from four randomized clinical trials suggest.

The latest trial to evaluate the association, the VITAL-RHYTHM study, showed that using a low dose of omega-3 fatty acids or a vitamin D supplement had no significant effect on the risks of developing incident AFib.

The trial, first reported at last year’s American Heart Association meeting, was  published online March 16 in the Journal of the American Medical Association.

Together with three other randomized clinical trials, however, these results suggest a possible dose-related effect of omega-3 fatty acids on the risk for AFib, an accompanying “Editor’s Note” suggests.

The note, by JAMA deputy editor Gregory Curfman, MD, points out that in the past 2 years, four randomized clinical trials have provided data on the risk of AFib with omega-3 fatty acid intake.

In the STRENGTH and REDUCE-IT trials, both of which evaluated high doses (4 g/day) of omega-3 fatty acids in patients with heart disease (or at high risk for it), there was a highly statistically significant increase in risk for AFib in the omega-3 groups vs. controls in both trials.

In the OMEMI trial in elderly patients with a recent myocardial infarction, an intermediate dose (1.8 g/day) of omega-3 fatty acids also showed an increase in AFib risk (hazard ratio, 1.84) but this was not significant. And now, the VITAL-RHYTHM trial shows no significant effect of a low dose (840 mg/day) of omega-3 fatty acids on the risk of developing AFib in a primary prevention population.

“Patients who choose to take omega-3 fatty acids, especially in high doses, should be informed of the risk of AF [AFib] and followed up for the possible development of this common and potentially hazardous arrhythmia,” Dr. Curfman concludes.

The authors of the VITAL-RHYTHM trial, led by Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center, Los Angeles, Calif., explain that the trial was conducted after observational studies had shown that individuals with low blood levels of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D₃ have higher risks of incident AFib, but data on dietary or supplemental intake of these nutrients on AFib risk were mixed.

“To our knowledge, this study is the first randomized, placebo-controlled trial to prospectively test the effect of any intervention on incident AF and is the only trial to test alternative upstream preventive agents for AF in a large enough population over a long enough time period to provide an assessment of the plausible benefits and risks,” they write.

The VITAL-RHYTHM study was an ancillary trial embedded within the Vitamin D and Omega-3 (VITAL) trial, which used a 2 x 2 factorial design to evaluate daily supplementation with 2,000 IU of vitamin D₃ and/or 840 mg of marine omega-3 fatty acids (460 mg EPA and 380 mg DHA), in the primary prevention of cardiovascular disease and cancer in 25,871 men and women age 50 and older in the United States.

Results showed that over a median 5.3 years of treatment and follow-up, the primary endpoint of incident AFib occurred in 3.6% of the study population. For the omega-3 part of the trial, incident AFib events occurred in 3.7% of patients taking EPA/DHA vs. 3.4% of the placebo group, giving a hazard ratio of 1.09, which was not significant (P = .19).

For the vitamin D₃ vs. placebo comparison, results were very similar, with incident AFib events occurring in 3.7% vs. 3.4% of participants, respectively, giving a hazard ratio of 1.09, which was again not significant (P = .19). There was no evidence for interaction between the two study agents.

“Overall, these findings do not support the use of supplemental EPA-DHA or vitamin D₃ for the primary prevention of AFib and provide reassurance regarding lack of a major risk of AFib incidence associated with these commonly used supplements at these doses,” the authors conclude.

Noting that significant increases in AFib have been seen with much higher doses of omega-3 fatty acids in the REDUCE-IT and STRENGTH trials, they add: “Potentially, the adverse effect on AF risk may be dose related, and the higher dosages of EPA used in these other studies might account for the significant adverse effect on AF.”

The researchers say that, to their knowledge, this is the only randomized trial to assess the effect of vitamin D₃ supplementation on AFib risk and results suggest a null effect. They add that subgroup analyses in patients with vitamin D levels considered deficient (<20 ng/mL) did not suggest a benefit; however, the power to detect a benefit in this much smaller subset of the population was limited.

They point out that, while there were no significant differences in incident AFib for either omega-3 fatty acid or vitamin D in the overall study population, an increased risk for incident AFib associated with randomized treatment was observed in selected subgroups.

For omega-3 fatty acids, AFib risk was modestly increased in taller individuals, and for vitamin D₃, elevations in AFib risk were observed in younger individuals and participants who drank less alcohol.

“Although the hazard ratios and tests for interaction were significant, the P values associated with these subgroup analyses have not been adjusted for multiple comparisons. Thus, these findings should be interpreted with caution and considered hypothesis generating,” they warn.

The VITAL Rhythm Study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Albert reported receipt of grants from St Jude Medical, Abbott, and Roche Diagnostics. Dr. Curfman reports no relevant disclosures.

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

There may be a dose-related risk for atrial fibrillation (AFib) with omega-3 fatty acid intake, data from four randomized clinical trials suggest.

The latest trial to evaluate the association, the VITAL-RHYTHM study, showed that using a low dose of omega-3 fatty acids or a vitamin D supplement had no significant effect on the risks of developing incident AFib.

The trial, first reported at last year’s American Heart Association meeting, was  published online March 16 in the Journal of the American Medical Association.

Together with three other randomized clinical trials, however, these results suggest a possible dose-related effect of omega-3 fatty acids on the risk for AFib, an accompanying “Editor’s Note” suggests.

The note, by JAMA deputy editor Gregory Curfman, MD, points out that in the past 2 years, four randomized clinical trials have provided data on the risk of AFib with omega-3 fatty acid intake.

In the STRENGTH and REDUCE-IT trials, both of which evaluated high doses (4 g/day) of omega-3 fatty acids in patients with heart disease (or at high risk for it), there was a highly statistically significant increase in risk for AFib in the omega-3 groups vs. controls in both trials.

In the OMEMI trial in elderly patients with a recent myocardial infarction, an intermediate dose (1.8 g/day) of omega-3 fatty acids also showed an increase in AFib risk (hazard ratio, 1.84) but this was not significant. And now, the VITAL-RHYTHM trial shows no significant effect of a low dose (840 mg/day) of omega-3 fatty acids on the risk of developing AFib in a primary prevention population.

“Patients who choose to take omega-3 fatty acids, especially in high doses, should be informed of the risk of AF [AFib] and followed up for the possible development of this common and potentially hazardous arrhythmia,” Dr. Curfman concludes.

The authors of the VITAL-RHYTHM trial, led by Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center, Los Angeles, Calif., explain that the trial was conducted after observational studies had shown that individuals with low blood levels of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D₃ have higher risks of incident AFib, but data on dietary or supplemental intake of these nutrients on AFib risk were mixed.

“To our knowledge, this study is the first randomized, placebo-controlled trial to prospectively test the effect of any intervention on incident AF and is the only trial to test alternative upstream preventive agents for AF in a large enough population over a long enough time period to provide an assessment of the plausible benefits and risks,” they write.

The VITAL-RHYTHM study was an ancillary trial embedded within the Vitamin D and Omega-3 (VITAL) trial, which used a 2 x 2 factorial design to evaluate daily supplementation with 2,000 IU of vitamin D₃ and/or 840 mg of marine omega-3 fatty acids (460 mg EPA and 380 mg DHA), in the primary prevention of cardiovascular disease and cancer in 25,871 men and women age 50 and older in the United States.

Results showed that over a median 5.3 years of treatment and follow-up, the primary endpoint of incident AFib occurred in 3.6% of the study population. For the omega-3 part of the trial, incident AFib events occurred in 3.7% of patients taking EPA/DHA vs. 3.4% of the placebo group, giving a hazard ratio of 1.09, which was not significant (P = .19).

For the vitamin D₃ vs. placebo comparison, results were very similar, with incident AFib events occurring in 3.7% vs. 3.4% of participants, respectively, giving a hazard ratio of 1.09, which was again not significant (P = .19). There was no evidence for interaction between the two study agents.

“Overall, these findings do not support the use of supplemental EPA-DHA or vitamin D₃ for the primary prevention of AFib and provide reassurance regarding lack of a major risk of AFib incidence associated with these commonly used supplements at these doses,” the authors conclude.

Noting that significant increases in AFib have been seen with much higher doses of omega-3 fatty acids in the REDUCE-IT and STRENGTH trials, they add: “Potentially, the adverse effect on AF risk may be dose related, and the higher dosages of EPA used in these other studies might account for the significant adverse effect on AF.”

The researchers say that, to their knowledge, this is the only randomized trial to assess the effect of vitamin D₃ supplementation on AFib risk and results suggest a null effect. They add that subgroup analyses in patients with vitamin D levels considered deficient (<20 ng/mL) did not suggest a benefit; however, the power to detect a benefit in this much smaller subset of the population was limited.

They point out that, while there were no significant differences in incident AFib for either omega-3 fatty acid or vitamin D in the overall study population, an increased risk for incident AFib associated with randomized treatment was observed in selected subgroups.

For omega-3 fatty acids, AFib risk was modestly increased in taller individuals, and for vitamin D₃, elevations in AFib risk were observed in younger individuals and participants who drank less alcohol.

“Although the hazard ratios and tests for interaction were significant, the P values associated with these subgroup analyses have not been adjusted for multiple comparisons. Thus, these findings should be interpreted with caution and considered hypothesis generating,” they warn.

The VITAL Rhythm Study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Albert reported receipt of grants from St Jude Medical, Abbott, and Roche Diagnostics. Dr. Curfman reports no relevant disclosures.

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