Acute Coronary Syndromes

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

Treatment with sacubitril/valsartan, a pillar of therapy for patients with chronic heart failure with below-normal ejection fraction, came suggestively close to showing efficacy for preventing cardiovascular death or heart failure events in patients who have just had an MI but have no history of heart failure in a controlled trial with more than 5,600 patients.

Although sacubitril/valsartan (Entresto) fell short of producing a significant benefit, it did show good safety that was similar to the study’s comparator treatment, ramipril, an agent from the angiotensin-converting enzyme inhibitor class that is a mainstay of treatment in these patients.

“To say that, with no run-in, sacubitril/valsartan is as well tolerated and as safe as one of the best-studied ACE inhibitors – ramipril – in acutely ill MI patients, is a big statement,” said Marc A. Pfeffer, MD, at the annual scientific sessions of the American College of Cardiology. This high level of safety without gradual uptitration of sacubitril/valsartan (Entresto) “should lower barriers” to broader use of the dual-drug formulation for its approved indication in patients with chronic heart failure, especially patients with a left ventricular ejection fraction that is below normal. In addition, results from the PARADISE-MI trial suggested that “patients seemed to benefit before they develop heart failure. We couldn’t prove that, but we should build on this, and make it easier for patients to use this treatment,” Dr. Pfeffer said during a press briefing following his talk at the sessions.

Preventing heart failures to come

Treatment with sacubitril/valsartan in acute MI patients within a few days of their event “is perhaps addressing prevention of the heart failure that’s to come,” commented Lynne W. Stevenson, MD, designated discussant for the report and professor of medicine at Vanderbilt University Medical Center in Nashville. “Patients who are destined to develop heart failure are beginning their treatment early. The subgroup analyses suggest that it’s the sicker patients who benefited the most,” she said.

But Dr. Pfeffer stressed that “I don’t think this is a subgroup discussion. I would like to pursue this, but that’s up to the sponsor,” Novartis, the company that markets sacubitril/valsartan.

‘Exceedingly reassuring’ safety

The safety data that Dr. Pfeffer reported “are exceedingly reassuring. We didn’t see a signal of harm, and in some of the exploratory endpoints there was some evidence of benefit, so we need to encourage you to continue,” commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation program at Ascension St. Vincent Heart Center of Indiana in Indianapolis.

The PARADISE-MI (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) trial enrolled 5,669 patients with no history of heart failure within an average of 4 days following an acute MI at 495 sites in 41 countries during 2016-2020, with 8% of enrolled patients from the United States. Patients averaged 64 years of age, about three-quarters were men, about 43% had a history of diabetes, and only 1% were Black; Dr. Pfeffer noted that this is because most patients came from countries with low Black populations. The enrollment criteria required a left ventricular ejection fraction no greater than 40%, and among the enrolled patients this averaged about 37%.

A 10% nonsignificant relative risk reduction for the primary endpoint

The study’s primary endpoint was the combined first-event rate of cardiovascular death, hospitalization for heart failure, or an outpatient visit for heart failure. During a median follow-up of 23 months, this occurred at a rate of 7.4/100 patient years in the ramipril arm and 6.7/100 patient years in the sacubitril/valsartan arm, a 10% relative risk reduction with sacubitril/valsartan that was not significant, which meant all other efficacy analyses were exploratory, Dr. Pfeffer stressed.

Several secondary efficacy analyses showed significant benefits from sacubitril/valsartan, compared with ramipril, including the total number of events that comprised the primary endpoint, with a 21% relative risk reduction associated with sacubitril/valsartan, as well as investigator-reported events. The primary-endpoint benefit from sacubitril/valsartan was also significant in two subgroup analyses: patients aged 65 years or older (roughly half the study cohort), who had a 24% relative risk reduction on sacubitril/valsartan, compared with ramipril, and the 88% of patients who received treatment with percutaneous coronary intervention for their acute MI, who had a 19% relative risk reduction on sacubitril/valsartan, compared with patients who received ramipril.

The study’s safety data showed nearly identical rates in the two treatment arms for total adverse events, serious adverse events, adverse events that led to stopping the study drug, as well as in laboratory measures. The biggest between-treatment differences were a modest excess of hypotension on sacubitril valsartan, 28%, compared with 22% on ramipril, and a modest excess rate of cough on ramipril, 13%, compared with 9% on sacubitril/valsartan.

The added insight the results provide about sacubitril/valsartan comes at a time when U.S. patients continue to struggle to get health insurance coverage for an agent that has been approved for U.S. use in treating heart failure since 2015.

“Our patients do not have access to this important treatment,” declared Dr. Walsh during the press briefing. “The prior authorization process is unbelievable, and some patients have no access unless they pay the full cost on their own. This is an important, real-world problem that we face with this drug.”

PARADISE-MI was sponsored by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Pfeffer has received research funding from and is a consultant to Novartis. He is also a consultant to AstraZeneca, Boehringer Ingelheim, Corvidia, DalCor, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Peerbridge, and Sanofi, and he holds equity in DalCor and Peerbridge. Dr. Stevenson has received honoraria from LivaNova and has received research support from Abbott. Dr. Walsh had no disclosures.

[email protected]

Treatment with sacubitril/valsartan, a pillar of therapy for patients with chronic heart failure with below-normal ejection fraction, came suggestively close to showing efficacy for preventing cardiovascular death or heart failure events in patients who have just had an MI but have no history of heart failure in a controlled trial with more than 5,600 patients.

Although sacubitril/valsartan (Entresto) fell short of producing a significant benefit, it did show good safety that was similar to the study’s comparator treatment, ramipril, an agent from the angiotensin-converting enzyme inhibitor class that is a mainstay of treatment in these patients.

“To say that, with no run-in, sacubitril/valsartan is as well tolerated and as safe as one of the best-studied ACE inhibitors – ramipril – in acutely ill MI patients, is a big statement,” said Marc A. Pfeffer, MD, at the annual scientific sessions of the American College of Cardiology. This high level of safety without gradual uptitration of sacubitril/valsartan (Entresto) “should lower barriers” to broader use of the dual-drug formulation for its approved indication in patients with chronic heart failure, especially patients with a left ventricular ejection fraction that is below normal. In addition, results from the PARADISE-MI trial suggested that “patients seemed to benefit before they develop heart failure. We couldn’t prove that, but we should build on this, and make it easier for patients to use this treatment,” Dr. Pfeffer said during a press briefing following his talk at the sessions.

Preventing heart failures to come

Treatment with sacubitril/valsartan in acute MI patients within a few days of their event “is perhaps addressing prevention of the heart failure that’s to come,” commented Lynne W. Stevenson, MD, designated discussant for the report and professor of medicine at Vanderbilt University Medical Center in Nashville. “Patients who are destined to develop heart failure are beginning their treatment early. The subgroup analyses suggest that it’s the sicker patients who benefited the most,” she said.

But Dr. Pfeffer stressed that “I don’t think this is a subgroup discussion. I would like to pursue this, but that’s up to the sponsor,” Novartis, the company that markets sacubitril/valsartan.

‘Exceedingly reassuring’ safety

The safety data that Dr. Pfeffer reported “are exceedingly reassuring. We didn’t see a signal of harm, and in some of the exploratory endpoints there was some evidence of benefit, so we need to encourage you to continue,” commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation program at Ascension St. Vincent Heart Center of Indiana in Indianapolis.

The PARADISE-MI (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) trial enrolled 5,669 patients with no history of heart failure within an average of 4 days following an acute MI at 495 sites in 41 countries during 2016-2020, with 8% of enrolled patients from the United States. Patients averaged 64 years of age, about three-quarters were men, about 43% had a history of diabetes, and only 1% were Black; Dr. Pfeffer noted that this is because most patients came from countries with low Black populations. The enrollment criteria required a left ventricular ejection fraction no greater than 40%, and among the enrolled patients this averaged about 37%.

A 10% nonsignificant relative risk reduction for the primary endpoint

The study’s primary endpoint was the combined first-event rate of cardiovascular death, hospitalization for heart failure, or an outpatient visit for heart failure. During a median follow-up of 23 months, this occurred at a rate of 7.4/100 patient years in the ramipril arm and 6.7/100 patient years in the sacubitril/valsartan arm, a 10% relative risk reduction with sacubitril/valsartan that was not significant, which meant all other efficacy analyses were exploratory, Dr. Pfeffer stressed.

Several secondary efficacy analyses showed significant benefits from sacubitril/valsartan, compared with ramipril, including the total number of events that comprised the primary endpoint, with a 21% relative risk reduction associated with sacubitril/valsartan, as well as investigator-reported events. The primary-endpoint benefit from sacubitril/valsartan was also significant in two subgroup analyses: patients aged 65 years or older (roughly half the study cohort), who had a 24% relative risk reduction on sacubitril/valsartan, compared with ramipril, and the 88% of patients who received treatment with percutaneous coronary intervention for their acute MI, who had a 19% relative risk reduction on sacubitril/valsartan, compared with patients who received ramipril.

The study’s safety data showed nearly identical rates in the two treatment arms for total adverse events, serious adverse events, adverse events that led to stopping the study drug, as well as in laboratory measures. The biggest between-treatment differences were a modest excess of hypotension on sacubitril valsartan, 28%, compared with 22% on ramipril, and a modest excess rate of cough on ramipril, 13%, compared with 9% on sacubitril/valsartan.

The added insight the results provide about sacubitril/valsartan comes at a time when U.S. patients continue to struggle to get health insurance coverage for an agent that has been approved for U.S. use in treating heart failure since 2015.

“Our patients do not have access to this important treatment,” declared Dr. Walsh during the press briefing. “The prior authorization process is unbelievable, and some patients have no access unless they pay the full cost on their own. This is an important, real-world problem that we face with this drug.”

PARADISE-MI was sponsored by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Pfeffer has received research funding from and is a consultant to Novartis. He is also a consultant to AstraZeneca, Boehringer Ingelheim, Corvidia, DalCor, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Peerbridge, and Sanofi, and he holds equity in DalCor and Peerbridge. Dr. Stevenson has received honoraria from LivaNova and has received research support from Abbott. Dr. Walsh had no disclosures.

[email protected]

Treatment with sacubitril/valsartan, a pillar of therapy for patients with chronic heart failure with below-normal ejection fraction, came suggestively close to showing efficacy for preventing cardiovascular death or heart failure events in patients who have just had an MI but have no history of heart failure in a controlled trial with more than 5,600 patients.

Although sacubitril/valsartan (Entresto) fell short of producing a significant benefit, it did show good safety that was similar to the study’s comparator treatment, ramipril, an agent from the angiotensin-converting enzyme inhibitor class that is a mainstay of treatment in these patients.

“To say that, with no run-in, sacubitril/valsartan is as well tolerated and as safe as one of the best-studied ACE inhibitors – ramipril – in acutely ill MI patients, is a big statement,” said Marc A. Pfeffer, MD, at the annual scientific sessions of the American College of Cardiology. This high level of safety without gradual uptitration of sacubitril/valsartan (Entresto) “should lower barriers” to broader use of the dual-drug formulation for its approved indication in patients with chronic heart failure, especially patients with a left ventricular ejection fraction that is below normal. In addition, results from the PARADISE-MI trial suggested that “patients seemed to benefit before they develop heart failure. We couldn’t prove that, but we should build on this, and make it easier for patients to use this treatment,” Dr. Pfeffer said during a press briefing following his talk at the sessions.

Preventing heart failures to come

Treatment with sacubitril/valsartan in acute MI patients within a few days of their event “is perhaps addressing prevention of the heart failure that’s to come,” commented Lynne W. Stevenson, MD, designated discussant for the report and professor of medicine at Vanderbilt University Medical Center in Nashville. “Patients who are destined to develop heart failure are beginning their treatment early. The subgroup analyses suggest that it’s the sicker patients who benefited the most,” she said.

But Dr. Pfeffer stressed that “I don’t think this is a subgroup discussion. I would like to pursue this, but that’s up to the sponsor,” Novartis, the company that markets sacubitril/valsartan.

‘Exceedingly reassuring’ safety

The safety data that Dr. Pfeffer reported “are exceedingly reassuring. We didn’t see a signal of harm, and in some of the exploratory endpoints there was some evidence of benefit, so we need to encourage you to continue,” commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation program at Ascension St. Vincent Heart Center of Indiana in Indianapolis.

The PARADISE-MI (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) trial enrolled 5,669 patients with no history of heart failure within an average of 4 days following an acute MI at 495 sites in 41 countries during 2016-2020, with 8% of enrolled patients from the United States. Patients averaged 64 years of age, about three-quarters were men, about 43% had a history of diabetes, and only 1% were Black; Dr. Pfeffer noted that this is because most patients came from countries with low Black populations. The enrollment criteria required a left ventricular ejection fraction no greater than 40%, and among the enrolled patients this averaged about 37%.

A 10% nonsignificant relative risk reduction for the primary endpoint

The study’s primary endpoint was the combined first-event rate of cardiovascular death, hospitalization for heart failure, or an outpatient visit for heart failure. During a median follow-up of 23 months, this occurred at a rate of 7.4/100 patient years in the ramipril arm and 6.7/100 patient years in the sacubitril/valsartan arm, a 10% relative risk reduction with sacubitril/valsartan that was not significant, which meant all other efficacy analyses were exploratory, Dr. Pfeffer stressed.

Several secondary efficacy analyses showed significant benefits from sacubitril/valsartan, compared with ramipril, including the total number of events that comprised the primary endpoint, with a 21% relative risk reduction associated with sacubitril/valsartan, as well as investigator-reported events. The primary-endpoint benefit from sacubitril/valsartan was also significant in two subgroup analyses: patients aged 65 years or older (roughly half the study cohort), who had a 24% relative risk reduction on sacubitril/valsartan, compared with ramipril, and the 88% of patients who received treatment with percutaneous coronary intervention for their acute MI, who had a 19% relative risk reduction on sacubitril/valsartan, compared with patients who received ramipril.

The study’s safety data showed nearly identical rates in the two treatment arms for total adverse events, serious adverse events, adverse events that led to stopping the study drug, as well as in laboratory measures. The biggest between-treatment differences were a modest excess of hypotension on sacubitril valsartan, 28%, compared with 22% on ramipril, and a modest excess rate of cough on ramipril, 13%, compared with 9% on sacubitril/valsartan.

The added insight the results provide about sacubitril/valsartan comes at a time when U.S. patients continue to struggle to get health insurance coverage for an agent that has been approved for U.S. use in treating heart failure since 2015.

“Our patients do not have access to this important treatment,” declared Dr. Walsh during the press briefing. “The prior authorization process is unbelievable, and some patients have no access unless they pay the full cost on their own. This is an important, real-world problem that we face with this drug.”

PARADISE-MI was sponsored by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Pfeffer has received research funding from and is a consultant to Novartis. He is also a consultant to AstraZeneca, Boehringer Ingelheim, Corvidia, DalCor, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Peerbridge, and Sanofi, and he holds equity in DalCor and Peerbridge. Dr. Stevenson has received honoraria from LivaNova and has received research support from Abbott. Dr. Walsh had no disclosures.

[email protected]

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.

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.

Finerenone, an investigational agent from a new drug class, just scored a second pivotal trial win after showing significant benefit for slowing progression of diabetic kidney disease in patients with type 2 diabetes in the FIDELIO-DKD pivotal trial with more than 5,700 patients.

Top-line results from FIGARO-DKD showed significant benefit for the primary endpoint of cardiovascular death and nonfatal cardiovascular disease endpoints in a placebo-controlled trial with about 7,400 patients with type 2 diabetes, reported Bayer, the company developing finerenone in statement released on May 10, 2021.

Based on the FIDELIO-DKD results, finerenone is currently under review by the U.S. Food and Drug Administration for marketing approval as a treatment for patients with type 2 diabetes and chronic kidney disease. FIDELIO-DKD, in addition to the primary endpoint that focused on slowing progression of diabetic kidney disease, had a secondary endpoint that assessed the combined incidence on treatment of cardiovascular death, or nonfatal episodes of stroke, MI, or hospitalization for heart failure. Results from the study published in 2020 in the New England Journal of Medicine showed that finerenone was safe and effective for both endpoints.

In the current study, FIGARO-DKD, run at more than 1,000 sites in 47 countries, these endpoints flipped. The primary outcome was a composite of cardiovascular death or nonfatal cardiovascular disease events, and the secondary outcome was prevention of DKD progression.

Other than stating the results significantly fulfilled FIGARO-DKD’s primary endpoint of reducing the incidence of combined cardiovascular disease endpoints, the release gave no further outcome details. The release noted that the enrolled patient cohort in FIGARO-DKD included more patients with earlier-stage chronic kidney disease, compared with FIDELIO-DKD.

Finerenone is a first-in-class investigational nonsteroidal, selective mineralocorticoid receptor antagonist (MRA). As an MRA it shares certain activities with the steroidal MRAs spironolactone and eplerenone. But the absence of a steroidal structure means that finerenone does not cause steroidal adverse effects such as gynecomastia. Results in FIDELIO-DKD showed that finerenone caused more hyperkalemia than placebo, but the level of hyperkalemia that it causes relative to spironolactone or eplerenone remains uncertain.

[email protected]

Finerenone, an investigational agent from a new drug class, just scored a second pivotal trial win after showing significant benefit for slowing progression of diabetic kidney disease in patients with type 2 diabetes in the FIDELIO-DKD pivotal trial with more than 5,700 patients.

Top-line results from FIGARO-DKD showed significant benefit for the primary endpoint of cardiovascular death and nonfatal cardiovascular disease endpoints in a placebo-controlled trial with about 7,400 patients with type 2 diabetes, reported Bayer, the company developing finerenone in statement released on May 10, 2021.

Based on the FIDELIO-DKD results, finerenone is currently under review by the U.S. Food and Drug Administration for marketing approval as a treatment for patients with type 2 diabetes and chronic kidney disease. FIDELIO-DKD, in addition to the primary endpoint that focused on slowing progression of diabetic kidney disease, had a secondary endpoint that assessed the combined incidence on treatment of cardiovascular death, or nonfatal episodes of stroke, MI, or hospitalization for heart failure. Results from the study published in 2020 in the New England Journal of Medicine showed that finerenone was safe and effective for both endpoints.

In the current study, FIGARO-DKD, run at more than 1,000 sites in 47 countries, these endpoints flipped. The primary outcome was a composite of cardiovascular death or nonfatal cardiovascular disease events, and the secondary outcome was prevention of DKD progression.

Other than stating the results significantly fulfilled FIGARO-DKD’s primary endpoint of reducing the incidence of combined cardiovascular disease endpoints, the release gave no further outcome details. The release noted that the enrolled patient cohort in FIGARO-DKD included more patients with earlier-stage chronic kidney disease, compared with FIDELIO-DKD.

Finerenone is a first-in-class investigational nonsteroidal, selective mineralocorticoid receptor antagonist (MRA). As an MRA it shares certain activities with the steroidal MRAs spironolactone and eplerenone. But the absence of a steroidal structure means that finerenone does not cause steroidal adverse effects such as gynecomastia. Results in FIDELIO-DKD showed that finerenone caused more hyperkalemia than placebo, but the level of hyperkalemia that it causes relative to spironolactone or eplerenone remains uncertain.

[email protected]

Finerenone, an investigational agent from a new drug class, just scored a second pivotal trial win after showing significant benefit for slowing progression of diabetic kidney disease in patients with type 2 diabetes in the FIDELIO-DKD pivotal trial with more than 5,700 patients.

Top-line results from FIGARO-DKD showed significant benefit for the primary endpoint of cardiovascular death and nonfatal cardiovascular disease endpoints in a placebo-controlled trial with about 7,400 patients with type 2 diabetes, reported Bayer, the company developing finerenone in statement released on May 10, 2021.

Based on the FIDELIO-DKD results, finerenone is currently under review by the U.S. Food and Drug Administration for marketing approval as a treatment for patients with type 2 diabetes and chronic kidney disease. FIDELIO-DKD, in addition to the primary endpoint that focused on slowing progression of diabetic kidney disease, had a secondary endpoint that assessed the combined incidence on treatment of cardiovascular death, or nonfatal episodes of stroke, MI, or hospitalization for heart failure. Results from the study published in 2020 in the New England Journal of Medicine showed that finerenone was safe and effective for both endpoints.

In the current study, FIGARO-DKD, run at more than 1,000 sites in 47 countries, these endpoints flipped. The primary outcome was a composite of cardiovascular death or nonfatal cardiovascular disease events, and the secondary outcome was prevention of DKD progression.

Other than stating the results significantly fulfilled FIGARO-DKD’s primary endpoint of reducing the incidence of combined cardiovascular disease endpoints, the release gave no further outcome details. The release noted that the enrolled patient cohort in FIGARO-DKD included more patients with earlier-stage chronic kidney disease, compared with FIDELIO-DKD.

Finerenone is a first-in-class investigational nonsteroidal, selective mineralocorticoid receptor antagonist (MRA). As an MRA it shares certain activities with the steroidal MRAs spironolactone and eplerenone. But the absence of a steroidal structure means that finerenone does not cause steroidal adverse effects such as gynecomastia. Results in FIDELIO-DKD showed that finerenone caused more hyperkalemia than placebo, but the level of hyperkalemia that it causes relative to spironolactone or eplerenone remains uncertain.

[email protected]

What started as an attempt to standardize care for acute myocardial infarction with cardiogenic shock at a handful of Detroit-area hospitals has led to markedly better survival rates than the traditional flip of a coin, in a nationwide analysis.

Final results from the National Cardiogenic Shock Initiative (NCSI) show 71% of patients survived to discharge and 68% were alive at 30 days.

Patients presenting in stage C or D shock, who comprised the bulk of patients in previous trials, had survival rates of 79% and 77%, respectively.

Among stage E patients, who are in extremis and have typical survival rates of less than 20%, survival was 54% at discharge and 49% at 30 days, co–principal investigator Babar Basir, DO, Henry Ford Hospital, Detroit, reported at the Society for Cardiovascular Angiography and Interventions (SCAI) annual scientific sessions, held virtually.

“This is the first push to really be able to consistently get survival rates over 50%, particularly in those patients who presented in stage C and D shock,” he said. “Really, it’s important to emphasize here the hard work it’s taken to get to this point and all the research that’s been done.”

The NCSI protocol emphasizes rapid identification and support of cardiogenic shock (door to support time <90 minutes), early placement of the Impella (Abiomed) ventricular assist device prior to percutaneous coronary intervention (PCI), and right heart monitoring to reduce the use of inotropes and vasopressors.

Co–principal investigator William O’Neill, MD, also from Henry Ford, previously reported results from the pilot study showing 84% of 30 patients survived to discharge.

The present analysis was based on outcomes of 406 consecutive acute MI patients (mean age, 63.7 years; 24% female) who presented with cardiogenic shock at 32 academic and 48 community hospitals in 29 states and the District of Columbia.

Dr. Basir emphasized that this is the largest prospective North American acute MI cardiogenic shock study in 20 years and recruited “one of the sickest cohorts ever studied.” The average blood pressure among the patients was 77/50 mm Hg; 77% had a lactate of at least 2 mmol/L (mean, 4.8 mmol/L), and 25% were in stage E shock.

One-quarter of patients were transferred from other institutions, 82% presented with ST-segment elevation MI, two-thirds had multivessel disease, and 13% had a left main culprit lesion.

Right heart catheterization was used in 90% of patients, an Impella CP device in 92%, an Impella 2.5 device in 5%, femoral access PCI in 78%, and aspiration thrombectomy in a full 27%.

Despite this sick cohort, survival at 30 days was better than in any previous study of cardiogenic shock, Dr. Basir said. In comparison, 30-day survival rates were 53%, 60%, and 49% in the SHOCK, IABP SHOCK, and CULPRIT SHOCK trials, respectively.

That said, survival over the course of the first year fell to 53% in the entire cohort, 62% in patients with stage C or D shock, and 31% in those in stage E shock.

“One-year mortality continues to be a problem for these patients and emphasizes the need for goal-directed medical therapy, early advanced heart failure follow-up, and novel therapies such as what we are planning with the evaluation of [supersaturated oxygen] SSO₂ to reduce infarct sizes in the ISO-SHOCK trial,” set to begin later this year, Dr. Basir said.

Given the promising results in the NCSI, the randomized controlled RECOVER IV trial is planned to begin in 2022, he noted. It will assess whether Impella pre-PCI is superior to PCI without Impella in patients with inclusion criteria similar to that of the NCSI. The DanGer Shock randomized trial is ongoing in Denmark and Germany and assessing all-cause mortality at 6 months with the Impella CP device compared with standard of care.

“We hypothesize that greater utilization of this protocol, and refinement of the escalation strategies will consistently lead to a survival rate greater than 80%,” Dr. Basir concluded.

Past SCAI president Kirk Garratt, MD, Christiana Care, Newark, Del., who moderated a press conference where the data were highlighted, noted that late complications led to a roughly 20% absolute mortality increase from discharge to 1 year, and questioned what percentage could be attributed to the mechanical support offered.

Dr. Basir said that information was not specifically tracked but that many patients presented with multiorgan failure and, irrespective of that, the majority died from ongoing heart failure.

During the formal presentation, panelist Ron Waksman, MD, MedStar Heart Institute, Washington, questioned whether results were different between academic and community centers, but also pointed to the lack of a comparator in the single-arm study.

“It’s very hard to do any comparison historically; we do need to have a control group,” he said. “If you would have opened it to any treatment at the time of the initiative, which is great, but not just limit it to use of the Impella devices, we would have better understanding if there is really a differentiation between one device versus the other devices.”

Dr. Basir replied, “I think that is a very reasonable comment and, in regard to your question, it is always difficult to differentiate between academic and community centers, but these were large community programs that have all of the technologies available in an academic center.”

NCIS is funded in part by unrestricted grants from Abiomed and Chiesi. Dr. Basir reported consulting for Abbott Vascular, Abiomed, Cardiovascular Systems, Chiesi, Procyrion, and Zoll.

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

What started as an attempt to standardize care for acute myocardial infarction with cardiogenic shock at a handful of Detroit-area hospitals has led to markedly better survival rates than the traditional flip of a coin, in a nationwide analysis.

Final results from the National Cardiogenic Shock Initiative (NCSI) show 71% of patients survived to discharge and 68% were alive at 30 days.

Patients presenting in stage C or D shock, who comprised the bulk of patients in previous trials, had survival rates of 79% and 77%, respectively.

Among stage E patients, who are in extremis and have typical survival rates of less than 20%, survival was 54% at discharge and 49% at 30 days, co–principal investigator Babar Basir, DO, Henry Ford Hospital, Detroit, reported at the Society for Cardiovascular Angiography and Interventions (SCAI) annual scientific sessions, held virtually.

“This is the first push to really be able to consistently get survival rates over 50%, particularly in those patients who presented in stage C and D shock,” he said. “Really, it’s important to emphasize here the hard work it’s taken to get to this point and all the research that’s been done.”

The NCSI protocol emphasizes rapid identification and support of cardiogenic shock (door to support time <90 minutes), early placement of the Impella (Abiomed) ventricular assist device prior to percutaneous coronary intervention (PCI), and right heart monitoring to reduce the use of inotropes and vasopressors.

Co–principal investigator William O’Neill, MD, also from Henry Ford, previously reported results from the pilot study showing 84% of 30 patients survived to discharge.

The present analysis was based on outcomes of 406 consecutive acute MI patients (mean age, 63.7 years; 24% female) who presented with cardiogenic shock at 32 academic and 48 community hospitals in 29 states and the District of Columbia.

Dr. Basir emphasized that this is the largest prospective North American acute MI cardiogenic shock study in 20 years and recruited “one of the sickest cohorts ever studied.” The average blood pressure among the patients was 77/50 mm Hg; 77% had a lactate of at least 2 mmol/L (mean, 4.8 mmol/L), and 25% were in stage E shock.

One-quarter of patients were transferred from other institutions, 82% presented with ST-segment elevation MI, two-thirds had multivessel disease, and 13% had a left main culprit lesion.

Right heart catheterization was used in 90% of patients, an Impella CP device in 92%, an Impella 2.5 device in 5%, femoral access PCI in 78%, and aspiration thrombectomy in a full 27%.

Despite this sick cohort, survival at 30 days was better than in any previous study of cardiogenic shock, Dr. Basir said. In comparison, 30-day survival rates were 53%, 60%, and 49% in the SHOCK, IABP SHOCK, and CULPRIT SHOCK trials, respectively.

That said, survival over the course of the first year fell to 53% in the entire cohort, 62% in patients with stage C or D shock, and 31% in those in stage E shock.

“One-year mortality continues to be a problem for these patients and emphasizes the need for goal-directed medical therapy, early advanced heart failure follow-up, and novel therapies such as what we are planning with the evaluation of [supersaturated oxygen] SSO₂ to reduce infarct sizes in the ISO-SHOCK trial,” set to begin later this year, Dr. Basir said.

Given the promising results in the NCSI, the randomized controlled RECOVER IV trial is planned to begin in 2022, he noted. It will assess whether Impella pre-PCI is superior to PCI without Impella in patients with inclusion criteria similar to that of the NCSI. The DanGer Shock randomized trial is ongoing in Denmark and Germany and assessing all-cause mortality at 6 months with the Impella CP device compared with standard of care.

“We hypothesize that greater utilization of this protocol, and refinement of the escalation strategies will consistently lead to a survival rate greater than 80%,” Dr. Basir concluded.

Past SCAI president Kirk Garratt, MD, Christiana Care, Newark, Del., who moderated a press conference where the data were highlighted, noted that late complications led to a roughly 20% absolute mortality increase from discharge to 1 year, and questioned what percentage could be attributed to the mechanical support offered.

Dr. Basir said that information was not specifically tracked but that many patients presented with multiorgan failure and, irrespective of that, the majority died from ongoing heart failure.

During the formal presentation, panelist Ron Waksman, MD, MedStar Heart Institute, Washington, questioned whether results were different between academic and community centers, but also pointed to the lack of a comparator in the single-arm study.

“It’s very hard to do any comparison historically; we do need to have a control group,” he said. “If you would have opened it to any treatment at the time of the initiative, which is great, but not just limit it to use of the Impella devices, we would have better understanding if there is really a differentiation between one device versus the other devices.”

Dr. Basir replied, “I think that is a very reasonable comment and, in regard to your question, it is always difficult to differentiate between academic and community centers, but these were large community programs that have all of the technologies available in an academic center.”

NCIS is funded in part by unrestricted grants from Abiomed and Chiesi. Dr. Basir reported consulting for Abbott Vascular, Abiomed, Cardiovascular Systems, Chiesi, Procyrion, and Zoll.

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

What started as an attempt to standardize care for acute myocardial infarction with cardiogenic shock at a handful of Detroit-area hospitals has led to markedly better survival rates than the traditional flip of a coin, in a nationwide analysis.

Final results from the National Cardiogenic Shock Initiative (NCSI) show 71% of patients survived to discharge and 68% were alive at 30 days.

Patients presenting in stage C or D shock, who comprised the bulk of patients in previous trials, had survival rates of 79% and 77%, respectively.

Among stage E patients, who are in extremis and have typical survival rates of less than 20%, survival was 54% at discharge and 49% at 30 days, co–principal investigator Babar Basir, DO, Henry Ford Hospital, Detroit, reported at the Society for Cardiovascular Angiography and Interventions (SCAI) annual scientific sessions, held virtually.

“This is the first push to really be able to consistently get survival rates over 50%, particularly in those patients who presented in stage C and D shock,” he said. “Really, it’s important to emphasize here the hard work it’s taken to get to this point and all the research that’s been done.”

The NCSI protocol emphasizes rapid identification and support of cardiogenic shock (door to support time <90 minutes), early placement of the Impella (Abiomed) ventricular assist device prior to percutaneous coronary intervention (PCI), and right heart monitoring to reduce the use of inotropes and vasopressors.

Co–principal investigator William O’Neill, MD, also from Henry Ford, previously reported results from the pilot study showing 84% of 30 patients survived to discharge.

The present analysis was based on outcomes of 406 consecutive acute MI patients (mean age, 63.7 years; 24% female) who presented with cardiogenic shock at 32 academic and 48 community hospitals in 29 states and the District of Columbia.

Dr. Basir emphasized that this is the largest prospective North American acute MI cardiogenic shock study in 20 years and recruited “one of the sickest cohorts ever studied.” The average blood pressure among the patients was 77/50 mm Hg; 77% had a lactate of at least 2 mmol/L (mean, 4.8 mmol/L), and 25% were in stage E shock.

One-quarter of patients were transferred from other institutions, 82% presented with ST-segment elevation MI, two-thirds had multivessel disease, and 13% had a left main culprit lesion.

Right heart catheterization was used in 90% of patients, an Impella CP device in 92%, an Impella 2.5 device in 5%, femoral access PCI in 78%, and aspiration thrombectomy in a full 27%.

Despite this sick cohort, survival at 30 days was better than in any previous study of cardiogenic shock, Dr. Basir said. In comparison, 30-day survival rates were 53%, 60%, and 49% in the SHOCK, IABP SHOCK, and CULPRIT SHOCK trials, respectively.

That said, survival over the course of the first year fell to 53% in the entire cohort, 62% in patients with stage C or D shock, and 31% in those in stage E shock.

“One-year mortality continues to be a problem for these patients and emphasizes the need for goal-directed medical therapy, early advanced heart failure follow-up, and novel therapies such as what we are planning with the evaluation of [supersaturated oxygen] SSO₂ to reduce infarct sizes in the ISO-SHOCK trial,” set to begin later this year, Dr. Basir said.

Given the promising results in the NCSI, the randomized controlled RECOVER IV trial is planned to begin in 2022, he noted. It will assess whether Impella pre-PCI is superior to PCI without Impella in patients with inclusion criteria similar to that of the NCSI. The DanGer Shock randomized trial is ongoing in Denmark and Germany and assessing all-cause mortality at 6 months with the Impella CP device compared with standard of care.

“We hypothesize that greater utilization of this protocol, and refinement of the escalation strategies will consistently lead to a survival rate greater than 80%,” Dr. Basir concluded.

Past SCAI president Kirk Garratt, MD, Christiana Care, Newark, Del., who moderated a press conference where the data were highlighted, noted that late complications led to a roughly 20% absolute mortality increase from discharge to 1 year, and questioned what percentage could be attributed to the mechanical support offered.

Dr. Basir said that information was not specifically tracked but that many patients presented with multiorgan failure and, irrespective of that, the majority died from ongoing heart failure.

During the formal presentation, panelist Ron Waksman, MD, MedStar Heart Institute, Washington, questioned whether results were different between academic and community centers, but also pointed to the lack of a comparator in the single-arm study.

“It’s very hard to do any comparison historically; we do need to have a control group,” he said. “If you would have opened it to any treatment at the time of the initiative, which is great, but not just limit it to use of the Impella devices, we would have better understanding if there is really a differentiation between one device versus the other devices.”

Dr. Basir replied, “I think that is a very reasonable comment and, in regard to your question, it is always difficult to differentiate between academic and community centers, but these were large community programs that have all of the technologies available in an academic center.”

NCIS is funded in part by unrestricted grants from Abiomed and Chiesi. Dr. Basir reported consulting for Abbott Vascular, Abiomed, Cardiovascular Systems, Chiesi, Procyrion, and Zoll.

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

COVID-19 patients with ST-segment elevation MI (STEMI) represent a population with unique demographic and clinical features resulting in a high risk for mortality, according to initial findings from the North American Cardiovascular COVID-19 Myocardial Infarction (NACMI) Registry.

Floaria Bicher/iStock/Getty Images Plus

“This is the largest registry of COVID-positive patients presenting with STEMI [and] the results clearly illustrate the challenges and uniqueness of this patient population that deserves prompt and special attention,” study cochair Timothy Henry, MD, president-elect of the Society for Cardiovascular Angiography & Interventions, said in a news release.

The NACMI registry is a collaborative effort between the SCAI, the American College of Cardiology Interventional Council, and the Canadian Association of Interventional Cardiology.

“The rapid development of this ongoing, critically important prospective registry reflects the strong and unique collaboration of all three societies. It was gratifying to be part of this process and hopefully the results will improve the care of our patients and stimulate further research,” Dr. Henry said in the news release.

The registry has enrolled 1,185 patients presenting with STEMI at 64 sites across the United States and Canada. Participants include 230 COVID-positive STEMI patients; 495 STEMI patients suspected but ultimately confirmed not to have COVID-19; and 460 age-and sex-matched control STEMI patients treated prior to the pandemic who are part of the Midwest STEMI Consortium.

The initial findings from the registry were published online in the Journal of the American College of Cardiology.
 

Atypical symptoms may explain high death rate

The primary outcome – a composite of in-hospital death, stroke, recurrent MI, or repeat unplanned revascularization – occurred in 36% of COVID-positive patients, compared with 13% of COVID-negative patients and 5% of control patients (P < .001 relative to controls). 

This difference was driven largely by a “very high” in-hospital death rate in COVID-positive patients, lead author Santiago Garcia, MD, Minneapolis Heart Institute Foundation, said in an interview.

The in-hospital death rate was 33% in COVID-positive patients, compared with 11% in COVID-negative patients and 4% in controls. Stroke also occurred more often in COVID-positive patients at 3% versus 2% in COVID-negative and 0% in controls.

These initial findings suggest that the combination of STEMI and COVID-19 infection “confers a poor prognosis, with one in three patients succumbing to the disease, even among patients selected for invasive angiography (28% mortality),” the investigators wrote.

The data also show that STEMI in COVID-positive patients disproportionately affects ethnic minorities (23% Hispanic and 24% Black) with diabetes, which was present in 46% of COVID-positive patients.

COVID-positive patients with STEMI are more likely to present with atypical symptoms such as dyspnea (54%), pulmonary infiltrates on chest x-ray (46%), and high-risk conditions such as cardiogenic shock (18%), “which may explain the high fatality rate,” Dr. Garcia said.

Despite these high-risk features, COVID-positive patients are less apt to undergo invasive angiography when compared with COVID-negative and control STEMI patients (78% vs. 96% vs. 100%).

The majority of patients (71%) who did under angiography received primary percutaneous coronary intervention (PPCI) with very small treatment delays (at 15 minutes) during the pandemic.

Another notable finding is that “many patients (23%) have ‘no culprit’ vessel and may represent different etiologies of ST-segment elevation including microemboli, myocarditis, Takotsubo cardiomyopathy,” Dr. Garcia said in an interview.

“In line with current guidelines, patients with suspected STEMI should be managed with PPCI, without delay while the safety of health care providers is ensured,” Ran Kornowski, MD, and Katia Orvin, MD, both with Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, wrote in a linked editorial.  

“In this case, PPCI should be performed routinely, even if the patient is presumed to have COVID-19, because PPCI should not be postponed. Confirmation of SARS-CoV-2 infection should not delay urgent decision management concerning reperfusion strategy,” they advised.

Looking ahead, Garcia said plans for the registry include determining predictors of in-hospital mortality and studying demographic and treatment trends as the pandemic continues with more virulent strains of the virus.

Various subgroup analyses are also planned as well as an independent angiographic and electrocardiographic core lab analysis. A comparative analysis of data from the US and Canada is also planned.

This work was supported by an ACC Accreditation Grant, Saskatchewan Health Research Foundation, and grants from Medtronic and Abbott Vascular to SCAI. Dr. Garcia has received institutional research grants from Edwards Lifesciences, BSCI, Medtronic, and Abbott Vascular; has served as a consultant for Medtronic and BSCI; and has served as a proctor for Edwards Lifesciences. Dr. Kornowski and Dr. Orvin disclosed no relevant financial relationships.

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

COVID-19 patients with ST-segment elevation MI (STEMI) represent a population with unique demographic and clinical features resulting in a high risk for mortality, according to initial findings from the North American Cardiovascular COVID-19 Myocardial Infarction (NACMI) Registry.

Floaria Bicher/iStock/Getty Images Plus

“This is the largest registry of COVID-positive patients presenting with STEMI [and] the results clearly illustrate the challenges and uniqueness of this patient population that deserves prompt and special attention,” study cochair Timothy Henry, MD, president-elect of the Society for Cardiovascular Angiography & Interventions, said in a news release.

The NACMI registry is a collaborative effort between the SCAI, the American College of Cardiology Interventional Council, and the Canadian Association of Interventional Cardiology.

“The rapid development of this ongoing, critically important prospective registry reflects the strong and unique collaboration of all three societies. It was gratifying to be part of this process and hopefully the results will improve the care of our patients and stimulate further research,” Dr. Henry said in the news release.

The registry has enrolled 1,185 patients presenting with STEMI at 64 sites across the United States and Canada. Participants include 230 COVID-positive STEMI patients; 495 STEMI patients suspected but ultimately confirmed not to have COVID-19; and 460 age-and sex-matched control STEMI patients treated prior to the pandemic who are part of the Midwest STEMI Consortium.

The initial findings from the registry were published online in the Journal of the American College of Cardiology.
 

Atypical symptoms may explain high death rate

The primary outcome – a composite of in-hospital death, stroke, recurrent MI, or repeat unplanned revascularization – occurred in 36% of COVID-positive patients, compared with 13% of COVID-negative patients and 5% of control patients (P < .001 relative to controls). 

This difference was driven largely by a “very high” in-hospital death rate in COVID-positive patients, lead author Santiago Garcia, MD, Minneapolis Heart Institute Foundation, said in an interview.

The in-hospital death rate was 33% in COVID-positive patients, compared with 11% in COVID-negative patients and 4% in controls. Stroke also occurred more often in COVID-positive patients at 3% versus 2% in COVID-negative and 0% in controls.

These initial findings suggest that the combination of STEMI and COVID-19 infection “confers a poor prognosis, with one in three patients succumbing to the disease, even among patients selected for invasive angiography (28% mortality),” the investigators wrote.

The data also show that STEMI in COVID-positive patients disproportionately affects ethnic minorities (23% Hispanic and 24% Black) with diabetes, which was present in 46% of COVID-positive patients.

COVID-positive patients with STEMI are more likely to present with atypical symptoms such as dyspnea (54%), pulmonary infiltrates on chest x-ray (46%), and high-risk conditions such as cardiogenic shock (18%), “which may explain the high fatality rate,” Dr. Garcia said.

Despite these high-risk features, COVID-positive patients are less apt to undergo invasive angiography when compared with COVID-negative and control STEMI patients (78% vs. 96% vs. 100%).

The majority of patients (71%) who did under angiography received primary percutaneous coronary intervention (PPCI) with very small treatment delays (at 15 minutes) during the pandemic.

Another notable finding is that “many patients (23%) have ‘no culprit’ vessel and may represent different etiologies of ST-segment elevation including microemboli, myocarditis, Takotsubo cardiomyopathy,” Dr. Garcia said in an interview.

“In line with current guidelines, patients with suspected STEMI should be managed with PPCI, without delay while the safety of health care providers is ensured,” Ran Kornowski, MD, and Katia Orvin, MD, both with Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, wrote in a linked editorial.  

“In this case, PPCI should be performed routinely, even if the patient is presumed to have COVID-19, because PPCI should not be postponed. Confirmation of SARS-CoV-2 infection should not delay urgent decision management concerning reperfusion strategy,” they advised.

Looking ahead, Garcia said plans for the registry include determining predictors of in-hospital mortality and studying demographic and treatment trends as the pandemic continues with more virulent strains of the virus.

Various subgroup analyses are also planned as well as an independent angiographic and electrocardiographic core lab analysis. A comparative analysis of data from the US and Canada is also planned.

This work was supported by an ACC Accreditation Grant, Saskatchewan Health Research Foundation, and grants from Medtronic and Abbott Vascular to SCAI. Dr. Garcia has received institutional research grants from Edwards Lifesciences, BSCI, Medtronic, and Abbott Vascular; has served as a consultant for Medtronic and BSCI; and has served as a proctor for Edwards Lifesciences. Dr. Kornowski and Dr. Orvin disclosed no relevant financial relationships.

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

COVID-19 patients with ST-segment elevation MI (STEMI) represent a population with unique demographic and clinical features resulting in a high risk for mortality, according to initial findings from the North American Cardiovascular COVID-19 Myocardial Infarction (NACMI) Registry.

Floaria Bicher/iStock/Getty Images Plus

“This is the largest registry of COVID-positive patients presenting with STEMI [and] the results clearly illustrate the challenges and uniqueness of this patient population that deserves prompt and special attention,” study cochair Timothy Henry, MD, president-elect of the Society for Cardiovascular Angiography & Interventions, said in a news release.

The NACMI registry is a collaborative effort between the SCAI, the American College of Cardiology Interventional Council, and the Canadian Association of Interventional Cardiology.

“The rapid development of this ongoing, critically important prospective registry reflects the strong and unique collaboration of all three societies. It was gratifying to be part of this process and hopefully the results will improve the care of our patients and stimulate further research,” Dr. Henry said in the news release.

The registry has enrolled 1,185 patients presenting with STEMI at 64 sites across the United States and Canada. Participants include 230 COVID-positive STEMI patients; 495 STEMI patients suspected but ultimately confirmed not to have COVID-19; and 460 age-and sex-matched control STEMI patients treated prior to the pandemic who are part of the Midwest STEMI Consortium.

The initial findings from the registry were published online in the Journal of the American College of Cardiology.
 

Atypical symptoms may explain high death rate

The primary outcome – a composite of in-hospital death, stroke, recurrent MI, or repeat unplanned revascularization – occurred in 36% of COVID-positive patients, compared with 13% of COVID-negative patients and 5% of control patients (P < .001 relative to controls). 

This difference was driven largely by a “very high” in-hospital death rate in COVID-positive patients, lead author Santiago Garcia, MD, Minneapolis Heart Institute Foundation, said in an interview.

The in-hospital death rate was 33% in COVID-positive patients, compared with 11% in COVID-negative patients and 4% in controls. Stroke also occurred more often in COVID-positive patients at 3% versus 2% in COVID-negative and 0% in controls.

These initial findings suggest that the combination of STEMI and COVID-19 infection “confers a poor prognosis, with one in three patients succumbing to the disease, even among patients selected for invasive angiography (28% mortality),” the investigators wrote.

The data also show that STEMI in COVID-positive patients disproportionately affects ethnic minorities (23% Hispanic and 24% Black) with diabetes, which was present in 46% of COVID-positive patients.

COVID-positive patients with STEMI are more likely to present with atypical symptoms such as dyspnea (54%), pulmonary infiltrates on chest x-ray (46%), and high-risk conditions such as cardiogenic shock (18%), “which may explain the high fatality rate,” Dr. Garcia said.

Despite these high-risk features, COVID-positive patients are less apt to undergo invasive angiography when compared with COVID-negative and control STEMI patients (78% vs. 96% vs. 100%).

The majority of patients (71%) who did under angiography received primary percutaneous coronary intervention (PPCI) with very small treatment delays (at 15 minutes) during the pandemic.

Another notable finding is that “many patients (23%) have ‘no culprit’ vessel and may represent different etiologies of ST-segment elevation including microemboli, myocarditis, Takotsubo cardiomyopathy,” Dr. Garcia said in an interview.

“In line with current guidelines, patients with suspected STEMI should be managed with PPCI, without delay while the safety of health care providers is ensured,” Ran Kornowski, MD, and Katia Orvin, MD, both with Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, wrote in a linked editorial.  

“In this case, PPCI should be performed routinely, even if the patient is presumed to have COVID-19, because PPCI should not be postponed. Confirmation of SARS-CoV-2 infection should not delay urgent decision management concerning reperfusion strategy,” they advised.

Looking ahead, Garcia said plans for the registry include determining predictors of in-hospital mortality and studying demographic and treatment trends as the pandemic continues with more virulent strains of the virus.

Various subgroup analyses are also planned as well as an independent angiographic and electrocardiographic core lab analysis. A comparative analysis of data from the US and Canada is also planned.

This work was supported by an ACC Accreditation Grant, Saskatchewan Health Research Foundation, and grants from Medtronic and Abbott Vascular to SCAI. Dr. Garcia has received institutional research grants from Edwards Lifesciences, BSCI, Medtronic, and Abbott Vascular; has served as a consultant for Medtronic and BSCI; and has served as a proctor for Edwards Lifesciences. Dr. Kornowski and Dr. Orvin disclosed no relevant financial relationships.

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

A study using data from Veterans Health Administration (VHA) electronic medical records shows a significant association between posttraumatic stress disorder (PTSD) among female veterans and an increased risk for incident ischemic heart disease (IHD).

The increased risk for IHD was highest among women younger than 40 with PTSD, and among racial and ethnic minorities.

“These women have been emerging as important targets for cardiovascular prevention, and our study suggests that PTSD may be an important psychosocial risk factor for IHD in these individuals,” wrote the researchers, led by Ramin Ebrahimi, MD, department of medicine, cardiology section, Veterans Affairs Greater Los Angeles Health Care System. “With the number of women veterans growing, it is critical to appreciate the health care needs of this relatively young and diverse patient population.”

The study results also have “important implications for earlier and more aggressive IHD risk assessment, monitoring and management in vulnerable women veterans,” they added. “Indeed, our findings support recent calls for cardiovascular risk screening in younger individuals and for the need to harness a broad range of clinicians who routinely treat younger women to maximize prevention efforts.”

The article was published online in JAMA Cardiology on March 17.
 

Increasing number of VHA users

“As an interventional cardiologist and the director of the cardiac catheterization laboratory, I noticed a significant number of the patients referred to the cath lab carried a diagnosis of posttraumatic stress disorder,” Dr. Ebrahimi said in an interview. “This intrigued me and started my journey into trying to understand how psychiatric disorders in general, and PTSD, may impact/interact with cardiovascular disorders,” he added.

The number of female veterans in the military has been increasing, and they now make up about 10% of the 20 million American veterans; that number is projected to exceed 2.2 million in the next 20 years, the authors wrote. Female veterans are also the fastest growing group of users of the VHA, they added.

IHD is the leading cause of death in women in the United States, despite the advancements in prevention and treatment. Although women are twice as likely to develop PTSD as are men, and it is even more likely in female veterans, much of the research has predominately been on male veterans, the authors wrote.

For this retrospective study, which used data from the VHA Corporate Data Warehouse, the authors examined a cohort of female veterans who were 18 years or older who had used the VHA health care system between Jan. 1, 2000, and Dec. 31, 2017.

Of the 828,997 female veterans, 151,030 had PTSD. Women excluded from the study were those who did not have any clinical encounters after their index visit, participants who had a diagnosis of IHD at or before the index visit, and those with incident IHD within 90 days of the index visit, allowing time between a PTSD diagnosis and IHD.

Propensity score matching on age at index visit, the number of previous visits, and the presence of traditional and female-specific cardiovascular risk factors, as well as mental and physical health conditions, was conducted to identify female veterans ever diagnosed with PTSD, who were matched in a 1:2 ratio to those never diagnosed with PTSD. In all, 132,923 women with PTSD and 265,846 women without PTSD were included, and data were analyzed for the period of Oct. 1, 2018, to Oct. 30, 2020.

IHD was defined as new-onset coronary artery disease, angina, or myocardial infarction–based ICD-9 and ICD-10 diagnostic codes. Age, race, and ethnicity were self-reported.

The analytic sample consisted of relatively young female veterans (mean [SD] age at baseline, 40.1 [12.2] years) of various races (White, 57.6%; Black, 29.8%) and ethnicities, the authors reported.

Of the 9,940 women who experienced incident IHD during follow-up, 5,559 did not have  PTSD (2.1% of the overall population examined) and 4,381 had PTSD (3.3%). PTSD was significantly associated with an increased risk for IHD. Over the median follow-up of 4.9 years, female veterans with PTSD had a 44% higher rate of developing incident IHD compared with the female veterans without PTSD (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.38-1.50).

In addition, those with PTSD who developed IHD were younger at diagnosis (mean [SD] age, 55.5 [9.7]) than were patients without PTSD (mean [SD] age, 57.8 [10.7]). Effect sizes were largest in the group younger than 40 years (HR, 1.72; 95% CI, 1.55-1.90) and decreased for older participants (HR for those ≥60 years, 1.24; 95% CI, 1.12-1.38)

The authors found a 49% to 66% increase in risk for IHD associated with PTSD in Black women (HR, 1.49; 95% CI, 1.38-1.62) and those identified as non-White and non-Black (HR, 1.66; 95%, 1.33-2.08).

Women of all ethnic groups with PTSD were at higher risk of developing IHD, but this was especially true for Hispanic/Latina women (HR, 1.50; 95% CI 1.22-1.84), they noted.

The authors reported some limitations to their findings. The analytic sample could result in a lower ascertainment of certain conditions, such as psychiatric disorders, they wrote. Substance disorders were low in this study, possibly because of the younger age of female veterans in the sample. Because this study used VHA electronic medical records data, medical care outside of the VHA that was not paid for by the VHA could not be considered.

In addition, although this study used a large sample of female veterans, the findings cannot be generalized to female veterans outside of the VHA system, nonveteran women, or men, the researchers wrote.


 

A call to action

In an accompanying comment, Beth E. Cohen, MD, of the University of California, San Francisco, and the San Francisco Veterans Affairs Health Care System, points out that the physical implications for psychosocial conditions, including depression and PTSD, have been recognized for quite some time. For example, results of the INTERHEART case-control study of 30,000 people showed stress, depression, and stressful life events accounted for one-third the population-attributable risk for myocardial infarction.

As was also noted by Dr. Ebrahimi and colleagues, much of the current research has been on male veterans, yet types of trauma differ among genders; women experience higher rates of military sexual trauma but lower rates of combat trauma, Dr. Cohen wrote. The PTSD symptoms, trajectory, and biological effects can differ for women and men, as can the pathogenesis, presentation, and outcomes of cardiovascular disease (CVD).

These findings, she said, “are an important extension of the prior literature and represent the largest study in female veterans to date. Although methods differ across studies, the magnitude of risk associated with PTSD was consistent with that found in prior studies of male veterans and nonveteran samples.”

The assessment of age-specific risk is also a strength of the study, “and has implications for clinical practice, because PTSD-associated risk was greatest in a younger group in whom CVD may be overlooked.”

Dr. Cohen addressed the limitations outlined by the authors, including ascertainment bias, severity of PTSD symptoms, and their chronicity, but added that “even in the context of these limitations, this study illustrates the importance of PTSD to the health of women veterans and the additional work needed to reduce their CVD risk.”

Clinical questions remain, she added. Screens for PTSD are widely used in the VHA, yet no studies have examined whether screening or early detection decrease CVD risk. In addition, no evidence suggests that screening for or treatment of PTSD improves cardiovascular outcomes.

“Given the challenges of answering these questions in observational studies, it will be important to incorporate measures of CVD risk and outcomes in trials of behavioral and medical therapies for patients with PTSD,” she wrote.

She added that collaborations among multidisciplinary patient care teams will be important. “The findings of this study represent a call to action for this important work to understand the cardiovascular effects of PTSD and improve the health and well-being of women veterans,” Dr. Cohen concluded.

This research was supported by Investigator-Initiated Research Award from the Department of Defense U.S. Army Medical Research and Material Command Congressionally Directed Medical Research Programs (Dr. Ebrahimi) and in part by grants from the VA Informatics and Computing Infrastructure and the Offices of Research and Development at the Northport, Durham, and Greater Los Angeles Veterans Affairs medical centers. Dr. Ebrahimi reported receiving grants from the Department of Defense during the conduct of the study. Disclosures for other authors are available in the paper. Dr. Cohen reports no disclosures.
 

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

A study using data from Veterans Health Administration (VHA) electronic medical records shows a significant association between posttraumatic stress disorder (PTSD) among female veterans and an increased risk for incident ischemic heart disease (IHD).

The increased risk for IHD was highest among women younger than 40 with PTSD, and among racial and ethnic minorities.

“These women have been emerging as important targets for cardiovascular prevention, and our study suggests that PTSD may be an important psychosocial risk factor for IHD in these individuals,” wrote the researchers, led by Ramin Ebrahimi, MD, department of medicine, cardiology section, Veterans Affairs Greater Los Angeles Health Care System. “With the number of women veterans growing, it is critical to appreciate the health care needs of this relatively young and diverse patient population.”

The study results also have “important implications for earlier and more aggressive IHD risk assessment, monitoring and management in vulnerable women veterans,” they added. “Indeed, our findings support recent calls for cardiovascular risk screening in younger individuals and for the need to harness a broad range of clinicians who routinely treat younger women to maximize prevention efforts.”

The article was published online in JAMA Cardiology on March 17.
 

Increasing number of VHA users

“As an interventional cardiologist and the director of the cardiac catheterization laboratory, I noticed a significant number of the patients referred to the cath lab carried a diagnosis of posttraumatic stress disorder,” Dr. Ebrahimi said in an interview. “This intrigued me and started my journey into trying to understand how psychiatric disorders in general, and PTSD, may impact/interact with cardiovascular disorders,” he added.

The number of female veterans in the military has been increasing, and they now make up about 10% of the 20 million American veterans; that number is projected to exceed 2.2 million in the next 20 years, the authors wrote. Female veterans are also the fastest growing group of users of the VHA, they added.

IHD is the leading cause of death in women in the United States, despite the advancements in prevention and treatment. Although women are twice as likely to develop PTSD as are men, and it is even more likely in female veterans, much of the research has predominately been on male veterans, the authors wrote.

For this retrospective study, which used data from the VHA Corporate Data Warehouse, the authors examined a cohort of female veterans who were 18 years or older who had used the VHA health care system between Jan. 1, 2000, and Dec. 31, 2017.

Of the 828,997 female veterans, 151,030 had PTSD. Women excluded from the study were those who did not have any clinical encounters after their index visit, participants who had a diagnosis of IHD at or before the index visit, and those with incident IHD within 90 days of the index visit, allowing time between a PTSD diagnosis and IHD.

Propensity score matching on age at index visit, the number of previous visits, and the presence of traditional and female-specific cardiovascular risk factors, as well as mental and physical health conditions, was conducted to identify female veterans ever diagnosed with PTSD, who were matched in a 1:2 ratio to those never diagnosed with PTSD. In all, 132,923 women with PTSD and 265,846 women without PTSD were included, and data were analyzed for the period of Oct. 1, 2018, to Oct. 30, 2020.

IHD was defined as new-onset coronary artery disease, angina, or myocardial infarction–based ICD-9 and ICD-10 diagnostic codes. Age, race, and ethnicity were self-reported.

The analytic sample consisted of relatively young female veterans (mean [SD] age at baseline, 40.1 [12.2] years) of various races (White, 57.6%; Black, 29.8%) and ethnicities, the authors reported.

Of the 9,940 women who experienced incident IHD during follow-up, 5,559 did not have  PTSD (2.1% of the overall population examined) and 4,381 had PTSD (3.3%). PTSD was significantly associated with an increased risk for IHD. Over the median follow-up of 4.9 years, female veterans with PTSD had a 44% higher rate of developing incident IHD compared with the female veterans without PTSD (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.38-1.50).

In addition, those with PTSD who developed IHD were younger at diagnosis (mean [SD] age, 55.5 [9.7]) than were patients without PTSD (mean [SD] age, 57.8 [10.7]). Effect sizes were largest in the group younger than 40 years (HR, 1.72; 95% CI, 1.55-1.90) and decreased for older participants (HR for those ≥60 years, 1.24; 95% CI, 1.12-1.38)

The authors found a 49% to 66% increase in risk for IHD associated with PTSD in Black women (HR, 1.49; 95% CI, 1.38-1.62) and those identified as non-White and non-Black (HR, 1.66; 95%, 1.33-2.08).

Women of all ethnic groups with PTSD were at higher risk of developing IHD, but this was especially true for Hispanic/Latina women (HR, 1.50; 95% CI 1.22-1.84), they noted.

The authors reported some limitations to their findings. The analytic sample could result in a lower ascertainment of certain conditions, such as psychiatric disorders, they wrote. Substance disorders were low in this study, possibly because of the younger age of female veterans in the sample. Because this study used VHA electronic medical records data, medical care outside of the VHA that was not paid for by the VHA could not be considered.

In addition, although this study used a large sample of female veterans, the findings cannot be generalized to female veterans outside of the VHA system, nonveteran women, or men, the researchers wrote.


 

A call to action

In an accompanying comment, Beth E. Cohen, MD, of the University of California, San Francisco, and the San Francisco Veterans Affairs Health Care System, points out that the physical implications for psychosocial conditions, including depression and PTSD, have been recognized for quite some time. For example, results of the INTERHEART case-control study of 30,000 people showed stress, depression, and stressful life events accounted for one-third the population-attributable risk for myocardial infarction.

As was also noted by Dr. Ebrahimi and colleagues, much of the current research has been on male veterans, yet types of trauma differ among genders; women experience higher rates of military sexual trauma but lower rates of combat trauma, Dr. Cohen wrote. The PTSD symptoms, trajectory, and biological effects can differ for women and men, as can the pathogenesis, presentation, and outcomes of cardiovascular disease (CVD).

These findings, she said, “are an important extension of the prior literature and represent the largest study in female veterans to date. Although methods differ across studies, the magnitude of risk associated with PTSD was consistent with that found in prior studies of male veterans and nonveteran samples.”

The assessment of age-specific risk is also a strength of the study, “and has implications for clinical practice, because PTSD-associated risk was greatest in a younger group in whom CVD may be overlooked.”

Dr. Cohen addressed the limitations outlined by the authors, including ascertainment bias, severity of PTSD symptoms, and their chronicity, but added that “even in the context of these limitations, this study illustrates the importance of PTSD to the health of women veterans and the additional work needed to reduce their CVD risk.”

Clinical questions remain, she added. Screens for PTSD are widely used in the VHA, yet no studies have examined whether screening or early detection decrease CVD risk. In addition, no evidence suggests that screening for or treatment of PTSD improves cardiovascular outcomes.

“Given the challenges of answering these questions in observational studies, it will be important to incorporate measures of CVD risk and outcomes in trials of behavioral and medical therapies for patients with PTSD,” she wrote.

She added that collaborations among multidisciplinary patient care teams will be important. “The findings of this study represent a call to action for this important work to understand the cardiovascular effects of PTSD and improve the health and well-being of women veterans,” Dr. Cohen concluded.

This research was supported by Investigator-Initiated Research Award from the Department of Defense U.S. Army Medical Research and Material Command Congressionally Directed Medical Research Programs (Dr. Ebrahimi) and in part by grants from the VA Informatics and Computing Infrastructure and the Offices of Research and Development at the Northport, Durham, and Greater Los Angeles Veterans Affairs medical centers. Dr. Ebrahimi reported receiving grants from the Department of Defense during the conduct of the study. Disclosures for other authors are available in the paper. Dr. Cohen reports no disclosures.
 

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

A study using data from Veterans Health Administration (VHA) electronic medical records shows a significant association between posttraumatic stress disorder (PTSD) among female veterans and an increased risk for incident ischemic heart disease (IHD).

The increased risk for IHD was highest among women younger than 40 with PTSD, and among racial and ethnic minorities.

“These women have been emerging as important targets for cardiovascular prevention, and our study suggests that PTSD may be an important psychosocial risk factor for IHD in these individuals,” wrote the researchers, led by Ramin Ebrahimi, MD, department of medicine, cardiology section, Veterans Affairs Greater Los Angeles Health Care System. “With the number of women veterans growing, it is critical to appreciate the health care needs of this relatively young and diverse patient population.”

The study results also have “important implications for earlier and more aggressive IHD risk assessment, monitoring and management in vulnerable women veterans,” they added. “Indeed, our findings support recent calls for cardiovascular risk screening in younger individuals and for the need to harness a broad range of clinicians who routinely treat younger women to maximize prevention efforts.”

The article was published online in JAMA Cardiology on March 17.
 

Increasing number of VHA users

“As an interventional cardiologist and the director of the cardiac catheterization laboratory, I noticed a significant number of the patients referred to the cath lab carried a diagnosis of posttraumatic stress disorder,” Dr. Ebrahimi said in an interview. “This intrigued me and started my journey into trying to understand how psychiatric disorders in general, and PTSD, may impact/interact with cardiovascular disorders,” he added.

The number of female veterans in the military has been increasing, and they now make up about 10% of the 20 million American veterans; that number is projected to exceed 2.2 million in the next 20 years, the authors wrote. Female veterans are also the fastest growing group of users of the VHA, they added.

IHD is the leading cause of death in women in the United States, despite the advancements in prevention and treatment. Although women are twice as likely to develop PTSD as are men, and it is even more likely in female veterans, much of the research has predominately been on male veterans, the authors wrote.

For this retrospective study, which used data from the VHA Corporate Data Warehouse, the authors examined a cohort of female veterans who were 18 years or older who had used the VHA health care system between Jan. 1, 2000, and Dec. 31, 2017.

Of the 828,997 female veterans, 151,030 had PTSD. Women excluded from the study were those who did not have any clinical encounters after their index visit, participants who had a diagnosis of IHD at or before the index visit, and those with incident IHD within 90 days of the index visit, allowing time between a PTSD diagnosis and IHD.

Propensity score matching on age at index visit, the number of previous visits, and the presence of traditional and female-specific cardiovascular risk factors, as well as mental and physical health conditions, was conducted to identify female veterans ever diagnosed with PTSD, who were matched in a 1:2 ratio to those never diagnosed with PTSD. In all, 132,923 women with PTSD and 265,846 women without PTSD were included, and data were analyzed for the period of Oct. 1, 2018, to Oct. 30, 2020.

IHD was defined as new-onset coronary artery disease, angina, or myocardial infarction–based ICD-9 and ICD-10 diagnostic codes. Age, race, and ethnicity were self-reported.

The analytic sample consisted of relatively young female veterans (mean [SD] age at baseline, 40.1 [12.2] years) of various races (White, 57.6%; Black, 29.8%) and ethnicities, the authors reported.

Of the 9,940 women who experienced incident IHD during follow-up, 5,559 did not have  PTSD (2.1% of the overall population examined) and 4,381 had PTSD (3.3%). PTSD was significantly associated with an increased risk for IHD. Over the median follow-up of 4.9 years, female veterans with PTSD had a 44% higher rate of developing incident IHD compared with the female veterans without PTSD (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.38-1.50).

In addition, those with PTSD who developed IHD were younger at diagnosis (mean [SD] age, 55.5 [9.7]) than were patients without PTSD (mean [SD] age, 57.8 [10.7]). Effect sizes were largest in the group younger than 40 years (HR, 1.72; 95% CI, 1.55-1.90) and decreased for older participants (HR for those ≥60 years, 1.24; 95% CI, 1.12-1.38)

The authors found a 49% to 66% increase in risk for IHD associated with PTSD in Black women (HR, 1.49; 95% CI, 1.38-1.62) and those identified as non-White and non-Black (HR, 1.66; 95%, 1.33-2.08).

Women of all ethnic groups with PTSD were at higher risk of developing IHD, but this was especially true for Hispanic/Latina women (HR, 1.50; 95% CI 1.22-1.84), they noted.

The authors reported some limitations to their findings. The analytic sample could result in a lower ascertainment of certain conditions, such as psychiatric disorders, they wrote. Substance disorders were low in this study, possibly because of the younger age of female veterans in the sample. Because this study used VHA electronic medical records data, medical care outside of the VHA that was not paid for by the VHA could not be considered.

In addition, although this study used a large sample of female veterans, the findings cannot be generalized to female veterans outside of the VHA system, nonveteran women, or men, the researchers wrote.


 

A call to action

In an accompanying comment, Beth E. Cohen, MD, of the University of California, San Francisco, and the San Francisco Veterans Affairs Health Care System, points out that the physical implications for psychosocial conditions, including depression and PTSD, have been recognized for quite some time. For example, results of the INTERHEART case-control study of 30,000 people showed stress, depression, and stressful life events accounted for one-third the population-attributable risk for myocardial infarction.

As was also noted by Dr. Ebrahimi and colleagues, much of the current research has been on male veterans, yet types of trauma differ among genders; women experience higher rates of military sexual trauma but lower rates of combat trauma, Dr. Cohen wrote. The PTSD symptoms, trajectory, and biological effects can differ for women and men, as can the pathogenesis, presentation, and outcomes of cardiovascular disease (CVD).

These findings, she said, “are an important extension of the prior literature and represent the largest study in female veterans to date. Although methods differ across studies, the magnitude of risk associated with PTSD was consistent with that found in prior studies of male veterans and nonveteran samples.”

The assessment of age-specific risk is also a strength of the study, “and has implications for clinical practice, because PTSD-associated risk was greatest in a younger group in whom CVD may be overlooked.”

Dr. Cohen addressed the limitations outlined by the authors, including ascertainment bias, severity of PTSD symptoms, and their chronicity, but added that “even in the context of these limitations, this study illustrates the importance of PTSD to the health of women veterans and the additional work needed to reduce their CVD risk.”

Clinical questions remain, she added. Screens for PTSD are widely used in the VHA, yet no studies have examined whether screening or early detection decrease CVD risk. In addition, no evidence suggests that screening for or treatment of PTSD improves cardiovascular outcomes.

“Given the challenges of answering these questions in observational studies, it will be important to incorporate measures of CVD risk and outcomes in trials of behavioral and medical therapies for patients with PTSD,” she wrote.

She added that collaborations among multidisciplinary patient care teams will be important. “The findings of this study represent a call to action for this important work to understand the cardiovascular effects of PTSD and improve the health and well-being of women veterans,” Dr. Cohen concluded.

This research was supported by Investigator-Initiated Research Award from the Department of Defense U.S. Army Medical Research and Material Command Congressionally Directed Medical Research Programs (Dr. Ebrahimi) and in part by grants from the VA Informatics and Computing Infrastructure and the Offices of Research and Development at the Northport, Durham, and Greater Los Angeles Veterans Affairs medical centers. Dr. Ebrahimi reported receiving grants from the Department of Defense during the conduct of the study. Disclosures for other authors are available in the paper. Dr. Cohen reports no disclosures.
 

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

Early use of tocilizumab (Actemra) does not reduce myocardial infarct size but modestly increases myocardial salvage in patients with acute ST-segment elevation MI (STEMI), results of the ASSAIL-MI trial suggest.

“We’re among the first to show that you can actually affect the reperfusion injury through anti-inflammatory treatment – it’s sort of a new attack point for treatments in STEMI,” lead author Kaspar Broch, MD, PhD, Oslo University Hospital Rikshospitalet, said in an interview. “What we do now is reperfuse as soon as we can and then add drugs in order to prevent new events, but we don’t really attack the reperfusion injury that occurs when you perform PCI [percutaneous coronary intervention], which has been shown to actually account for some 50% of the final injury.”

The phase 2, proof-of-concept study was prompted by the team’s earlier work in non-STEMI patients, in which a single dose of the interleukin-6 receptor antagonist cut C-reactive protein (CRP) levels by more than 50% during hospitalization and reduced troponin T release after PCI.

For ASSAIL-MI, Dr. Broch and colleagues randomly assigned 199 patients presenting with acute STEMI within 6 hours of symptom onset to a single intravenous injection of 280 mg tocilizumab or placebo during PCI. Patients, study personnel, and caretakers were blinded to treatment. Data were available for 195 patients for the primary endpoint of myocardial salvage index.

As reported in the Journal of the American College of Cardiology, tocilizumab was associated with a higher adjusted myocardial salvage index on cardiac MRI 3-7 days after PCI than placebo (69.3% vs. 63.6%; P = .04).

The extent of microvascular obstruction was less with tocilizumab (0% vs. 4%; P = .03), as was the area under the curve of CRP during hospitalization (1.9 vs. 8.6 mg/L per hour; P < .001).

The final infarct size at 6 months was 21% lower in the tocilizumab group but the difference did not reach statistical significance (7.2% vs. 9.1% of left ventricular mass; P = .08).

There were no between-group differences in troponin T area under the curve during hospitalization (1,614 vs. 2,357 ng/L per hour; P = .13), N-terminal of the prohormone brain natriuretic peptide concentrations at 6 months (79 vs. 63 ng/L; P = .25), or baseline-adjusted left ventricular end-diastolic volume at 6 months (157 vs. 160 mL; P = .54).

Subgroup analyses suggested the positive effect of tocilizumab on myocardial salvage index is limited to patients presenting at least 3 hours after symptom onset versus 3 hours or less (P = .034), with a trend for greater benefit among men versus women (P = .053).

Dr. Broch noted that the absolute effect of tocilizumab on myocardial necrosis was smaller than anticipated when the trial was designed, which may explain the lack of significant reduction in infarct size.

“We were aiming for patients with larger infarctions than we actually ended up with, which is partly due to the strict inclusion criteria and the fact that, with modern treatments, patients don’t end up with large myocardial infarctions,” he said. “But if they had been larger, I think that 20% absolute reduction would have meant a lot in terms of clinical events.”

The study also used a very modest dose of tocilizumab, compared with that used for inflammatory diseases, to minimize a potential negative effect on myocardial healing, for instance, myocardial ruptures, Dr. Broch said. “I’m not sure whether you gain anything by giving a larger dose.”

Serious adverse events were similar in the tocilizumab and placebo groups (19 vs. 15; P = .57). There were no myocardial ruptures, and no patient died or developed heart failure. LDL cholesterol, triglycerides, and liver enzymes increased in the tocilizumab group but were similar at 3 and 6 months.

Frontline Medical News

“IL-6 is a central cytokine involved in all stages of plaque growth, progression, and rupture,” Paul Ridker, MD, MPH, of the Brigham and Women’s Hospital in Boston, and a long-standing investigator in inflammation and atherothrombosis, said in an interview. “These preliminary data in STEMI, like the authors’ prior data in non-STEMI, are consistent with the idea that inhibiting IL-6 could have clinical benefit, a concept that will be taken into a major cardiovascular outcomes trial later this year.”

The cardiovascular outcomes trial, known as ZEUS, will test the novel IL-6 inhibitor ziltivekimab among more than 6,000 very-high-risk atherosclerosis patients who have moderate to severe chronic kidney disease and high sensitivity CRP greater than 2 mg/L, he noted.

Moving beyond IL-1b blockade as done in CANTOS to direct downstream inhibition of IL-6 represents a “logical next scientific step” in the development of anti-inflammatory therapies for acute ischemia and chronic atherosclerosis, Dr. Ridker, who led the CANTOS trial, noted in an accompanying editorial.

“Preventive cardiologists, however, need not wait until outcome trials are complete to use this evolving biological knowledge to their patient’s advantage,” he wrote. “As recently confirmed in the pages of the Journal, exercise, smoking cessation, and a healthy diet reduce both C-reactive protein and IL-6, and clearly have lifelong benefits. Our immediate task is thus to incorporate inflammation inhibition through lifestyle management into our daily practice.”

The study was supported by the South-Eastern Norway Regional Health Authority, Central Norway Regional Health Authority, and Roche, which provided the medicinal products and an unrestricted grant. Dr. Broch has disclosed no relevant financial relationships. Dr. Ridker has received investigator-initiated research grant support from Kowa, Novartis, Amarin, Pfizer, and the National Heart, Lung, and Blood Institute; and has served as a consultant to Novartis, Janssen, Agepha, Flame, Civi Biopharma, Inflazome, Corvidia, Novo Nordisk, SOCAR, IQVIA, and AstraZeneca.

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

Early use of tocilizumab (Actemra) does not reduce myocardial infarct size but modestly increases myocardial salvage in patients with acute ST-segment elevation MI (STEMI), results of the ASSAIL-MI trial suggest.

“We’re among the first to show that you can actually affect the reperfusion injury through anti-inflammatory treatment – it’s sort of a new attack point for treatments in STEMI,” lead author Kaspar Broch, MD, PhD, Oslo University Hospital Rikshospitalet, said in an interview. “What we do now is reperfuse as soon as we can and then add drugs in order to prevent new events, but we don’t really attack the reperfusion injury that occurs when you perform PCI [percutaneous coronary intervention], which has been shown to actually account for some 50% of the final injury.”

The phase 2, proof-of-concept study was prompted by the team’s earlier work in non-STEMI patients, in which a single dose of the interleukin-6 receptor antagonist cut C-reactive protein (CRP) levels by more than 50% during hospitalization and reduced troponin T release after PCI.

For ASSAIL-MI, Dr. Broch and colleagues randomly assigned 199 patients presenting with acute STEMI within 6 hours of symptom onset to a single intravenous injection of 280 mg tocilizumab or placebo during PCI. Patients, study personnel, and caretakers were blinded to treatment. Data were available for 195 patients for the primary endpoint of myocardial salvage index.

As reported in the Journal of the American College of Cardiology, tocilizumab was associated with a higher adjusted myocardial salvage index on cardiac MRI 3-7 days after PCI than placebo (69.3% vs. 63.6%; P = .04).

The extent of microvascular obstruction was less with tocilizumab (0% vs. 4%; P = .03), as was the area under the curve of CRP during hospitalization (1.9 vs. 8.6 mg/L per hour; P < .001).

The final infarct size at 6 months was 21% lower in the tocilizumab group but the difference did not reach statistical significance (7.2% vs. 9.1% of left ventricular mass; P = .08).

There were no between-group differences in troponin T area under the curve during hospitalization (1,614 vs. 2,357 ng/L per hour; P = .13), N-terminal of the prohormone brain natriuretic peptide concentrations at 6 months (79 vs. 63 ng/L; P = .25), or baseline-adjusted left ventricular end-diastolic volume at 6 months (157 vs. 160 mL; P = .54).

Subgroup analyses suggested the positive effect of tocilizumab on myocardial salvage index is limited to patients presenting at least 3 hours after symptom onset versus 3 hours or less (P = .034), with a trend for greater benefit among men versus women (P = .053).

Dr. Broch noted that the absolute effect of tocilizumab on myocardial necrosis was smaller than anticipated when the trial was designed, which may explain the lack of significant reduction in infarct size.

“We were aiming for patients with larger infarctions than we actually ended up with, which is partly due to the strict inclusion criteria and the fact that, with modern treatments, patients don’t end up with large myocardial infarctions,” he said. “But if they had been larger, I think that 20% absolute reduction would have meant a lot in terms of clinical events.”

The study also used a very modest dose of tocilizumab, compared with that used for inflammatory diseases, to minimize a potential negative effect on myocardial healing, for instance, myocardial ruptures, Dr. Broch said. “I’m not sure whether you gain anything by giving a larger dose.”

Serious adverse events were similar in the tocilizumab and placebo groups (19 vs. 15; P = .57). There were no myocardial ruptures, and no patient died or developed heart failure. LDL cholesterol, triglycerides, and liver enzymes increased in the tocilizumab group but were similar at 3 and 6 months.

Frontline Medical News

“IL-6 is a central cytokine involved in all stages of plaque growth, progression, and rupture,” Paul Ridker, MD, MPH, of the Brigham and Women’s Hospital in Boston, and a long-standing investigator in inflammation and atherothrombosis, said in an interview. “These preliminary data in STEMI, like the authors’ prior data in non-STEMI, are consistent with the idea that inhibiting IL-6 could have clinical benefit, a concept that will be taken into a major cardiovascular outcomes trial later this year.”

The cardiovascular outcomes trial, known as ZEUS, will test the novel IL-6 inhibitor ziltivekimab among more than 6,000 very-high-risk atherosclerosis patients who have moderate to severe chronic kidney disease and high sensitivity CRP greater than 2 mg/L, he noted.

Moving beyond IL-1b blockade as done in CANTOS to direct downstream inhibition of IL-6 represents a “logical next scientific step” in the development of anti-inflammatory therapies for acute ischemia and chronic atherosclerosis, Dr. Ridker, who led the CANTOS trial, noted in an accompanying editorial.

“Preventive cardiologists, however, need not wait until outcome trials are complete to use this evolving biological knowledge to their patient’s advantage,” he wrote. “As recently confirmed in the pages of the Journal, exercise, smoking cessation, and a healthy diet reduce both C-reactive protein and IL-6, and clearly have lifelong benefits. Our immediate task is thus to incorporate inflammation inhibition through lifestyle management into our daily practice.”

The study was supported by the South-Eastern Norway Regional Health Authority, Central Norway Regional Health Authority, and Roche, which provided the medicinal products and an unrestricted grant. Dr. Broch has disclosed no relevant financial relationships. Dr. Ridker has received investigator-initiated research grant support from Kowa, Novartis, Amarin, Pfizer, and the National Heart, Lung, and Blood Institute; and has served as a consultant to Novartis, Janssen, Agepha, Flame, Civi Biopharma, Inflazome, Corvidia, Novo Nordisk, SOCAR, IQVIA, and AstraZeneca.

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

Early use of tocilizumab (Actemra) does not reduce myocardial infarct size but modestly increases myocardial salvage in patients with acute ST-segment elevation MI (STEMI), results of the ASSAIL-MI trial suggest.

“We’re among the first to show that you can actually affect the reperfusion injury through anti-inflammatory treatment – it’s sort of a new attack point for treatments in STEMI,” lead author Kaspar Broch, MD, PhD, Oslo University Hospital Rikshospitalet, said in an interview. “What we do now is reperfuse as soon as we can and then add drugs in order to prevent new events, but we don’t really attack the reperfusion injury that occurs when you perform PCI [percutaneous coronary intervention], which has been shown to actually account for some 50% of the final injury.”

The phase 2, proof-of-concept study was prompted by the team’s earlier work in non-STEMI patients, in which a single dose of the interleukin-6 receptor antagonist cut C-reactive protein (CRP) levels by more than 50% during hospitalization and reduced troponin T release after PCI.

For ASSAIL-MI, Dr. Broch and colleagues randomly assigned 199 patients presenting with acute STEMI within 6 hours of symptom onset to a single intravenous injection of 280 mg tocilizumab or placebo during PCI. Patients, study personnel, and caretakers were blinded to treatment. Data were available for 195 patients for the primary endpoint of myocardial salvage index.

As reported in the Journal of the American College of Cardiology, tocilizumab was associated with a higher adjusted myocardial salvage index on cardiac MRI 3-7 days after PCI than placebo (69.3% vs. 63.6%; P = .04).

The extent of microvascular obstruction was less with tocilizumab (0% vs. 4%; P = .03), as was the area under the curve of CRP during hospitalization (1.9 vs. 8.6 mg/L per hour; P < .001).

The final infarct size at 6 months was 21% lower in the tocilizumab group but the difference did not reach statistical significance (7.2% vs. 9.1% of left ventricular mass; P = .08).

There were no between-group differences in troponin T area under the curve during hospitalization (1,614 vs. 2,357 ng/L per hour; P = .13), N-terminal of the prohormone brain natriuretic peptide concentrations at 6 months (79 vs. 63 ng/L; P = .25), or baseline-adjusted left ventricular end-diastolic volume at 6 months (157 vs. 160 mL; P = .54).

Subgroup analyses suggested the positive effect of tocilizumab on myocardial salvage index is limited to patients presenting at least 3 hours after symptom onset versus 3 hours or less (P = .034), with a trend for greater benefit among men versus women (P = .053).

Dr. Broch noted that the absolute effect of tocilizumab on myocardial necrosis was smaller than anticipated when the trial was designed, which may explain the lack of significant reduction in infarct size.

“We were aiming for patients with larger infarctions than we actually ended up with, which is partly due to the strict inclusion criteria and the fact that, with modern treatments, patients don’t end up with large myocardial infarctions,” he said. “But if they had been larger, I think that 20% absolute reduction would have meant a lot in terms of clinical events.”

The study also used a very modest dose of tocilizumab, compared with that used for inflammatory diseases, to minimize a potential negative effect on myocardial healing, for instance, myocardial ruptures, Dr. Broch said. “I’m not sure whether you gain anything by giving a larger dose.”

Serious adverse events were similar in the tocilizumab and placebo groups (19 vs. 15; P = .57). There were no myocardial ruptures, and no patient died or developed heart failure. LDL cholesterol, triglycerides, and liver enzymes increased in the tocilizumab group but were similar at 3 and 6 months.

Frontline Medical News

“IL-6 is a central cytokine involved in all stages of plaque growth, progression, and rupture,” Paul Ridker, MD, MPH, of the Brigham and Women’s Hospital in Boston, and a long-standing investigator in inflammation and atherothrombosis, said in an interview. “These preliminary data in STEMI, like the authors’ prior data in non-STEMI, are consistent with the idea that inhibiting IL-6 could have clinical benefit, a concept that will be taken into a major cardiovascular outcomes trial later this year.”

The cardiovascular outcomes trial, known as ZEUS, will test the novel IL-6 inhibitor ziltivekimab among more than 6,000 very-high-risk atherosclerosis patients who have moderate to severe chronic kidney disease and high sensitivity CRP greater than 2 mg/L, he noted.

Moving beyond IL-1b blockade as done in CANTOS to direct downstream inhibition of IL-6 represents a “logical next scientific step” in the development of anti-inflammatory therapies for acute ischemia and chronic atherosclerosis, Dr. Ridker, who led the CANTOS trial, noted in an accompanying editorial.

“Preventive cardiologists, however, need not wait until outcome trials are complete to use this evolving biological knowledge to their patient’s advantage,” he wrote. “As recently confirmed in the pages of the Journal, exercise, smoking cessation, and a healthy diet reduce both C-reactive protein and IL-6, and clearly have lifelong benefits. Our immediate task is thus to incorporate inflammation inhibition through lifestyle management into our daily practice.”

The study was supported by the South-Eastern Norway Regional Health Authority, Central Norway Regional Health Authority, and Roche, which provided the medicinal products and an unrestricted grant. Dr. Broch has disclosed no relevant financial relationships. Dr. Ridker has received investigator-initiated research grant support from Kowa, Novartis, Amarin, Pfizer, and the National Heart, Lung, and Blood Institute; and has served as a consultant to Novartis, Janssen, Agepha, Flame, Civi Biopharma, Inflazome, Corvidia, Novo Nordisk, SOCAR, IQVIA, and AstraZeneca.

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

Cardiovascular disease was the leading cause of death among the over 16,000 patients with type 2 diabetes (T2DM) who were enrolled in the SAVOR-TIMI 53 trial.

Two-thirds (66.3%) of all 798 deaths after a median 2.1 years of follow-up were caused by one of five cardiovascular (CV) conditions, with sudden cardiac death accounting for the largest share (30.1%) of the total, Ilaria Cavallari, MD, PhD, and associates said in the Journal of the American College of Cardiology.

Most common among the non-CV causes was malignancy at 13.9% of all deaths in a T2DM population at high/very high risk for CV disease (n = 16,492), followed by infection (9.3%), the members of the TIMI Study Group noted.

After variables independently associated with overall mortality were identified, a subdistribution of competing risks was constructed using a competing-risk analysis based on the proportional hazards model, they explained.

Prior heart failure was the clinical variable most associated with CV death and could, along with older age, worse glycemic control, prior CV events, peripheral artery disease, and kidney complications, “identify a subgroup of T2DM patients at high risk of mortality who are likely to achieve the greatest benefit from aggressive management of modifiable risk factors and newer glucose-lowering agents,” the investigators wrote.

It was a pair of laboratory measurements, however, that had the largest subdistribution hazard ratios. “Interestingly, the magnitude of associations of abnormal N-terminal pro–B-type natriuretic peptide [sHR, 2.82] and high-sensitivity troponin T [sHR, 2.46] measured in a stable population were greater than clinical variables in the prediction of all causes of death,” Dr. Cavallari and associates said.

[email protected]

Cardiovascular disease was the leading cause of death among the over 16,000 patients with type 2 diabetes (T2DM) who were enrolled in the SAVOR-TIMI 53 trial.

Two-thirds (66.3%) of all 798 deaths after a median 2.1 years of follow-up were caused by one of five cardiovascular (CV) conditions, with sudden cardiac death accounting for the largest share (30.1%) of the total, Ilaria Cavallari, MD, PhD, and associates said in the Journal of the American College of Cardiology.

Most common among the non-CV causes was malignancy at 13.9% of all deaths in a T2DM population at high/very high risk for CV disease (n = 16,492), followed by infection (9.3%), the members of the TIMI Study Group noted.

After variables independently associated with overall mortality were identified, a subdistribution of competing risks was constructed using a competing-risk analysis based on the proportional hazards model, they explained.

Prior heart failure was the clinical variable most associated with CV death and could, along with older age, worse glycemic control, prior CV events, peripheral artery disease, and kidney complications, “identify a subgroup of T2DM patients at high risk of mortality who are likely to achieve the greatest benefit from aggressive management of modifiable risk factors and newer glucose-lowering agents,” the investigators wrote.

It was a pair of laboratory measurements, however, that had the largest subdistribution hazard ratios. “Interestingly, the magnitude of associations of abnormal N-terminal pro–B-type natriuretic peptide [sHR, 2.82] and high-sensitivity troponin T [sHR, 2.46] measured in a stable population were greater than clinical variables in the prediction of all causes of death,” Dr. Cavallari and associates said.

[email protected]

Cardiovascular disease was the leading cause of death among the over 16,000 patients with type 2 diabetes (T2DM) who were enrolled in the SAVOR-TIMI 53 trial.

Two-thirds (66.3%) of all 798 deaths after a median 2.1 years of follow-up were caused by one of five cardiovascular (CV) conditions, with sudden cardiac death accounting for the largest share (30.1%) of the total, Ilaria Cavallari, MD, PhD, and associates said in the Journal of the American College of Cardiology.

Most common among the non-CV causes was malignancy at 13.9% of all deaths in a T2DM population at high/very high risk for CV disease (n = 16,492), followed by infection (9.3%), the members of the TIMI Study Group noted.

After variables independently associated with overall mortality were identified, a subdistribution of competing risks was constructed using a competing-risk analysis based on the proportional hazards model, they explained.

Prior heart failure was the clinical variable most associated with CV death and could, along with older age, worse glycemic control, prior CV events, peripheral artery disease, and kidney complications, “identify a subgroup of T2DM patients at high risk of mortality who are likely to achieve the greatest benefit from aggressive management of modifiable risk factors and newer glucose-lowering agents,” the investigators wrote.

It was a pair of laboratory measurements, however, that had the largest subdistribution hazard ratios. “Interestingly, the magnitude of associations of abnormal N-terminal pro–B-type natriuretic peptide [sHR, 2.82] and high-sensitivity troponin T [sHR, 2.46] measured in a stable population were greater than clinical variables in the prediction of all causes of death,” Dr. Cavallari and associates said.

[email protected]