ACC 2015

SAN DIEGO– The antithrombin drug bivalirudin received a boost, compared with unfractionated heparin, as the safer drug for preventing ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention in results from a multicenter, randomized trial with more than 7,000 patients.

Although the two primary endpoints from this head-to-head comparison showed no statistically significant differences between the two agents, prespecified secondary endpoints showed that treatment with bivalirudin (Angiomax) during percutaneous coronary intervention (PCI) resulted in significantly fewer deaths after 30 days and significantly fewer major bleeding events, compared with unfractionated heparin (UFH), Dr. Marco Valgimigli said at the annual meeting of the American College of Cardiology. Participating physicians administered the UFH with an antiplatelet glycoprotein IIb/IIIa inhibitor (at the operator’s discretion) 26% of the time.

In the antithrombin-randomization analysis of the MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial, which included 7,213 of the 8,404 acute coronary syndrome patients enrolled in MATRIX, treatment with bivalirudin or UFH led to similar combined rates of all-cause death, myocardial infarction, or stroke, as well as similar rates of death, MI, stroke, and major bleeds, said Dr. Valgimigli, an interventional cardiologist at Erasmus University Medical Center in Rotterdam, the Netherlands. A separate analysis of MATRIX focused on PCI outcomes with transradial vs. transfemoral access (Lancet 2015 [doi:10.1016/S0140-6736(15)60292-6]).

But treatment with bivalirudin cut the 30-day rate of all-cause death by an absolute 0.6%, driven by a concurrent cut in cardiovascular death by 0.7%, which meant that treatment with bivalirudin reduced 30-day cardiovascular deaths by one event for about every 150 patients treated, compared with patients treated with UFH, he reported. Another secondary-endpoint analysis showed that bivalirudin treatment cut the 30-day rate of major bleeding events by an absolute 1.1%, but also increased the rate of definite stent thrombosis by an absolute 0.4%, both statistically significant differences. These important differences got diluted in the primary, combined endpoints by a relatively large number of periprocedural MIs that occurred at an equal rate in both arms of the study, Dr. Valgimigli said.

The antithrombin results from MATRIX followed mixed results in several prior comparisons of bivalirudin and UFH for percutaneous coronary intervention acute coronary syndrome patients (JAMA 2015 [doi:10.1001/jama.2015.2345]). A year ago, results from the HEAT-PCI (Unfractionated Heparin Versus Bivalirudin in Primary Percutaneous Coronary Intervention) trial (Lancet 2014;384:1849-58), which enrolled 1,829 ST-elevation MI patients at one U.K. center, showed a significant reduction in ischemic events and no increased bleeding in patients treated with UFH, compared with those who received bivalirudin, a finding that experts now say seemed to lead to increased use of UFH in both U.S. and global practice relative to the more expensive bivalirudin. But the MATRIX results, as well as results published on the same day as the MATRIX report from the Chinese BRIGHT (Bivalirudin vs. Heparin With or Without Tirofiban During Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction) study (JAMA 2015 [doi:10.1001/jama.2015.232]) that also compared bivalirudin and UFH, seemed to throw the balance of evidence back in bivalirudin’s favor.

MATRIX “was a win for bivalirudin,” commented Dr. Sanjit S. Jolly, an interventional cardiologist at McMaster University in Hamilton, Ont. “Clearly mortality is the most important endpoint, and the totality of data from all the trials suggest that bivalirudin reduced mortality, compared with UFH. I think that physicians who stopped using bivalirudin after HEAT-PCI may go back to bivalirudin,” he said during a press conference at the meeting.

“Following HEAT-PCI there was a shift to greater use of UFH and more selective use of bivalirudin, even in the United States, and especially for patients with ST-elevation MI,” commented Dr. David E. Kandzari , director of interventional cardiology at the Piedmont Heart Institute in Atlanta. The new MATRIX findings “will probably prompt clinicians to revisit this given that MATRIX was the largest study to compare bivalirudin and UFH. That is not to discount the HEAT-PCI findings, but that was a much smaller trial and at a single center.”

Bivalirudin treatment results in additional expense, compared with UFH, and physicians are “under pressure to cut costs, so following the HEAT-PCI results, there was a big reduction in bivalirudin use. But with the subsequent BRIGHT results and now the MATRIX results, I think there will be an uptick again in bivalirudin use,” commented Dr. Cindy L. Grines, an interventional cardiologist at the Detroit Medical Center. The MATRIX results make her “more confident about the benefit from bivalirudin,” she said in an interview.

MATRIX was an investigator-initiated study that received grant support from Terumo and the Medicines Co. Dr. Valgimigli had no disclosures. Dr. Jolly has been a consultant to AstraZeneca, a speaker on behalf of St. Jude, and received research grants from Medtronic. Dr. Kandzari has been a consultant to Medtronic and Boston Scientific and has received research support from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic. Dr. Grines has been a consultant to and received honoraria from Abbott Vascular, the Medicines Co., Merck, and the Volcano Group.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO– The antithrombin drug bivalirudin received a boost, compared with unfractionated heparin, as the safer drug for preventing ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention in results from a multicenter, randomized trial with more than 7,000 patients.

Although the two primary endpoints from this head-to-head comparison showed no statistically significant differences between the two agents, prespecified secondary endpoints showed that treatment with bivalirudin (Angiomax) during percutaneous coronary intervention (PCI) resulted in significantly fewer deaths after 30 days and significantly fewer major bleeding events, compared with unfractionated heparin (UFH), Dr. Marco Valgimigli said at the annual meeting of the American College of Cardiology. Participating physicians administered the UFH with an antiplatelet glycoprotein IIb/IIIa inhibitor (at the operator’s discretion) 26% of the time.

In the antithrombin-randomization analysis of the MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial, which included 7,213 of the 8,404 acute coronary syndrome patients enrolled in MATRIX, treatment with bivalirudin or UFH led to similar combined rates of all-cause death, myocardial infarction, or stroke, as well as similar rates of death, MI, stroke, and major bleeds, said Dr. Valgimigli, an interventional cardiologist at Erasmus University Medical Center in Rotterdam, the Netherlands. A separate analysis of MATRIX focused on PCI outcomes with transradial vs. transfemoral access (Lancet 2015 [doi:10.1016/S0140-6736(15)60292-6]).

But treatment with bivalirudin cut the 30-day rate of all-cause death by an absolute 0.6%, driven by a concurrent cut in cardiovascular death by 0.7%, which meant that treatment with bivalirudin reduced 30-day cardiovascular deaths by one event for about every 150 patients treated, compared with patients treated with UFH, he reported. Another secondary-endpoint analysis showed that bivalirudin treatment cut the 30-day rate of major bleeding events by an absolute 1.1%, but also increased the rate of definite stent thrombosis by an absolute 0.4%, both statistically significant differences. These important differences got diluted in the primary, combined endpoints by a relatively large number of periprocedural MIs that occurred at an equal rate in both arms of the study, Dr. Valgimigli said.

The antithrombin results from MATRIX followed mixed results in several prior comparisons of bivalirudin and UFH for percutaneous coronary intervention acute coronary syndrome patients (JAMA 2015 [doi:10.1001/jama.2015.2345]). A year ago, results from the HEAT-PCI (Unfractionated Heparin Versus Bivalirudin in Primary Percutaneous Coronary Intervention) trial (Lancet 2014;384:1849-58), which enrolled 1,829 ST-elevation MI patients at one U.K. center, showed a significant reduction in ischemic events and no increased bleeding in patients treated with UFH, compared with those who received bivalirudin, a finding that experts now say seemed to lead to increased use of UFH in both U.S. and global practice relative to the more expensive bivalirudin. But the MATRIX results, as well as results published on the same day as the MATRIX report from the Chinese BRIGHT (Bivalirudin vs. Heparin With or Without Tirofiban During Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction) study (JAMA 2015 [doi:10.1001/jama.2015.232]) that also compared bivalirudin and UFH, seemed to throw the balance of evidence back in bivalirudin’s favor.

MATRIX “was a win for bivalirudin,” commented Dr. Sanjit S. Jolly, an interventional cardiologist at McMaster University in Hamilton, Ont. “Clearly mortality is the most important endpoint, and the totality of data from all the trials suggest that bivalirudin reduced mortality, compared with UFH. I think that physicians who stopped using bivalirudin after HEAT-PCI may go back to bivalirudin,” he said during a press conference at the meeting.

“Following HEAT-PCI there was a shift to greater use of UFH and more selective use of bivalirudin, even in the United States, and especially for patients with ST-elevation MI,” commented Dr. David E. Kandzari , director of interventional cardiology at the Piedmont Heart Institute in Atlanta. The new MATRIX findings “will probably prompt clinicians to revisit this given that MATRIX was the largest study to compare bivalirudin and UFH. That is not to discount the HEAT-PCI findings, but that was a much smaller trial and at a single center.”

Bivalirudin treatment results in additional expense, compared with UFH, and physicians are “under pressure to cut costs, so following the HEAT-PCI results, there was a big reduction in bivalirudin use. But with the subsequent BRIGHT results and now the MATRIX results, I think there will be an uptick again in bivalirudin use,” commented Dr. Cindy L. Grines, an interventional cardiologist at the Detroit Medical Center. The MATRIX results make her “more confident about the benefit from bivalirudin,” she said in an interview.

MATRIX was an investigator-initiated study that received grant support from Terumo and the Medicines Co. Dr. Valgimigli had no disclosures. Dr. Jolly has been a consultant to AstraZeneca, a speaker on behalf of St. Jude, and received research grants from Medtronic. Dr. Kandzari has been a consultant to Medtronic and Boston Scientific and has received research support from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic. Dr. Grines has been a consultant to and received honoraria from Abbott Vascular, the Medicines Co., Merck, and the Volcano Group.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO– The antithrombin drug bivalirudin received a boost, compared with unfractionated heparin, as the safer drug for preventing ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention in results from a multicenter, randomized trial with more than 7,000 patients.

Although the two primary endpoints from this head-to-head comparison showed no statistically significant differences between the two agents, prespecified secondary endpoints showed that treatment with bivalirudin (Angiomax) during percutaneous coronary intervention (PCI) resulted in significantly fewer deaths after 30 days and significantly fewer major bleeding events, compared with unfractionated heparin (UFH), Dr. Marco Valgimigli said at the annual meeting of the American College of Cardiology. Participating physicians administered the UFH with an antiplatelet glycoprotein IIb/IIIa inhibitor (at the operator’s discretion) 26% of the time.

In the antithrombin-randomization analysis of the MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial, which included 7,213 of the 8,404 acute coronary syndrome patients enrolled in MATRIX, treatment with bivalirudin or UFH led to similar combined rates of all-cause death, myocardial infarction, or stroke, as well as similar rates of death, MI, stroke, and major bleeds, said Dr. Valgimigli, an interventional cardiologist at Erasmus University Medical Center in Rotterdam, the Netherlands. A separate analysis of MATRIX focused on PCI outcomes with transradial vs. transfemoral access (Lancet 2015 [doi:10.1016/S0140-6736(15)60292-6]).

But treatment with bivalirudin cut the 30-day rate of all-cause death by an absolute 0.6%, driven by a concurrent cut in cardiovascular death by 0.7%, which meant that treatment with bivalirudin reduced 30-day cardiovascular deaths by one event for about every 150 patients treated, compared with patients treated with UFH, he reported. Another secondary-endpoint analysis showed that bivalirudin treatment cut the 30-day rate of major bleeding events by an absolute 1.1%, but also increased the rate of definite stent thrombosis by an absolute 0.4%, both statistically significant differences. These important differences got diluted in the primary, combined endpoints by a relatively large number of periprocedural MIs that occurred at an equal rate in both arms of the study, Dr. Valgimigli said.

The antithrombin results from MATRIX followed mixed results in several prior comparisons of bivalirudin and UFH for percutaneous coronary intervention acute coronary syndrome patients (JAMA 2015 [doi:10.1001/jama.2015.2345]). A year ago, results from the HEAT-PCI (Unfractionated Heparin Versus Bivalirudin in Primary Percutaneous Coronary Intervention) trial (Lancet 2014;384:1849-58), which enrolled 1,829 ST-elevation MI patients at one U.K. center, showed a significant reduction in ischemic events and no increased bleeding in patients treated with UFH, compared with those who received bivalirudin, a finding that experts now say seemed to lead to increased use of UFH in both U.S. and global practice relative to the more expensive bivalirudin. But the MATRIX results, as well as results published on the same day as the MATRIX report from the Chinese BRIGHT (Bivalirudin vs. Heparin With or Without Tirofiban During Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction) study (JAMA 2015 [doi:10.1001/jama.2015.232]) that also compared bivalirudin and UFH, seemed to throw the balance of evidence back in bivalirudin’s favor.

MATRIX “was a win for bivalirudin,” commented Dr. Sanjit S. Jolly, an interventional cardiologist at McMaster University in Hamilton, Ont. “Clearly mortality is the most important endpoint, and the totality of data from all the trials suggest that bivalirudin reduced mortality, compared with UFH. I think that physicians who stopped using bivalirudin after HEAT-PCI may go back to bivalirudin,” he said during a press conference at the meeting.

“Following HEAT-PCI there was a shift to greater use of UFH and more selective use of bivalirudin, even in the United States, and especially for patients with ST-elevation MI,” commented Dr. David E. Kandzari , director of interventional cardiology at the Piedmont Heart Institute in Atlanta. The new MATRIX findings “will probably prompt clinicians to revisit this given that MATRIX was the largest study to compare bivalirudin and UFH. That is not to discount the HEAT-PCI findings, but that was a much smaller trial and at a single center.”

Bivalirudin treatment results in additional expense, compared with UFH, and physicians are “under pressure to cut costs, so following the HEAT-PCI results, there was a big reduction in bivalirudin use. But with the subsequent BRIGHT results and now the MATRIX results, I think there will be an uptick again in bivalirudin use,” commented Dr. Cindy L. Grines, an interventional cardiologist at the Detroit Medical Center. The MATRIX results make her “more confident about the benefit from bivalirudin,” she said in an interview.

MATRIX was an investigator-initiated study that received grant support from Terumo and the Medicines Co. Dr. Valgimigli had no disclosures. Dr. Jolly has been a consultant to AstraZeneca, a speaker on behalf of St. Jude, and received research grants from Medtronic. Dr. Kandzari has been a consultant to Medtronic and Boston Scientific and has received research support from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic. Dr. Grines has been a consultant to and received honoraria from Abbott Vascular, the Medicines Co., Merck, and the Volcano Group.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO – Maintenance of long-term weight loss in obese or overweight individuals with atrial fibrillation was associated with nearly a sixfold greater likelihood of freedom from recurrent AF during nearly 5 years of active follow-up in the LEGACY study.

“The effect was dose dependent. The most important finding is that 46% of patients with at least a 10% weight loss were free from AF without the use of drugs or ablation procedures through nearly 5 years, versus 22% of those with 3%-9% weight loss, and just 13% with less than a 3% weight loss,” Dr. Rajeev K. Pathak said at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study) included 355 overweight or obese participants with paroxsymal or persistent AF who were offered the chance to participate in a dedicated weight-loss clinic. Regular participation in this clinic proved to be a key factor in losing weight, keeping it off, and reducing AF burden; the more frequently patients attended the quarterly sessions the better the outcomes, noted Dr. Pathak, a cardiologist and electrophysiology fellow at the University of Adelaide (Australia).

Of the 355 participants, 135 lost at least 10% of their body weight, 103 had a 3%-9% drop in body weight, and 117 had less than a 3% loss or a weight gain.

Year-by-year weight trends had a significant impact on outcome. The 141 patients with linear weight loss had a 76% AF-free rate with or without the use of drugs or ablation, compared with a 59% in the 179 patients with weight fluctuations and the 38% rate in those with no loss or a weight gain. Atrial fibrillation status was assessed by 7-day Holter monitoring at least annually.

Weight fluctuation – defined as a 1% or greater change in weight between two consecutive annual follow-ups – dampened the benefits conferred by weight loss. Patients who experienced more than a 5% weight fluctuation were 2.2-fold more likely to experience AF recurrence than were those without weight fluctuation.

Patients with a sustained 10% weight loss were 5.6-fold more likely to achieve long-term freedom from AF than were patients with lesser or no weight loss. The goal was 10% weight loss rather than a body mass index of 25 kg/m² or less because once AF patients get down to a BMI below 27 kg/m² the incremental benefit of each additional 1 BMI point in terms of freedom from AF becomes much smaller, said Dr. Pathak.

Weight loss also showed a dose-dependent effect on various cardiovascular risk factors. For example, mean systolic blood pressure fell by 18 mm Hg in subjects with at least a 10% weight loss, by 10 mm Hg with a 3%-9% loss, and by 7 mm Hg with a lesser weight loss. Triglycerides, LDL cholesterol, and glycemic control improved in similar fashion. In addition, weight loss showed beneficial effects on cardiac structure, with dose-dependent reductions in left atrial volume indexed for body surface area as well as interventricular septal thickness, Dr. Pathak continued.

He described the weight loss clinic as a “very simple” structured motivational and goal-directed program with face-to-face counseling.

“We have one patient, one physician, no props. We sit with the patient, discuss areas we can improve, then we devise a low-carb, low-fat, high-protein diet in consultation with the patient. Patients maintain a lifestyle journal where they log their meals and exercise. We prescribe at least 200 minutes of moderate-intensity activity per week. Eating is a behavioral pattern, and we have found this approach to be a very effective behavioral tool. Because the plan is developed in consultation with the patient, we’ve found patients tend to adhere to what they have planned,” he explained.

Discussant Dr. Bernard J. Gersh praised LEGACY as “a really wonderful study – very important.

“There are years of epidemiologic evidence suggesting that obesity contributes in a major way to the epidemic of atrial fibrillation, and you’ve taken it a step further,” added Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

Playing devil’s advocate, he asked whether the observed reduction in AF might have nothing to do with weight loss, but could be explained simply by LEGACY perhaps having enrolled a highly compliant group of patients who agreed to attend a clinic and were more willing to take their medications.

Dr. Pathak rejected the compliance factor as an explanation for the results. He noted that while cardiovascular risk factors improved with greater weight loss, the need for antihypertensive, lipid-lowering, and antiarrhythmic medications decreased.

“The effect can’t possibly be due to increased compliance with medications, but rather it’s a true effect of the weight loss itself. So I think this is a true clinical effect and not an epiphenomenon,” he replied.

Dr. Pathak added that he and his coinvestigators are organizing a randomized controlled confirmatory study.

Dr. Prediman K. Shah, who chaired a press conference where the LEGACY study was highlighted, said the study provided him with one of the major take-home lessons from ACC 15.

“We can argue about the mechanism of atrial fibrillation till kingdom come, but the fact is that the association is very strong that weight loss is associated with a reduced burden of atrial fibrillation, and with a very robust magnitude of benefit. That’s one of the messages that I’ll take home with me from this meeting: The next time I see my fat patient with atrial fibrillation, I’m putting him on a weight-reducing diet as the first approach,” declared Dr. Shah, professor of medicine at UCLA and director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.

Dr. Pathak reported having no financial conflicts regarding this study, which was supported by university funds.

Simultaneously with Dr. Pathak’s presentation at ACC 15, the LEGACY study was published online (J. Am. Coll. Cardiol. 2015 [doi: 10.1016/j.jacc.2015.03.002])

[email protected]

SAN DIEGO – Maintenance of long-term weight loss in obese or overweight individuals with atrial fibrillation was associated with nearly a sixfold greater likelihood of freedom from recurrent AF during nearly 5 years of active follow-up in the LEGACY study.

“The effect was dose dependent. The most important finding is that 46% of patients with at least a 10% weight loss were free from AF without the use of drugs or ablation procedures through nearly 5 years, versus 22% of those with 3%-9% weight loss, and just 13% with less than a 3% weight loss,” Dr. Rajeev K. Pathak said at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study) included 355 overweight or obese participants with paroxsymal or persistent AF who were offered the chance to participate in a dedicated weight-loss clinic. Regular participation in this clinic proved to be a key factor in losing weight, keeping it off, and reducing AF burden; the more frequently patients attended the quarterly sessions the better the outcomes, noted Dr. Pathak, a cardiologist and electrophysiology fellow at the University of Adelaide (Australia).

Of the 355 participants, 135 lost at least 10% of their body weight, 103 had a 3%-9% drop in body weight, and 117 had less than a 3% loss or a weight gain.

Year-by-year weight trends had a significant impact on outcome. The 141 patients with linear weight loss had a 76% AF-free rate with or without the use of drugs or ablation, compared with a 59% in the 179 patients with weight fluctuations and the 38% rate in those with no loss or a weight gain. Atrial fibrillation status was assessed by 7-day Holter monitoring at least annually.

Weight fluctuation – defined as a 1% or greater change in weight between two consecutive annual follow-ups – dampened the benefits conferred by weight loss. Patients who experienced more than a 5% weight fluctuation were 2.2-fold more likely to experience AF recurrence than were those without weight fluctuation.

Patients with a sustained 10% weight loss were 5.6-fold more likely to achieve long-term freedom from AF than were patients with lesser or no weight loss. The goal was 10% weight loss rather than a body mass index of 25 kg/m² or less because once AF patients get down to a BMI below 27 kg/m² the incremental benefit of each additional 1 BMI point in terms of freedom from AF becomes much smaller, said Dr. Pathak.

Weight loss also showed a dose-dependent effect on various cardiovascular risk factors. For example, mean systolic blood pressure fell by 18 mm Hg in subjects with at least a 10% weight loss, by 10 mm Hg with a 3%-9% loss, and by 7 mm Hg with a lesser weight loss. Triglycerides, LDL cholesterol, and glycemic control improved in similar fashion. In addition, weight loss showed beneficial effects on cardiac structure, with dose-dependent reductions in left atrial volume indexed for body surface area as well as interventricular septal thickness, Dr. Pathak continued.

He described the weight loss clinic as a “very simple” structured motivational and goal-directed program with face-to-face counseling.

“We have one patient, one physician, no props. We sit with the patient, discuss areas we can improve, then we devise a low-carb, low-fat, high-protein diet in consultation with the patient. Patients maintain a lifestyle journal where they log their meals and exercise. We prescribe at least 200 minutes of moderate-intensity activity per week. Eating is a behavioral pattern, and we have found this approach to be a very effective behavioral tool. Because the plan is developed in consultation with the patient, we’ve found patients tend to adhere to what they have planned,” he explained.

Discussant Dr. Bernard J. Gersh praised LEGACY as “a really wonderful study – very important.

“There are years of epidemiologic evidence suggesting that obesity contributes in a major way to the epidemic of atrial fibrillation, and you’ve taken it a step further,” added Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

Playing devil’s advocate, he asked whether the observed reduction in AF might have nothing to do with weight loss, but could be explained simply by LEGACY perhaps having enrolled a highly compliant group of patients who agreed to attend a clinic and were more willing to take their medications.

Dr. Pathak rejected the compliance factor as an explanation for the results. He noted that while cardiovascular risk factors improved with greater weight loss, the need for antihypertensive, lipid-lowering, and antiarrhythmic medications decreased.

“The effect can’t possibly be due to increased compliance with medications, but rather it’s a true effect of the weight loss itself. So I think this is a true clinical effect and not an epiphenomenon,” he replied.

Dr. Pathak added that he and his coinvestigators are organizing a randomized controlled confirmatory study.

Dr. Prediman K. Shah, who chaired a press conference where the LEGACY study was highlighted, said the study provided him with one of the major take-home lessons from ACC 15.

“We can argue about the mechanism of atrial fibrillation till kingdom come, but the fact is that the association is very strong that weight loss is associated with a reduced burden of atrial fibrillation, and with a very robust magnitude of benefit. That’s one of the messages that I’ll take home with me from this meeting: The next time I see my fat patient with atrial fibrillation, I’m putting him on a weight-reducing diet as the first approach,” declared Dr. Shah, professor of medicine at UCLA and director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.

Dr. Pathak reported having no financial conflicts regarding this study, which was supported by university funds.

Simultaneously with Dr. Pathak’s presentation at ACC 15, the LEGACY study was published online (J. Am. Coll. Cardiol. 2015 [doi: 10.1016/j.jacc.2015.03.002])

[email protected]

SAN DIEGO – Maintenance of long-term weight loss in obese or overweight individuals with atrial fibrillation was associated with nearly a sixfold greater likelihood of freedom from recurrent AF during nearly 5 years of active follow-up in the LEGACY study.

“The effect was dose dependent. The most important finding is that 46% of patients with at least a 10% weight loss were free from AF without the use of drugs or ablation procedures through nearly 5 years, versus 22% of those with 3%-9% weight loss, and just 13% with less than a 3% weight loss,” Dr. Rajeev K. Pathak said at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study) included 355 overweight or obese participants with paroxsymal or persistent AF who were offered the chance to participate in a dedicated weight-loss clinic. Regular participation in this clinic proved to be a key factor in losing weight, keeping it off, and reducing AF burden; the more frequently patients attended the quarterly sessions the better the outcomes, noted Dr. Pathak, a cardiologist and electrophysiology fellow at the University of Adelaide (Australia).

Of the 355 participants, 135 lost at least 10% of their body weight, 103 had a 3%-9% drop in body weight, and 117 had less than a 3% loss or a weight gain.

Year-by-year weight trends had a significant impact on outcome. The 141 patients with linear weight loss had a 76% AF-free rate with or without the use of drugs or ablation, compared with a 59% in the 179 patients with weight fluctuations and the 38% rate in those with no loss or a weight gain. Atrial fibrillation status was assessed by 7-day Holter monitoring at least annually.

Weight fluctuation – defined as a 1% or greater change in weight between two consecutive annual follow-ups – dampened the benefits conferred by weight loss. Patients who experienced more than a 5% weight fluctuation were 2.2-fold more likely to experience AF recurrence than were those without weight fluctuation.

Patients with a sustained 10% weight loss were 5.6-fold more likely to achieve long-term freedom from AF than were patients with lesser or no weight loss. The goal was 10% weight loss rather than a body mass index of 25 kg/m² or less because once AF patients get down to a BMI below 27 kg/m² the incremental benefit of each additional 1 BMI point in terms of freedom from AF becomes much smaller, said Dr. Pathak.

Weight loss also showed a dose-dependent effect on various cardiovascular risk factors. For example, mean systolic blood pressure fell by 18 mm Hg in subjects with at least a 10% weight loss, by 10 mm Hg with a 3%-9% loss, and by 7 mm Hg with a lesser weight loss. Triglycerides, LDL cholesterol, and glycemic control improved in similar fashion. In addition, weight loss showed beneficial effects on cardiac structure, with dose-dependent reductions in left atrial volume indexed for body surface area as well as interventricular septal thickness, Dr. Pathak continued.

He described the weight loss clinic as a “very simple” structured motivational and goal-directed program with face-to-face counseling.

“We have one patient, one physician, no props. We sit with the patient, discuss areas we can improve, then we devise a low-carb, low-fat, high-protein diet in consultation with the patient. Patients maintain a lifestyle journal where they log their meals and exercise. We prescribe at least 200 minutes of moderate-intensity activity per week. Eating is a behavioral pattern, and we have found this approach to be a very effective behavioral tool. Because the plan is developed in consultation with the patient, we’ve found patients tend to adhere to what they have planned,” he explained.

Discussant Dr. Bernard J. Gersh praised LEGACY as “a really wonderful study – very important.

“There are years of epidemiologic evidence suggesting that obesity contributes in a major way to the epidemic of atrial fibrillation, and you’ve taken it a step further,” added Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

Playing devil’s advocate, he asked whether the observed reduction in AF might have nothing to do with weight loss, but could be explained simply by LEGACY perhaps having enrolled a highly compliant group of patients who agreed to attend a clinic and were more willing to take their medications.

Dr. Pathak rejected the compliance factor as an explanation for the results. He noted that while cardiovascular risk factors improved with greater weight loss, the need for antihypertensive, lipid-lowering, and antiarrhythmic medications decreased.

“The effect can’t possibly be due to increased compliance with medications, but rather it’s a true effect of the weight loss itself. So I think this is a true clinical effect and not an epiphenomenon,” he replied.

Dr. Pathak added that he and his coinvestigators are organizing a randomized controlled confirmatory study.

Dr. Prediman K. Shah, who chaired a press conference where the LEGACY study was highlighted, said the study provided him with one of the major take-home lessons from ACC 15.

“We can argue about the mechanism of atrial fibrillation till kingdom come, but the fact is that the association is very strong that weight loss is associated with a reduced burden of atrial fibrillation, and with a very robust magnitude of benefit. That’s one of the messages that I’ll take home with me from this meeting: The next time I see my fat patient with atrial fibrillation, I’m putting him on a weight-reducing diet as the first approach,” declared Dr. Shah, professor of medicine at UCLA and director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.

Dr. Pathak reported having no financial conflicts regarding this study, which was supported by university funds.

Simultaneously with Dr. Pathak’s presentation at ACC 15, the LEGACY study was published online (J. Am. Coll. Cardiol. 2015 [doi: 10.1016/j.jacc.2015.03.002])

[email protected]

SAN DIEGO – Preventive cardiovascular medicine will get “a big boost” from ongoing major randomized controlled trials due to report results during the next several years, Dr. Eric D. Peterson predicted at the annual meeting of the American College of Cardiology.

He presented an overview of eagerly anticipated clinical trials approaching completion in three of the hottest areas of research in general cardiology: new cardiovascular prevention agents and strategies; innovative health policy initiatives; and optimal antithrombotic regimens across the range of chronic coronary artery disease, peripheral vascular disease, patients with atrial fibrillation who’ve undergone percutaneous coronary intervention, and cerebrovascular disease.

Dr. Peterson is executive director of the Duke Clinical Research Institute (DCRI), a major player in some of these studies. To gain additional perspective regarding what’s in store, he consulted a who’s who list of eminent American cardiology clinical trialists as to what’s going to be big in 2016-2017 and shortly beyond.

One thing’s clear looking out at the research horizon: Megatrials enrolling tens of thousands of patients to answer key clinical questions are not a thing of the past.

Far from it.

Cardiovascular prevention

Exciting pivotal phase III cardiovascular prevention trials are well underway in the areas of lipid modification, diabetes, and hypertension. In addition, the possible preventive effect of vitamin D and omega-3 free fatty acid supplementation seen in hypothesis-generating epidemiologic studies is finally being put to a definitive test in a 26,000-subject randomized trial known as VITAL (the Vitamin D and omega-3 trial).

Lipids: All eyes are on ongoing pivotal phase III randomized clinical outcome trials of three monoclonal antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9): the 22,500-patient FOURIER trial of evolocumab, which includes 9,000 patients older than 65 years; the 18,000-patient ODYSSEY Outcomes trial of alirocumab; and the SPIRE-1 and SPIRE-2 trials of bococizumab totaling 18,300 patients.

In phase II studies, these agents have generated enormous excitement, because they safely achieve unprecedented LDL lowering, with early hints of improved clinical outcomes beyond what’s achievable with today’s drugs, noted Dr. Peterson, professor of medicine at Duke University in Durham, N.C.

CETP inhibitors: The cholesteryl ester transfer protein inhibitors torcetrapib and dalcetrapib flamed out in clinical trials because of safety concerns and lack of clinical benefit. But pivotal phase III trials of two other CETP inhibitors are well underway: anacetrapib, which is the focus of the 30,000-patient REVEAL trial; and evacetrapib, featured in the 11,000-patient ACCELERATE trial. The CETP inhibitors simultaneously boost HDL while reducing LDL.

Diabetes: The search continues for new drugs that not only enhance diabetes control but also improve cardiovascular outcomes, or at the very least are safe in diabetes patients with coronary disease.

Next up is the nearly 15,000-patient Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), coordinated by the DCRI and University of Oxford. It’s due to be presented in June at the annual meeting of the American Diabetes Association in Boston. Trials of other dipeptidyl peptidase-4 inhibitors have shown evidence of an increased risk of heart failure, specifically with saxagliptin in the SAVOR-TIMI 53 trial and alogliptin in EXAMINE, so a lot is riding on TECOS.

The glucagon-like peptide-1 (GLP-1) agonists are under study in cardiovascular event-driven randomized clinical trials collectively totaling more than 33,000 patients with type 2 diabetes. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL), also coordinated by the DCRI and University of Oxford, includes 14,000 randomized patients. Other major trials of GLP-1 agonists are ELIXA (lixisenatide), LEADER (liraglutide), and REWIND (dulaglutide).

In addition, ongoing phase III trials of sodium glucose cotransporter 2 (SGLT-2) inhibitors with cardiovascular endpoints include the Canagliflozin Cardiovascular Assessment Study (CANVAS) and a 7,000-patient study of empagliflozin known as EMPA-REG OUTCOME.

Hypertension: The Systolic Blood Pressure Intervention Trial (SPRINT) is an NIH-funded, randomized trial designed to finally answer a question bothering physicians for years: What’s the right amount of blood pressure lowering?

Nearly 9,400 high-risk patients with clinical or subclinical cardiovascular disease have been randomized to a target systolic blood pressure of less than 120 mm Hg, compared with less than 140 mm Hg. The primary composite endpoint is cardiovascular death, nonfatal MI or stroke, or hospitalization for acute coronary syndrome. Secondary endpoints focus on cognitive impairment, dementia, and rates of progression of chronic kidney disease. Results are expected in 2018.

Vitamin D: The VITAL trial, also sponsored by the NIH, has randomized 25,875 initially healthy men and women to 2,000 IU of vitamin D₃ per day or placebo, and further randomized them to 1 g/day of omega-3 fatty acids or placebo. Key endpoints are total cancers, MI, stroke, and cardiovascular death. Results are coming in 2017.

Optimal antithrombotic therapy

Chronic coronary artery disease: It’s remarkable that physicians still don’t know the right dose of aspirin to use, even though the drug has been around since 1897. The answer is finally on the way. It will come from the ADAPTABLE eTrial, the first comparative effectiveness research project funded by the Patient-Centered Outcomes Research Institute (PCORI).

Twenty thousand U.S. patients with known atherosclerotic cardiovascular disease and at least one extra risk factor will be randomized to daily aspirin at 81 mg or 325 mg and followed for a maximum of 30 months. The primary efficacy endpoint is all-cause mortality, nonfatal MI, or nonfatal stroke. The primary safety endpoint is major bleeding.

This is a groundbreaking innovative study: It’s a 20,000-patient trial budgeted at a mere $10 million – peanuts in the world of megatrials. By comparison, the NIH-funded SPRINT hypertension trial includes less than half as many patients, yet the price tag is $114 million.

The bargain-basement cost of the aspirin trial is possible because follow-up will be via electronic medical records and claims data provided every 3 months by 29 health data networks participating in PCORI’s National Patient-Centered Clinical Research Network (PCORnet). The aspirin study is sort of a shakedown cruise for an exciting new cost-effective approach to conducting comparative effectiveness research.

“This study could be a game changer,” Dr. Peterson declared. “Whether you think the research question is important or not, the ability to utilize electronic health records in long-term patient follow-up in randomized trials will be revolutionary in terms of answering key clinical questions cost effectively.”

Peripheral vascular disease: In search of the antithrombotic regimen that optimizes limb salvage while minimizing vascular event rate, the EUCLID trial has randomized 13,500 patients with symptomatic peripheral artery disease to ticagrelor at 90 mg BID or clopidogrel at 75 mg/day. Follow-up will be for 18 months, with the primary endpoint a composite of cardiovascular death, nonfatal MI, or ischemic stroke.

Atrial fibrillation patients who undergo coronary stent placement: The 2,100-patient PIONEER AF-PCI study, now recruiting, is evaluating different combinations of rivaroxaban in various dosing regimens coupled with clopidogrel, warfarin, and/or aspirin.

Stroke: The SOCRATES trial is recruiting 9,600 patients with acute ischemic stroke or high-risk transient ischemic attack to be randomized within 24 hours to ticagrelor at 90 mg BID or aspirin at 100 mg/day. As with PIONEER, results from SOCRATES are anticipated next year.

Health policy and implementation

The ARTEMIS study poses the question of whether providing a guideline-directed medication gratis will improve patient adherence and/or clinical outcomes.

Some 9,000 high-cardiovascular-risk patients at 300 sites are being randomized to free ticagrelor or clopidogrel – no copay – for 1 year or to usual care. Outcomes include choice of medication, adherence, and major adverse cardiovascular events.

“If this works, there’s the possibility that insurers can be persuaded to pay for medications and basically give them away as a means of ultimately resulting in better outcomes for patients and lower costs,” Dr. Peterson said.

IMPACT AF is an international quality improvement project aimed at improving the use of oral anticoagulation therapy in high-risk patients with atrial fibrillation in Argentina, Brazil, China, India, and Romania. Participating centers will be randomized to receive a provider education and feedback program or not. The primary outcome is a change from baseline through year 1 in the proportion of patients with atrial fibrillation taking an oral anticoagulant.

In summing up the state of research in general cardiology, Dr. Peterson observed, “The way we do trials is changing. The size of the studies is changing. But ultimately, we will find better ways to treat patients, and perhaps we can find better ways to encourage patients to take their medications long term.”

Dr. Peterson reported serving as a consultant to AstraZeneca Boehringer Ingelheim, Genentech, Janssen, and Sanofi, and receiving research funding from Eli Lilly and Janssen.

[email protected]


SAN DIEGO – Preventive cardiovascular medicine will get “a big boost” from ongoing major randomized controlled trials due to report results during the next several years, Dr. Eric D. Peterson predicted at the annual meeting of the American College of Cardiology.

He presented an overview of eagerly anticipated clinical trials approaching completion in three of the hottest areas of research in general cardiology: new cardiovascular prevention agents and strategies; innovative health policy initiatives; and optimal antithrombotic regimens across the range of chronic coronary artery disease, peripheral vascular disease, patients with atrial fibrillation who’ve undergone percutaneous coronary intervention, and cerebrovascular disease.

Dr. Peterson is executive director of the Duke Clinical Research Institute (DCRI), a major player in some of these studies. To gain additional perspective regarding what’s in store, he consulted a who’s who list of eminent American cardiology clinical trialists as to what’s going to be big in 2016-2017 and shortly beyond.

One thing’s clear looking out at the research horizon: Megatrials enrolling tens of thousands of patients to answer key clinical questions are not a thing of the past.

Far from it.

Cardiovascular prevention

Exciting pivotal phase III cardiovascular prevention trials are well underway in the areas of lipid modification, diabetes, and hypertension. In addition, the possible preventive effect of vitamin D and omega-3 free fatty acid supplementation seen in hypothesis-generating epidemiologic studies is finally being put to a definitive test in a 26,000-subject randomized trial known as VITAL (the Vitamin D and omega-3 trial).

Lipids: All eyes are on ongoing pivotal phase III randomized clinical outcome trials of three monoclonal antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9): the 22,500-patient FOURIER trial of evolocumab, which includes 9,000 patients older than 65 years; the 18,000-patient ODYSSEY Outcomes trial of alirocumab; and the SPIRE-1 and SPIRE-2 trials of bococizumab totaling 18,300 patients.

In phase II studies, these agents have generated enormous excitement, because they safely achieve unprecedented LDL lowering, with early hints of improved clinical outcomes beyond what’s achievable with today’s drugs, noted Dr. Peterson, professor of medicine at Duke University in Durham, N.C.

CETP inhibitors: The cholesteryl ester transfer protein inhibitors torcetrapib and dalcetrapib flamed out in clinical trials because of safety concerns and lack of clinical benefit. But pivotal phase III trials of two other CETP inhibitors are well underway: anacetrapib, which is the focus of the 30,000-patient REVEAL trial; and evacetrapib, featured in the 11,000-patient ACCELERATE trial. The CETP inhibitors simultaneously boost HDL while reducing LDL.

Diabetes: The search continues for new drugs that not only enhance diabetes control but also improve cardiovascular outcomes, or at the very least are safe in diabetes patients with coronary disease.

Next up is the nearly 15,000-patient Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), coordinated by the DCRI and University of Oxford. It’s due to be presented in June at the annual meeting of the American Diabetes Association in Boston. Trials of other dipeptidyl peptidase-4 inhibitors have shown evidence of an increased risk of heart failure, specifically with saxagliptin in the SAVOR-TIMI 53 trial and alogliptin in EXAMINE, so a lot is riding on TECOS.

The glucagon-like peptide-1 (GLP-1) agonists are under study in cardiovascular event-driven randomized clinical trials collectively totaling more than 33,000 patients with type 2 diabetes. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL), also coordinated by the DCRI and University of Oxford, includes 14,000 randomized patients. Other major trials of GLP-1 agonists are ELIXA (lixisenatide), LEADER (liraglutide), and REWIND (dulaglutide).

In addition, ongoing phase III trials of sodium glucose cotransporter 2 (SGLT-2) inhibitors with cardiovascular endpoints include the Canagliflozin Cardiovascular Assessment Study (CANVAS) and a 7,000-patient study of empagliflozin known as EMPA-REG OUTCOME.

Hypertension: The Systolic Blood Pressure Intervention Trial (SPRINT) is an NIH-funded, randomized trial designed to finally answer a question bothering physicians for years: What’s the right amount of blood pressure lowering?

Nearly 9,400 high-risk patients with clinical or subclinical cardiovascular disease have been randomized to a target systolic blood pressure of less than 120 mm Hg, compared with less than 140 mm Hg. The primary composite endpoint is cardiovascular death, nonfatal MI or stroke, or hospitalization for acute coronary syndrome. Secondary endpoints focus on cognitive impairment, dementia, and rates of progression of chronic kidney disease. Results are expected in 2018.

Vitamin D: The VITAL trial, also sponsored by the NIH, has randomized 25,875 initially healthy men and women to 2,000 IU of vitamin D₃ per day or placebo, and further randomized them to 1 g/day of omega-3 fatty acids or placebo. Key endpoints are total cancers, MI, stroke, and cardiovascular death. Results are coming in 2017.

Optimal antithrombotic therapy

Chronic coronary artery disease: It’s remarkable that physicians still don’t know the right dose of aspirin to use, even though the drug has been around since 1897. The answer is finally on the way. It will come from the ADAPTABLE eTrial, the first comparative effectiveness research project funded by the Patient-Centered Outcomes Research Institute (PCORI).

Twenty thousand U.S. patients with known atherosclerotic cardiovascular disease and at least one extra risk factor will be randomized to daily aspirin at 81 mg or 325 mg and followed for a maximum of 30 months. The primary efficacy endpoint is all-cause mortality, nonfatal MI, or nonfatal stroke. The primary safety endpoint is major bleeding.

This is a groundbreaking innovative study: It’s a 20,000-patient trial budgeted at a mere $10 million – peanuts in the world of megatrials. By comparison, the NIH-funded SPRINT hypertension trial includes less than half as many patients, yet the price tag is $114 million.

The bargain-basement cost of the aspirin trial is possible because follow-up will be via electronic medical records and claims data provided every 3 months by 29 health data networks participating in PCORI’s National Patient-Centered Clinical Research Network (PCORnet). The aspirin study is sort of a shakedown cruise for an exciting new cost-effective approach to conducting comparative effectiveness research.

“This study could be a game changer,” Dr. Peterson declared. “Whether you think the research question is important or not, the ability to utilize electronic health records in long-term patient follow-up in randomized trials will be revolutionary in terms of answering key clinical questions cost effectively.”

Peripheral vascular disease: In search of the antithrombotic regimen that optimizes limb salvage while minimizing vascular event rate, the EUCLID trial has randomized 13,500 patients with symptomatic peripheral artery disease to ticagrelor at 90 mg BID or clopidogrel at 75 mg/day. Follow-up will be for 18 months, with the primary endpoint a composite of cardiovascular death, nonfatal MI, or ischemic stroke.

Atrial fibrillation patients who undergo coronary stent placement: The 2,100-patient PIONEER AF-PCI study, now recruiting, is evaluating different combinations of rivaroxaban in various dosing regimens coupled with clopidogrel, warfarin, and/or aspirin.

Stroke: The SOCRATES trial is recruiting 9,600 patients with acute ischemic stroke or high-risk transient ischemic attack to be randomized within 24 hours to ticagrelor at 90 mg BID or aspirin at 100 mg/day. As with PIONEER, results from SOCRATES are anticipated next year.

Health policy and implementation

The ARTEMIS study poses the question of whether providing a guideline-directed medication gratis will improve patient adherence and/or clinical outcomes.

Some 9,000 high-cardiovascular-risk patients at 300 sites are being randomized to free ticagrelor or clopidogrel – no copay – for 1 year or to usual care. Outcomes include choice of medication, adherence, and major adverse cardiovascular events.

“If this works, there’s the possibility that insurers can be persuaded to pay for medications and basically give them away as a means of ultimately resulting in better outcomes for patients and lower costs,” Dr. Peterson said.

IMPACT AF is an international quality improvement project aimed at improving the use of oral anticoagulation therapy in high-risk patients with atrial fibrillation in Argentina, Brazil, China, India, and Romania. Participating centers will be randomized to receive a provider education and feedback program or not. The primary outcome is a change from baseline through year 1 in the proportion of patients with atrial fibrillation taking an oral anticoagulant.

In summing up the state of research in general cardiology, Dr. Peterson observed, “The way we do trials is changing. The size of the studies is changing. But ultimately, we will find better ways to treat patients, and perhaps we can find better ways to encourage patients to take their medications long term.”

Dr. Peterson reported serving as a consultant to AstraZeneca Boehringer Ingelheim, Genentech, Janssen, and Sanofi, and receiving research funding from Eli Lilly and Janssen.

[email protected]


SAN DIEGO – Preventive cardiovascular medicine will get “a big boost” from ongoing major randomized controlled trials due to report results during the next several years, Dr. Eric D. Peterson predicted at the annual meeting of the American College of Cardiology.

He presented an overview of eagerly anticipated clinical trials approaching completion in three of the hottest areas of research in general cardiology: new cardiovascular prevention agents and strategies; innovative health policy initiatives; and optimal antithrombotic regimens across the range of chronic coronary artery disease, peripheral vascular disease, patients with atrial fibrillation who’ve undergone percutaneous coronary intervention, and cerebrovascular disease.

Dr. Peterson is executive director of the Duke Clinical Research Institute (DCRI), a major player in some of these studies. To gain additional perspective regarding what’s in store, he consulted a who’s who list of eminent American cardiology clinical trialists as to what’s going to be big in 2016-2017 and shortly beyond.

One thing’s clear looking out at the research horizon: Megatrials enrolling tens of thousands of patients to answer key clinical questions are not a thing of the past.

Far from it.

Cardiovascular prevention

Exciting pivotal phase III cardiovascular prevention trials are well underway in the areas of lipid modification, diabetes, and hypertension. In addition, the possible preventive effect of vitamin D and omega-3 free fatty acid supplementation seen in hypothesis-generating epidemiologic studies is finally being put to a definitive test in a 26,000-subject randomized trial known as VITAL (the Vitamin D and omega-3 trial).

Lipids: All eyes are on ongoing pivotal phase III randomized clinical outcome trials of three monoclonal antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9): the 22,500-patient FOURIER trial of evolocumab, which includes 9,000 patients older than 65 years; the 18,000-patient ODYSSEY Outcomes trial of alirocumab; and the SPIRE-1 and SPIRE-2 trials of bococizumab totaling 18,300 patients.

In phase II studies, these agents have generated enormous excitement, because they safely achieve unprecedented LDL lowering, with early hints of improved clinical outcomes beyond what’s achievable with today’s drugs, noted Dr. Peterson, professor of medicine at Duke University in Durham, N.C.

CETP inhibitors: The cholesteryl ester transfer protein inhibitors torcetrapib and dalcetrapib flamed out in clinical trials because of safety concerns and lack of clinical benefit. But pivotal phase III trials of two other CETP inhibitors are well underway: anacetrapib, which is the focus of the 30,000-patient REVEAL trial; and evacetrapib, featured in the 11,000-patient ACCELERATE trial. The CETP inhibitors simultaneously boost HDL while reducing LDL.

Diabetes: The search continues for new drugs that not only enhance diabetes control but also improve cardiovascular outcomes, or at the very least are safe in diabetes patients with coronary disease.

Next up is the nearly 15,000-patient Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), coordinated by the DCRI and University of Oxford. It’s due to be presented in June at the annual meeting of the American Diabetes Association in Boston. Trials of other dipeptidyl peptidase-4 inhibitors have shown evidence of an increased risk of heart failure, specifically with saxagliptin in the SAVOR-TIMI 53 trial and alogliptin in EXAMINE, so a lot is riding on TECOS.

The glucagon-like peptide-1 (GLP-1) agonists are under study in cardiovascular event-driven randomized clinical trials collectively totaling more than 33,000 patients with type 2 diabetes. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL), also coordinated by the DCRI and University of Oxford, includes 14,000 randomized patients. Other major trials of GLP-1 agonists are ELIXA (lixisenatide), LEADER (liraglutide), and REWIND (dulaglutide).

In addition, ongoing phase III trials of sodium glucose cotransporter 2 (SGLT-2) inhibitors with cardiovascular endpoints include the Canagliflozin Cardiovascular Assessment Study (CANVAS) and a 7,000-patient study of empagliflozin known as EMPA-REG OUTCOME.

Hypertension: The Systolic Blood Pressure Intervention Trial (SPRINT) is an NIH-funded, randomized trial designed to finally answer a question bothering physicians for years: What’s the right amount of blood pressure lowering?

Nearly 9,400 high-risk patients with clinical or subclinical cardiovascular disease have been randomized to a target systolic blood pressure of less than 120 mm Hg, compared with less than 140 mm Hg. The primary composite endpoint is cardiovascular death, nonfatal MI or stroke, or hospitalization for acute coronary syndrome. Secondary endpoints focus on cognitive impairment, dementia, and rates of progression of chronic kidney disease. Results are expected in 2018.

Vitamin D: The VITAL trial, also sponsored by the NIH, has randomized 25,875 initially healthy men and women to 2,000 IU of vitamin D₃ per day or placebo, and further randomized them to 1 g/day of omega-3 fatty acids or placebo. Key endpoints are total cancers, MI, stroke, and cardiovascular death. Results are coming in 2017.

Optimal antithrombotic therapy

Chronic coronary artery disease: It’s remarkable that physicians still don’t know the right dose of aspirin to use, even though the drug has been around since 1897. The answer is finally on the way. It will come from the ADAPTABLE eTrial, the first comparative effectiveness research project funded by the Patient-Centered Outcomes Research Institute (PCORI).

Twenty thousand U.S. patients with known atherosclerotic cardiovascular disease and at least one extra risk factor will be randomized to daily aspirin at 81 mg or 325 mg and followed for a maximum of 30 months. The primary efficacy endpoint is all-cause mortality, nonfatal MI, or nonfatal stroke. The primary safety endpoint is major bleeding.

This is a groundbreaking innovative study: It’s a 20,000-patient trial budgeted at a mere $10 million – peanuts in the world of megatrials. By comparison, the NIH-funded SPRINT hypertension trial includes less than half as many patients, yet the price tag is $114 million.

The bargain-basement cost of the aspirin trial is possible because follow-up will be via electronic medical records and claims data provided every 3 months by 29 health data networks participating in PCORI’s National Patient-Centered Clinical Research Network (PCORnet). The aspirin study is sort of a shakedown cruise for an exciting new cost-effective approach to conducting comparative effectiveness research.

“This study could be a game changer,” Dr. Peterson declared. “Whether you think the research question is important or not, the ability to utilize electronic health records in long-term patient follow-up in randomized trials will be revolutionary in terms of answering key clinical questions cost effectively.”

Peripheral vascular disease: In search of the antithrombotic regimen that optimizes limb salvage while minimizing vascular event rate, the EUCLID trial has randomized 13,500 patients with symptomatic peripheral artery disease to ticagrelor at 90 mg BID or clopidogrel at 75 mg/day. Follow-up will be for 18 months, with the primary endpoint a composite of cardiovascular death, nonfatal MI, or ischemic stroke.

Atrial fibrillation patients who undergo coronary stent placement: The 2,100-patient PIONEER AF-PCI study, now recruiting, is evaluating different combinations of rivaroxaban in various dosing regimens coupled with clopidogrel, warfarin, and/or aspirin.

Stroke: The SOCRATES trial is recruiting 9,600 patients with acute ischemic stroke or high-risk transient ischemic attack to be randomized within 24 hours to ticagrelor at 90 mg BID or aspirin at 100 mg/day. As with PIONEER, results from SOCRATES are anticipated next year.

Health policy and implementation

The ARTEMIS study poses the question of whether providing a guideline-directed medication gratis will improve patient adherence and/or clinical outcomes.

Some 9,000 high-cardiovascular-risk patients at 300 sites are being randomized to free ticagrelor or clopidogrel – no copay – for 1 year or to usual care. Outcomes include choice of medication, adherence, and major adverse cardiovascular events.

“If this works, there’s the possibility that insurers can be persuaded to pay for medications and basically give them away as a means of ultimately resulting in better outcomes for patients and lower costs,” Dr. Peterson said.

IMPACT AF is an international quality improvement project aimed at improving the use of oral anticoagulation therapy in high-risk patients with atrial fibrillation in Argentina, Brazil, China, India, and Romania. Participating centers will be randomized to receive a provider education and feedback program or not. The primary outcome is a change from baseline through year 1 in the proportion of patients with atrial fibrillation taking an oral anticoagulant.

In summing up the state of research in general cardiology, Dr. Peterson observed, “The way we do trials is changing. The size of the studies is changing. But ultimately, we will find better ways to treat patients, and perhaps we can find better ways to encourage patients to take their medications long term.”

Dr. Peterson reported serving as a consultant to AstraZeneca Boehringer Ingelheim, Genentech, Janssen, and Sanofi, and receiving research funding from Eli Lilly and Janssen.

[email protected]


SAN DIEGO – Patients aged 80 years and older benefit from more invasive early treatment after non-ST-elevation myocardial infarction or unstable angina, the After Eighty Trial showed.

After a median follow-up of 1.5 years, an invasive strategy that included coronary angiography significantly reduced the primary endpoint of myocardial infarction (MI), need for urgent revascularization, stroke, and death from 61% with optimal medical treatment to 41% (risk ratio, 0.48; P value < .00001).

That drop was driven primarily by significantly fewer MIs (17% vs. 30%; RR, 0.50; P = .0003) and urgent revascularizations (2% vs. 11%; RR, 0.19; P = .0001), lead author Dr. Nicolai Tegn reported at the American College of Cardiology/Cardiovascular Research Foundation Innovation in Intervention Summit.

There were no significant differences between the invasive and conservative strategy groups in rates of stroke (3% vs. 6%; RR, 0.61; P = .26) or all-cause death (25% vs. 27%; RR, 0.87; P = .53).

The composite of death and MI, however, significantly favored the invasive group (35% vs. 48%; RR, 0.54; P < .0001), he said during a latebreaking clinical trial session.

After Eighty randomly assigned 457 patients, aged 80 years or older, to either optimal medical therapy with no invasive treatments or coronary angiography at a percutaneous coronary intervention (PCI) center the day after inclusion, plus optimal medical therapy after about 4-5 hours if PCI was not performed or about 6-18 hours if it was. Of the 225 patients receiving angiography, 48% went on to balloon angioplasty and/or coronary stenting, and 3% had bypass surgery.

Patients 80 years or older account for roughly one-third of all patients with non-STEMI and unstable angina, but they are underrepresented in clinical trials. As a result, the role of an early invasive strategy, and even an invasive strategy at all, in those elderly patients is still a subject of debate, observed Dr. Tegn, a cardiologist from Rikshospitalet, Oslo University Hospital, Oslo.

The study demonstrated that an invasive strategy is superior to a conservative strategy in patients at least 80 years with NSTEMI or unstable angina, he concluded.

After Eighty is a welcome study because of the under-representation of the elderly in clinical trials, Dr. David Kandzari, director of interventional cardiology at the Piedmont Heart Center in Atlanta, said during a press briefing at the meeting. But it raises the challenge of identifying patients in clinical practice with the same qualifying characteristics, he added, given that the study population represents only 10% of the entire screened population,

There was also a fairly high prevalence of patients who angiographically did not have significant coronary artery disease, yet MI and stroke rates were quite considerable.

That said, “the study in other ways reminds us that the coronary anatomy does not know the age of the patient, meaning that the findings of a benefit of an early invasive strategy seem consistent with previous studies we know across the management of patients with acute coronary syndromes,” Dr. Kandzari said.

After Eighty investigators screened 4,187 elderly patients presenting at 17 community hospitals in Norway with non-STEMI or unstable angina, with or without ST-segment depression in ECG, and normal or elevated troponin T or I levels. Patients had to have no chest pain or other ischemic symptoms after medical treatment and mobilization.

In all, 3,730 patients were excluded for life expectancy less than 12 months because of a serious comorbidity; ongoing or recent bleeding; inability to comply with protocol; clinically unstable including ongoing ischemia; refusal to participate; logistic reasons; or other reasons.

The average age was 84.7 years in the invasive group (range 80-93 years) and 84.9 years in the conservative group (range 80-94 years).

Medical treatment during the index admission included 75 mg aspirin in 97% of both the invasive and conservative groups, clopidogrel (85% vs. 82%), ticagrelor (both 5%), angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARB) (43% vs. 50%), beta blocker (83% vs. 85%), statins (90% vs. 85%), loop or thiazide diuretics (41% vs. 33%), calcium channel blocker (20% vs. 21%), nitrates (45% vs. 55%), warfarin (17% vs. 9%), low molecular-weight heparin (both 76% ), and dabigatran in one patient in each group.

Medical therapy at discharge in the invasive and conservative groups was aspirin (both 93%), clopidogrel (both 72%), ticagrelor (both 4%), ACE inhibitor/ARB (52% vs. 54%), beta blockers (both 84%), statins (90% vs. 86%), diuretics (45% vs. 38%), calcium channel blocker (24% vs. 23%), nitrates (34% vs. 48%), warfarin (21% vs. 14%), rivaroxaban (three patients in both groups), and dabigatran (one patient vs. six patients).

There were no differences in bleeding rates between the two groups, Dr. Tegn said. Four major bleeding events were reported in both groups, while 23 patients in the invasive group and 16 patients in the conservative group had minor bleeds.

The Norwegian Health Association sponsored the study. Dr. Tegn reported nothing to disclose. Dr. Kandazari reported research and grant support from Abbott Vascular, Biotronic, Boston Scientific, and Medtronic, and minor consulting honoraria from Boston Scientific and Medtronic.

[email protected]

SAN DIEGO – Patients aged 80 years and older benefit from more invasive early treatment after non-ST-elevation myocardial infarction or unstable angina, the After Eighty Trial showed.

After a median follow-up of 1.5 years, an invasive strategy that included coronary angiography significantly reduced the primary endpoint of myocardial infarction (MI), need for urgent revascularization, stroke, and death from 61% with optimal medical treatment to 41% (risk ratio, 0.48; P value < .00001).

That drop was driven primarily by significantly fewer MIs (17% vs. 30%; RR, 0.50; P = .0003) and urgent revascularizations (2% vs. 11%; RR, 0.19; P = .0001), lead author Dr. Nicolai Tegn reported at the American College of Cardiology/Cardiovascular Research Foundation Innovation in Intervention Summit.

There were no significant differences between the invasive and conservative strategy groups in rates of stroke (3% vs. 6%; RR, 0.61; P = .26) or all-cause death (25% vs. 27%; RR, 0.87; P = .53).

The composite of death and MI, however, significantly favored the invasive group (35% vs. 48%; RR, 0.54; P < .0001), he said during a latebreaking clinical trial session.

After Eighty randomly assigned 457 patients, aged 80 years or older, to either optimal medical therapy with no invasive treatments or coronary angiography at a percutaneous coronary intervention (PCI) center the day after inclusion, plus optimal medical therapy after about 4-5 hours if PCI was not performed or about 6-18 hours if it was. Of the 225 patients receiving angiography, 48% went on to balloon angioplasty and/or coronary stenting, and 3% had bypass surgery.

Patients 80 years or older account for roughly one-third of all patients with non-STEMI and unstable angina, but they are underrepresented in clinical trials. As a result, the role of an early invasive strategy, and even an invasive strategy at all, in those elderly patients is still a subject of debate, observed Dr. Tegn, a cardiologist from Rikshospitalet, Oslo University Hospital, Oslo.

The study demonstrated that an invasive strategy is superior to a conservative strategy in patients at least 80 years with NSTEMI or unstable angina, he concluded.

After Eighty is a welcome study because of the under-representation of the elderly in clinical trials, Dr. David Kandzari, director of interventional cardiology at the Piedmont Heart Center in Atlanta, said during a press briefing at the meeting. But it raises the challenge of identifying patients in clinical practice with the same qualifying characteristics, he added, given that the study population represents only 10% of the entire screened population,

There was also a fairly high prevalence of patients who angiographically did not have significant coronary artery disease, yet MI and stroke rates were quite considerable.

That said, “the study in other ways reminds us that the coronary anatomy does not know the age of the patient, meaning that the findings of a benefit of an early invasive strategy seem consistent with previous studies we know across the management of patients with acute coronary syndromes,” Dr. Kandzari said.

After Eighty investigators screened 4,187 elderly patients presenting at 17 community hospitals in Norway with non-STEMI or unstable angina, with or without ST-segment depression in ECG, and normal or elevated troponin T or I levels. Patients had to have no chest pain or other ischemic symptoms after medical treatment and mobilization.

In all, 3,730 patients were excluded for life expectancy less than 12 months because of a serious comorbidity; ongoing or recent bleeding; inability to comply with protocol; clinically unstable including ongoing ischemia; refusal to participate; logistic reasons; or other reasons.

The average age was 84.7 years in the invasive group (range 80-93 years) and 84.9 years in the conservative group (range 80-94 years).

Medical treatment during the index admission included 75 mg aspirin in 97% of both the invasive and conservative groups, clopidogrel (85% vs. 82%), ticagrelor (both 5%), angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARB) (43% vs. 50%), beta blocker (83% vs. 85%), statins (90% vs. 85%), loop or thiazide diuretics (41% vs. 33%), calcium channel blocker (20% vs. 21%), nitrates (45% vs. 55%), warfarin (17% vs. 9%), low molecular-weight heparin (both 76% ), and dabigatran in one patient in each group.

Medical therapy at discharge in the invasive and conservative groups was aspirin (both 93%), clopidogrel (both 72%), ticagrelor (both 4%), ACE inhibitor/ARB (52% vs. 54%), beta blockers (both 84%), statins (90% vs. 86%), diuretics (45% vs. 38%), calcium channel blocker (24% vs. 23%), nitrates (34% vs. 48%), warfarin (21% vs. 14%), rivaroxaban (three patients in both groups), and dabigatran (one patient vs. six patients).

There were no differences in bleeding rates between the two groups, Dr. Tegn said. Four major bleeding events were reported in both groups, while 23 patients in the invasive group and 16 patients in the conservative group had minor bleeds.

The Norwegian Health Association sponsored the study. Dr. Tegn reported nothing to disclose. Dr. Kandazari reported research and grant support from Abbott Vascular, Biotronic, Boston Scientific, and Medtronic, and minor consulting honoraria from Boston Scientific and Medtronic.

[email protected]

SAN DIEGO – Patients aged 80 years and older benefit from more invasive early treatment after non-ST-elevation myocardial infarction or unstable angina, the After Eighty Trial showed.

After a median follow-up of 1.5 years, an invasive strategy that included coronary angiography significantly reduced the primary endpoint of myocardial infarction (MI), need for urgent revascularization, stroke, and death from 61% with optimal medical treatment to 41% (risk ratio, 0.48; P value < .00001).

That drop was driven primarily by significantly fewer MIs (17% vs. 30%; RR, 0.50; P = .0003) and urgent revascularizations (2% vs. 11%; RR, 0.19; P = .0001), lead author Dr. Nicolai Tegn reported at the American College of Cardiology/Cardiovascular Research Foundation Innovation in Intervention Summit.

There were no significant differences between the invasive and conservative strategy groups in rates of stroke (3% vs. 6%; RR, 0.61; P = .26) or all-cause death (25% vs. 27%; RR, 0.87; P = .53).

The composite of death and MI, however, significantly favored the invasive group (35% vs. 48%; RR, 0.54; P < .0001), he said during a latebreaking clinical trial session.

After Eighty randomly assigned 457 patients, aged 80 years or older, to either optimal medical therapy with no invasive treatments or coronary angiography at a percutaneous coronary intervention (PCI) center the day after inclusion, plus optimal medical therapy after about 4-5 hours if PCI was not performed or about 6-18 hours if it was. Of the 225 patients receiving angiography, 48% went on to balloon angioplasty and/or coronary stenting, and 3% had bypass surgery.

Patients 80 years or older account for roughly one-third of all patients with non-STEMI and unstable angina, but they are underrepresented in clinical trials. As a result, the role of an early invasive strategy, and even an invasive strategy at all, in those elderly patients is still a subject of debate, observed Dr. Tegn, a cardiologist from Rikshospitalet, Oslo University Hospital, Oslo.

The study demonstrated that an invasive strategy is superior to a conservative strategy in patients at least 80 years with NSTEMI or unstable angina, he concluded.

After Eighty is a welcome study because of the under-representation of the elderly in clinical trials, Dr. David Kandzari, director of interventional cardiology at the Piedmont Heart Center in Atlanta, said during a press briefing at the meeting. But it raises the challenge of identifying patients in clinical practice with the same qualifying characteristics, he added, given that the study population represents only 10% of the entire screened population,

There was also a fairly high prevalence of patients who angiographically did not have significant coronary artery disease, yet MI and stroke rates were quite considerable.

That said, “the study in other ways reminds us that the coronary anatomy does not know the age of the patient, meaning that the findings of a benefit of an early invasive strategy seem consistent with previous studies we know across the management of patients with acute coronary syndromes,” Dr. Kandzari said.

After Eighty investigators screened 4,187 elderly patients presenting at 17 community hospitals in Norway with non-STEMI or unstable angina, with or without ST-segment depression in ECG, and normal or elevated troponin T or I levels. Patients had to have no chest pain or other ischemic symptoms after medical treatment and mobilization.

In all, 3,730 patients were excluded for life expectancy less than 12 months because of a serious comorbidity; ongoing or recent bleeding; inability to comply with protocol; clinically unstable including ongoing ischemia; refusal to participate; logistic reasons; or other reasons.

The average age was 84.7 years in the invasive group (range 80-93 years) and 84.9 years in the conservative group (range 80-94 years).

Medical treatment during the index admission included 75 mg aspirin in 97% of both the invasive and conservative groups, clopidogrel (85% vs. 82%), ticagrelor (both 5%), angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARB) (43% vs. 50%), beta blocker (83% vs. 85%), statins (90% vs. 85%), loop or thiazide diuretics (41% vs. 33%), calcium channel blocker (20% vs. 21%), nitrates (45% vs. 55%), warfarin (17% vs. 9%), low molecular-weight heparin (both 76% ), and dabigatran in one patient in each group.

Medical therapy at discharge in the invasive and conservative groups was aspirin (both 93%), clopidogrel (both 72%), ticagrelor (both 4%), ACE inhibitor/ARB (52% vs. 54%), beta blockers (both 84%), statins (90% vs. 86%), diuretics (45% vs. 38%), calcium channel blocker (24% vs. 23%), nitrates (34% vs. 48%), warfarin (21% vs. 14%), rivaroxaban (three patients in both groups), and dabigatran (one patient vs. six patients).

There were no differences in bleeding rates between the two groups, Dr. Tegn said. Four major bleeding events were reported in both groups, while 23 patients in the invasive group and 16 patients in the conservative group had minor bleeds.

The Norwegian Health Association sponsored the study. Dr. Tegn reported nothing to disclose. Dr. Kandazari reported research and grant support from Abbott Vascular, Biotronic, Boston Scientific, and Medtronic, and minor consulting honoraria from Boston Scientific and Medtronic.

[email protected]

SAN DIEGO – No adverse interaction occurred between the dipeptidyl peptidase–4 inhibitor alogliptin and ACE inhibitors in patients with high cardiovascular risk and type 2 diabetes enrolled in the EXAMINE trial.

This is reassuring news that puts to rest concerns that patients on these two classes of medications might experience an increase in cardiovascular events, Dr. Christopher P. Cannon said at the annual meeting of the American College of Cardiology.

These concerns arose from evidence suggesting the possibility that DPP-4 inhibition in the presence of higher-dose ACE inhibitor therapy might activate the sympathetic nervous system through an increase in substance P, with a resultant elevated risk of serious cardiovascular events.

This hypothesis was tested in a secondary analysis of the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. In EXAMINE, 5,380 patients with type 2 diabetes and a history of an acute coronary syndrome within the previous 90 days were randomized in a double-blind fashion to oral alogliptin (Nesina) or placebo on top of standard guideline-directed medical therapy for type 2 diabetes and cardiovascular risk factors. They were prospectively followed for a median of 18 months and a maximum of 40 months.

The primary results of EXAMINE have been reported previously: Among patients with type 2 diabetes and a recent acute coronary syndrome, major adverse cardiovascular events weren’t increased with agoliptin, compared with placebo (N. Engl. J. Med. 2013;369:1327-35). But because of subsequent theoretical safety questions raised about dual therapy with agoliptin and an ACE inhibitor – and in light of the fact that 3,323 participants in EXAMINE were on background ACE inhibitor therapy – the investigators decided to perform this new secondary analysis, according to Dr. Cannon, professor of medicine at Harvard Medical School, Boston.

The composite primary endpoint comprised of cardiovascular death, nonfatal MI, and nonfatal stroke occurred in 11.4% of subjects on alogliptin plus an ACE inhibitor, compared with 11.8% of those on placebo plus an ACE inhibitor, 11.2% of patients on alogliptin without an ACE inhibitor, and 11.9% of those not on alogliptin or an ACE inhibitor.

The secondary composite endpoint of cardiovascular death or hospitalization for heart failure occurred in 6.8% of patients on alogliptin and an ACE inhibitor, 7.2% of those on placebo plus an ACE inhibitor, 8.5% of subjects on alogliptin but no ACE inhibitor, and 8.0% of those on neither – again, with no significant differences.

The EXAMINE trial was funded by Takeda Pharmaceuticals. Dr. Cannon reported serving as a consultant to that company and numerous other pharmaceutical companies.

[email protected]

SAN DIEGO – No adverse interaction occurred between the dipeptidyl peptidase–4 inhibitor alogliptin and ACE inhibitors in patients with high cardiovascular risk and type 2 diabetes enrolled in the EXAMINE trial.

This is reassuring news that puts to rest concerns that patients on these two classes of medications might experience an increase in cardiovascular events, Dr. Christopher P. Cannon said at the annual meeting of the American College of Cardiology.

These concerns arose from evidence suggesting the possibility that DPP-4 inhibition in the presence of higher-dose ACE inhibitor therapy might activate the sympathetic nervous system through an increase in substance P, with a resultant elevated risk of serious cardiovascular events.

This hypothesis was tested in a secondary analysis of the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. In EXAMINE, 5,380 patients with type 2 diabetes and a history of an acute coronary syndrome within the previous 90 days were randomized in a double-blind fashion to oral alogliptin (Nesina) or placebo on top of standard guideline-directed medical therapy for type 2 diabetes and cardiovascular risk factors. They were prospectively followed for a median of 18 months and a maximum of 40 months.

The primary results of EXAMINE have been reported previously: Among patients with type 2 diabetes and a recent acute coronary syndrome, major adverse cardiovascular events weren’t increased with agoliptin, compared with placebo (N. Engl. J. Med. 2013;369:1327-35). But because of subsequent theoretical safety questions raised about dual therapy with agoliptin and an ACE inhibitor – and in light of the fact that 3,323 participants in EXAMINE were on background ACE inhibitor therapy – the investigators decided to perform this new secondary analysis, according to Dr. Cannon, professor of medicine at Harvard Medical School, Boston.

The composite primary endpoint comprised of cardiovascular death, nonfatal MI, and nonfatal stroke occurred in 11.4% of subjects on alogliptin plus an ACE inhibitor, compared with 11.8% of those on placebo plus an ACE inhibitor, 11.2% of patients on alogliptin without an ACE inhibitor, and 11.9% of those not on alogliptin or an ACE inhibitor.

The secondary composite endpoint of cardiovascular death or hospitalization for heart failure occurred in 6.8% of patients on alogliptin and an ACE inhibitor, 7.2% of those on placebo plus an ACE inhibitor, 8.5% of subjects on alogliptin but no ACE inhibitor, and 8.0% of those on neither – again, with no significant differences.

The EXAMINE trial was funded by Takeda Pharmaceuticals. Dr. Cannon reported serving as a consultant to that company and numerous other pharmaceutical companies.

[email protected]

SAN DIEGO – No adverse interaction occurred between the dipeptidyl peptidase–4 inhibitor alogliptin and ACE inhibitors in patients with high cardiovascular risk and type 2 diabetes enrolled in the EXAMINE trial.

This is reassuring news that puts to rest concerns that patients on these two classes of medications might experience an increase in cardiovascular events, Dr. Christopher P. Cannon said at the annual meeting of the American College of Cardiology.

These concerns arose from evidence suggesting the possibility that DPP-4 inhibition in the presence of higher-dose ACE inhibitor therapy might activate the sympathetic nervous system through an increase in substance P, with a resultant elevated risk of serious cardiovascular events.

This hypothesis was tested in a secondary analysis of the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. In EXAMINE, 5,380 patients with type 2 diabetes and a history of an acute coronary syndrome within the previous 90 days were randomized in a double-blind fashion to oral alogliptin (Nesina) or placebo on top of standard guideline-directed medical therapy for type 2 diabetes and cardiovascular risk factors. They were prospectively followed for a median of 18 months and a maximum of 40 months.

The primary results of EXAMINE have been reported previously: Among patients with type 2 diabetes and a recent acute coronary syndrome, major adverse cardiovascular events weren’t increased with agoliptin, compared with placebo (N. Engl. J. Med. 2013;369:1327-35). But because of subsequent theoretical safety questions raised about dual therapy with agoliptin and an ACE inhibitor – and in light of the fact that 3,323 participants in EXAMINE were on background ACE inhibitor therapy – the investigators decided to perform this new secondary analysis, according to Dr. Cannon, professor of medicine at Harvard Medical School, Boston.

The composite primary endpoint comprised of cardiovascular death, nonfatal MI, and nonfatal stroke occurred in 11.4% of subjects on alogliptin plus an ACE inhibitor, compared with 11.8% of those on placebo plus an ACE inhibitor, 11.2% of patients on alogliptin without an ACE inhibitor, and 11.9% of those not on alogliptin or an ACE inhibitor.

The secondary composite endpoint of cardiovascular death or hospitalization for heart failure occurred in 6.8% of patients on alogliptin and an ACE inhibitor, 7.2% of those on placebo plus an ACE inhibitor, 8.5% of subjects on alogliptin but no ACE inhibitor, and 8.0% of those on neither – again, with no significant differences.

The EXAMINE trial was funded by Takeda Pharmaceuticals. Dr. Cannon reported serving as a consultant to that company and numerous other pharmaceutical companies.

[email protected]