Catherine Hackett

Washington – Heart teams will have more options when making treatment decisions for patients with severe aortic stenosis who are at intermediate risk, now that the results of the SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) trial have been presented.

Those results showed that transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis at intermediate risk was not only noninferior to surgical replacement, “but in my mind superior, because you don’t get your chest cracked, you get home earlier, and you have fewer strokes [in this trial], Roxana Mehran, MD, professor and director of interventional cardiovascular research at Mount Sinai Hospital in New York, said in a video interview at the annual meeting of the American College of Cardiology.

In SURTAVI, which used Medtronic’s self-expanding CoreValve and Evolut-R bioprostheses in 863 patients randomized to TAVR, 12.6% met the study’s primary endpoint – death from any cause or disabling stroke at 24 months – versus 14% of the 796 patients randomized to surgery, a statistically nonsignificant difference. Notably, the risk of any type of stroke at 30 days was statistically superior for TAVR, 3.4%, compared with 5.6% for surgical replacement.

“It’s tremendously important to see the change in how we’re going to be evaluating patients with aortic stenosis,” Dr. Mehran said.

[email protected]

Washington – Heart teams will have more options when making treatment decisions for patients with severe aortic stenosis who are at intermediate risk, now that the results of the SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) trial have been presented.

Those results showed that transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis at intermediate risk was not only noninferior to surgical replacement, “but in my mind superior, because you don’t get your chest cracked, you get home earlier, and you have fewer strokes [in this trial], Roxana Mehran, MD, professor and director of interventional cardiovascular research at Mount Sinai Hospital in New York, said in a video interview at the annual meeting of the American College of Cardiology.

In SURTAVI, which used Medtronic’s self-expanding CoreValve and Evolut-R bioprostheses in 863 patients randomized to TAVR, 12.6% met the study’s primary endpoint – death from any cause or disabling stroke at 24 months – versus 14% of the 796 patients randomized to surgery, a statistically nonsignificant difference. Notably, the risk of any type of stroke at 30 days was statistically superior for TAVR, 3.4%, compared with 5.6% for surgical replacement.

“It’s tremendously important to see the change in how we’re going to be evaluating patients with aortic stenosis,” Dr. Mehran said.

[email protected]

Washington – Heart teams will have more options when making treatment decisions for patients with severe aortic stenosis who are at intermediate risk, now that the results of the SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) trial have been presented.

Those results showed that transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis at intermediate risk was not only noninferior to surgical replacement, “but in my mind superior, because you don’t get your chest cracked, you get home earlier, and you have fewer strokes [in this trial], Roxana Mehran, MD, professor and director of interventional cardiovascular research at Mount Sinai Hospital in New York, said in a video interview at the annual meeting of the American College of Cardiology.

In SURTAVI, which used Medtronic’s self-expanding CoreValve and Evolut-R bioprostheses in 863 patients randomized to TAVR, 12.6% met the study’s primary endpoint – death from any cause or disabling stroke at 24 months – versus 14% of the 796 patients randomized to surgery, a statistically nonsignificant difference. Notably, the risk of any type of stroke at 30 days was statistically superior for TAVR, 3.4%, compared with 5.6% for surgical replacement.

“It’s tremendously important to see the change in how we’re going to be evaluating patients with aortic stenosis,” Dr. Mehran said.

[email protected]

The emphasis on this year’s American Heart Association Scientific Sessions in New Orleans is bigness: “Big science, big technology, and big networking opportunities,” the AHA 16 website says.

And so the 19 abstracts out of thousands submitted that got the biggest score from program committee for AHA 2016, led by Frank Sellke, MD, were chosen for presentation at four Late-Breaking Clinical Trials session previewed the late-breaking science.

CrackerClips/Thinkstock

Big trials for big questions

The first late-breaker session, on Sunday, Nov. 13, at 3:45 p.m., CT, is titled will, as its title says present the long-awaited results of four trials with large enrollment and long-term outcomes.

EUCLID (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease) randomized an estimated 16,000 patients with symptomatic PAD to long-term antiplatelet monotherapy with either ticagrelor or clopidogrel to see which one would be superior in preventing the composite of cardiovascular death, myocardial infarction and ischemic stroke up to 40 months. Secondarily, it looked at acute limb ischemia, need for revascularization, and disease progression. “This could have tremendous implications for patients treat for pad trying to prevent CV disease,” Dr. Sellke said.

PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen) harks back to 2005, when the Food and Drug Administration, wrestling with the growing evidence that NSAIDs were linked with cardiovascular events, asked for a large, cardiovascular outcomes trial. PRECISION, sponsored by Pfizer but run by an academic-led steering committee led by Steven Nissen, MD, now chief of cardiovascular medicine at the Cleveland Clinic, randomized some 20,000 arthritis patients with or at risk for cardiovascular disease to long-term pain treatment with celecoxib, naproxen, or ibuprofen for a planned follow-up of 2 years. The primary endpoint is a composite of cardiovascular death, nonfatal MI, and nonfatal stroke. Dr. Sellke noted that the results will be important for many physicians and patients wanting to minimize the risks associated with NSAIDs.

HOPE 3 (Heart Outcomes Evaluation 3), presented in April this year at the American College of Cardiology meeting in Chicago, showed the combination of rosuvastatin plus candesartan and hydrochlorothiazide reduced cardiovascular events in intermediate-risk patients with hypertension, regardless of their baseline LDL cholesterol and inflammatory biomarker levels. The analysis to be presented at AHA will show whether the combination has any effect on cognitive function. As evidence builds of the cardiovascular benefit of aggressive treatment of hypertension, as in the SPRINT trial, the results could be tremendously important, Dr. Sellke said.

TRUE AHF (Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure) randomized about 2,150 patients with acute decompensated heart failure to receive a 48-hour intravenous infusion of the natriuretic peptide ularitide or placebo. The primary outcome is a composite of 48-hour improved in-hospital worsening or unchanged clinical conditions, as well as long-term cardiovascular mortality with a median follow-up of 7 months. Because there are no effective treatments for acute systolic heart failure, the results of TRUE AHF could be of tremendous benefit, Dr. Sellke said.

Pioneering the Future of HeART Interventions

The trials with the greatest impact for practice to be presented at AHA 2015, according to the Dr. Sellke’s admitted bias as a cardiothoracic surgeon, will all be presented in this second of the late-breaker sessions, on Monday, Nov. 14, at 10:45 a.m., CT.

ART (Arterial Revascularization Trial) was a comparison of single vs. bilateral internal mammary artery grafting in more than 3,000 randomized patients undergoing coronary artery bypass surgery (CABG). The outcomes of mortality, stroke, MI, and repeat revascularization were published in 2010, showing no differences between groups. The 5-year results to be presented on Monday may resolve some of the controversy surrounding the two methods, as surgeons and cardiologists are strongly divided on the benefits and risks of single, compared with double, internal mammary artery grafting.

FUTURE (Functional Testing Underlying Coronary Revascularization) compared fractional flow reserve–guided management with conventional management in roughly 900 patients undergoing revascularization with multivessel coronary artery disease. The primary outcome is a composite of death, MI, coronary revascularization, and stroke. FFR has received a lot of attention recently, Dr. Sellke said, because it looks at the physiologic, rather than the anatomic, effects of lesion on catheterization. The results will show whether there’s clinical benefit to adding FFR to angiography that will offset the additional time it takes to perform before PCI or CABG.

PIONEER AF-PCI (An Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) addressed the conundrum of treating anticoagulated patients with atrial fibrillation who are undergoing PCI with adequate dual-antiplatelet therapy – and avoiding bleeding events. About 2,000 patients were randomized to varying combinations of rivaroxaban or warfarin plus aspirin, ticagrelor prasugrel, and/or clopidogrel for 1 year. The primary outcome is significant bleeding. Dr. Sellke said that because drug-eluting stents require at least a year of DAPT, the PIONEER AF-PCI results will add knowledge in an important and controversial area.

GERMANY is a report from the German Aortic Valve Registry (GARY) on the 1-year outcomes of patients with intermediate-risk severe aortic stenosis who underwent either transcatheter or surgical aortic replacement on the efficacy and outcomes of the two approaches. Dr. Sellke noted that these results will be important because the patients in this registry were not at high risk or ineligible for surgical aortic replacement.

Insights from New Therapeutic Trials for Lipids

Of the five trials presented in this session on Tuesday, Nov. 15, at 10:45 a.m., CT, only one is in an approved treatment for lowering lipids. That is GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound), is looking at whether LDL lowering with the PCSK9 inhibitor evolocumab reduces atheroma volume in almost 1,000 patients.

Guiding the Momentum to Effect HF Outcomes – Ironing Out the Wrinkles

Two of the six heart failure trials presented in this session on Wednesday, Nov. 16, at 10:45 a.m., CT, study cardiorespiratory effects of iron, thus the title, Dr. Sellke said.

REDUCE LAP HF (A Study to Evaluate the DC Devices, Inc. IASD System II to REDUCE Elevated Left Atrial Pressure in Patients With Heart Failure). The primary outcome is a composite of death, stroke, MI, or a systemic embolic event at 6 months. The trial evaluated a transcatheter interatrial shunt device to left atrial pressure in patients with heart failure with preserved ejection fraction (HFpEF). In this type of diastolic heart failure in which patients’ hearts cannot relax, there is really no treatment, Dr. Sellke said. So although this treatment seems “hokey,” a positive result could be important.

ATHENA HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) tested the diuretic spironolactone in heart failure. The investigators randomized 360 patients to high-dose spironolactone or usual care to see whether they could provide greater reductions of n-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels within 96 hours. There’s evidence that spironolactone can provide symptomatic relief for patients with heart failure, so these results could be important, Dr. Sellke said.

IRONOUT HF (Oral Iron Repletion Effects on Oxygen Up Take in Heart Failure) randomized heart failure patients with iron deficiency to oral iron supplementation or placebo and measured peak oxygen uptake at 16 weeks.

EFFECT-HF (Effect of Ferric Carboxymaltose on Exercise Capacity in Patients with Iron Deficiency and Chronic Heart Failure) also studied the effect of iron supplementation, intravenous in this case, on exercise capacity in heart failure patients at 24 weeks. Iron depletion is a hallmark of heart failure, Dr. Sellke pointed out, so iron repletion could be a simple way to improve functional capacity.

MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HM3) evaluated the safety and effectiveness of the Thoratec HeartMate 3 left-ventricular assist device employing MagLev technology, which is said to facilitate the free flow of blood through the device. Roughly 1,000 patients with advanced, refractory heart failure were randomized to receive either the investigational HeartMate 3 or the HeartMate 2. The primary outcomes included short- and long-term survival and freedom from debilitating stroke. Trials such as this are very important, Dr. Sellke said, because the need for donor hearts far exceeds demand and better, cheaper LVADs that last longer could extend the lives of many thousands of patients every year.

MultiSENSE (Evaluation of Multisensor Data in Heart Failure Patients With Implanted Devices) collected information taken from sensors in an implanted cardiac synchronization therapy device in 1,000 patients to develop algorithms that would detect worsening heart failure. Multiple readmissions for heart failure are frequent and ineffective, and detecting the onset of worsening heart failure has the potential to bring those admissions way down, Dr. Sellke said.

[email protected]

The emphasis on this year’s American Heart Association Scientific Sessions in New Orleans is bigness: “Big science, big technology, and big networking opportunities,” the AHA 16 website says.

And so the 19 abstracts out of thousands submitted that got the biggest score from program committee for AHA 2016, led by Frank Sellke, MD, were chosen for presentation at four Late-Breaking Clinical Trials session previewed the late-breaking science.

CrackerClips/Thinkstock

Big trials for big questions

The first late-breaker session, on Sunday, Nov. 13, at 3:45 p.m., CT, is titled will, as its title says present the long-awaited results of four trials with large enrollment and long-term outcomes.

EUCLID (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease) randomized an estimated 16,000 patients with symptomatic PAD to long-term antiplatelet monotherapy with either ticagrelor or clopidogrel to see which one would be superior in preventing the composite of cardiovascular death, myocardial infarction and ischemic stroke up to 40 months. Secondarily, it looked at acute limb ischemia, need for revascularization, and disease progression. “This could have tremendous implications for patients treat for pad trying to prevent CV disease,” Dr. Sellke said.

PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen) harks back to 2005, when the Food and Drug Administration, wrestling with the growing evidence that NSAIDs were linked with cardiovascular events, asked for a large, cardiovascular outcomes trial. PRECISION, sponsored by Pfizer but run by an academic-led steering committee led by Steven Nissen, MD, now chief of cardiovascular medicine at the Cleveland Clinic, randomized some 20,000 arthritis patients with or at risk for cardiovascular disease to long-term pain treatment with celecoxib, naproxen, or ibuprofen for a planned follow-up of 2 years. The primary endpoint is a composite of cardiovascular death, nonfatal MI, and nonfatal stroke. Dr. Sellke noted that the results will be important for many physicians and patients wanting to minimize the risks associated with NSAIDs.

HOPE 3 (Heart Outcomes Evaluation 3), presented in April this year at the American College of Cardiology meeting in Chicago, showed the combination of rosuvastatin plus candesartan and hydrochlorothiazide reduced cardiovascular events in intermediate-risk patients with hypertension, regardless of their baseline LDL cholesterol and inflammatory biomarker levels. The analysis to be presented at AHA will show whether the combination has any effect on cognitive function. As evidence builds of the cardiovascular benefit of aggressive treatment of hypertension, as in the SPRINT trial, the results could be tremendously important, Dr. Sellke said.

TRUE AHF (Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure) randomized about 2,150 patients with acute decompensated heart failure to receive a 48-hour intravenous infusion of the natriuretic peptide ularitide or placebo. The primary outcome is a composite of 48-hour improved in-hospital worsening or unchanged clinical conditions, as well as long-term cardiovascular mortality with a median follow-up of 7 months. Because there are no effective treatments for acute systolic heart failure, the results of TRUE AHF could be of tremendous benefit, Dr. Sellke said.

Pioneering the Future of HeART Interventions

The trials with the greatest impact for practice to be presented at AHA 2015, according to the Dr. Sellke’s admitted bias as a cardiothoracic surgeon, will all be presented in this second of the late-breaker sessions, on Monday, Nov. 14, at 10:45 a.m., CT.

ART (Arterial Revascularization Trial) was a comparison of single vs. bilateral internal mammary artery grafting in more than 3,000 randomized patients undergoing coronary artery bypass surgery (CABG). The outcomes of mortality, stroke, MI, and repeat revascularization were published in 2010, showing no differences between groups. The 5-year results to be presented on Monday may resolve some of the controversy surrounding the two methods, as surgeons and cardiologists are strongly divided on the benefits and risks of single, compared with double, internal mammary artery grafting.

FUTURE (Functional Testing Underlying Coronary Revascularization) compared fractional flow reserve–guided management with conventional management in roughly 900 patients undergoing revascularization with multivessel coronary artery disease. The primary outcome is a composite of death, MI, coronary revascularization, and stroke. FFR has received a lot of attention recently, Dr. Sellke said, because it looks at the physiologic, rather than the anatomic, effects of lesion on catheterization. The results will show whether there’s clinical benefit to adding FFR to angiography that will offset the additional time it takes to perform before PCI or CABG.

PIONEER AF-PCI (An Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) addressed the conundrum of treating anticoagulated patients with atrial fibrillation who are undergoing PCI with adequate dual-antiplatelet therapy – and avoiding bleeding events. About 2,000 patients were randomized to varying combinations of rivaroxaban or warfarin plus aspirin, ticagrelor prasugrel, and/or clopidogrel for 1 year. The primary outcome is significant bleeding. Dr. Sellke said that because drug-eluting stents require at least a year of DAPT, the PIONEER AF-PCI results will add knowledge in an important and controversial area.

GERMANY is a report from the German Aortic Valve Registry (GARY) on the 1-year outcomes of patients with intermediate-risk severe aortic stenosis who underwent either transcatheter or surgical aortic replacement on the efficacy and outcomes of the two approaches. Dr. Sellke noted that these results will be important because the patients in this registry were not at high risk or ineligible for surgical aortic replacement.

Insights from New Therapeutic Trials for Lipids

Of the five trials presented in this session on Tuesday, Nov. 15, at 10:45 a.m., CT, only one is in an approved treatment for lowering lipids. That is GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound), is looking at whether LDL lowering with the PCSK9 inhibitor evolocumab reduces atheroma volume in almost 1,000 patients.

Guiding the Momentum to Effect HF Outcomes – Ironing Out the Wrinkles

Two of the six heart failure trials presented in this session on Wednesday, Nov. 16, at 10:45 a.m., CT, study cardiorespiratory effects of iron, thus the title, Dr. Sellke said.

REDUCE LAP HF (A Study to Evaluate the DC Devices, Inc. IASD System II to REDUCE Elevated Left Atrial Pressure in Patients With Heart Failure). The primary outcome is a composite of death, stroke, MI, or a systemic embolic event at 6 months. The trial evaluated a transcatheter interatrial shunt device to left atrial pressure in patients with heart failure with preserved ejection fraction (HFpEF). In this type of diastolic heart failure in which patients’ hearts cannot relax, there is really no treatment, Dr. Sellke said. So although this treatment seems “hokey,” a positive result could be important.

ATHENA HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) tested the diuretic spironolactone in heart failure. The investigators randomized 360 patients to high-dose spironolactone or usual care to see whether they could provide greater reductions of n-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels within 96 hours. There’s evidence that spironolactone can provide symptomatic relief for patients with heart failure, so these results could be important, Dr. Sellke said.

IRONOUT HF (Oral Iron Repletion Effects on Oxygen Up Take in Heart Failure) randomized heart failure patients with iron deficiency to oral iron supplementation or placebo and measured peak oxygen uptake at 16 weeks.

EFFECT-HF (Effect of Ferric Carboxymaltose on Exercise Capacity in Patients with Iron Deficiency and Chronic Heart Failure) also studied the effect of iron supplementation, intravenous in this case, on exercise capacity in heart failure patients at 24 weeks. Iron depletion is a hallmark of heart failure, Dr. Sellke pointed out, so iron repletion could be a simple way to improve functional capacity.

MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HM3) evaluated the safety and effectiveness of the Thoratec HeartMate 3 left-ventricular assist device employing MagLev technology, which is said to facilitate the free flow of blood through the device. Roughly 1,000 patients with advanced, refractory heart failure were randomized to receive either the investigational HeartMate 3 or the HeartMate 2. The primary outcomes included short- and long-term survival and freedom from debilitating stroke. Trials such as this are very important, Dr. Sellke said, because the need for donor hearts far exceeds demand and better, cheaper LVADs that last longer could extend the lives of many thousands of patients every year.

MultiSENSE (Evaluation of Multisensor Data in Heart Failure Patients With Implanted Devices) collected information taken from sensors in an implanted cardiac synchronization therapy device in 1,000 patients to develop algorithms that would detect worsening heart failure. Multiple readmissions for heart failure are frequent and ineffective, and detecting the onset of worsening heart failure has the potential to bring those admissions way down, Dr. Sellke said.

[email protected]

The emphasis on this year’s American Heart Association Scientific Sessions in New Orleans is bigness: “Big science, big technology, and big networking opportunities,” the AHA 16 website says.

And so the 19 abstracts out of thousands submitted that got the biggest score from program committee for AHA 2016, led by Frank Sellke, MD, were chosen for presentation at four Late-Breaking Clinical Trials session previewed the late-breaking science.

CrackerClips/Thinkstock

Big trials for big questions

The first late-breaker session, on Sunday, Nov. 13, at 3:45 p.m., CT, is titled will, as its title says present the long-awaited results of four trials with large enrollment and long-term outcomes.

EUCLID (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease) randomized an estimated 16,000 patients with symptomatic PAD to long-term antiplatelet monotherapy with either ticagrelor or clopidogrel to see which one would be superior in preventing the composite of cardiovascular death, myocardial infarction and ischemic stroke up to 40 months. Secondarily, it looked at acute limb ischemia, need for revascularization, and disease progression. “This could have tremendous implications for patients treat for pad trying to prevent CV disease,” Dr. Sellke said.

PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen) harks back to 2005, when the Food and Drug Administration, wrestling with the growing evidence that NSAIDs were linked with cardiovascular events, asked for a large, cardiovascular outcomes trial. PRECISION, sponsored by Pfizer but run by an academic-led steering committee led by Steven Nissen, MD, now chief of cardiovascular medicine at the Cleveland Clinic, randomized some 20,000 arthritis patients with or at risk for cardiovascular disease to long-term pain treatment with celecoxib, naproxen, or ibuprofen for a planned follow-up of 2 years. The primary endpoint is a composite of cardiovascular death, nonfatal MI, and nonfatal stroke. Dr. Sellke noted that the results will be important for many physicians and patients wanting to minimize the risks associated with NSAIDs.

HOPE 3 (Heart Outcomes Evaluation 3), presented in April this year at the American College of Cardiology meeting in Chicago, showed the combination of rosuvastatin plus candesartan and hydrochlorothiazide reduced cardiovascular events in intermediate-risk patients with hypertension, regardless of their baseline LDL cholesterol and inflammatory biomarker levels. The analysis to be presented at AHA will show whether the combination has any effect on cognitive function. As evidence builds of the cardiovascular benefit of aggressive treatment of hypertension, as in the SPRINT trial, the results could be tremendously important, Dr. Sellke said.

TRUE AHF (Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure) randomized about 2,150 patients with acute decompensated heart failure to receive a 48-hour intravenous infusion of the natriuretic peptide ularitide or placebo. The primary outcome is a composite of 48-hour improved in-hospital worsening or unchanged clinical conditions, as well as long-term cardiovascular mortality with a median follow-up of 7 months. Because there are no effective treatments for acute systolic heart failure, the results of TRUE AHF could be of tremendous benefit, Dr. Sellke said.

Pioneering the Future of HeART Interventions

The trials with the greatest impact for practice to be presented at AHA 2015, according to the Dr. Sellke’s admitted bias as a cardiothoracic surgeon, will all be presented in this second of the late-breaker sessions, on Monday, Nov. 14, at 10:45 a.m., CT.

ART (Arterial Revascularization Trial) was a comparison of single vs. bilateral internal mammary artery grafting in more than 3,000 randomized patients undergoing coronary artery bypass surgery (CABG). The outcomes of mortality, stroke, MI, and repeat revascularization were published in 2010, showing no differences between groups. The 5-year results to be presented on Monday may resolve some of the controversy surrounding the two methods, as surgeons and cardiologists are strongly divided on the benefits and risks of single, compared with double, internal mammary artery grafting.

FUTURE (Functional Testing Underlying Coronary Revascularization) compared fractional flow reserve–guided management with conventional management in roughly 900 patients undergoing revascularization with multivessel coronary artery disease. The primary outcome is a composite of death, MI, coronary revascularization, and stroke. FFR has received a lot of attention recently, Dr. Sellke said, because it looks at the physiologic, rather than the anatomic, effects of lesion on catheterization. The results will show whether there’s clinical benefit to adding FFR to angiography that will offset the additional time it takes to perform before PCI or CABG.

PIONEER AF-PCI (An Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) addressed the conundrum of treating anticoagulated patients with atrial fibrillation who are undergoing PCI with adequate dual-antiplatelet therapy – and avoiding bleeding events. About 2,000 patients were randomized to varying combinations of rivaroxaban or warfarin plus aspirin, ticagrelor prasugrel, and/or clopidogrel for 1 year. The primary outcome is significant bleeding. Dr. Sellke said that because drug-eluting stents require at least a year of DAPT, the PIONEER AF-PCI results will add knowledge in an important and controversial area.

GERMANY is a report from the German Aortic Valve Registry (GARY) on the 1-year outcomes of patients with intermediate-risk severe aortic stenosis who underwent either transcatheter or surgical aortic replacement on the efficacy and outcomes of the two approaches. Dr. Sellke noted that these results will be important because the patients in this registry were not at high risk or ineligible for surgical aortic replacement.

Insights from New Therapeutic Trials for Lipids

Of the five trials presented in this session on Tuesday, Nov. 15, at 10:45 a.m., CT, only one is in an approved treatment for lowering lipids. That is GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound), is looking at whether LDL lowering with the PCSK9 inhibitor evolocumab reduces atheroma volume in almost 1,000 patients.

Guiding the Momentum to Effect HF Outcomes – Ironing Out the Wrinkles

Two of the six heart failure trials presented in this session on Wednesday, Nov. 16, at 10:45 a.m., CT, study cardiorespiratory effects of iron, thus the title, Dr. Sellke said.

REDUCE LAP HF (A Study to Evaluate the DC Devices, Inc. IASD System II to REDUCE Elevated Left Atrial Pressure in Patients With Heart Failure). The primary outcome is a composite of death, stroke, MI, or a systemic embolic event at 6 months. The trial evaluated a transcatheter interatrial shunt device to left atrial pressure in patients with heart failure with preserved ejection fraction (HFpEF). In this type of diastolic heart failure in which patients’ hearts cannot relax, there is really no treatment, Dr. Sellke said. So although this treatment seems “hokey,” a positive result could be important.

ATHENA HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) tested the diuretic spironolactone in heart failure. The investigators randomized 360 patients to high-dose spironolactone or usual care to see whether they could provide greater reductions of n-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels within 96 hours. There’s evidence that spironolactone can provide symptomatic relief for patients with heart failure, so these results could be important, Dr. Sellke said.

IRONOUT HF (Oral Iron Repletion Effects on Oxygen Up Take in Heart Failure) randomized heart failure patients with iron deficiency to oral iron supplementation or placebo and measured peak oxygen uptake at 16 weeks.

EFFECT-HF (Effect of Ferric Carboxymaltose on Exercise Capacity in Patients with Iron Deficiency and Chronic Heart Failure) also studied the effect of iron supplementation, intravenous in this case, on exercise capacity in heart failure patients at 24 weeks. Iron depletion is a hallmark of heart failure, Dr. Sellke pointed out, so iron repletion could be a simple way to improve functional capacity.

MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HM3) evaluated the safety and effectiveness of the Thoratec HeartMate 3 left-ventricular assist device employing MagLev technology, which is said to facilitate the free flow of blood through the device. Roughly 1,000 patients with advanced, refractory heart failure were randomized to receive either the investigational HeartMate 3 or the HeartMate 2. The primary outcomes included short- and long-term survival and freedom from debilitating stroke. Trials such as this are very important, Dr. Sellke said, because the need for donor hearts far exceeds demand and better, cheaper LVADs that last longer could extend the lives of many thousands of patients every year.

MultiSENSE (Evaluation of Multisensor Data in Heart Failure Patients With Implanted Devices) collected information taken from sensors in an implanted cardiac synchronization therapy device in 1,000 patients to develop algorithms that would detect worsening heart failure. Multiple readmissions for heart failure are frequent and ineffective, and detecting the onset of worsening heart failure has the potential to bring those admissions way down, Dr. Sellke said.

[email protected]

ROME – Treating patients with heterozygous familial hypercholesterolemia (HeFH) with PCSK9 inhibitors can reduce their need for lipoprotein apheresis and its associated costs, Patrick M. Moriarty, MD, said in a video interview at the annual congress of the European Society of Cardiology.

In the randomized, phase III ODYSSEY ESCAPE trial, HeFH patients who underwent weekly apheresis were treated with either alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, or placebo. At the end of the study, the alirocumab-treated patients had a 75% greater reduction in need for apheresis, compared with those on placebo – a statistically significant difference.

With a price tag of $50,000-$75,000 a year for lipoprotein apheresis, compared with the roughly $12,000 cost for a PCSK9 inhibitor, this represents a significant savings for patients with HeFH, which occurs in roughly 1 in 200 people worldwide, Dr. Moriarty of the University of Kansas, Kansas City, told reporter Bruce Jancin.

ROME – Treating patients with heterozygous familial hypercholesterolemia (HeFH) with PCSK9 inhibitors can reduce their need for lipoprotein apheresis and its associated costs, Patrick M. Moriarty, MD, said in a video interview at the annual congress of the European Society of Cardiology.

In the randomized, phase III ODYSSEY ESCAPE trial, HeFH patients who underwent weekly apheresis were treated with either alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, or placebo. At the end of the study, the alirocumab-treated patients had a 75% greater reduction in need for apheresis, compared with those on placebo – a statistically significant difference.

With a price tag of $50,000-$75,000 a year for lipoprotein apheresis, compared with the roughly $12,000 cost for a PCSK9 inhibitor, this represents a significant savings for patients with HeFH, which occurs in roughly 1 in 200 people worldwide, Dr. Moriarty of the University of Kansas, Kansas City, told reporter Bruce Jancin.

ROME – Treating patients with heterozygous familial hypercholesterolemia (HeFH) with PCSK9 inhibitors can reduce their need for lipoprotein apheresis and its associated costs, Patrick M. Moriarty, MD, said in a video interview at the annual congress of the European Society of Cardiology.

In the randomized, phase III ODYSSEY ESCAPE trial, HeFH patients who underwent weekly apheresis were treated with either alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, or placebo. At the end of the study, the alirocumab-treated patients had a 75% greater reduction in need for apheresis, compared with those on placebo – a statistically significant difference.

With a price tag of $50,000-$75,000 a year for lipoprotein apheresis, compared with the roughly $12,000 cost for a PCSK9 inhibitor, this represents a significant savings for patients with HeFH, which occurs in roughly 1 in 200 people worldwide, Dr. Moriarty of the University of Kansas, Kansas City, told reporter Bruce Jancin.

ROME – Treating patients with heterozygous familial hypercholesterolemia (HeFH) with PCSK9 inhibitors can reduce their need for lipoprotein apheresis and its associated costs, Patrick M. Moriarty, MD, said in a video interview at the annual congress of the European Society of Cardiology.

In the randomized, phase III ODYSSEY ESCAPE trial, HeFH patients who underwent weekly apheresis were treated with either alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, or placebo. At the end of the study, the alirocumab-treated patients had a 75% greater reduction in need for apheresis, compared with those on placebo – a statistically significant difference.

With a price tag of $50,000-$75,000 a year for lipoprotein apheresis, compared with the roughly $12,000 cost for a PCSK9 inhibitor, this represents a significant savings for patients with HeFH, which occurs in roughly 1 in 200 people worldwide, Dr. Moriarty of the University of Kansas, Kansas City, told reporter Bruce Jancin.

[email protected]

ROME – Treating patients with heterozygous familial hypercholesterolemia (HeFH) with PCSK9 inhibitors can reduce their need for lipoprotein apheresis and its associated costs, Patrick M. Moriarty, MD, said in a video interview at the annual congress of the European Society of Cardiology.

In the randomized, phase III ODYSSEY ESCAPE trial, HeFH patients who underwent weekly apheresis were treated with either alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, or placebo. At the end of the study, the alirocumab-treated patients had a 75% greater reduction in need for apheresis, compared with those on placebo – a statistically significant difference.

With a price tag of $50,000-$75,000 a year for lipoprotein apheresis, compared with the roughly $12,000 cost for a PCSK9 inhibitor, this represents a significant savings for patients with HeFH, which occurs in roughly 1 in 200 people worldwide, Dr. Moriarty of the University of Kansas, Kansas City, told reporter Bruce Jancin.

[email protected]

ROME – Treating patients with heterozygous familial hypercholesterolemia (HeFH) with PCSK9 inhibitors can reduce their need for lipoprotein apheresis and its associated costs, Patrick M. Moriarty, MD, said in a video interview at the annual congress of the European Society of Cardiology.

In the randomized, phase III ODYSSEY ESCAPE trial, HeFH patients who underwent weekly apheresis were treated with either alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, or placebo. At the end of the study, the alirocumab-treated patients had a 75% greater reduction in need for apheresis, compared with those on placebo – a statistically significant difference.

With a price tag of $50,000-$75,000 a year for lipoprotein apheresis, compared with the roughly $12,000 cost for a PCSK9 inhibitor, this represents a significant savings for patients with HeFH, which occurs in roughly 1 in 200 people worldwide, Dr. Moriarty of the University of Kansas, Kansas City, told reporter Bruce Jancin.

[email protected]

ROME – “Unfounded” concerns about cardiovascular effects have contributed to underuse of varenicline for smoking cessation, Kornelia Kotseva, MD, said at the annual congress of the European Society of Cardiology.

In an exclusive video interview, Dr. Kotseva of Imperial College, London, told our reporter Bruce Jancin that meta-analyses have shown no significant difference in serious cardiovascular events between varenicline-treated patients and those on placebo, regardless of whether the patients had underlying cardiovascular disease.

Varenicline use for smoking cessation reduces the risk of cardiovascular events by 36%, she reported, more than reductions seen with either nicotine replacement therapy or bupropion.

[email protected]

ROME – “Unfounded” concerns about cardiovascular effects have contributed to underuse of varenicline for smoking cessation, Kornelia Kotseva, MD, said at the annual congress of the European Society of Cardiology.

In an exclusive video interview, Dr. Kotseva of Imperial College, London, told our reporter Bruce Jancin that meta-analyses have shown no significant difference in serious cardiovascular events between varenicline-treated patients and those on placebo, regardless of whether the patients had underlying cardiovascular disease.

Varenicline use for smoking cessation reduces the risk of cardiovascular events by 36%, she reported, more than reductions seen with either nicotine replacement therapy or bupropion.

[email protected]

ROME – “Unfounded” concerns about cardiovascular effects have contributed to underuse of varenicline for smoking cessation, Kornelia Kotseva, MD, said at the annual congress of the European Society of Cardiology.

In an exclusive video interview, Dr. Kotseva of Imperial College, London, told our reporter Bruce Jancin that meta-analyses have shown no significant difference in serious cardiovascular events between varenicline-treated patients and those on placebo, regardless of whether the patients had underlying cardiovascular disease.

Varenicline use for smoking cessation reduces the risk of cardiovascular events by 36%, she reported, more than reductions seen with either nicotine replacement therapy or bupropion.

[email protected]

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

[email protected]

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

[email protected]

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

[email protected]

CHICAGO – Results from the HOPE-3 trial confirm what guidelines have already recommended: patients with intermediate risk for cardiovascular disease should be treated for primary prevention of coronary event, Dr. Prakash Deedwania said in an interview at the annual meeting of the American College of Cardiology.

In the Heart Outcomes Prevention Evaluation (HOPE)-3 trial, nearly 13,000 intermediate-risk men and women with no baseline cardiovascular disease were randomized to either lipid lowering with rosuvastatin at 10 mg/day or placebo, dual-antihypertensive therapy with candesartan plus chlorothiazide or placebo regardless of baseline blood pressure, or all three drugs or placebo. After a median of 5.6 years, the combined-therapy group had a 29% reduction in the composite of cardiovascular death or nonfatal MI or stroke, compared with placebo-treated controls, regardless of baseline LDL-cholesterol level. However, only subjects with a baseline pressure of greater than 143.5 mm Hg benefited from the dual-antihypertensive therapy.

In a video interview, Dr. Deedwania, professor of medicine at the University of California, San Francisco, Fresno, gave three takeaways from the HOPE-3 trial regarding primary prevention of cardiovascular events in patients at intermediate risk, how the results of the dual-antihypertensive treatment arm match up to guidelines, and whether there’s a future for the polypill.

Dr. Deedwania has received consultant fees and/or honoraria from Amgen, Pfizer, and Sanofi.

[email protected]

CHICAGO – Results from the HOPE-3 trial confirm what guidelines have already recommended: patients with intermediate risk for cardiovascular disease should be treated for primary prevention of coronary event, Dr. Prakash Deedwania said in an interview at the annual meeting of the American College of Cardiology.

In the Heart Outcomes Prevention Evaluation (HOPE)-3 trial, nearly 13,000 intermediate-risk men and women with no baseline cardiovascular disease were randomized to either lipid lowering with rosuvastatin at 10 mg/day or placebo, dual-antihypertensive therapy with candesartan plus chlorothiazide or placebo regardless of baseline blood pressure, or all three drugs or placebo. After a median of 5.6 years, the combined-therapy group had a 29% reduction in the composite of cardiovascular death or nonfatal MI or stroke, compared with placebo-treated controls, regardless of baseline LDL-cholesterol level. However, only subjects with a baseline pressure of greater than 143.5 mm Hg benefited from the dual-antihypertensive therapy.

In a video interview, Dr. Deedwania, professor of medicine at the University of California, San Francisco, Fresno, gave three takeaways from the HOPE-3 trial regarding primary prevention of cardiovascular events in patients at intermediate risk, how the results of the dual-antihypertensive treatment arm match up to guidelines, and whether there’s a future for the polypill.

Dr. Deedwania has received consultant fees and/or honoraria from Amgen, Pfizer, and Sanofi.

[email protected]

CHICAGO – Results from the HOPE-3 trial confirm what guidelines have already recommended: patients with intermediate risk for cardiovascular disease should be treated for primary prevention of coronary event, Dr. Prakash Deedwania said in an interview at the annual meeting of the American College of Cardiology.

In the Heart Outcomes Prevention Evaluation (HOPE)-3 trial, nearly 13,000 intermediate-risk men and women with no baseline cardiovascular disease were randomized to either lipid lowering with rosuvastatin at 10 mg/day or placebo, dual-antihypertensive therapy with candesartan plus chlorothiazide or placebo regardless of baseline blood pressure, or all three drugs or placebo. After a median of 5.6 years, the combined-therapy group had a 29% reduction in the composite of cardiovascular death or nonfatal MI or stroke, compared with placebo-treated controls, regardless of baseline LDL-cholesterol level. However, only subjects with a baseline pressure of greater than 143.5 mm Hg benefited from the dual-antihypertensive therapy.

In a video interview, Dr. Deedwania, professor of medicine at the University of California, San Francisco, Fresno, gave three takeaways from the HOPE-3 trial regarding primary prevention of cardiovascular events in patients at intermediate risk, how the results of the dual-antihypertensive treatment arm match up to guidelines, and whether there’s a future for the polypill.

Dr. Deedwania has received consultant fees and/or honoraria from Amgen, Pfizer, and Sanofi.

[email protected]

ROCKET-AF investigators are standing by the results of the pivotal trial of rivaroxaban in patients with nonvalvular atrial fibrillation, even though the anticoagulation monitoring device used in the control group was later found to be defective.

Results of a new analysis “are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR [international normalized ratio] measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial,” the study investigators concluded in a letter to the editor of the New England Journal of Medicine published online on Feb. 3 that included the new analysis (2016 Feb 3;doi: 10.1056/NEJMc1515842).

On the same day, the BMJ published a feature on that very topic, saying that “doctors and scientists are calling for an independent investigation” and questioning the validity of the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) results until such an analysis is completed.

“A falsely low reading could mean that patients had their warfarin dose unnecessarily increased, leading to a greater risk of bleeding. In terms of the trial results, it could make rivaroxaban [Xarelto] seem safer than it was in terms of the risk of bleeding and throws doubt on outcomes used to support the use of the world’s best-selling new oral anticoagulant,” Dr. Deborah Cohen, associate editor of BMJ, wrote (2016;352:i575 doi: 10.1136/bmj.i575).

At the center of this controversy is the Alere INRatio Monitor System, which was used in ROCKET-AF, the pivotal trial comparing the safety and efficacy of rivaroxaban with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, to measure the INR in the patients receiving warfarin (N Engl J Med. 2011;365:883-91). That device was recalled by the Food and Drug Administration and European regulators in 2014, 4 years after ROCKET-AF’s completion, because “it may provide an INR result that is lower than expected [compared with the] result obtained using a laboratory INR method,” particularly in patients with medical conditions such as “anemia, conditions associated with elevated fibrinogen levels, or unusual bleeding or bruising.”

In the new analysis, Dr. Manesh R. Patel of the Duke Clinical Research Institute in Durham, N.C., and his coinvestigators reviewed the medical records and any on-trial adverse events of the participants, looking for conditions that were identified in the recall of the INRatio device. They compared major efficacy and safety outcomes in the patients in the overall population (14,236 patients) first with those without any recall conditions (8,942, 63%), and second with those who had recall conditions (5,294, 37%).

Neither analysis revealed any significant differences in safety and efficacy outcomes from the overall population, with all groups showing the noninferiority of rivaroxaban to warfarin in preventing strokes, similar rates of overall bleeding, lower rates of fatal and intracranial bleeding, and higher rates of gastrointestinal bleeding. However, in the patients with any recall conditions, all measures of bleeding were higher in both the warfarin- and rivaroxaban-treated groups. Furthermore, the risk of major bleeding was higher in the rivaroxaban patients than in the warfarin patients, with a hazard ratio of 1.18 (P = .04).

“This finding does not support the hypothesis that device malfunction led to an increased risk of bleeding in the warfarin group of the trial,” Dr. Patel and his colleagues said.

But this conclusion is not shared by all. In the BMJ investigative article, former team leader in the FDA’s Cardiovascular & Renal Drug Products Division, Dr. Thomas Marciniak is quoted as saying that he would not rely on any reanalyses done by Duke, Johnson & Johnson, or the FDA, and that releasing the full datasets would be “the only solution that would lead to unbiased analyses.”

Furthermore, Dr. Harlan Krumholz, professor of medicine (cardiology) and director of the Center for Outcomes Research and Evaluation at Yale University, New Haven, Conn., told the BMJ that ROCKET-AF “should be considered of uncertain validity until a more-thorough review can be done,” and that there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”

In the middle ground is Dr. Sanjay Kaul, who served on the FDA advisory panel that evaluated rivaroxaban for its atrial fibrillation indication in 2010. He was reassured by the investigators’ analysis, while still calling for an independent review. “It was claimed [by the BMJ] that underestimation of INR by the recalled device could have resulted in erroneously increasing warfarin dose and associated bleeding, thereby making rivaroxaban appear safer relative to warfarin, he said. But in the analysis, “although bleeding was increased nearly twofold in both treatment groups in the subset with recalled conditions, the HR of 1.18 for rivaroxaban contradicts this claim.”

Mitchel L. Zoler/IMNG Medical Media

Because a legitimate question regarding reliability of INR measurements has been raised, it would seem prudent to reassess safety and efficacy data, said Dr. Kaul, professor of medicine at the University of California, Los Angeles, in an interview. “Ideally, this should be done by an independent party as was done for the RECORD trial of rosiglitazone by Duke investigators who were not involved in the clinical trial. Personally, I am not sure if the benefit-risk balance will be materially altered. Potential overestimation of safety of rivaroxaban related to spuriously low INR with warfarin will likely be counterbalanced by underestimation of efficacy.” If there are data from INR assessments performed centrally in a core lab, independent investigators could use those to reassess efficacy and safety, he continued. “At least the investigators should use the core lab INR to verify their assumptions in the research letter published in NEJM that conditions of recall were truly associated with low INR values. Otherwise, their results are open to question.”

Of note, Dr. Robert M. Califf, who was a ROCKET-AF study cochair and is now FDA Deputy Commissioner for Medical Products and Tobacco, was not involved in the analysis. Dr. Califf is awaiting confirmation from Congress on his nomination to head the FDA.

Dr. Patel received support from Johnson & Johnson, Bayer, and Janssen in relation to ROCKET-AF, and from eight other drug and device companies, as well as the National Heart, Lung, and Blood Institute. Disclosures for all the investigators are at nejm.org. Dr. Kaul has stock interest in J&J, which sponsored ROCKET-AF, and serves as a consultant to Boehringer Ingelheim and Bristol-Myers Squibb.

[email protected]

ROCKET-AF investigators are standing by the results of the pivotal trial of rivaroxaban in patients with nonvalvular atrial fibrillation, even though the anticoagulation monitoring device used in the control group was later found to be defective.

Results of a new analysis “are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR [international normalized ratio] measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial,” the study investigators concluded in a letter to the editor of the New England Journal of Medicine published online on Feb. 3 that included the new analysis (2016 Feb 3;doi: 10.1056/NEJMc1515842).

On the same day, the BMJ published a feature on that very topic, saying that “doctors and scientists are calling for an independent investigation” and questioning the validity of the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) results until such an analysis is completed.

“A falsely low reading could mean that patients had their warfarin dose unnecessarily increased, leading to a greater risk of bleeding. In terms of the trial results, it could make rivaroxaban [Xarelto] seem safer than it was in terms of the risk of bleeding and throws doubt on outcomes used to support the use of the world’s best-selling new oral anticoagulant,” Dr. Deborah Cohen, associate editor of BMJ, wrote (2016;352:i575 doi: 10.1136/bmj.i575).

At the center of this controversy is the Alere INRatio Monitor System, which was used in ROCKET-AF, the pivotal trial comparing the safety and efficacy of rivaroxaban with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, to measure the INR in the patients receiving warfarin (N Engl J Med. 2011;365:883-91). That device was recalled by the Food and Drug Administration and European regulators in 2014, 4 years after ROCKET-AF’s completion, because “it may provide an INR result that is lower than expected [compared with the] result obtained using a laboratory INR method,” particularly in patients with medical conditions such as “anemia, conditions associated with elevated fibrinogen levels, or unusual bleeding or bruising.”

In the new analysis, Dr. Manesh R. Patel of the Duke Clinical Research Institute in Durham, N.C., and his coinvestigators reviewed the medical records and any on-trial adverse events of the participants, looking for conditions that were identified in the recall of the INRatio device. They compared major efficacy and safety outcomes in the patients in the overall population (14,236 patients) first with those without any recall conditions (8,942, 63%), and second with those who had recall conditions (5,294, 37%).

Neither analysis revealed any significant differences in safety and efficacy outcomes from the overall population, with all groups showing the noninferiority of rivaroxaban to warfarin in preventing strokes, similar rates of overall bleeding, lower rates of fatal and intracranial bleeding, and higher rates of gastrointestinal bleeding. However, in the patients with any recall conditions, all measures of bleeding were higher in both the warfarin- and rivaroxaban-treated groups. Furthermore, the risk of major bleeding was higher in the rivaroxaban patients than in the warfarin patients, with a hazard ratio of 1.18 (P = .04).

“This finding does not support the hypothesis that device malfunction led to an increased risk of bleeding in the warfarin group of the trial,” Dr. Patel and his colleagues said.

But this conclusion is not shared by all. In the BMJ investigative article, former team leader in the FDA’s Cardiovascular & Renal Drug Products Division, Dr. Thomas Marciniak is quoted as saying that he would not rely on any reanalyses done by Duke, Johnson & Johnson, or the FDA, and that releasing the full datasets would be “the only solution that would lead to unbiased analyses.”

Furthermore, Dr. Harlan Krumholz, professor of medicine (cardiology) and director of the Center for Outcomes Research and Evaluation at Yale University, New Haven, Conn., told the BMJ that ROCKET-AF “should be considered of uncertain validity until a more-thorough review can be done,” and that there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”

In the middle ground is Dr. Sanjay Kaul, who served on the FDA advisory panel that evaluated rivaroxaban for its atrial fibrillation indication in 2010. He was reassured by the investigators’ analysis, while still calling for an independent review. “It was claimed [by the BMJ] that underestimation of INR by the recalled device could have resulted in erroneously increasing warfarin dose and associated bleeding, thereby making rivaroxaban appear safer relative to warfarin, he said. But in the analysis, “although bleeding was increased nearly twofold in both treatment groups in the subset with recalled conditions, the HR of 1.18 for rivaroxaban contradicts this claim.”

Mitchel L. Zoler/IMNG Medical Media

Because a legitimate question regarding reliability of INR measurements has been raised, it would seem prudent to reassess safety and efficacy data, said Dr. Kaul, professor of medicine at the University of California, Los Angeles, in an interview. “Ideally, this should be done by an independent party as was done for the RECORD trial of rosiglitazone by Duke investigators who were not involved in the clinical trial. Personally, I am not sure if the benefit-risk balance will be materially altered. Potential overestimation of safety of rivaroxaban related to spuriously low INR with warfarin will likely be counterbalanced by underestimation of efficacy.” If there are data from INR assessments performed centrally in a core lab, independent investigators could use those to reassess efficacy and safety, he continued. “At least the investigators should use the core lab INR to verify their assumptions in the research letter published in NEJM that conditions of recall were truly associated with low INR values. Otherwise, their results are open to question.”

Of note, Dr. Robert M. Califf, who was a ROCKET-AF study cochair and is now FDA Deputy Commissioner for Medical Products and Tobacco, was not involved in the analysis. Dr. Califf is awaiting confirmation from Congress on his nomination to head the FDA.

Dr. Patel received support from Johnson & Johnson, Bayer, and Janssen in relation to ROCKET-AF, and from eight other drug and device companies, as well as the National Heart, Lung, and Blood Institute. Disclosures for all the investigators are at nejm.org. Dr. Kaul has stock interest in J&J, which sponsored ROCKET-AF, and serves as a consultant to Boehringer Ingelheim and Bristol-Myers Squibb.

[email protected]

ROCKET-AF investigators are standing by the results of the pivotal trial of rivaroxaban in patients with nonvalvular atrial fibrillation, even though the anticoagulation monitoring device used in the control group was later found to be defective.

Results of a new analysis “are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR [international normalized ratio] measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial,” the study investigators concluded in a letter to the editor of the New England Journal of Medicine published online on Feb. 3 that included the new analysis (2016 Feb 3;doi: 10.1056/NEJMc1515842).

On the same day, the BMJ published a feature on that very topic, saying that “doctors and scientists are calling for an independent investigation” and questioning the validity of the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) results until such an analysis is completed.

“A falsely low reading could mean that patients had their warfarin dose unnecessarily increased, leading to a greater risk of bleeding. In terms of the trial results, it could make rivaroxaban [Xarelto] seem safer than it was in terms of the risk of bleeding and throws doubt on outcomes used to support the use of the world’s best-selling new oral anticoagulant,” Dr. Deborah Cohen, associate editor of BMJ, wrote (2016;352:i575 doi: 10.1136/bmj.i575).

At the center of this controversy is the Alere INRatio Monitor System, which was used in ROCKET-AF, the pivotal trial comparing the safety and efficacy of rivaroxaban with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, to measure the INR in the patients receiving warfarin (N Engl J Med. 2011;365:883-91). That device was recalled by the Food and Drug Administration and European regulators in 2014, 4 years after ROCKET-AF’s completion, because “it may provide an INR result that is lower than expected [compared with the] result obtained using a laboratory INR method,” particularly in patients with medical conditions such as “anemia, conditions associated with elevated fibrinogen levels, or unusual bleeding or bruising.”

In the new analysis, Dr. Manesh R. Patel of the Duke Clinical Research Institute in Durham, N.C., and his coinvestigators reviewed the medical records and any on-trial adverse events of the participants, looking for conditions that were identified in the recall of the INRatio device. They compared major efficacy and safety outcomes in the patients in the overall population (14,236 patients) first with those without any recall conditions (8,942, 63%), and second with those who had recall conditions (5,294, 37%).

Neither analysis revealed any significant differences in safety and efficacy outcomes from the overall population, with all groups showing the noninferiority of rivaroxaban to warfarin in preventing strokes, similar rates of overall bleeding, lower rates of fatal and intracranial bleeding, and higher rates of gastrointestinal bleeding. However, in the patients with any recall conditions, all measures of bleeding were higher in both the warfarin- and rivaroxaban-treated groups. Furthermore, the risk of major bleeding was higher in the rivaroxaban patients than in the warfarin patients, with a hazard ratio of 1.18 (P = .04).

“This finding does not support the hypothesis that device malfunction led to an increased risk of bleeding in the warfarin group of the trial,” Dr. Patel and his colleagues said.

But this conclusion is not shared by all. In the BMJ investigative article, former team leader in the FDA’s Cardiovascular & Renal Drug Products Division, Dr. Thomas Marciniak is quoted as saying that he would not rely on any reanalyses done by Duke, Johnson & Johnson, or the FDA, and that releasing the full datasets would be “the only solution that would lead to unbiased analyses.”

Furthermore, Dr. Harlan Krumholz, professor of medicine (cardiology) and director of the Center for Outcomes Research and Evaluation at Yale University, New Haven, Conn., told the BMJ that ROCKET-AF “should be considered of uncertain validity until a more-thorough review can be done,” and that there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”

In the middle ground is Dr. Sanjay Kaul, who served on the FDA advisory panel that evaluated rivaroxaban for its atrial fibrillation indication in 2010. He was reassured by the investigators’ analysis, while still calling for an independent review. “It was claimed [by the BMJ] that underestimation of INR by the recalled device could have resulted in erroneously increasing warfarin dose and associated bleeding, thereby making rivaroxaban appear safer relative to warfarin, he said. But in the analysis, “although bleeding was increased nearly twofold in both treatment groups in the subset with recalled conditions, the HR of 1.18 for rivaroxaban contradicts this claim.”

Mitchel L. Zoler/IMNG Medical Media

Because a legitimate question regarding reliability of INR measurements has been raised, it would seem prudent to reassess safety and efficacy data, said Dr. Kaul, professor of medicine at the University of California, Los Angeles, in an interview. “Ideally, this should be done by an independent party as was done for the RECORD trial of rosiglitazone by Duke investigators who were not involved in the clinical trial. Personally, I am not sure if the benefit-risk balance will be materially altered. Potential overestimation of safety of rivaroxaban related to spuriously low INR with warfarin will likely be counterbalanced by underestimation of efficacy.” If there are data from INR assessments performed centrally in a core lab, independent investigators could use those to reassess efficacy and safety, he continued. “At least the investigators should use the core lab INR to verify their assumptions in the research letter published in NEJM that conditions of recall were truly associated with low INR values. Otherwise, their results are open to question.”

Of note, Dr. Robert M. Califf, who was a ROCKET-AF study cochair and is now FDA Deputy Commissioner for Medical Products and Tobacco, was not involved in the analysis. Dr. Califf is awaiting confirmation from Congress on his nomination to head the FDA.

Dr. Patel received support from Johnson & Johnson, Bayer, and Janssen in relation to ROCKET-AF, and from eight other drug and device companies, as well as the National Heart, Lung, and Blood Institute. Disclosures for all the investigators are at nejm.org. Dr. Kaul has stock interest in J&J, which sponsored ROCKET-AF, and serves as a consultant to Boehringer Ingelheim and Bristol-Myers Squibb.

[email protected]