ACC 2013 Scientific Sessions
San Francisco, CA
The American College of Cardiology’s (ACC) 62nd Scientific Sessions featured over 2100 abstracts and 22 late-breaking clinical trials across 5 sessions. More than 22,000 people attended the 3-day conference, which focused on the transformation of cardiovascular care from discovery to delivery.
Cardiology Review is highlighting 8 study presentations from ACC 2013: PEITHO, ASTRONAUT, SELECT-ACS, REMINDER, CHAMPION-PHOENIX, ACRIN PA 4005, RED-HF, and RELAX.
Reduction of Events by Darbepoetin in Heart Failure
The Reduction of Events with Darbepoetin Alfa in Heart Failure (RED-HF) trial tested darbepoetin alfa (Aranesp) in heart failure (HF) patients with anemia. This phase 3 trial started in 2006 and enrolled 2278 patients with symptomatic systolic HF and anemia. Patients were randomized in a 1:1 ratio to darbepoetin alfa or placebo. The trial was designed to evaluate whether the treatment of anemia could improve morbidity and mortality in systolic HF patients.
Results showed no difference between the treatment and placebo arms in the composite end point of time to death from any cause or first hospital admission for worsening HF (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.90-1.13). The goal in the treatment group was a target hemoglobin of at least 13.0 g/dL. The primary end point was a composite of time to death from any cause or first hospitalization for worsening HF in subjects with HF and anemia.
No new safety issues emerged in RED-HF. In June 2011 the FDA advised tailored dosing for erythropoieisis-stimulating agents in patients with chronic kidney disease (CKD) because of an increased risk of cardiovascular events. This action followed reports of an increased risk of stroke for diabetic patients with CKD who were not yet on dialysis and were taking darbepoetin (see 2009 TREAT trial: http://www.nejm.org/doi/full/10.1056/NEJMoa0907845).
Pulmonary Embolism Thrombolysis Study
Analysis of the Pulmonary Embolism Thrombolysis Study (PEITHO), the largest trial of thrombolysis for intermediate- risk pulmonary embolism (PE) ever done, shows that the addition of tenecteplase to standard treatment with heparin in patients with intermediate-risk PE significantly reduced the primary end point of death or hemodynamic collapse within 7 days of randomization. However, the benefit came with a significantly increased risk of major hemorrhage.
Study coauthor Stavros Konstantinides, MD, of the University of Mainz, Germany, said, “There is a price to pay, and we would not say that everybody in this group should receive thrombolysis.” He said that an analysis by age was performed, and showed that age might be an important factor. Patients less than 75 years of age had most of the benefit and a tendency toward fewer hemorrhagic strokes. Dr Konstantinides said the dose of drug that was used could be lowered in older patients, and alternative ways to deliver thrombolytics could be explored.
PEITHO was conducted in 1006 patients, mean age 70 years, in 13 countries (Europe and Israel) from 2007 to mid-2012. Patients were randomized to heparin plus placebo or heparin plus a weight-adapted bolus of tenecteplase.
The primary end point was reduced by 56% in patients treated with tenecteplase and heparin, compared with the heparin-only group (2.6% in the tenecteplase group vs 5.6% in the placebo group; P = 0.015). However, major bleeding was significantly increased with tenecteplase: 6.3% vs 1.5% in the placebo group (P <0.001). There were 10 hemorrhages in the tenecteplase group and 1 in the placebo group.
Tenecteplase is not FDA approved for acute PE. Dr. Konstantinides said further research is needed to better identify patients who will benefit most with less risk of bleeding.
PEITHO was sponsored by Assistance Publique-Hopitaux de Paris and funded by the French Ministry of Health, the German Ministry of Education and Research, and by a grant from Boehringer Ingelheim to the sponsor.
Safety and Efficacy of Early Eplerenone in Patients With Acute MI
Data from the REMINDER trial suggest that early use of eplerenone (Inspra) can improve the outlook of patients with acute ST-elevation myocardial infarction (STEMI). This double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of early treatment with eplerenone in patients with acute myocardial infarction (MI) involved patients identified during emergency department or ambulance evaluation and diagnosis of acute STEMI in the absence of HF. Those who agreed to participate were randomized and given an initial dose of either eplerenone or placebo within 12 to 24 hours of initial onset of symptoms of an acute MI.
REMINDER data were presented by Gilles Montalescot, MD, professor at the Institute of Cardiology, Centre Hospitalier Pitié- Salpêtrière, Paris. It is the first large study to examine the safety profile of eplerenone for early administration, with no prior potassium check.
Eplerenone’s once-daily dosing of 25 mg/d or 50 mg/d was based on serum potassium and eGFR levels. A total of 88.6% of patients received the 50-mg/d dose. Patients in both arms of the trial also received standard medical care for acute STEMI. A total of 1012 patients were randomized, 506 to each arm.
The primary end point was a composite of cardiovascular mortality, ventricular arrhythmia, clinical or subclinical heart failure as determined by left ventricle ejection fraction (LVEF) <40%, or elevated brain natriuretic peptide (BNP)/N terminal (NT)-proBNP 1 month or longer after enrollment.
A mean follow-up of 10.5 months found 93 patients (18.4%) in the eplerenone group had reached the primary end point versus 150 patients (29.6%) in the placebo group. Eplerenone had an overall hazard ratio (HR) of 0.57 (P <0.0001) for the primary end point. A high BNP/NT-proBNP level was observed in 18 patients in the eplerenone group compared with 131 patients in the placebo group after the same follow-up period. The eplerenone HR for high BNP/NT-proBNP was 0.58 (P >0.0002).
Adverse event rates were similar in both groups.
SELECT-ACS Results Pique Interest in More Research
A small phase 2 study of the P-selectin antagonist inclacumab suggests that it may be able to reduce myocardial damage in patients undergoing percutaneous coronary intervention (PCI) for non-ST-elevation myocardial infarction (NSTEMI). P-selectin is a cell-adhesion molecule expressed on endothelial cells and platelets, and is known to play a part in leukocyte and platelet rolling. Earlier research suggests that inhibiting P-selectin may limit macrophage accumulation and neointimal formation after injury by decreasing neutrophil and platelet adhesion.
Lead author Jean-Claude Tardif, MD, of the Montreal Heart Institute, presented the findings, which he said were early but nonetheless interesting, and should lead to additional studies in a phase 3 trial.
In SELECT-ACS, 544 NSTEMI patients scheduled for coronary angioplasty were randomized to placebo infusion of either a 5-mg/kg or 20-mg/kg infusion of inclacumab. Of these, 340 patients went on to have PCI; their peak troponin I (the primary end point for the 16- and 24-hour time points) and creatine kinase-myoglobin (CK-MB) values were measured at intervals after the procedure. Safety visits were also conducted with all patients at 30 and 120 days.
After 24 hours, peak troponin I was reduced in the 20-mg/kg dose—but not in the 5-mg/kg dose—compared with placebo. The P value was only marginally significant, however. At 16 hours a trend in the same direction did not reach statistical significance. CK-MB followed a similar pattern; the placebo-adjusted change also failed to reach statistical significance.
Few serious adverse events were reported, but there were more of them in the treatment groups (they were not statistically significant). No deaths occurred in the placebo group; there were 4 in the 5-mg/kg group and 2 in the 20-mg/kg group. Nonfatal MI rates were also more common in the treatment groups, but event rates were small. There was no increased bleeding or infection reported.
Study results were simultaneously published online in the Journal of the American College of Cardiology.
Cangrelor Reduces Complications at PCI Versus Clopidogrel
The experimental IV antiplatelet agent cangrelor, administered at the time of PCI, reduces ischemic complications better than clopidogrel, according to results of the CHAMPION- PHOENIX trial. However, some kinds of bleeding were more common with cangrelor.
The trial included 11,145 patients getting urgent or elective PCI who were randomized to double-blind, double-dummy treatment with a bolus and infusion of cangrelor (30 μg/kg, then 4 μg/ kg/min) or a loading dose of 600 mg or 300 mg clopidogrel. All patients were to get dual antiplatelet therapy with aspirin and clopidogrel in the first 48 hours after the procedure.
CHAMPION-PHOENIX followed 2 earlier phase 3 studies of cangrelor (CHAMPION PCI and CHAMPION PLATFORM), in which the medication did not achieve its primary goals versus a control group given a clopidogrel 600-mg loading dose in the first trial and 60 mg after stenting in the second.
Co-lead researcher Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital and the Boston VA Healthcare System, said the composite rate of heart attack, death, or revascularization due to ischemia was 4.7% with cangrelor versus 5.9% with a standard loading dose of clopidogrel at 48 hours (P = 0.005)—a 22% reduction in ischemic complications (number needed to treat [NNT] with cangrelor, 84). The risk of severe bleeding wasn’t significantly different between the groups. Need for glycoprotein IIb/IIIa inhibitors as rescue therapy during the procedure was less common with cangrelor (2.3% vs 3.5%, P <0.001). Cangrelor also had an advantage on the secondary end point of stent thrombosis at 48 hours, with a rate of 0.8% versus 1.4% in the clopidogrel group (odds ratio [OR], 0.6; P = 0.01).
Like clopidogrel, prasugrel, and ticagrelor, cangrelor targets platelet activation by P2Y12 inhibition, but with immediate onset and a short half-life of just 3 to 5 minutes; platelet function resumes normal levels within 1 hour of stopping infusion. The researchers said that the reduction in the ischemic complication rate was driven by fewer periprocedural MIs.
CHAMPION-PHOENIX was simultaneously published in The New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMoa1300815).
The trial was funded by the Medicines Company, the sponsor of cangrelor. Dr. Bhatt reported grant funds to his institutions from the Medicine Company; board membership with Medscape Cardiology, Boston VA Research Institute, and the Society of Chest Pain Centers; and payment for developing education presentations from WebMD. He also reported grants to his institution from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, and sanofi-aventis.
Aliskiren Trial on Acute Heart Failure Outcomes
The addition of aliskiren (Tekturna) to other heart failure (HF) medications beginning less than 1 week after discharge from hospitalization for low-left ventricular ejection fraction (LVEF) HF made no significant difference to cardiovascular death or hospitalization at 6 months and had no clinical benefit up through 1 year, according to results of the ASTRONAUT trial.
ASTRONAUT was conducted at 316 centers in North and South America, Europe, and Asia and randomized 1639 stable patients with HF, LVEF ≤40% (mean, 28%), and elevated natriuretic peptides who had been discharged from a HF hospitalization an average of 5 days before. Approximately 40% had diabetes and 21% had renal insufficiency. Patients received either aliskiren or placebo in addition to standard HF medications.
However, treatment with aliskiren led to significant and sustained reductions in natriuretic peptide levels, according to lead author Mihai Gheorghiade, MD, of Northwestern University, Chicago, IL. Dr. Gheorghiade and colleagues said reduced natriuretic peptide levels were an indirect sign of possible HF improvement even if it did not translate clinically. Favorable effects on HF progression may have been offset clinically by adverse effects associated with the drug, such as hyperkalemia, hypotension, and renal dysfunction.
It had been hoped that further inhibition of the renin-angiotensin- aldosterone system (RAAS) through a mechanism different from angiotensin-converting enzyme (ACE) inhibition, angiotensin receptor blockers (ARBs), or aldosterone antagonists would add clinical value in HF treatment. It was thought that aliskiren might fit that bill, as it blocks the RAAS at its nearest step and might suppress compensatory renin increases seen with RAAS inhibition later in the pathway.
More than 50% of patients in the ASTRONAUT trial were already taking an aldosterone antagonist, 84% were taking an ACE inhibitor or ARB, and more than 80% were taking betablockers. A subgroup analysis suggested that the drug may have increased the risk of death from any cause at 12 months in the 41% of patients with a history of diabetes; those without diabetes showed a significant benefit for that end point and cardiovascular death/HF rehospitalization.
“At the end of the day the message is that the study was neutral,” said Dr. Gheorghiade. “We’ve generated 2 hypotheses that remain to be tested, that patients with diabetes are harmed by the drug, and that patients without diabetes are benefiting from it.”
The study was simultaneously published online in JAMA (http://jama.jamanetwork.com/article.aspx?articleid=1666394).
ASTRONAUT was sponsored by Novartis. Dr. Gheorghiade disclosed consulting for Novartis, Bayer HealthCare, Abbott, Astellas, AstraZeneca, Corthera, Cytokinetics, Debiopharm, Errekappa Terapeutici, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Otsuka, Pericor Therapeutics, Protein Design Laboratories, Sanofi, Sigma Tau, Solvay, and Takeda.
RELAX Trial Did Not Show Benefit of PDE-5 Inhibitors in HF-PEF Patients
The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic HF Trial (RELAX) was not able to show that sildenafil (Viagra/Revatio) might improve exercise capacity and improve clinical outcome in patients with heart failure (HF) with preserved ejection fraction (HF-PEF). The randomized trial, conducted at 26 centers in the United States and Canada, enrolled HF-PEF patients (LVEF ≥50%) in NYHA class 2-3. A total of 113 patients received sildenafil 20 mg 3 times daily for 3 months, followed by 60 mg 3 times daily for another 3 months, compared with the placebo control group (n = 103). The median patient age was 69 years.
Lead researcher Margaret Redfield, MD, of the Mayo Clinic (Rochester, MN) said there was no signal of benefit with the drug. “There was no increase in peak oxygen consumption, and none of the other plethora of data points that we collected—6-minute walk distance, echocardiographic structure, structure by cardiac MRI, hemodynamics by Doppler, and neurohormonal activation— were improved by the PDE-5 inhibitor.” Symptoms, clinical status, and quality of life indices also did not show improvement. RELAX showed no significant difference in the primary end point of change in peak oxygen consumption at 24 weeks.
While they didn’t reach significance, there were serious adverse events on sildenafil, Dr. Redfield said. “There was a signal that was quite unexpected of worsening renal function with sildenafil,” she noted. There were more (but not significantly more) patients in the sildenafil group who withdrew consent, died, or were too ill to perform the cardiopulmonary exercise test, and patients treated with sildenafil had a higher incidence of vascular adverse events.
The study was published simultaneously in JAMA (http://jama.jamanetwork.com/article.aspx?articleid=1663257).
RELAX was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Redfield disclosed financial support from NIH and royalties from Annexon. Pfizer provided sildenafil and matched placebo.
1-Year Results for Trial of CTCA versus Traditional Care in ED Assessment of ACS
According to 1-year results from the ACRIN PA 4005 study, coronary computed tomography angiography (CCTA) is better than traditional “rule out” approaches for identifying patients in the emergency department (ED) with chest pain who do not have significant coronary disease. ACTIN PA 4005 is a multicenter, randomized controlled trial of more than 1300 patients carried out by the American College of Radiology Imaging Network (ACRIN) Institutions and funded by the Pennsylvania Department of Health.
Judd E. Hollander, MD, Professor and Clinical Research Director in the Department of Emergency Medicine at the University of Pennsylvania in Philadelphia, presented the study’s findings, which showed that relying on CCTA for ED assessment of coronary disease is safe because the 1-year rate of death or myocardial infarction (MI) was found to be substantially below 1% in patients who were judged negative for coronary disease by CCTA. The findings confirmed preliminary data presented a year ago at the 2012 ACC Congress (NEJM. 2012;366:1393-1403).
Dr. Hollander stressed that although the findings supported a routine use for CCTA to assess the kinds of patients enrolled in ACTIN PA 4005, CCTA is not needed for every patient in the ED with questionable chest pain and should be used as an exclusionary test for patients who need an exclusionary test. He noted that there is a risk from radiation and physicians must carefully weigh the need for the CCTA test.
Approximately two-thirds of patients were randomized to CCTA assessment and the remaining third underwent traditional assessment including exercise treadmill testing, stress test with imaging, and echocardiography. During the 1-year follow-up of 1368 patients who began in the ACRIN study, 1 cardiac death and 1 MI occurred among the 825 patients randomized to the CCTA group, a 0.2% rate that was well under the trial’s safety goal of less than 1%.
There was no increase in resource use compared with ED chest—pain patients assessed by conventional methods. Overall use of cardiac testing, revascularization, readmission to hospital, and ED visits were similar in the 2 study groups. Dr Hollander further said that the data show that CCTA shifted resources to where they are most needed, with more CAD identified and treated and more patients without disease not being treated.
Dr. Holland discloses that he has received research funding from Abbott, Alere, Brahms, and Siemens, and that he has been a consultant for Behring, Janssen, Luitpold, and Radiometer.