First Report®

American Heart Association (AHA) 2012 Scientific Sessions

November 3-7, 2012; Los Angeles, CA

Dabigatran Etexilate Well Tolerated Following Knee or Hip Replacement Surgery

An open-label, prospective, observational study found that dabigatran etexilate was effective and well tolerated in patients undergoing total knee or hip replacement surgery.

The incidence of symptomatic venous thromboemolic events (VTEs) and all-cause mortality, the primary efficacy end point, was lower in patients who underwent total hip replacement surgery. The incidence of major bleeding events, the primary safety end point, was comparable in the two groups. Results were presented at the AHA meeting during a poster session. 

In October 2010, the US Food and Drug Administration approved dabigatran etexilate to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The drug, a direct thrombin inhibitor, has also been approved in more than 80 countries (not in the United States) for the primary prevention of VTEs after elective total knee or hip replacement surgery. The authors noted that phase 3 trials found 220 mg dabigatran etexilate taken daily was as effective as daily 40-mg doses of enoxaparin to prevent VTEs following total knee or hip replacement surgery.

In this study, 5292 patients between the ages of 18 and 75 years were treated with 220 mg dabigatran etexilate daily between March 2009 and July 2011. Exclusion criteria included concomitant amiodarone or quinidine treatment, an indication for quinidine or chronic anticoagulant therapy, renal or hepatic impairment, active clinically significant bleeding, or spontaneous or pharmacological impairment of haemostasis. All patients had three visits: at baseline (≤7 days before surgery); when discharged from the hospital or 24 to 48 hours after ending treatment (whichever came first); and at follow-up if they were discharged before finishing treatment.

Of the patients, 2734 underwent hip replacement surgery and 2558 underwent knee replacement surgery. The mean age was 62.6 years, 42.2% of patients were men, and 99.0% were white. The overall incidence of major bleeding events was 0.72% (95% confidence interval [CI], 0.51%-0.98%), and the incidence was similar in the hip replacement (0.69%; 95% CI, 0.42%-1.08%) and knee replacement (0.74%; 95% CI, 0.45%-1.16%) groups.

The authors defined major bleeding events as clinically overt bleeding; fatal, retroperitoneal, intracranial, intraocular, or intraspinal bleeding; or bleeding warranting treatment cessation or leading to reoperation.

In patients with at least one risk factor for bleeding, the incidence of major bleeding events was 0.76%, which was comparable to the 0.64% incidence among patients with no risk factors. The risk factors were active smoking, coronary artery disease, chronic heart failure, history of VTE, concomitant acetylsalicyclic acid use, and chronic use of nonsteroidal anti-inflammatory drugs.

An adverse event occurred in 18.7% of the population; 2.6% had a serious adverse event, and 4.9% had an adverse event that led to discontinuation of dabigatran etexilate. The incidence of symptomatic VTEs and all-cause mortality was 1.04% (95% CI, 0.78%-1.35%), including 0.55% (95% CI, 0.31%-0.90%) in patients undergoing hip replacement and 1.56% (95% CI, 1.12%-2.12%) in patients undergoing knee replacement. 

Patients with a history of VTE had a higher incidence than those without a history of VTE (odds ratio, 5.59; 95% CI, 2.53-11.08). The authors noted none of the other risk factors had much of an impact on the incidence of symptomatic VTEs and all-cause mortality.—Tim Casey

The study was sponsored by Boehringer Ingelheim.

Serelaxin Effective in Patients With Acute Heart Failure

Patients with acute heart failure who took serelaxin intravenously for 48 hours experienced an improvement in dyspnea, in-hospital signs and symptoms of acute heart failure, in-hospital worsening of heart failure, and 180-day cardiovascular and all-cause mortality compared with a placebo group, according to the results of RELAX-AHF (Relaxin in Acute Heart Failure), a phase 3, prospective, randomized, double-blind, placebo-controlled, parallel-group trial.

The serelaxin group had 45% fewer episodes of worsening heart failure symptoms during hospitalization and spent nearly a full day less in the hospital than those in the placebo group. The drug, a peptide hormone and a recombinant form of the human hormone relaxin-2, had no effect on rehospitalization rates, and it was deemed safe, demonstrating a similar profile to placebo.

John Teerlink, MD, the study’s co-lead author and professor of medicine, University of California in San Francisco, presented the findings in a late-breaking abstract session at the AHA meeting. Results were also published in The Lancet (2013;381[9860]:29-39).

When introducing the trial, Teerlink explained that serelaxin is a derivative of relaxin, a pregnancy hormone. Pregnancy requires “tremendous” improvement in cardiac output and vascular and renal performance. In previous trials, relaxin mediated the adaptations associated with pregnancy and had anti-ischemic, anti-inflammatory, and antifibrotic effects. These principles were applied to RELAX-AHF.

The researchers began with a phase 2 pilot study of 234 patients that found the 30 µg/kg serelaxin daily led to improvement in dyspnea, provided other in-hospital benefits, and resulted in  potential improvement in cardiovascular and all-cause survival. Teerlink added that the drug was safe and well tolerated with no significant adverse events.

Patients were included if they were 18 years of age or older (mean age, 72 years), hospitalized for acute heart failure, received at least 40 mg furosemide administered intravenously between the time of admission to emergency services and study screening, had systolic blood pressure above 125 mm Hg, impaired renal function, and weighed  less than 160 kg. The exclusion criteria included treatment with any intravenous therapies; stroke within 60 days; acute coronary syndrome within 45 days; major surgery within 30 days; and presence of acute myocarditis, significant valvular heart disease, or hypertrophic/restrictive/constrictive cardiomyopathy.

The authors randomized patients in a 1:1 ratio to receive 30 µg/kg serelaxin or placebo daily, administered intravenously for 48 hours. Patients were enrolled between October 2009 and February 2012 at 96 sites across 11 countries. They received the medication within 16 hours of hospitalization. Most patients had elevated systolic blood pressure (mean, 142 mm Hg).

Over an 180-day follow-up, there was a significant improvement favoring the serelaxin group in cardiovascular mortality (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.96; P=.028) as well as in all-cause death (HR, 0.63; 95% CI, 0.43-0.93; P=.02). There were also significant improvements in the signs and symptoms of congestion at day 2.

From baseline through day 5, there was a 19.4% increase in the area under the curve for dyspnea relief in patients who took serelaxin compared with placebo (P=.0075). Teerlink said that results showed serelaxin improved survival according to the authors’ prespecified criteria. No significant difference in cardiovascular death or heart failure rehospitalization through day 60 was observed (HR, 1.02; 95% CI, 0.74-1.41; P=.89). There was a 30% reduction in cardiovascular deaths in the serelaxin group but a 20% increase in rehospitalizations in patients who took serelaxin, although the differences were not statistically significant.—Tim Casey

The study was funded by Corthera, a Novartis affiliate company.

Use of Daily Multivitamin Does Not Reduce Risk of Cardiovascular Disease

Older male physicians who took a multivitamin every day for more than a decade had similar rates of major cardiovascular events, total myocardial infarction, and total stroke compared with a group that took a placebo, according to a randomized, double-blind, placebo-controlled, factorial design study.

Lead author Howard D. Sesso, MD, associate professor, Brigham and Women’s Hospital, Boston, MA, presented the findings in a late-breaking abstract session at the AHA meeting. Results were simultaneously published online in the Journal of the American Medical Association(2012;308[17]:1751-1760). The trial was part of the Physicians’ Health Study II that includes 14,641 male physicians in the United States who are 50 years of age or older. Of the participants, 7641 had enrolled in the Physicians’ Health Study I from 1982 through 1996, during which they received aspirin and beta-carotene via mail to test if the products prevented cardiovascular disease and cancer. The remaining 7000 physicians were from part 2 of the study, which began in 1997 and is ongoing.

Sesso said more than half of adults in the United States take vitamin supplements, and more than one-third take multivitamins. He indicated that components of multivitamins might reduce the risk of cardiovascular disease, although observational studies have not demonstrated that association. This is the first large, long-term, randomized trial testing multivitamins in preventing cardiovascular disease and other chronic diseases, according to Sesso. He said the individual trials tested higher doses of vitamins and minerals, whereas multivitamins contain lower doses of the individual vitamins and minerals in combination.

Participants in the study took a multivitamin (n=7317) or placebo (n=7324) daily. Cardiovascular disease and cancer were the primary outcomes, while eye disease and cognitive function were secondary outcomes. The primary cardiovascular outcome was major cardiovascular events, defined as the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death.

The researchers used a monthly calendar pack to help physicians adhere to their regimens. The mean follow-up was 11.2 years. At 4 years, 77% of participants adhered to the multivitamin regimen; at 8 years, the adherence rate was 72%; and at study end, the rate was 67%. The groups were well balanced. The mean age was 64 years, and mean body mass index was 26.0 kg/m2. The participants were healthy: approximately 3.5% were smokers, 62% exercised at least once per week, 77% took aspirin, and daily intake of fruits and vegetables was higher compared with the general population, according to Sesso.

There were 876 major cardiovascular events in the multivitamin group and 856 in the placebo group (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.91-1.10; P=.91). Total myocardial infarctions were 317 and 335, respectively (HR, 0.93; 95% CI, 0.80-1.91; P=.39), while instances of total stroke were 332 and 311, respectively (HR, 1.06; 95% CI, 0.91-1.23; P=.48).

There was also no effect for primary or secondary prevention of cardiovascular disease among participants with or without a history of cardiovascular disease. Sesso noted that there were 27 deaths due to myocardial infarction in the multivitamin group compared with 43 in the placebo group, which he deemed as a “borderline reduction” (HR, 0.61; 95% CI, 0.38-0.995; P=.048). “We had a very small number of events,” Sesso said. “We consider that to be interesting but exploratory at this point.”—Tim Casey

The study was funded by the National Institutes of Health and the BASF Corporation. Study packaging was provided by DSM 
Nutritional Products Inc.