COMMENTARY

Eplerenone and CRT Rule and Nesiritide DESCENDS: Heart Failure Essentials -- From AHA 2010

Melissa Walton-Shirley, MD

Disclosures

November 16, 2010

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Hi, I'm Dr. Melissa Walton-Shirley, coming to you from Chicago, where we're attending the 2010 American Heart Association meeting. This morning's late-breaking clinical trials addressed our country's most expensive DRG [diagnosis-related group], congestive heart failure. I'll be discussing the EMPHASIS [Eplerenone in Mild Patients Hospitalization And Survival Study] trial, looking at eplerenone; RAFT [Resynchronization/defibrillation for Ambulatory Heart-Failure Trial], which addresses the efficacy of CRT [cardiac resynchronization therapy]; ADVANCE [Left Ventricular Assist Device System for the Treatment of Advanced Heart Failure], which studied a new left ventricular (LV) assist device; and ASCEND-HF [Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure], which might be the final word on nesiritide.

The first trial, EMPHASIS-HF, looking at eplerenone in class II heart failure patients, was presented by Dr. Faiez Zannad of the University of Nancy. The entry criteria included an ejection fraction (EF) of less than 35%, or if the EF was between 30% to 35%, then a QRS duration of greater than 130 milliseconds was required. The patients were already on a background of the recommended or maximally tolerated doses of angiotensin-converting enzyme (ACE) and/or angiotensin-receptor blocker (ARB), and a beta-blocker, unless contraindicated.

Enrollment requirements included hospitalization in the last 6 months for a cardiovascular reason, or B-type natriuretic peptide (BNP) greater than 250 pg/dL, or an N-terminal pro-BNP (NT proBNP) greater than 500 pg/mL in men and 750 in women. Patients who had a potassium level of greater than 5 mEq/L, or a GFR (glomerular filtration rate) of less than 30 mL/minute/1.73m2 were excluded. A total of 1364 patients were randomly assigned to eplerenone (25 mg to 50 mg), and 1373 patients were randomly assigned to placebo, with a follow-up of approximately 21 months.

Approximately 69% of the patients had ischemic heart disease. The primary endpoint of cardiovascular death or hospitalization was reduced 37% by eplerenone, and mortality was reduced by 24%. Heart failure hospitalization was decreased an astounding 42%. The effect of eplerenone was consistent across all prespecified subgroups, with a number needed to treat (NNT) of 19 to prevent the primary endpoint. To postpone death, the NNT was 51.

Interestingly, the incidence of hyperkalemia leading to drug withdrawal was only 1.1% in the treatment arm and 0.9% in the placebo arm; therefore, the presenter was proud to underscore both the safety and efficacy of this therapy, now also met for patients with mild to moderate heart failure.

The question asked by the next trial was simply this: "Will adding CRT to [the treatment of] patients with mild to moderate heart failure reduce mortality and improve symptomatology, just as it's been shown to benefit those with severe heart failure?" The RAFT trial, presented by Dr. Anthony Tang and sponsored by the Canadian Institutes of Health, randomly assigned 1800 patients with a QRS duration of greater than 120 milliseconds. In paced patients, a QRS of 200 milliseconds was required, and an LV systolic ejection fraction of ≤ 30% derived by MUGA [multiple gated acquisition] scan or echocardiography was also an inclusion criterion.

This was a trial of mostly class II heart failure patients on optimal medical therapy. Twelve percent had persistent atrial fibrillation or flutter. At the 6-month follow-up, there was an impressive 25% reduction in mortality and heart failure hospitalization in those who received CRT, as well as an impressive similar reduction in all-cause mortality. It appears now that patients with mild to moderate heart failure can expect benefits from CRT similar to those that had previously been demonstrated in those with severe heart failure.

The ADVANCE trial compared an experimental LV pump, referred to as an HVAD, implanted in the pericardial space with the traditional subcutaneously situated left ventricular assist devices (LVADs) which require a pocket. This was a nonrandomized trial, for which enrollment required a listing for cardiac transplantation and for which patients with major renal, hepatic, or pulmonary dysfunction were excluded. Severe right ventricular failure or aortic insufficiency with no plans for correction were also among the exclusion criteria.

This small device provides up to 10 liters per minute of continuous flow and has a thin, 4.2-mm drive line with fatigue-resistant cables. Patients were followed to transplant, device explant for recovery, or death at 180 days. The treatment group was compared with a control group of patients already enrolled in the interagency registry for mechanical assisted circulatory support who had already received the standard LVAD as a bridge to transplant.

Success was defined as survival on the originally implanted device, transplant, or explant for recovery, and the ability to survive post explant for 60 days, and patients were then followed to 180 days. This trial, presented by Dr. Keith Aaronson of the University of Michigan, did have limitations, such as the lack of randomization, with potential differences in data collection and adjudication, but nonetheless produced a very exciting finding of non-inferiority, and hinted at less bleeding, with the hope of fewer infections. The device is certainly garnering large quality of life and functional improvements that are similar to those seen with the standard LVAD.

Finally, one of the most widely discussed presentations of the day was that of Dr. Rob Califf of Duke University. The ASCEND-HF trial looked at the utilization of nesiritide, a manufactured drug derived from human BNP. It made its debut in the heart failure world in 2001 and enjoyed growing popularity in the inpatient arena over time. It was widely utilized in the outpatient setting until safety concerns were raised, particularly about renal function and mortality, after 2 meta-analyses were published in 2005.

The FUSION-2 [Follow-Up Serial Infusions of Nesiritide] trial, designed by Dr. Clyde Yancy, effectively demonstrated no efficacy in the outpatient setting, and therefore, an independent panel, convened by Scios, recommended that the ASCEND-HF study be performed to formerly address safety and efficacy issues. This trial randomly assigned 7141 patients with acute, severe heart failure to either nesiritide or placebo. They found that nesiritide slightly improved breathing function at 6 hours posttreatment and moderately at 24 hours posttreatment, but there was no statistical significance with regard to the prespecified endpoint for dyspnea; furthermore, there was no mortality benefit or statistically significant hospitalization benefit at 30 days posttreatment.

The presenter concluded that nesiritide, although widely utilized, came to market with inadequate trial data. Although this medication reduced dyspnea to a modest degree, it did not reduce the rate of recurrent heart failure, hospitalization, or death at 30 days.

That's it for the first day of the 2010 American Heart Association meeting. Thanks for joining us, and I hope you enjoy our coverage and find it beneficial in the everyday management of your patients. Please join us again tomorrow for yet another exciting day in review, your window into some of the most important late-breaking clinical trials in cardiology today.

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