ROCKVILLE, MD. — The angiotensin receptor blocker candesartan should be approved as a treatment for heart failure in patients who are on an ACE inhibitor, a Food and Drug Administration advisory panel has unanimously recommended.
The FDA's cardiovascular and renal drugs advisory committee backed the approval on the basis of results of one of the three Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials.
In CHARM-Added, candesartan (titrated to a target dose of 32 mg/day) was compared with placebo in 2,548 patients with New York Heart Association (NYHA) class II-IV heart failure (HF) and a left ventricular ejection fraction (LVEF) at or below 40% who were on an ACE inhibitor and standard therapy. The results showed that adding an ARB to standard treatment that included an ACE inhibitor added an incremental benefit in this population: The relative risk of cardiovascular mortality or HF hospitalization—the primary end point—was reduced by 15% in those on candesartan during a median follow-up of 41 months. The benefits were also seen in patients treated with β-blockers, which suggested no adverse interactions among β-blockers, candesartan, and ACE inhibitors, as was noted in the Valsartan Heart Failure Trial (Val-HeFT), in which HF morbidity was worse in patients on an ACE inhibitor, β-blocker, and valsartan, according to the FDA.
The purpose of the panel meeting was to determine, according to the FDA's agenda, “whether CHARM-Added provides compelling evidence that candesartan should, under some circumstances, be recommended for use in patients on an ACE inhibitor.”
But a large portion of the meeting was spent discussing whether patients in the trial were on optimal ACE inhibitor doses and whether the same benefits might have been achieved by increasing the dose of the ACE inhibitor.
Although panelists said a forced titration of ACE inhibitor therapy in the study protocol would have been ideal, they said they felt comfortable that the ACE inhibitor doses used fell into the ranges considered adequate or optimal. The “final doses of ACE inhibitor achieved were quite substantial” and in line with the doses seen in other trials of ACE inhibitor therapy, said Blasé Carabello, M.D., professor of medicine at Baylor University, Houston. In addition, an analysis of a subset of patients on high doses of ACE inhibitors “all go in the same direction” favoring the benefit.
The FDA usually follows the recommendations of its advisory panels, which are made up of outside experts. If approved, candesartan (marketed as Atacand by AstraZeneca Pharmaceuticals LP) will be the first ARB approved for use with an ACE inhibitor. Shortly before the panel meeting, the agency approved candesartan for patients with NYHA class II-IV heart failure, and an LVEF at or below 40%, who are not on an ACE inhibitor, to reduce the risk of death from cardiovascular causes and reduce HF hospitalization based on the CHARM-Alternative trial.
Speaking for AstraZeneca at the meeting, John McMurray, M.D., the principal investigator of CHARM-Added, said that 96% of the patients in the trial were taking an “individualized, optimum” dose of an ACE inhibitor at baseline, and about 80% of patients were on one of five ACE inhibitors that were considered preferred because of randomized controlled outcome studies of these drugs, said Dr. McMurray, professor of medical cardiology, Western Infirmary, Glasgow, Scotland.
Speaking on the study's efficacy for AstraZeneca, Marc Pfeffer, M.D., interim chair of medicine at Brigham and Women's Hospital, Boston, and cochair of the CHARM executive committee, said that in CHARM-Added, there was there was no evidence that the beneficial effect of candesartan on cardiovascular death or HF hospitalization, was modified “based on ACE inhibitor dose or choice of ACE inhibitor.”
James Hainer, M.D., senior director of clinical research at AstraZeneca, said that as expected, due to a greater degree of renin-angiotensin-aldosterone system inhibition, rates of hypotension, abnormal renal function, and hyperkalemia were greater with candesartan. However, these adverse events did not translate into any increases in all-cause hospitalization and/or mortality, sudden death, renal failure, or ventricular fibrillation, he said.
These risks will be addressed on the label in warnings and precautions about hypotension, renal dysfunction, and hyperkalemia and recommendations for monitoring and reducing risk, and through interactions with major societies and treatment guidelines committees, he said.
Dr. McMurray said that on balance, the risk was “substantially” in favor of candesartan: A cost analysis found that for every 1,000 patients treated with candesartan, there were 1,900 fewer days spent in the hospital for worsening heart failure, he told the panel.