STOCKHOLM – Patients with moderate to severe systolic heart failure and an elevated heart rate had a marked drop in their rate of heart failure death and hospitalization when they were treated with the heart-rate–lowering drug ivabradine in a phase III, randomized trial with more than 6,500 patients.
In addition to making ivabradine an important new agent for treating many heart failure patients, the findings proved that heart rate is an effective intervention target for this disease. Patients who received the drug on top of a standard heart failure regimen had a 5% absolute and 18% relative drop in their incidence of cardiovascular mortality and heart failure hospitalization, the study’s primary end point, during a median treatment duration of 23 months, Dr. Michel Komajda said on Aug. 29 at the European Society of Cardiology Congress 2010.
Heart failure mortality fell by 2%, a 26% relative drop that was statistically significant, reported Dr. Komajda, head of the cardiovascular department at Piti?-Salpetri?re Hospital in Paris. Also well tolerated, ivabradine had a serious adverse event rate of 45%, significantly better than the 48% rate in the placebo arm. “We are very happy to see one positive trial in chronic heart failure after several years of disappointments,” he said.
This safety finding and the significant impact of the investigational drug both on the combined primary end point of the study and on heart failure mortality should give ivabradine a clear path toward Food and Drug Administration approval, followed by widespread adoption in practice, predicted U.S. heart failure experts.
“Once you have the mortality benefit, it’s very hard to go back” and do a second placebo-controlled trial, commented Dr. Bertram Pitt, a cardiologist at the University of Michigan in Ann Arbor. “These are compelling data. I would use this” on my patients, he said in an interview.
Analysis of results from SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) also showed the critical role that heart rate played in the rate of the primary end point, both patients’ heart rate at entry into the study, and their achieved heart rate after 4 weeks on ivabradine. When the primary end point analysis dichotomized the enrolled patients by their median baseline heart rate of 77 bpm, those with an entry rate of 76 bpm or lower showed no significant benefit from ivabradine treatment, whereas those at 77 bpm or greater had a significant benefit, leading Dr. Komajda to call patients with a rate of at least 77 bpm the target population for the drug.
In addition, patients with a baseline heart rate of 80-86 bpm had a significant, 80% relative increased rate of the primary end point, compared with patients who entered the study with the lowest heart rates allowed by the enrollment criteria (70-72 bpm). Patients who entered with a rate of 87 bpm or higher had a greater-than-twofold increased risk for the primary end point.
Once treatment started and ran for 28 days, patients who achieved a heart rate lower than 60 bpm had a 17% rate of the primary end point during complete follow-up, whereas those with a heart rate of 75 bpm or greater after 28 days had an eventual 32% rate of cardiovascular death or heart failure hospitalization, also a statistically significant difference. The average achieved heart rate after 28 days was 64 bpm on ivabradine, compared with 75 bpm in placebo patients. At 1 year, the rates averaged 67 bpm and 75 bpm, respectively.
“SHIFT confirms the importance of heart rate in the pathophysiology of heart failure,” commented Dr. Inder Anand, professor of medicine at the University of Minnesota in Minneapolis.
Based on this finding, a physician who treats heart failure patients with ivabradine should titrate the dosage to a target heart rate of 60 bpm, assuming the patient remains tolerant, said Dr. Karl Swedberg, professor of medicine at the G?teborg (Sweden) University, who led the study along with Dr. Komajda.
Simultaneously with the meeting report, the SHIFT results appeared online in two Lancet articles (2010 Aug. 29 [doi:10.1016/S0140-6736(10)61198-1]; 2010 Aug. 29 [doi:10.1016/S0140-6736(10)61259-1]).
SHIFT randomized 6,558 patients with systolic heart failure at 677 centers in 37 countries. (No U.S. center participated.) Patients could have New York Heart Association class II-IV heart failure, with a left ventricular ejection fraction of 35% or less and a heart rate of at least 70 bpm. Their average age was 60 years and their median heart rate was 77 bpm; roughly half had class II heart failure and the other half class III disease.