PARIS – The heart rate lowering agent, ivabradine, significantly improved left ventricular volume indexes and left ventricular ejection fraction in patients with heart failure and systolic dysfunction, according to the findings of an echocardiography substudy of a large randomized controlled trial.
"These results suggest that ivabradine modifies disease progression in patients with heart failure receiving background therapy," Dr. Jean-Claude Tardif said at the annual congress of the European Society of Cardiology. The results are also clinically important because left ventricular enlargement and reduced ejection fraction are powerful predictors of outcomes in heart failure.
Dr. Jean-Claude Tardif
Notably, among the 411 patients analyzed, those who had the greatest reduction in heart rate had better remodeling and outcomes.
Investigators reported at last year’s congress that in SHIFT (Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial), ivabradine (Procoralan), a selective If channel blocker, led to an 18% reduction in the composite primary end point of cardiovascular death and heart failure hospitalization, compared with placebo, in 6,558 patients with chronic heart failure, a left ventricular ejection fraction (LVEF) of 35% or less, and resting heart rate of at least 70 beats per minute (Lancet 2010;376:875-85).
In the prespecified substudy, echocardiography was used to assess left ventricular modeling in 208 patients treated with ivabradine, 5 mg twice daily, and 203 patients given placebo. Baseline background treatment included beta-blockers (92%), an ACE inhibitor/angiotensin-receptor blocker (96%), or an aldosterone antagonist (72%). Their mean LVEF was 32%.
Eight months of treatment with ivabradine resulted in a statistically significant 7 mL/m2 reduction in the primary end point of left ventricular end-systolic volume index (LVESVI), compared with a 0.9 mL/m2 reduction in the placebo group (P = .0002), reported Dr. Tardif, with the Montreal Heart Institute at the University of Montreal. The change in LVESVI was independent of beta-blocker use, heart failure etiology and baseline LVEF.
A reduction in LVESVI of at least 15% was observed in significantly more patients with ivabradine than placebo (38% vs. 25%, P = .005)
Ivabradine significantly improved the secondary end points of left ventricular end-diastolic volume index (-7.9 mL/m2 vs. -1.8 mL/m2, P = .002) and LVEF (2.4% vs. -0.1%, P = .0003), he said.
Significantly more patients experienced a clinically relevant improvement in LVEF of 5% or more with ivabradine than placebo (36% vs. 23%, P = .003).
"The significant reductions in LV volumes in favor of ivabradine were parallel with the reduction in heart rate at eight months achieved with ivabradine versus placebo [-14.7 bpm vs. -5.8 bpm, P less than .0001]," Dr. Tardif said.
Discussant Dr. Burkert Pieske, with the division of cardiology at the Medical University of Graz (Austria), said that the substudy findings underscore the importance of reverse remodeling as a marker for improved outcome, and provides solid, mechanistic data to encourage the use of ivabradine as an add-on medication in patients in sinus rhythm and a heart rate above 7 beats/minute.
"The reduction in LVESVI of about 6 mL/m2 is more or less comparable with other pharmacologic interventions, and importantly it adds on to the beneficial effect of beta blockers and ACE inhibitors," he said.
In contrast to cardiac resynchronization, ivabradine can be started by every heart failure physician without great expense, Dr. Pieske and his colleague Dr. Friedrich Fruhwald, wrote in an accompanying editorial in the European Heart Journal (Eur. Heart J. 2011 Sept. 2 [doi:10.1093/eurheartj/ehr317]).
They pointed out, however, that ivabradine only works in heart failure patients with sinus rhythm and that relevant reverse modeling was seen in only a third of these patients.
"So, we have to identify the right patients we need to treat with ivabradine," said Dr. Pieske, adding that further testing is warranted in such conditions as acute heart failure or heart failure with preserved ejection fraction.
Findings from a second SHIFT substudy suggest that reduction in heart rate with ivabradine is associated with improved health-related quality of life.
At 12 months, the change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score was significantly greater in the ivabradine group than the placebo group (6.7 vs. 4.3, P less than .001).
This also was true for the KCCQ clinical summary score (5.0 vs. 3.3, P = .018), reported Dr. Inger Ekman from the Institute of Health Care Sciences, Sahlgrenska Academy in Gothenburg, Sweden. A change of 5 units is considered a clinically meaningful change in KCCQ scoring.
The magnitude of heart rate reduction with ivabradine was directly related to the degree of improvement in health-related quality of life, she said.