Take-home Messages from Recent Heart Failure Trials: Heart Rate as a Target JEFFREY S. BORER, M.D. Professor and Chairman, Department of Medicine and Chief, Division of Cardiovascular Medicine; Director, The Howard Gilman Institute for Heart Valve Disease and The Cardiovascular Translational Research Institute STATE UNIVERSITY OF NEW YORK DOWNSTATE MEDICAL CENTER and COLLEGE OF MEDICINE EUROPEAN SOCIETY OF CARDIOLOGY Paris, 2011, August 29, 2011
DISCLOSURE I am a paid consultant to Servier Laboratoires, manufacturer of ivabradine, and am a member of the Executive Committee for the SHIFT study
Background Goals of therapy for heart failure
Background Goals of therapy for heart failure Improve survival
Background Goals of therapy for heart failure Improve survival Reduce heart failure hospitalizations and, thus, the very high economic burden of disease
Background Goals of therapy for heart failure Improve survival Reduce heart failure hospitalizations and, thus, the very high economic burden of disease Improve quality of life during survival
Heart rate is directly associated with poor outcomes (CV death and/or HF hospitalizations) in patients with chronic HF (placebo group in SHIFT, n=3264) Boehm et al. Lancet 2010; 376: 886-894 Increase in risk by 2.9% per 1 bpm, 15.6% per 5 bpm
Objectives of SHIFT Evaluate prospectively whether heart rate slowing with ivabradine improves cardiovascular outcomes (survival and heart failure hospitalizations), symptoms (quality of life) and left ventricular size/performance in patients with moderate to severe (Class II to IV NYHA) chronic heart failure with LV systolic dysfunction (LVEF<35%) heart rate 70 bpm in sinus rhythm and receiving guidelines-based recommended therapy Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81
Ivabradine improves outcomes (CV death or hospitalization for HF) in patients with chronic systolic HF CV death or hospitalization for HF (%) 40 30 HR (95% CI), 0.82 (0.75 0.90), p<0.0001 Placebo - 18% 20 Ivabradine 10 0 0 6 12 18 24 30 Swedberg K, et al. Lancet 2010;376: 875-885. Months NNT for 1 year = 26
Ivabradine significantly reduces hospitalization for HF Hospitalization for HF (%) 30 20 HR (95% CI), 0.74 (0.66 0.83), p<0.0001 Placebo - 26% Ivabradine 10 0 0 6 12 18 24 30 Swedberg K, et al. Lancet 2010;376: 875-885. Months
Ivabradine significantly reduces death from HF Death from HF (%) 10 5 HR (95% CI), 0.74 (0.58 0.94), p=0.014 Placebo - 26% Ivabradine 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet 2010;376: 875-885.
Background Goals of therapy for heart failure Improve survival Reduce heart failure hospitalizations and, thus, the very high economic burden of disease
Background Goals of therapy for heart failure Improve survival Reduce heart failure hospitalizations and, thus, the very high economic burden of disease Improve quality of life, the subjective perception of health, during survival
Quality of Life (QoL and HQoL) is particularly poor in chronic HF Juenger J et al. Heart 2002;87:235 41. Therefore, improving HQoL in heart failure is an important goal of therapy
Background: QoL in heart failure Therapies that have survival benefits either have a modest effect (ACEIs) or no impact (Beta Blockers) on QoL
Background: QoL in heart failure Therapies that have survival benefits either have a modest effect (ACEIs) or no impact (Beta Blockers) on QoL Some therapies that improve QoL (eg, inotropic agents) do not improve survival
SHIFT HQoL Substudy Therefore, SHIFT prospectively included a study of the effect of heart rate slowing with ivabradine on HQoL, using the Kansas City Cardiomyoapthy Questionnaire (KCCQ) as the measurement tool. The study included 2282 patients from 24 countries rather than all SHIFT participants: some participating countries could not be included because the KCCQ has not been translated into the vernacular language for those countries.
SHIFT HQoL Substudy Design: Inclusion only if KCCQ translated to vernacular 2282 patients from 24 countries N= 1129 ivabradine N=1153 placebo Excluded = 161 Excluded = 177 KCCQ assessed in 1944 patients N=968 ivabradine N=976 placebo Median study duration: 24.5 months; maximum: 41.7 months
Kansas City Cardiomyopathy Questionnaire (KCCQ) 23 items, within 8 domains, scores ranging from 0 to 100 (higher score = better HQoL) physical limitation symptoms (frequency, severity, recent change over time) quality of health social interference self-efficacy Clinical Summary Score (CSS): mean of the physical limitation and total symptom domains scores (symptom frequency, symptom burden) Overall Summary Score (OSS): CCS + quality of health and social limitation scores Green CP et al. J Am Coll Cardiol 2000;35:1245-55.
Incidence (%) Primary composite SHIFT endpoint by KCCQ: OSS in placebo group Log rank p=0.007) KCCQ OSS <50 50-<75 75 Time (months)
HQoL: KCCQ-OSS Change from baseline to last post-baseline value (Analysis of surviving patients) 75 Difference = 2.6 (0.8), p < 0.001 Baseline Last post-baseline Baseline Last post-baseline 5.3 (18.3) 3.0 (18.8) KCCQ - OSS -"Surviving analysis" 70 65 60 65.0 70.4 64.6 67.5 55 Ivabradine (N=966) Placebo (N=974) Ekman, et al, ESC Heart Failure, May, 2011; EHJ in press
Mean KCCQ OSS change according to HR change
Conclusions Heart rate slowing with ivabradine in pts with chronic systolic HF in sinus rhythm with HR 70 bpm Improves survival or heart failure hospitalizations (improving length of life and/or reducing health care costs) Improves HQoL (uniquely when compared with standard therapies for chronic systolic HF) These benefits may be important in defining management plans for patients with chronic systolic HF
Is there a plausible basis for these benefits? Does heart rate slowing with ivabradine reverse the LV remodeling of HF? Does heart rate slowing with ivabradine cause LV functional improvement? Are ivabradine-mediated changes consistent with the clinical improvement?
Prospective Echo Sub-study in SHIFT Echo at baseline and after 8 months of therapy 611 patients included from 89 centers in 21 countries 304 patients Ivabradine 307 patients Placebo Excluded N=96 Excluded N=104 Ivabradine n=208 patients Placebo n=203 patients Follow-up after 8-month echocardiogram: 16.1 months
Background Treatment: Echo substudy participants Ivabradine N=304 Placebo N=307 Beta-blocker, % 92 92 ACE inhibitor, % 80 83 ARB, % 17 12 Diuretic (excluding antialdo), % 87 87 Aldosterone antagonist, % 74 71 Digitalis, % 27 32 Devices, % 3 4
Primary Endpoint: change ( ) in Left Ventricular End Systolic Volume Index (LVESVI) from baseline to 8 months 75 = -5.8; p = 0.0002 70-7.0 ml/m 2-0.9 ml/m 2 65 ml/m 2 60 55 50 0 Baseline M 8 Ivabradine N=208 Baseline M 8 Placebo N=203
LVESVI vs primary SHIFT endpoint Placebo group divided at median LVESVI HR 1.62, p=0.04 LVESVI > 59 ml/m 2 LVESVI < 59 ml/m 2
Secondary endpoint: LV End Diastolic Volume Index (LVEDVI) from baseline to 8 months 100 95-5.5; p = 0.0019-7.9 ml/m 2-1.8 ml/m 2 LVEDVI, ml/m 2 90 85 80 75 0 Baseline M 8 Ivabradine N=204 Baseline M 8 Placebo N=199
LVEF (%) Secondary endpoint: LV Ejection Fraction (EF) from baseline to 8 months = 2.7; p = 0.0003 40 35 30 25 20 = +2.4 % = - 0.1 % 65.2 ± 29.1 15 10 5 0 Baseline M 8 Ivabradine N=204 Baseline M 8 Placebo N=199
Conclusions Heart rate slowing with ivabradine in pts with chronic systolic HF in sinus rhythm with HR 70 bpm Improves survival or heart failure hospitalizations (improving length of life and/or reducing health care costs) Improves HQoL (uniquely when compared with standard therapies for chronic systolic HF) These findings are plausible: heart rate slowing with ivabradine reverses the LV remodeling of HF and improves LV systolic function
Take-Home Message Heart rate slowing with ivabradine should be considered as standard adjunctive therapy in patients with chronic systolic heart failure in sinus rhtyhm with heart rate 70 bpm