Objectives: In the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), slowing of the heart rate with ivabradine reduced cardiovascular death or heart failure hospitalizations among patients with systolic chronic heart failure (CHF). Subsequently, in the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) slowing of the heart rate in patients without CHF provided no benefit for cardiovascular death or nonfatal myocardial infarction (primary composite end point), with secondary analyses suggesting possible harm in the angina subgroup. Therefore, we examined the impact of ivabradine in the patients with CHF plus angina in SHIFT. Methods: SHIFT enrolled adults with stable, symptomatic CHF, a left ventricular ejection fraction ≤35% and a sinus rhythm with a resting heart rate ≥70 bpm. Outcomes were the SHIFT and SIGNIFY primary composite end points and their components. Results: Of 6,505 patients in SHIFT, 2,220 (34%) reported angina at randomization. Ivabradine numerically, but not significantly, reduced the SIGNIFY primary composite end point by 8, 11 and 11% in the SHIFT angina subgroup, nonangina subgroup and overall population, respectively. Ivabradine also reduced the SHIFT primary composite end point in all 3 subgroups. Conclusions: In SHIFT, ivabradine showed consistent reduction of cardiovascular outcomes in patients with CHF; similar results were seen in the subgroup of SHIFT patients with angina.

Keywords:
Angina, Chronic heart failure, Heart rate, Ivabradine
1.
Lechat P, Hulot JS, Escolano S, Mallet A, Leizorovicz A, Werhlen-Grandjean M, Pochmalicki G, Dargie H: Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II trial. Circulation 2001;103:1428-1433.
2.
Pocock SJ, Wang D, Pfeffer MA, Yusuf S, McMurray JJ, Swedberg KB, Ostergren J, Michelson EL, Pieper KS, Granger CB: Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 2006;27:65-75.
3.
Kjekshus J, Gullestad L: Heart rate as a therapeutic target in heart failure. Eur Heart J Suppl 1999;1:64-69.
4.
McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW: Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009;150:784-794.
5.
Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators: Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875-885.
6.
Diaz A, Bourassa MG, Guertin MC, Tardif JC: Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005;26:967-974.
7.
Kolloch R, Legler UF, Champion A, Cooper-Dehoff RM, Handberg E, Zhou Q, Pepine CJ: Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the International Verapamil-SR/Trandolapril Study (INVEST). Eur Heart J 2008;29:1327-1334.
8.
Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators: Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014;371:1091-1099.
9.
Fox K, Ford I, Steg PG, Tendera M, Ferrari R: Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:807-816.
10.
McMurray JJ: It is BEAUTIFUL we should be concerned about, not SIGNIFY: is ivabradine less effective in ischaemic compared with non-ischaemic LVSD? Eur Heart J 2015;36:2047-2049.
11.
Borer JS: Heart rate: from risk marker to risk factor. Eur Heart J Suppl 2008;10:F2-F6.
12.
Ferrari R, Fox KM: The role of heart rate may differ according to pathophysiological setting: from SHIFT to SIGNIFY. Eur Heart J 2015;36:2042-2046.
13.
Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R: Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008;372:817-821.
14.
Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators: Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J 2009;30:2337-2345.
15.
Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, Kubo SH, Rudin-Toretsky E, Yusuf S: Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724-1729.
16.
Reil JC, Tardif JC, Ford I, Lloyd SM, O'Meara E, Komajda M, Borer JS, Tavazzi L, Swedberg K, Böhm M: Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J Am Coll Cardiol 2013;62:1977-1985.
17.
Casey DP, Curry TB, Joyner MJ, Charkoudian N, Hart EC: Acute β-adrenergic blockade increases aortic wave reflection in young men and women: differing mechanisms between sexes. Hypertension 2012;59:145-150.
18.
Dillinger JG, Maher V, Vitale C, Henry P, Logeart D, Manzo Silberman S, Allee G, Levy BI: Impact of ivabradine on central aortic blood pressure and myocardial perfusion in patients with stable coronary artery disease. Hypertension 2015;66:1138-1144.
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2016
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