Table 1.

Relevant clinical trials on ivabradine use: an overview about their characteristics and limitations

Trial	Number of pts	Treatment	Outcome	Results	Limitations
BEAUTIFUL study25,26	10,917	5,479 ivabradine pts vs 5,438 placebo pts	Primary endpoint: composite of cardiovascular death, admission for acute MI, admission for new onset/worsening HF	No influence on the primary composite endpoint: HR: 1.00, 95% CI: 0.91–1.1, P=0.94 When heart rate ≥70 bpm, ivabradine did not influence the primary composite outcome (HR: 0.91, 95% CI: 0.81–1.04, P=0.17), while reduced secondary endpoints: admission to hospital for fatal and non-fatal MI (HR: 0.64, 95% CI: 0.49–0.84, P=0.001) and coronary revascularization (HR: 0.70, 95% CI: 0.52–0.93, P=0.016)	– Only secondary endpoints revealed statistical significant evidences – Ivabradine efficacy only for ischemic endpoints – Although pts ≥70 bpm with regards to numbers were similar to those <70 bpm according to β-blockers, no dose nor type of such drugs were provided – No consideration of valvular heart disease as able to generate compensatory higher heart rate – No consideration of hemoglobin and hematocrit
SHIFT trial68	6,505	3,241 ivabradine pts vs 3,264 placebo pts	Composite of cardiovascular death or hospital admission for worsening HF	Primary endpoint event: HR: 0.82, 95% CI: 0.75–0.90, P<0.0001. Hospital admissions for worsening HF: HR: 0.74, 95% CI: 0.66–0.83; P<0.0001. Deaths due to HF: HR: 0.74, 95% CI: 0.58–0.94, P=0.014. No reduction in the total death numbers Adverse events incidence: a. Symptomatic bradycardia (5% in ivabradine vs 1% in placebo, P<0.0001) b. V isual side-effects (phosphenes) (3% in ivabradine vs 1% in placebo, P<0.0001)	– Low percentage of female patients (only 24%) – Disproportion between the number of ischemic and non-ischemic pts (68% vs 32%) – Only 1% underwent CRT – β-blockers underused (target dose only in 26% of pts; half target dose only in 50% of pts) – Only 10% of pts >75 years old (HF pts are often >75 years old) – No AF presence: although this is due to drug actions, AF is present in one-third of HF pts → atypical HF population
SIGNIfY trial85	19,102	Ivabradine or placebo in ≥55 years old, stable CAD, LVEF >40%	Primary endpoint: composite of cardiovascular death or nonfatal MI	It is an ongoing trial. The results are expected to be ready in 2014	– Did not evaluate valvular heart diseases – The role of hemoglobin and hematocrit levels should be considered
ASSOCIATE trial23,86	889	Stable CAD pts receiving atenolol 50 mg/day, then randomized to ivabradine or placebo	To evaluate anti-anginal and anti-ischemic efficacy of ivabradine in CAD + β-blockers therapy	Higher total exercise duration in ivabradine than placebo (24.3±65.3 seconds vs 7.7±63.8 seconds, P<0.001). Ivabradine improved all exercise test stages (P<0.001) and exercise capacity (time to limiting angina, angina onset, and 1 mm ST segment depression, all P<0.05) more than placebo	– Pts enrolled were not at their maximum dose of β-blockers – The follow-up period of 4 months was too short – No evaluation of morbidity and mortality, safety and efficacy of the association at the maximum dose of both drugs
REDUCTION trial24	4,954	Stable CAD pts receiving ivabradine	To evaluate the efficacy and safety of ivabradine in everyday routine practice	Angina pectoris attacks were reduced from 2.4±3.1 to 0.4±1.5 per week (P<0.0001), as well as nitrate use (P<0.0001) Good efficacy (97%) and tolerance (98%) for the treated patients	– The follow-up period of 4 months was too short – No placebo group – Observational nature of the study – Pts’ therapy not targeted to the maximum dose – Extreme heterogeneity of the pts
Amosova et al64	29	Stable CAD, LVEF <45%, in bisoprolol 5 mg OD: Group 1 (17): ivabradine (5–7.5 mg bid) + bisoprolol 5 mg OD; Group 2 (12): bisoprolol 10 mg OD	To compare antianginal and anti-ischemic efficacy of ivabradine + 5 mg bisoprolol vs 10 mg bisoprolol	More patients became asymptomatic in group 1 than in group 2 Group 1 showed improved exercise capacity when compared to group 2 The same was for chronotropic reserve	– The follow-up period of 2 months was too short – The sample is very small – The population is too heterogeneous – The influence of other concomitant drug use was not considered

Abbreviations: AF, atrial fibrillation; bid, twice daily; bpm, beats per minute; CAD, coronary artery disease; CI, confidential interval; CRT, cardiac resynchronization therapy; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; OD, once daily; pts, patients; vs, versus.