Curr Atheroscler Rep (2014) 16:463 DOI 10.1007/s11883-014-0463-8

INVITED COMMENTARY

Ivabradine, Coronary Heart Disease, and Heart Failure: Time for Reappraisal Tomáš Štulc & Richard Češka

Published online: 10 October 2014 # Springer Science+Business Media New York 2014

Abstract Ivabradine is generally considered to be a safe drug with well-established and substantial benefits. Nevertheless, recently published results from the SIGNIFY trial suggest that ivabradine has rather inconsistent effects on cardiovascular outcomes. In addition, careful examination of all available data from ivabradine trials reveals signals of harm that have not yet been appropriately addressed, including a markedly increased incidence of atrial fibrillation and increased risk of cardiovascular events in patients with heart rates below 70 bpm. These concerns warrant consideration, since they could have implications for the future use of ivabradine. Keywords Ivabradine . Adverse effects . Atrial fibrillation . Cardiovascular risk . Heart rate Ivabradine is a novel heart rate-lowering agent that acts by inhibition of the ionic If current in the sinoatrial node. Ivabradine is currently approved for the treatment of i) chronic stable angina pectoris that is inadequately controlled with beta-blocker therapy for patients in sinus rhythm and a heart rate (HR) >60 bpm and ii) systolic heart failure (NYHA class II to IV) for patients in sinus rhythm and a HR ≥75 bpm receiving the maximum tolerated dose of beta-blocker therapy. Treatment with ivabradine is well tolerated and has been considered safe thus far. However, preliminary results of the SIGNIFY trial, which were announced earlier this year indicated harmful effects of ivabradine in a large subgroup of patients, and the European Electronic supplementary material The online version of this article (doi:10.1007/s11883-014-0463-8) contains supplementary material, which is available to authorized users. T. Štulc (*) : R. Češka 3rd Department of Internal Medicine, 1st Faculty of Medicine, Charles University, U Nemocnice 1, 128 21 Prague, Czech Republic e-mail: [email protected]

Medicines Agency has subsequently initiated a reevaluation of the drug. A full trial report was published recently [1]. In the total study population, ivabradine had no effect on cardiovascular events in patients with stable coronary artery disease without clinical heart failure but was associated with an increased incidence of the primary endpoint (by 18 %) among patients with activity-limiting angina. Also notable is the trend toward an increase in heart failure by 20 % (which was approaching statistical significance). These results appear to be counterintuitive and contradictory relative to the rest of the data regarding the cardiovascular effects of ivabradine. Nevertheless, the SIGNIFY trial results are actually less surprising than meets the eye: previous trials had already suggested rather inconsistent effects of ivabradine on cardiovascular outcomes. The BEAUTIFUL trial demonstrated some improvement in coronary heart disease outcomes but no effect on heart failure [2], while conversely, the SHIFT trial showed reduced heart failure outcomes [3] but no effect on coronary heart disease (or signal of harm; see pp. 37 and 38 in [4]). To that end, the SIGNIFY trial only further contributes to these inconsistencies. More importantly, careful examination of all available data from the ivabradine trials reveals signals of harm that have not yet been appropriately addressed, including increased incidence of atrial fibrillation and increased risk of cardiovascular events in patients with a HR 60 bpm) than that of the other two trials (>70 bpm). On this basis, the authors of the meta-analysis suggest that patients with a higher baseline heart rate, who appear to derive the greatest benefit from ivabradine treatment, may also be at greatest risk of AF. This notion is supported by an analysis of BEAUTIFUL trial subgroups, which showed a markedly higher risk of AF in patients with a HR ≥70 bpm compared to patients with a lower HR (60– 70 bpm) [6, 7]. Given that AF is common in patients with cardiovascular diseases, the increase in relative risk translates into a remarkably high number of new cases of AF associated with ivabradine treatment (Table 2), corresponding to 1.5– 2 % of patients. In the major ivabradine trials, for approximately every 60 patients (with HR >70 bpm) treated, there was 1 new case of AF. In patients with heart failure, this number is comparable to the number of primary endpoint events avoided (3–6 cases of AF per 10 primary events). In the SIGNIFY trial (which suggested the harmful effect of ivabradine), the increase in new cases of AF was even greater than that of the increase in primary events. Obviously, this could shift the balance of benefits and risks of ivabradine close to equilibrium in heart failure patients and further calls for caution in patients with coronary heart disease, for whom ivabradine only provides symptomatic benefits.

Table 1 Effect of ivabradine on atrial fibrillation in ivabradine trials

BEAUTIFUL [2] HR 60–70 bpm HR ≥70 bpm SHIFT [3] SIGNIFY [1]

Ivabradine

Placebo

RR

286 (5.22) 91 (3.27) 195 (7.22) 306 (9.47) 508 (5.33)

264 (4.85) 115 (4.19) 149 (5.53) 251 (7.70) 362 (3.79)

1.08 0.78 1.31 1.23 1.40

Incidence is given as the number and percent (%) of patients with atrial fibrillation RR relative risk

Table 2 Incidence of primary composite endpoint and atrial fibrillation in ivabradine trials

SHIFT [3] PCI Atrial fibrillation SHIFT and BEAUTIFUL [7] PCI Atrial fibrillation SIGNIFY angina [1] PCI Atrial fibrillation

Ivabradine

Placebo

Difference

793 306

937 251

−144 55

1229 501

1379 400

−150 101

459 317

390 215

69 102

Incidence is given as the number of patients with an event PCI primary composite endpoint, SHIFT and BEAUTIFUL a pooled analysis of data from the SHIFT trial and from the subgroup of patients with HR ≥70 bpm from the BEAUTIFUL trial

Perhaps Not So Beautiful After All… Another important possible signal of the harmful effects of ivabradine arose from the BEAUTIFUL trial [2], which included patients with coronary heart disease and leftventricular systolic dysfunction who had a heart rate >60 bpm. The results of the BEAUTIFUL trial were neutral for the entire study population. The authors also analyzed results for a subgroup of patients with a HR ≥70 bpm (comprising approximately half of all patients), which showed some favorable effects. However, the authors did not report a complementary analysis for the other half of the patients who had a baseline HR between 60 and 70 bpm. By simple reasoning, these patients must necessarily have shown unfavorable results. Although not reported, results for this subgroup can be calculated from the published data, and as expected, these calculations reveal an increase in almost all endpoints (Supplementary Table 2). These findings are consistent with evidence indicating that benefits of ivabradine in patients with heart failure increase with increasing heart rate, suggesting that, in the opposite direction, these benefits may decrease (or may even reverse to the point of harm) as the baseline heart rate decreases (Supplementary Table 3). This is relevant for both of the approved indications of ivabradine. Most importantly, ivabradine is currently used in patients with angina and a HR >60 bpm. Given that the SIGNIFY trial demonstrated an increased risk of cardiovascular events following ivabradine use in angina patients with a HR >70 bpm, the increased risk would likely be even greater in angina patients with a HR of 60–70 bpm. Therefore, if approval for ivabradine use for stable angina is not withdrawn completely, its use should certainly be limited to patients with a HR >70 bpm. In patients with heart failure, most benefits of ivabradine were seen in

Curr Atheroscler Rep (2014) 16:463

patients with a HR >75 bpm and the current indication is quite in line with this. However, many drugs are frequently used outside their labeling by clinicians. It is therefore important to emphasize that ivabradine should only be used in strict accordance with current labeling in patients with heart failure, as it provides little benefit to patients with heart rates

Ivabradine, coronary heart disease, and heart failure: time for reappraisal.

Ivabradine is generally considered to be a safe drug with well-established and substantial benefits. Nevertheless, recently published results from the...
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