Regulatory Decision Summary for Lancora

A single pivotal Phase 3 clinical study (SHIFT trial), including more than 6,500 chronic heart failure patients with baseline resting heart rate (HR) ≥ 70 beats per min (bpm), was provided in support of the proposed indication. Patients were treated with standard chronic heart failure therapies and were either randomised to ivabradine or placebo at a starting dose of 5 mg twice daily (bid) which could be titrated up to a maximum dose of 7.5 mg bid depending on the patients resting heart rate. The heart rate range to achieve was between 50 bpm and 60 bpm. Dosing could be reduced to 2.5 mg bid or be interrupted if the patient had a heart rate lower than 50 bpm or experienced symptoms of bradycardia. In the randomised set of the SHIFT trial, ivabradine was shown to statistically significantly reduce the incidence of the primary efficacy endpoint, a composite of first occurrence of cardiovascular (CV) death or hospitalization for worsening heart failure, compared to placebo. The treatment effect observed was mainly driven by the hospitalization for worsening heart failure component as no significant CV death benefit was observed. Efficacy results appeared consistent among the different subgroups analysed, although a significant interaction test (p = 0.0288) was noted when comparing patients with baseline resting heart rate ≥77 bpm vs. <77 bpm (77 bpm is the median resting heart rate at the baseline). Indeed, no statistically significant benefit was observed in patients with the baseline resting heart rate less than 77 bpm and the incidence of different mortality endpoints in these patients was numerically higher with ivabradine than with placebo, although the difference was not statistically significant. On the other hand, in patients with the baseline resting heart rate ≥77 bpm, ivabradine was shown to statistically significantly reduce the incidence of the primary efficacy endpoint compared to placebo and both components (i.e. CV death and hospitalization for worsening heart failure) were shown to contribute to the treatment effect seen in this subgroup of patients. The Kaplan-Meier plots showed that the ivabradine and placebo curves started to diverge slightly earlier in patient with baseline HR≥77 bpm compared to the overall study population (i.e. after 1 month vs. 3 months of treatment, respectively) and continued to diverge over the remaining study duration.

The median duration of exposure to ivabradine was 21.6 months. Bradycardia (symptomatic or asymptomatic), atrial fibrillation, blood pressure inadequately controlled and visual effects were common emergent adverse events, more frequently reported with ivabradine than with placebo. Patients aged ≥75 years in this study were shown to be at higher risk of bradycardia when treated with ivabradine, but showed efficacy results consistent with the overall study population. Cases of sinus node dysfunctions, severe cardiac arrhythmias (ventricular fibrillation and torsade de pointes) and heart conduction disorders, although less common, were also more frequently reported with ivabradine than with placebo. Serious cases of bradycardia and atrial fibrillation as well as fatal cases of ventricular fibrillation were more frequent with ivabradine than with placebo. All these risks associated with ivabradine treatment are addressed in the Warnings and Precautions section of the Product Monograph (PM) of Lancora which provides instructions to health care professionals on how to limit and appropriately manage these risks. The PM also includes several contraindications which limit the patient population suitable for treatment with ivabradine.

The ivabradine safety profile in the subgroup of patients with baseline resting heart rate ≥77 bpm was similar as the safety profile observed in the overall study population. Hence, given the more convincing efficacy results observed in this subpopulation, the benefit-risk profile of ivabradine is more favorable in patients with baseline resting heart rate ≥77 bpm than in the overall study population (randomised set: HR ≥70bpm). Therefore an indication was recommended for patients with baseline resting heart rate at or above 77 bpm.

Ivabradine is not meant to replace treatment with beta-blockers, well known to be effective in the treatment of heart failure patients. Every effort should be made by the treating physician to achieve the guideline-recommended target doses of the beta-blockers prior to considering initiating treatment with ivabradine. In addition, as ivabradine treatment decisions are based specific heart rate thresholds, serial heart rate measurements, conducted on at least three separate visits, are required to obtain an accurate measure of heart rate prior to initiating or modifying treatment with ivabradine. Clear directions are provided in the Product Monograph (PM).

Several important drug-drug interactions have been identified, namely with drugs affecting the Cytochrome P 450 3A4 isoform which may greatly affect ivabradine exposure; and with drugs known to also decrease heart rate which may increase the risk of bradycardia. Ivabradine heart rate lowering effect may also cause potential harms in some particular patients, by exposing these patients to risk of severe arrhythmias, namely, patients with existing QT interval prolongation or at risk of QT interval prolongation, and patients with hypokalemia. Ivabradine has been shown to be excreted in milk and to cause embryo-fetal toxicity and teratogenicity in animals at exposure levels comparable to clinical exposure. These items were addressed in the PM.

Ivabradine may be used off-label in patients with stable coronary artery disease for which no outcome benefit have recently been demonstrated, and in patients with supraventricular tachycardia. Cautionary statements have been included in this regard in the PM.

Some uncertainties remain after the review of the SHIFT trial. SHIFT provided limited information on the efficacy and safety beyond 30 months of treatment. Furthermore, efficacy and safety data are either lacking or insufficient to establish whether the benefit-harm profile of ivabradine would be acceptable in patients with New York Heart Association (NYHA) Class IV (severe heart failure); second degree atrioventricular block; aortic stenosis; recent stroke or transient ischemic attack; implanted cardiac devices; or hypotension (other than severe hypotension). Based on the data submitted and reviewed by Health Canada, the safety and efficacy of ivabradine in pediatric patients aged <18 years has not been established; therefore, an indication for pediatric use has not been granted.

A Risk Management Plan was submitted and reviewed by the Marketed Health Product Directorate (MHPD) and was found acceptable.