Objectives: The beneficial symptomatic effects of the selective heart rate reducing agent ivabradine, beta blockers and also the free combination of both in the treatment of stable angina pectoris have already been proven in clinical trials. However, data is still lacking on use of a new fixed-dose combination (FDC) therapy with these drugs. The current study aimed to evaluate the effectiveness and tolerability of the first FDC formulation of ivabradine and the beta blocker metoprolol in clinical practice.
Methods: 747 outpatients with stable angina pectoris were included in this prospective, multicenter, observational cohort study. Patients received a FDC of ivabradine and metoprolol (b.i.d.) for 4 months, in addition to cardiovascular standard therapy. Among other parameters, resting heart rate (HR), the number of angina attacks, short acting nitrate consumption, severity of symptoms (by CCS score) and tolerability were documented. Medication adherence was assessed by use of a modified Morisky questionnaire. Descriptive statistics were performed on all data.
Results: Mean age of the cohort was 66.4 years, 42% were ≥70 years, 10% were ≥80 years, 62% male, 31% had a history of myocardial infarction, 61% of PCI and/or CABG. 86% of all patients were already treated with a free combination of ivabradine (mean dose 9.9 mg/d) and beta-blocker at baseline. Other concomitant standard medication consisted of aspirin 67%, statins 71%, ACEI/ARB 76%, diuretics 35%, long acting nitrates 6%, calcium antagonists 15%, molsidomine 6%, ranolazine 4%. Most prevalent comorbidities were hypertension (86%), hyperlipidaemia (65%) and diabetes (35%).
After 4 months, follow-up data for all scheduled visits were available for 99.2% of patients (n=741). Switch to treatment with the FDC was associated with a significant reduction in mean HR by 10 bpm (from 77 bpm to 67 bpm). Proportion of patients with ≥1 angina attacks/week substantially decreased from 38% to 7%, along with reduction in nitrate use. Patients in CCS class 1 increased (25% to 63%), while proportion in CCS 3 declined (19% to 5%). “Complete adherence” (defined as absence of any adherence-related problems reported in questionnaire) was achieved in 58% of patients after 4 months, compared to 34% at baseline (p<0.001 for all changes from baseline). Mostly mild adverse events occurred in 5.4% of patients. All effects were comparable and consistent for a number of predefined subgroups (e.g. gender, age, CCS class, pretreatment, PCI).
Conclusion: In this study cohort of stable angina patients in a real-life setting, presenting with already intense antianginal pre-treatment at baseline, the ivabradine + metoprolol FDC additionally reduced HR and angina symptoms. Exercise capacity was improved as reflected by a significant shift of patients to lower CCS classes. These positive effects may be mainly mediated by the pronounced improvement in medication adherence with use of the FDC formulation.