Clinical evidence with ivabradine
Ivabradine relieves ischemia Ivabradine provides baseline-dependent heart rate reduction.
The mode of action of ivabradine is baseline-dependent, so heart rate reduction is more significant in patients with a higher baseline rate than in those with a lower rate.12
Superiority study shows that ivabradine is more effective than placebo. The first large-scale, international, multicenter, double-blind trial, in 360 patients with a >3-month history of chronic stable angina, reveals that ivabradine significantly and dose-dependently reduces resting and exercise heart rate vs placebo This was associated with improvements in the primary efficacy parameters of time to 1 mm ST segment depression and time to limiting angina at trough drug activity.13 Mean angina attack frequency and the consumption of short-acting nitrates were reduced significantly (P<0.001).13
Randomized trials have demonstrated the efficacy of ivabradine when compared with β-blockers and calcium channel blockers.
INITIATIVE, a multicenter, randomized, double-blind, 4 month trial14 (Figure 2), was designed to investigate the efficacy of ivabradine 7.5 mg bid relative to high-dose atenolol (100 mg od). The improvement in exercise capacity for each bpm of heart rate reduction was greater for ivabradine than for atenolol (Figure 2)15. This is a clear illustration of the greater anti-ischemic efficacy of pure heart rate reduction with ivabradine (ie, without any unwanted hemodynamic consequences) than of heart rate reduction with β blockade. In practice, this means that patients treated with ivabradine have a better adaptation to exercise, while also gaining the full benefits of heart rate reduction.
Figure 2. Changes in exercise capacity after heart rate reduction
Ivabradine has long-term efficacy. A randomized, double-blind, parallel-group study in 386 patients with chronic stable angina showed that ivabradine reduces angina attacks by more than 50%, even in patients receiving conventional treatment.
Figure 3. Ivabradine reduces angina attack frequency in the long term, even in patients receiving background antianginal therapy
The development of ivabradine involved a long-term study in more than 5000 patients, which demonstrated the anti-ischemic and antianginal efficacy of ivabradine and its safety and tolerability18.
Moreover, ivabradine can be safely administrated with various other drugs. The use of ivabradine in combination with β-blockers is currently being assessed in several large-scale studies in patients with stable coronary artery disease.
Efficacy of ivabradine in combination with β-blockers16
The ASSOCIATE study16 demonstrates that ivabradine provides increased anti-ischemic and antianginal efficacy when it is combined with the β-blockers in patients with stable angina.
Figure 4. Addition of ivabradine to the regimen of patients already receiving conventional recommended therapy including β–blockers further improves anti-ischemic and antianginal efficacy by improving all exercise test tolerance (ETT) parameters.
These results are even more impressive as patients were made to walk at speeds of up to 5.5 km/hour at inclinations up to 14% as recommended by the standardized Bruce protocole used.
In this 4-month, double-blind, placebo-controlled study in 20 countries, 889 stable angina patients already being treated with atenolol 50 mg once daily or other β-blockers at equivalent dosages for at least 3 months were randomized to ivabradine 5 mg ivabradine for 2 months and uptitrated to ivabradine 7.5 mg twice daily. The measurement of all exercise test tolerance parameters at trough of drug activity over 4 months of treatment was done following the standardized Bruce protocol, thus providing highly significant results.
The clinical benefits of ivabradine in angina patients already receiving β-blockers are evident with 5 mg bid and greatly increase with Procoralan 7.5 mg.
Ivabradine 5 mg improves their exercise capacity twofold and ivabradine 7.5 mg further improves their exercise capacity threefold. (Figure 5)
Figure 5. Ivrabradine provides a significant further improvement in exercise capacity, particularly in total exercise duration (TED) and the results are reinforced from M2 to M4.
This powerful evidence has been acknowledged in the European Heart Journal as the 'most compelling single demonstration of the benefit of any combination of antianginal drugs published to date'16
Moreover, the ASSOCIATE study31 confirms that the usage of ivabradine is very well tolerated and safe in patients already receiving β-blockers, and optimally lowers heart rate, with only 1.1% of patients experiencing symptomatic bradycardia.
Efficacy of ivabradine in a broad range of stable coronary patients17
Ivabradine significantly reduced the frequency of angina pectoris attacks from 59.7% to 53.2% and the consumption of nitrates from 57.3% to 44%, in the coronary patients studied:
- postmyocardial infarction
- postrevascularized
- diabetics
- asthmatics
- elderly persons
- women
- patients with peripheral vascular disease
Thus, this meta-analysis of data from the follow-up of 2525 patients with stable angina already receiving optimal treatment for angina (nitrates, ACE inhibitors, antithrombotics and β-blockers) shows that treatment with ivabradine for 3 or 4 months enhances the anti-ischemic and antianginal efficacy of ivabradine in a broad range of stable coronary patients17:
Ivabradine and its effect on cardiovascular prognosisThe main results from the BEAUTIFUL study demonstrate the benefit of ivabradine in reducing major cardiovascular events such as myocardial infaction, or the need for revascularization in stable coronary patients with a resting heart rate >70 bpm, that is those at higher risk of cardiovascular events.19