About ivabradine

Ivabradine provides pure heart rate reduction.

It is the first selective and specific If current inhibitor in the sinus node available for clinical use. Ivabradine slows heart rate by decreasing the velocity of diastolic depolarization (ie, by reducing the ‘steepness’ of the If current slope of diastolic depolarization) in sinus node cells.



Thus ivabradine is the first treatment to reduce heart rate exclusively while fully preserving myocardial contractility and relaxation, atrioventricular conduction, and ventricular repolarization, as well as blood pressure.

In contrast, β-blockers simultaneously reduce HR, contractility, and relaxation, thus decreasing both stroke volume and cardiac output.

Ivabradine provides baseline-dependent heart rate reduction.
The mode of action of ivabradine is baseline HR-dependent, so heart rate reduction is more significant in patients with a higher baseline HR than in those with a lower HR.


Clinical evidence with ivabradine in coronary artery disease

IVABRADINE RELIEVES ISCHEMIA AND REDUCES ANGINA EFFECTIVELY AND RAPIDLY

Randomised trials show that ivabradine improves exercise test parameters versus β-blockers
INITIATIVE, a multicenter, randomized, double-blind, 4 month trial 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. 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.
Along with the improvement in ischemia, Ivabradine provides powerful antianginal efficacy. This has been clearly demonstrated by the improvement in the time of limiting angina and reduction in the number of angina attacks. Antianginal efficacy was observed within 2 weeks of the administration of ivabradine.


Changes in exercise capacity after heart rate reduction

Change in time to limiting angina (exercise tolerance test) criteria with Ivabradine at trough of drug activity

Ivabradine provides synergistic benefits when combined with β-blockers
The clinical benefits of ivabradine in angina patients already receiving β-blockers are evident with 5 mg bid and greatly increase with ivabradine 7.5 mg. Ivabradine 5 mg improves their exercise capacity twofold and ivabradine 7.5 mg further improves their exercise capacity threefold.


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’.
Moreover, the ASSOCIATE study 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.

IVABRADINE IMPROVES THE CARDIOVASCULAR PROGNOSIS
The main results from the BEAUTIFUL study demonstrate the benefit of ivabradine in reducing major cardiovascular events such as myocardial infarction, or the need for revascularization in stable coronary patients with a resting heart rate >70 bpm, that is in those at higher risk of cardiovascular events.
A new analysis from the BEAUTIFUL study shows that ivabradine reduces the risk of cardiovascular death, hospitalization for myocardial infarction, and heart failure by 24% (P=0.048) in patients with limiting angina, and has a maximum effect on myocardial infarction with a 42% risk reduction (P=0.022). These results have been presented at the ESC 2009 Congress in Barcelona and published in the European Heart Journal.
The benefit of ivabradine was even more striking in angina patients with high resting heart rate (≥70 beats per minute), where ivabradine significantly reduces:

  • The primary end point of cardiovascular death, hospitalization for myocardial infarction, and heart failure by 31%
  • The risk of hospitalization for myocardial infarction by 73%
  • The need for coronary revascularization by 59%

Ivabradine reduces the risk of myocardial infarction in angina patients, with a greater benefit in patients with HR >70 bpm



These findings set ivabradine apart as an antianginal agent that has been documented to be able to increase cardiovascular benefits in symptomatic coronary patients.

IVABRADINE IS OF PROVEN LONG-TERM SAFETY AND EXCELLENT TOLERABILITY
The development of ivabradine involved a long-term study in more than 10000 patients, which demonstrated the clinical benefits of ivabradine and its safety and tolerability


Ivabradine may have a supplementary therapeutic role in patients with heart failure

Resting heart rate (HR) is an independent predicting factor of cardiovascular events in chronic heart failure. Clinical trials have demonstrated that reduction of HR is associated with the reduction of morbidity-mortality in such a disease.



β-blockers have become an important component of heart failure treatment as described in the latest ESC guidelines.
It was hypothesized that at least part of their effects on mortality and cardiac sudden death might be related to their effect on heart rate. Furthermore, it was demonstrated that the more the heart rate decreases, the higher the survival rates were, and the lower the number of hospital admissions were.

Besides their attenuation effect on heart rate, these agents have numerous other actions on the heart, including decreasing myocardial contractility, a reduction in blood pressure…

Therefore, it is a logical to think that pure heart rate reduction with ivabradine may be beneficial in heart failure patients without the other effects associated with β-blockers.

In a rat model of myocardial infarction, ivabradine was beneficial by improving LV systolic function, reducing collagen density in the non-infarcted myocardium and improving myocardial perfusion and the coronary reserve in rats with CHF.
Furthermore, pilot studies conducted in patients with moderate to severe chronic heart failure (NYHA class III and IV) already receiving β-blockers, show that the addition of ivabradine significantly reduces heart rate, and improves left ventricular function and NYHA class.



In patients with advanced heart failure and markedly depressed LV function, the acute administration of ivabradine is well tolerated and effectively reduces HR. Despite the marked HR reduction, cardiac output is preserved thanks to a marked increase in stroke volume.

Rationale for benefits of ivabradine in heart failure

  • Resting heart rate has an independent prognostic value in patients with CHF
  • Reduction of HR is associated with the reduction of morbidity-mortality in such a disease
  • Unique pharmacodynamic profile of ivabradine: heart rate reduction without  any deleterious impact on hemodynamics
  • Beneficial effects of ivabradine on cardiac remodelling, capillary density, and LV dysfunction



“Current epidemiological and clinical trial data suggest the appropriateness of assessing the value of pure heart rate reduction for improving natural history and symptom status in symptomatic patients with chronic heart failure and systolic dysfunction who are currently treated with a currently accepted optimized pharmacological treatment. The design of the SHIFT trial should enable this evaluation.”


Further development in the cardiovascular disease spectrum

SIGNIFY in patients with coronary artery disease without heart failure – results are expected in 2013




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