Ivabradine

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Coralan (Servier)
5 mg and 7.5 mg tablets
Approved indication: angina
Australian Medicines Handbook section 6.2

Atherosclerotic coronary disease can result in the myocardium not receiving all the oxygenated blood it needs. This inadequate perfusion can present as angina. One approach to managing angina is to reduce myocardial oxygen demand by slowing the heart rate. This is one of the actions of beta blockers.

Ivabradine slows the heart rate by its action on the pacemaker activity of the sinoatrial node. It inhibits a current known as the I_f current (F for funny as the current has unusual properties). The I_f current contributes to diastolic depolarisation, so blocking it reduces heart rate and therefore increases diastolic filling time and myocardial perfusion.

Although ivabradine is well absorbed its bioavailability is reduced to 40% by first-pass metabolism. Food delays absorption but increases bioavailability so the twice-daily doses should be taken with food. The metabolism of ivabradine involves cytochrome P450 3A4, so the concurrent use of potent inhibitors of this enzyme, such as macrolide antibiotics and azole antifungals, is contraindicated. Dose adjustment may be needed with less potent inhibitors, or inducers of CYP3A4. The metabolites of ivabradine are excreted in the urine and faeces.

A phase II study randomised 360 patients with chronic stable angina to take 2.5 mg, 5 mg or 10 mg ivabradine or a placebo twice daily for two weeks. This was followed by an open-label extension during which all patients took 10 mg ivabradine twice daily for two or three months and then a randomised withdrawal of treatment for one week. The heart rate reduced in proportion to the dose of ivabradine. After the first two weeks of treatment patients taking ivabradine could exercise for longer before the onset of ECG changes or angina. Exercise tolerance diminished in patients who were randomised to take a placebo during the withdrawal phase.¹

The efficacy of ivabradine has been compared with atenolol in a double-blind trial. After taking the recommended starting dose of 5 mg twice daily, 315 patients had their dose of ivabradine increased to 7.5 mg twice daily and 317 increased to 10 mg twice daily for 12 weeks. The beta blocker group increased their dose from 50 mg to 100 mg atenolol daily. All groups experienced an increase in the time they could exercise for during exercise tolerance tests. The mean number of angina attacks per week decreased by 2.2 with ivabradine 7.5 mg, 2.3 with ivabradine 10 mg and 2.7 with atenolol 100 mg. Overall ivabradine was not inferior to atenolol.²

Ivabradine has also been compared with the calcium channel blocker amlodipine in a trial lasting three months. Again all patients had an increase in total exercise duration at the end of the study. Another study added ivabradine or a placebo to treatment with amlodipine. After three months, exercise tests, at the peak of ivabradine activity, showed that the patients taking the drug could exercise for longer than those who added a placebo.

In the placebo-controlled trial the main difference in adverse effects was visual disturbances in the patients taking ivabradine.¹ These effects also appeared in the other trials. More than 14% of patients described transient increases in brightness in parts of their visual fields. Most of these 'phosphenes' resolved during treatment. Blurred vision is also common.

Some patients will develop bradycardia so ivabradine is contraindicated in patients with a heart rate less than 60 beats per minute. Heart block can also occur so ivabradine should not be used in patients with atrioventricular block (3rd degree). Other contraindications include sino-atrial block, sick sinus syndrome and heart failure (class III-IV). Ivabradine should not be used to treat arrhythmias or unstable angina. Prescribing it with drugs that prolong the QT interval is not recommended as is concurrent treatment with calcium channel blockers, such as verapamil and diltiazem, which can slow the heart rate.

Compared with placebo, ivabradine significantly delays the onset of angina during exercise testing, but the difference is a matter of seconds. For example, after the first two weeks of the placebo-controlled study, patients who had taken ivabradine 5 mg twice daily could exercise for approximately 14 seconds longer than the placebo group before the onset of angina.¹ In the study where it was added to amlodipine, ivabradine had no statistical advantage over placebo if the exercise tolerance test was done at the time of trough drug activity.

It is too early to say if ivabradine will reduce deaths from ischaemic heart disease. The data are limited, but the estimated incidence of death in the trial population is 3.1 per 100 patient years with placebo, 2.4 with ivabradine, 2.1 with amlodipine and 0.5 with atenolol.

As ivabradine appears to have no clear advantage, it seems appropriate to limit its indication to patients with chronic stable angina who are in sinus rhythm and have a contraindication or an intolerance of beta blockers. Unfortunately the main trials of ivabradine were not specifically in people who cannot take beta blockers and the 10 mg twice-daily dose used in some trials exceeds the dose recommended by the product information.