Angina pectoris - ivabradine
The common heart condition angina pectoris is widespread - more than 6 million people are estimated to suffer from it in the US alone.
The common heart condition angina pectoris is widespread - more than 6 million people are estimated to suffer from it in the US alone.
Attacks are usually set off by physical exertion, and patients experience pain in the chest. They result from an imbalance between myocardial perfusion and the metabolic demands of the myocardium, which leads to the heart needing more oxygen than its local blood supply can provide. It is one of the symptoms of coronary artery disease, where a narrowing of the arteries leads to an inefficiency of the blood supply.
There are several different forms of the disease, and the most common form, chronic stable angina, can have a significant impact on the lives of sufferers, leaving them unable to perform even simple everyday activities that involve minor levels of exertion. One way to treat angina is by reducing the heart rate, thus increasing the length of time the heart has to refill, and as a result improving myocardial perfusion. This can be done with β-blockers or calcium channel blockers, but all too often these drugs have side-effects such as a lowering of the blood pressure.
A drug that successfully reduces the heart rate without these side-effects would have great potential as a treatment for angina. The sinoatrial node is responsible for heart pacemaking, so if it could be modulated, this could be a possible alternative mode of action. Four different time dependent currents are believed to be responsible for heart pacemaking, and one of these, the If current, is thought to be the most important, and has been investigated as a potential drug target by Servier. It has developed ivabradine, formerly referred to as S-16257, which is a bradycardic agent that acts selectively at the sino-atrial node.1 It blocks the action of If, reducing the speed of diastolic depolarisation, thus decreasing the heart rate.
In a randomised, double blind, placebo-controlled trial in 60 healthy male volunteers, increasing intravenous bolus single doses of 1, 2, 4, 8 and 16mg ivabradine were given and their effects on maximal exercise parameters measured.2 Significant dose-dependent reductions in heart rate resulted, with no unwanted effects.
A further study in 60 healthy male volunteers looked at the effects of multiple doses.3 The subjects were given 8, 16, 20, 24, 28 or 32mg twice-a-day in a randomised, double blind, placebo-controlled parallel group trial for a week. The mean heart rates in those given the active were significantly lower on day 6, and on days 1, 2 and 7 after dosing, the heart rate at maximum load was substantially higher in those that had been treated with ivabradine.
A larger study has been carried out in 360 patients with chronic stable angina.4 A two-week randomised double blind placebo-controlled phase, in which subjects were given 2.5, 5 or 10mg oral ivabradine twice a day, was followed by two to three month open label extensions with a 10mg twice-a-day dose, and a one-week randomised withdrawal to further ivabradine or placebo. The drug was found to be safe, and gave dose-dependent improvements in exercise tolerance. Phase III trials continue.