IN-US-259-0172: The Effectiveness of Ranolazine in Reducing Cardiac Ischemia Induced by Chronic Total Occlusion of Coronary Arteries Grant uri icon

abstract

  • Anti-anginal drugs relieve ischaemia and symptoms by reducing myocardial oxygen demand by reducing heart rate and or contractility (beta-blockers, phenylalkylamine and benzothiazepineate classes of calcium antagonists) or vasodilatation of the venous system (fall in pre-load) and coronary vessels [1]. Late sodium channels remain open for longer in the presence of myocardial ischaemia. Ranolazine, a novel anti-anginal agent, acts by inhibiting the inward late inward sodium current (INaL), reducing intracellular sodium accumulation and consequently intracellular calcium overload via the sodium/calcium exchanger [2]. It is currently thought that this reduction in intracellular calcium reduces diastolic myocardial stiffness and therefore compression of the small coronary vessels. There is considerable animal data to support this theory [3, 4]. In 2010, a study in patients with stable angina by Stone et al, published data from the MARISA (Monotherapy Assessment of Ranolazine In Stable Angina) trial. Ranolazine exhibited a dose dependent reduction in the magnitude of reduction in ischaemia (as measured by ST depression on exercise ECG) that was greater than the relatively small reductions in rate pressure product (RPP) observed [5]. This strongly suggests that Ranolazine?s mechanism of action is likely to be mediated by an improvement in regional blood flow in ischemic myocardium [5, 6] . There are good theoretical reasons to postulate that patients with chronically occluded vessels may derive less benefit from conventional anti-anginal agents particularly vasodilators. The ischemic myocardium subtended by the occluded vessel will already be subject to significant concentrations of paracrine vasodilators such as adenosine. Ranolazine therefore may on the basis of its mechanism of action, provide greater relief of ischaemia in such patients. To test this hypothesis, one would wish to conduct a randomized study comparing addition of ranolazine to addition of a conventional anti-anginal agent in patients with chronic total occlusions. To be sufficiently powered, this would require a significant number of patients recruited in a multi-center trial. Therefore, I propose initially conducting a pilot study with placebo as the control.

date/time interval

  • October 2013 - March 2017