Selective late sodium current inhibition with ranolazine offers a novel approach to preventing the dangerous cycle of ischaemia in heart disease, a leading cardiologist has suggested
Speaking at the launch in Dublin recently of the newly available anti-anginal, Prof John Camm of St George’s at the University of London said late sodium current occured if the gating on the channel went wrong and did not close.
“Sodium continues to flow into the cell abnormally. This leads to an increased concentration of sodium within the cytosol and high intracellular calcium as a consequence. Calcium overload is the problem that develops during ischaemia and heart failure.”
“The consequence is diastolic relaxation failure, which increases myocardial oxygen consumption and reduces myocardial blood flow and oxygen supply,” the Professor of Clinical Cardiology explained.
QT interval
Sodium transport across its channel in the cardiac myocyte is a determinant of the QT interval. The sodium current peaks until the action potential reaches zero and then it decays, but during ischaemia, the sodium current is abnormal and the duration is longer.
“This enhanced late sodium current prolongs the action potential duration and the QT interval. It changes the characteristics of the mechanical response and it becomes delayed and moves into what should be the early part of diastole. As the muscle is contracting around the micro-vasculature, it means that coronary perfusion is reduced.
“So, late sodium current leads to reduced coronary perfusion and ischaemia. Ischaemia begets ischaemia,” said Prof Camm.
The resultant effect is that the heart goes into contracture, end diastolic pressure goes up and oxygen consumption increases.
“If you give a late sodium current inhibitor, it takes longer for the heart to go into contracture, left ventricular end diastolic pressure (LVEDP) stays low for longer and never gets as high and the amount of oxygen consumed is less,” he added.
Failing myocytes
The advantage of the selectivity of the piperazine derivative ranolazine is that in the normal situation, the sodium current is not affected at all. However, in the situation where there are failing myocytes and the late sodium current is enhanced, then ranolazine has the considerable benefit of reducing the current. This is different to other medications that alter sodium transport, including lidocaine and amiodarone, which are not as selective or as potent an inhibitor of the late sodium current.
Use of ranolazine in patients with the rare condition of long QTc, which is caused by a genetic defect and enhanced delayed sodium current, has shown it selectively reduces the QT interval by 20ms at low doses and up to 45-50ms at higher doses.
Prof Camm said that myocardial perfusion scans have shown a reduction in the perfusion defect when patients were given ranalozine.
Rate pressure product is an index of haemodynamic effect of exercise. Ranolazine was found to have an effect on exercise duration but little effect on the rate pressure product, indicating it acts independently of the haemodynamic effects of exercise.
Further evidence of this selective action comes from the fact it does not affect haemodynamic parameters such as heart rate and blood pressure.
Diastolic relaxation
“It works at the cycle where ischaemia produces impaired diastolic relaxation and increased LVEDP and decreased diastolic flow. If you interrupt this with a late sodium current inhibitor, these effects, which adversely affect the balance between oxygen supply and demand, will be reversed,” said Prof Camm.
Traditional anti-anginals and revascularisation procedures often fail to control the symptoms of refractive angina. Three trials — MARISA, CARISA and ERICA — have shown the benefit of ranolazine as an anti-anginal agent.
In MARISA, 500-1500 mg ranolazine twice daily was compared with placebo) and there was a significant improvement in the parameters of exercise duration, time to 1mm ST segment depression and time to onset of angina in the ranolazine-treated group.
In the large CARISA Trial of over 800 patients with chronic stable angina, twice-daily doses of the drug (750 or 1000 mg ranolazine or placebo plus maximum dose of other anti-anginals) increased exercise capacity independent of haemodynamic effects and provided additional benefit to patients already taking other anti-anginals. Angina frequency and nitroglycerine use were also shown to be reduced in the study in the drug-treated group.
A subset analysis in CARISA looked at those patients who could not take any more beta-blockers or calcium antagonists. In this analysis, the results were similar to the overall analysis when a subset of the patients with heart rate less than 60, blood pressure less than 100 and PR intervals less than 200ms were investigated.
These results were confirmed in the ERICA trial when it was shown that ranolazine had an additional benefit to treatment with maximum anti-anginal doses of amlodipine 10mg once daily. The primary endpoint of frequency of angina attacks and nitroglycerine consumption were significantly reduced.
An add-on therapy
The current EMEA approved indication for ranalozine is as an ‘add-on therapy for patients who cannot be adequately controlled or cannot tolerate first-line management with other anti-anginals.’ The initial recommended dose is 375mg given twice daily titrated up to 500mg twice daily in 2-4 weeks and then titrated up to a maximum dose of 750mg twice daily after a further 2-4 weeks if required.
Side-effects with ranolazine are generally uncommon with the recommended treatment doses and the most common experienced are dizziness, headache, constipation, vomiting, nausea and asthenia.
There are contraindications: moderate to severe hepatic failure, severe renal impairment and concomitant treatment with potent CYP3A4 inhibitors such as azo antifungals, some antibiotics like erythromycin and vancomycin and retroviral protease inhibitors used in HIV patients.
“It is only a very few drugs that are powerful CYP3A4 inhibitors and that are relevant and the rest are not. It can be used with the moderate CYP3A4 inhibitors such as diltiazem and verapamil,” said Prof Camm. Class 1a and class 3 anti-arrhythmic drugs are also contraindicated, but in Prof Camm’s view, this is purely precautionary — although in normal healthy individuals, ranolazine prolongs the QT interval slightly, if it is given to ischaemic patients (due to the late sodium current inhibition), the net effect is a reduction in the QT interval.
“It’s the first drug that has been shown in substantial trials not to have any hazard from QT prolongation and yet in normal volunteers to cause QT prolongation. It’s the one drug with benign or good QT prolongation,” Prof Camm concluded.
l References on request.
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