Chronic stable angina treatment newer antianginal agents


 * Associate Editor(s)-In-Chief: ; John Fani Srour, M.D.; Jinhui Wu, M.D.; Lakshmi Gopalakrishnan, M.B.B.S.

Overview
Ranolazine is a one of the newer FDA approved anti-anginal medication for management of chronic stable angina. Perhexiline is another anti-anginal, primarily used in Australia and New Zealand, being studied for use in the United States and UK. In patients with chronic stable angina, other effective agents with anti-anginal and anti-ischemic properties are ivabradine,trimetazidine and molsidomine.

Mechanisms of benefit

 * Ranolazine alters the trans-cellular late sodium current which remains open in pathologic states, such as ischemia and heart failure. The persistent opening of late sodium channel leads to intracellular sodium and calcium overload and a subsequent increase in diastolic stiffness. This stiffness can lead to compression of the intramural vessels that supply the myocardium with blood and oxygen. Therefore, inhibition of this effect results in improvement of ischemia and anginal symptoms.


 * Ivabradine selectively inhibits the pacemaker If activity of the sinus node and therefore is negatively chronotropic both at rest and during activity. Ivabradine also produces a dose-dependent improvement in exercise tolerance and time to development of ischemia during exercise.


 * Trimetazidine is a cyto-protective metabolic anti-anginal agent that promotes aerobic glycolysis by inhibiting anaerobic glycolysis and fatty acid metabolism. This mechanism ensures the proper functioning of ionic pumps and transmembranous sodium-potassium flow while maintaining cellular homeostasis in ischemic cells.


 * Molsidomine is a long acting vasodilator shown to reduce the incidence of anginal attacks by undergoing metabolism to form SIN-1 that subsequently releases nitric oxide.

Indication

 * Ranolazine is effective as both monotherapy and combination therapy for the treatment and prevention of anginal episodes, however is not effective to relieve an episode of angina that has already begun.


 * Ivabradine has shown to be as effective as beta-blockers and hence indicated symptomatic patients with a contra-indication to beta-blocker therapy.


 * In patients with stable angina, trimetazidine has shown to improve exercise parameters and reduce the incidence of anginal episodes. It is also shown to be effective both in monotherapy or when used in combination with standard anti-anginal agents.


 * In patients, refractory to optimal medical therapy who are not candidates for revascularization, perhexiline may be indicated.

Dosage
In asymptomatic patients, an initial dose of 500 mg twice daily of ranolazine may be required and a dose of 1000 mg twice daily may be required in symptomatic patients.

Adverse effects

 * Ranolazine by inhibiting the HERG channel causes prolongation of QT interval.  Other mild side effects include nausea, constipation, headache, dizziness, palpitations.


 * Side effects of perhexiline include hepatotoxicity and peripheral neuropathy.

Supportive trial data

 * In the MARISA trial, 191 patients with angina-limited exercise discontinued anti-anginal medications and were randomized to receive either, ranolazine or placebo treatments. The study reported patients with stable angina tolerated monotherapy better as evidenced by an increase in exercise performance and time to angina. However, the one-year survival did not decrease as expected (96.3 ± 1.7%).


 * In the CARISA trial, 823 patients with symptomatic chronic angina were randomized to receive either one of two doses of ranolazine or placebo. The study reported ranolazine offered additional anti-anginal and anti-ischemic efficacy as evidenced by increased exercise performance, time to angina and time to ST depression in patients with severe chronic angina who remain symptomatic while taking standard doses of atenolol, amlodipine, or diltiazem. There were no significant adverse long-term survival consequences over 1 to 2 years of therapy (One- and two-year survival rates of 98.4% and 95.9% respectively).


 * MERLIN TIMI 36 trial and its sub study are the most recent development in relation to ranolazine. In the MERLIN-TIMI 36 study, 6560 patients with prior chronic angina who received evidence based therapy (95% aspirin, 78% statins, 89% beta-blockers, average 2.9 antianginal agents) were randomized to receive either, ranolazine or placebo treatments. The primary end point of all cause mortality or non-fatal MI during a median follow-up of 1 year was less frequent with ranolazine (HR:0.86; 95% CI:0.75 to 0.97; p=0.017). The study concluded that ranolazine not only improved anti-ischemic effects in the 3565 patients with prior chronic stable angina (HR:0.77; 95% CI:0.59 to 1.00; p=0.048), but also showed anti-arrythmic effects with a decreased incidence of ventricular tachycardia, SVT and ventricular pauses in ranolazine study group.


 * In the ERICA trial, researchers enrolled a total population of 565 patients who were classified with stable coronary disease and more than three anginal attacks per week, despite recommended dosage of amlodipine (10 mg/day) and long acting nitrate therapy. Patients were randomized to receive either, 1,000 mg of ranolazine (n=281) or placebo (n=284) treatments twice a day for 6 weeks to assess the effect fo ranolazine on the frequency of anginal episodes per week. The enrolled patients had a baseline anginal frequency of 5.63 (+/- 0.18) episodes per week and nitroglycerin consumption of 4.72 (+/- 0.21) tablets per week. The study reported significant reduction in the frequency of anginal episodes between the two groups: 2.88 (+/- 0.19, p=0.028) episodes per week in the ranolazine group and 3.31 (+/- 0.22, p=0.028) episodes per week in the placebo group. In addition, there was also significant reduction in the nitroglycerin consumption observed between the two groups: 2.03 (+/- 0.20, p=0.014) tablets per week in the ranolazine group and 2.68 (+/- 0.22, p=0.014) tablets per week in the placebo group.


 * In a placebo-controlled trial, researchers enrolled 360 patients with symptomatic chronic stable angina to evaluate the anti-anginal and anti-ischemic effects of ivabradine. Patients were randomized to receive either, ivabradine or placebo treatments. Researchers reported that ivabradine produces a dose-dependent improvement in the exercise tolerance and time to the development of ischemia during exercise.


 * In the treatment of stable angina, a meta-analysis which evaluated the efficacy and tolerance of trimetazidine, in monotherapy and in combination with other antianginal agents, reported trimetazidine was well tolerated and significantly reduced the frequency of anginal attacks in coronary patients.


 * Another meta-analysis, which reviewed 23 randomized controlled trials data comparing trimetazidine with placebo or other conventional anti-anginal agents, collectively involving 1,378 patients with stable angina, was used to assess the efficacy and tolerability of trimetazidine. Researchers reported there was a significant reduction in the number of weekly anginal episodes (mean difference -1.44, 95% CI -2.10 to -0.79; p<0.0001) and improved exercise time to 1 mm ST segment depression (p=0.0002) observed in the trimetazidine group. One of the four small trials involving 263 patients, favored trimetazidine over nitrates and the remaining three trials favored other anti-anginal agents. Thus, researchers concluded that trimetazidine was shown to be effective in the treatment of stable angina when compared with placebo, alone or when used in combination with conventional anti-anginal agents. It has also been associated with fewer dropouts related to adverse effects from trimetazidine. Furthermore, the study proposed the need for large, long term trials comparing trimetazidine with other anti-anginal drugs to establish the clinical role of trimetazidine.


 * In the TRIMPOL II trial, 426 patients with stable, effort-induced angina and documented coronary artery disease were randomized to receive either trimetazidine or placebo to assess the anti-ischemic efficacy and tolerability of trimetazidine when used in combination with a beta blocker in patients with stable effort angina. At 12-week follow-up, the combined trimetazidine-beta blocker group showed significant improvement in the time to 1 mm ST segment depression during exercise, time to onset of angina and mean weekly number of anginal episodes. Thus, the study concluded that trimetazidine combined with a beta blocker is useful in patients with stable angina that is insufficiently controlled by beta blocker monotherapy.

Vote on and Suggest Revisions to the Current Guidelines

 * The Chronic Stable Angina Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines

Guidelines Resources

 * Guidelines on the management of stable angina pectoris: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology


 * The ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina


 * The ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina


 * The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina