Ranolazine Does Not Provide Mortality Benefit in Patients with Chronic Angina
Ranolazine has not been shown to provide a mortality benefit in patients with chronic angina, as clinical trials have not demonstrated a significant reduction in cardiovascular death or overall mortality compared to placebo. 1
Evidence on Mortality Outcomes
- The MERLIN-TIMI 36 trial, which is the largest study of ranolazine in patients with established coronary artery disease, found that cardiovascular death or myocardial infarction did not differ between ranolazine and placebo groups (HR: 0.97; 95% CI: 0.80 to 1.16; p = 0.71) 1
- Total mortality was also similar between ranolazine (6.2%) and placebo (6.4%) groups (p = 0.96) in this large-scale trial 1
- The Ranolazine Open Label Experience (ROLE) program reported an annual mortality of 2.8% in high-risk coronary heart disease patients treated with ranolazine, but this was an open-label study without a control group for direct mortality comparison 2
Clinical Benefits of Ranolazine (Non-Mortality)
- Ranolazine does provide significant benefits in reducing angina symptoms and improving exercise tolerance:
- Reduces recurrent ischemia (HR: 0.78; 95% CI: 0.67 to 0.91; p = 0.002) 1
- Decreases worsening angina (HR: 0.77; 95% CI: 0.59 to 1.00; p = 0.048) 1
- Reduces need for intensification of antianginal therapy (HR: 0.77; 95% CI: 0.64 to 0.92, p = 0.005) 1
- Improves exercise duration compared to placebo (514s vs. 482s, p = 0.002) 1
Mechanism of Action
- Ranolazine works primarily through inhibition of the late sodium current (late INa), which prevents intracellular calcium overload during ischemia 3
- Unlike traditional antianginal medications, ranolazine exerts its antianginal effects without significantly affecting heart rate, blood pressure, or myocardial perfusion 3, 4
Safety Considerations
- Ranolazine causes dose-dependent QT interval prolongation that requires monitoring, especially in patients with risk factors for arrhythmias 5, 3
- Despite QT prolongation, clinical trials have not reported increased incidence of torsades de pointes at therapeutic doses 3, 1
- Common side effects include constipation, nausea, dizziness, and headache 5, 4
- Ranolazine is contraindicated in patients with hepatic impairment or liver cirrhosis 5, 3
- Caution is advised when co-administering with digoxin, as ranolazine may increase digoxin concentration by 40-60% through P-glycoprotein inhibition 5, 6
Special Population Considerations
- Ranolazine may be particularly beneficial in patients with diabetes and chronic angina, as it has demonstrated favorable effects on glycated hemoglobin levels 6, 4
- Ranolazine should be limited to 500 mg twice daily in patients with severe renal impairment (CrCl <30 ml/min) 5
- Older patients (≥64 years) may have higher withdrawal rates from ranolazine therapy 2
Clinical Decision-Making
- Ranolazine should be considered as an add-on therapy when angina is not adequately controlled with first-line agents (beta-blockers, calcium channel blockers, nitrates) 7, 8
- When choosing between metabolic modulators, ranolazine has more robust clinical evidence from contemporary, double-blind, placebo-controlled trials compared to trimetazidine 6
- For patients with diabetes and chronic angina, ranolazine is preferred due to its proven benefits on glycemic control and angina symptoms 6