Ranolazine in Acute Coronary Syndrome: Not Indicated for Event Prevention
Ranolazine is NOT indicated for the treatment or prevention of major adverse cardiovascular events in ACS, but it may reduce recurrent ischemia symptoms during the acute phase and subsequent recovery period. 1, 2, 3
Primary Evidence: No Benefit for Hard Outcomes
The definitive MERLIN-TIMI 36 trial (n=6,560 patients with non-ST-elevation ACS) demonstrated that ranolazine:
- Did NOT reduce the primary composite endpoint of cardiovascular death, myocardial infarction, or recurrent ischemia (21.8% vs 23.5% placebo; HR 0.92,95% CI 0.83-1.02, P=0.11) 3
- Did NOT reduce cardiovascular death or MI (10.4% vs 10.5% placebo; HR 0.99, P=0.87) 3
- Did NOT reduce all-cause mortality (HR 0.99,95% CI 0.80-1.22, P=0.91) 3
- DID reduce recurrent ischemia (13.9% vs 16.1% placebo; HR 0.87,95% CI 0.76-0.99, P=0.03) 3
The FDA label explicitly states: "In a large (n=6560) placebo-controlled trial (MERLIN-TIMI 36) in patients with acute coronary syndrome, there was no benefit shown on outcome measures." 2
Guideline Recommendations for ACS
The 2011 ESC Guidelines for NSTE-ACS state that ranolazine "was not effective in reducing major cardiovascular events" but "reduced the rate of recurrent ischaemia" in the MERLIN-TIMI 36 study. 1 Importantly, ranolazine is NOT listed among the recommended anti-ischemic drugs for ACS management in the ESC NSTE-ACS guidelines. 1
Appropriate Clinical Context: Chronic Stable Angina Only
Ranolazine's FDA-approved indication is chronic angina only, not ACS. 2 Current guidelines support ranolazine use in:
- Chronic coronary syndrome as add-on therapy when beta-blockers and/or calcium channel blockers provide inadequate symptom control (Class IIa, Level B) 1
- Stable ischemic heart disease as a substitute for beta-blockers when they cause unacceptable side effects or are contraindicated (Class IIa, Level B) 1
Potential Limited Role: Symptom Management Post-ACS
While not indicated for acute event prevention, ranolazine may have a role in managing persistent angina symptoms after ACS stabilization:
- In patients with prior chronic angina who experienced ACS, ranolazine reduced recurrent ischemia regardless of whether PCI was performed (HR 0.69 with PCI, HR 0.81 without PCI) 4
- This represents symptom management rather than prognostic benefit 4
Safety Profile in ACS
The MERLIN-TIMI 36 trial provided reassurance regarding safety:
- No increase in symptomatic arrhythmias (3.0% ranolazine vs 3.1% placebo, P=0.84) 3
- No increase in mortality despite QTc prolongation 3
- Ventricular arrhythmias were actually less common with ranolazine 1, 2
Critical Contraindications and Precautions
Absolute contraindications that apply regardless of clinical setting:
- Liver cirrhosis or hepatic impairment (risk of drug accumulation) 5, 6, 2
- Strong CYP3A inhibitors (ketoconazole, clarithromycin, ritonavir, etc.) 2
- CYP3A inducers (rifampin, phenytoin, carbamazepine, St. John's wort) 2
Dose limitations:
- Maximum 500 mg twice daily with moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin) 2
- Maximum 500 mg twice daily in severe renal impairment (CrCl <30 mL/min) 5
Clinical Bottom Line
Do not initiate ranolazine during ACS with the expectation of reducing death, MI, or major adverse cardiovascular events. 2, 3 If a patient is already on ranolazine for chronic angina when they present with ACS, continuation appears safe but offers no prognostic benefit. 3 Consider ranolazine only after ACS stabilization if the patient develops chronic angina symptoms inadequately controlled by standard antianginal therapy (beta-blockers, calcium channel blockers, nitrates). 1