How does Ranolazine (ranolazine) help with chronic angina and what clinical trials support its efficacy?

Ranolazine for Chronic Angina: Mechanism and Clinical Evidence

Ranolazine is an effective antianginal medication that works primarily by inhibiting the late sodium current (late INa) in cardiac cells, preventing intracellular calcium overload during ischemia without significantly affecting heart rate or blood pressure. 1

Mechanism of Action

• Ranolazine exerts its antianginal effects through concentration-dependent, voltage-dependent, and frequency-dependent inhibition of the late sodium current (late INa), which prevents intracellular calcium overload during ischemia 1
• Unlike traditional antianginals, ranolazine does not significantly affect hemodynamic parameters such as heart rate (<2 bpm change) or blood pressure (<3 mmHg change) 2
• Ranolazine promotes glucose oxidation and improves anaerobic metabolism under ischemic conditions, decreasing oxygen demand and left ventricular wall tension 1
• The QT prolongation effect observed with ranolazine results from inhibition of IKr, which prolongs the ventricular action potential 2

Clinical Evidence Supporting Efficacy

Key Clinical Trials

• The CARISA (Combination Assessment of Ranolazine In Stable Angina) trial demonstrated that ranolazine 750 mg and 1000 mg twice daily significantly increased exercise duration compared to placebo (24-34 seconds greater) when added to standard antianginal therapy 2, 3
• In the CARISA trial, ranolazine also significantly improved time to angina onset and reduced weekly angina frequency (from 3.3 to 2.1-2.5 attacks/week) and nitroglycerin use (from 3.1 to 1.8-2.1 doses/week) 2
• The ERICA (Efficacy of Ranolazine In Chronic Angina) trial showed that ranolazine 1000 mg twice daily significantly decreased angina attack frequency (from 4.3 to 3.3 attacks/week) and nitroglycerin use (from 3.6 to 2.7 doses/week) when added to maximum-dose amlodipine 2
• Long-term safety data from the ROLE (Ranolazine Open Label Experience) program showed that 76.7% of patients remained on therapy after 2 years, with an annual mortality rate of 3.0%, lower than predicted for this high-risk population 4

Patient Populations and Response

• Ranolazine is particularly beneficial in patients with chronic stable angina who cannot tolerate or have inadequate symptom control with first-line agents 5
• Patients with diabetes may experience additional benefits as ranolazine reduces HbA1c levels 1, 2
• Patients with left ventricular hypertrophy might experience greater efficacy with ranolazine compared to other antianginal drugs 1
• The benefits of ranolazine appear to be considerably smaller in women than in men, with women showing about 33% of the improvement in exercise tolerance seen in men 2

Dosing and Administration

• Initial recommended dose: 500 mg orally twice daily 5, 2
• Maximum dose: 1000 mg twice daily 5, 2
• Steady state is generally achieved within 3 days of twice-daily dosing 2
• Ranolazine should not be used to treat acute angina episodes 2

Safety Profile and Precautions

• Common side effects include constipation, nausea, dizziness, and headache 6
• Ranolazine causes dose-dependent QT interval prolongation (mean change of about 6 msec at 1000 mg twice daily), though torsades de pointes has not been observed at therapeutic doses 2, 6
• Ranolazine is contraindicated in patients with hepatic impairment or liver cirrhosis due to the risk of drug accumulation 6
• Caution is advised when co-administering with digoxin, as ranolazine may increase digoxin concentration by 40-60% through P-glycoprotein inhibition 6
• Ranolazine should not be used with strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, ritonavir) 2

Clinical Considerations and Limitations

• Ranolazine does not improve major cardiovascular outcomes such as cardiovascular death or myocardial infarction in patients with non-ST-segment elevation acute coronary syndrome 1, 2
• The MERLIN-TIMI 36 trial showed no benefit on outcome measures in acute coronary syndrome, though there was no difference in all-cause mortality between ranolazine and placebo 2
• Tolerance to ranolazine does not develop after 12 weeks of therapy, and rebound increases in angina have not been observed following discontinuation 2
• Unlike nitrates, ranolazine does not require a nitrate-free interval to prevent tolerance 5

Ranolazine represents an important addition to the antianginal armamentarium, particularly for patients who remain symptomatic despite standard therapy or who cannot tolerate traditional antianginal medications due to their hemodynamic effects.