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CLINICAL RESEARCH: PHARMACOLOGIC STUDIES

Long-Term Safety of a Novel Antianginal Agent in Patients With Severe Chronic Stable Angina

The Ranolazine Open Label Experience (ROLE)

Michael J. Koren, MD, FACC^_*,_*, Michael R. Crager, PhD and Michael Sweeney, MD

^_* Jacksonville Center for Clinical Research, Jacksonville, Florida
CV Therapeutics, Inc., Palo Alto, California

Manuscript received August 14, 2006; revised manuscript received October 26, 2006, accepted October 30, 2006.

^_* Reprint requests and correspondence: Dr. Michael J. Koren, Jacksonville Center for Clinical Research, 4085 University Boulevard South, Suite 1, Jacksonville, Florida 32216. (Email: MichaelKoren{at}jaxresearch.com).

Objectives: This report describes safety and tolerability data from 746 chronic angina patients treated in the ROLE (Ranolazine Open Label Experience) program.

Background: Ranolazine treats angina without depressing hemodynamic status. The long-term safety and tolerability of ranolazine have not been previously reported.

Methods: Patients with severe functional impairment from angina (mean Duke Treadmill Score [DTS] of –14.4) who completed 1 of 2 randomized treadmill trials entered the ROLE program. Ranolazine was titrated to optimal dosages between 500 and 1,000 mg twice daily. Physical examination, laboratory tests, and adverse event reporting were performed periodically. We conducted analyses to evaluate possible predictors of ranolazine intolerance, such as advanced age, diabetes, poor exercise tolerance, or history of myocardial infarctions or congestive heart failure (CHF). The ROLE program's mortality was compared against the DTS predictive model and other contemporary cohorts of high-risk CHD patients.

Results: Mean follow-up was 2.82 years. Two years after initial dosing, 571 patients (76.7%) remained on therapy and 72 patients (9.7%) discontinued ranolazine due to adverse events. Among 6 factors evaluated, only age 64 years predicted for higher withdrawal rates. Patients with a history of CHF had lower withdrawal rates. Mean QTc interval was prolonged by 2.4 ms. No treatment discontinuations occurred due to QTc prolongation, and no Torsades de Pointes was reported. Sixty-four deaths occurred during a total of 2,102 patient-years (3.0% annually) during the ROLE program. When extending observations to all patients exposed to ranolazine during the double-blind trials (n = 972) preceding the ROLE program, annual mortality was 2.8% compared with >5% as predicted by DTS.

Conclusions: Long-term therapy with ranolazine seems well tolerated in high-risk CHD patients. Survival analyses suggest that symptomatic improvements attributable to ranolazine are not offset by increased mortality.

Abbreviations and Acronyms   AE = adverse event   CHD = coronary heart disease   CHF = congestive heart failure   DTS = Duke Treadmill Score   ECG = electrocardiogram/electrocardiographic   EECP = enhanced external counterpulsation   MI = myocardial infarction   SR = extended-release

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