SAN FRANCISCO — Treatment with ranolazine did not lower rates of ischemia-driven revascularization or hospitalization without revascularization in patients with a history of chronic angina who had incomplete revascularization after PCI, according to late-breaking clinical trial results presented at the annual TCT Scientific Symposium.
“Incomplete revascularization is common, present in 17% to 85% of patients following PCI — it depends on the definition — and has been strongly associated with increased rates of repeat revascularization and mortality,” Giora Weisz, MD, an interventional cardiologist at Columbia University in New York and Shaare Zedek Medical Center in Jerusalem, said during his presentation. “The primary objective of RIVER-PCI was to evaluate the efficacy of ranolazine as compared with placebo when used as part of standard medical therapy in patients with a history of chronic angina and incomplete revascularization after PCI.”
The multicenter, randomized, parallel-group, double blind, placebo-controlled, event-driven, intent-to-treat RIVER-PCI trial included 2,651 patients from 245 centers in 15 countries in Europe, Israel, Russia and the United States.
Patients were randomly assigned in a 1:1 fashion to twice-daily oral ranolazine (Ranexa, Gilead Sciences) at a 1,000-mg dose or matched placebo through an interactive, Web-based, block randomization system, with block sizes of 10. Randomization was stratified by the presence or absence of diabetes as well as acute vs. non-acute presentation of coronary syndrome. The primary endpoint was time to first occurrence of ischemia-driven revascularization or ischemia-driven hospitalization without revascularization. The trial was conducted between November 2011 and May 2013.
Major inclusion criteria included a history of chronic angina and angiographic evidence of incomplete revascularization after PCI. Major exclusion criteria was more extensive and included future planned revascularization (including staged procedures); an unprotected left main coronary artery lesion with stenosis of at least 50% in diameter; major complications during index PCI; New York Heart Association class III or IV HF; stroke within 90 days of enrollment or history of stroke with permanent major neurological disability; estimated glomerular filtration rate of less than 30 mL/min/1.73 m² and cirrhosis.
Patients also were excluded for parallel use of class IA, IC or class III antiarrhythmic drugs except for amiodarone, strong cytochrome P450 (CYP) 3A inhibitors, CYP3A4 or P-glycoprotein inducers and daily treatment with at least 20 mg simvastatin, 40 mg lovastatin or 1,000 mg metformin.
The group randomly assigned to treatment with ranolazine included 1,332 participants; there were 1,319 patients in the placebo-treated group. The final analysis included 98% (n = 2,604) of the original enrollment group.
At the median follow-up point of 643 days (interquartile range, 575-758 days), the composite primary endpoint occurred in 345 patients (26%) treated with ranolazine and 364 patients (28%) treated with placebo (HR = 0.95; 95% CI, 0.82-1.1). Incidence of ischemia-driven revascularization and ischemia-driven hospitalization did not differ significantly between groups, according to study results. More patients in the ranolazine group (n = 189; 14%) vs. the placebo group (n = 137; 11%) discontinued the study drug because of an adverse event (P = .04).
Weisz also reviewed the safety outcomes of RIVER-PCI.
“We found no differences between placebo and ranolazine in the safety outcomes of overall mortality, [CV] deaths, MACE [or] hospitalization for [HF] or stroke,” he said. “There was a little higher rate of [transient ischemic attack] with ranolazine as compared [with] placebo, but the numbers were very small, and we believe they were a matter of chance because there was no difference in the number of strokes between the two groups.”
The trial is the first prospective evaluation of patients with incomplete revascularization after PCI, according to Weisz.
“We have shown that the number of events in patients with incomplete revascularization was very high,” he said. “That confirms what we have seen in prior retrospective studies. What we have seen as well is that ranolazine, as a routine treatment for patients with incomplete revascularization, did not work — [it] did not change the primary endpoint as compared [with] placebo.” – by Julia Ernst, MS
Weisz G, et al. Plenary Session XIII. Late-Breaking Clinical Trials 2: Co-sponsored by The Lancet. Presented at: TCT Scientific Symposium; Oct. 11-15, 2015; San Francisco.
Weisz G, et al. Lancet. 2015;doi:10.1016/S0140-6736(15)00459-6.
Disclosure: The study was funded by Gilead and Menarini. Weisz reports serving on the medical advisory boards of AngioSlide, AstraZeneca, Calore, Corindus, Medtronic, Medivisor and MI Medical Incentives, and receives institutional research grants from AngioSlide and Corindus. Please see the full study for a list of all other authors’ relevant financial disclosures.