Ranolazine in Patients With Incomplete Revascularization After Percutaneous Coronary Intervention - RIVER-PCI

Contribution To Literature:

The RIVER-PCI trial showed that ranolazine is not superior to placebo for reducing ischemia-driven events in patients with angina and incomplete revascularization following PCI.


The goal of the trial was to assess the safety and efficacy of ranolazine in reducing ischemia-driven revascularization and rehospitalization in patients with chronic angina and incomplete revascularization following percutaneous coronary intervention (PCI).

Study Design

Patients with chronic angina and incomplete revascularization following PCI were randomized in a 1:1 ratio to either ranolazine 1000 mg (n = 1,317) or placebo (n = 1,287).

  • Total number of enrollees: 2,604
  • Duration of follow-up: 1.8 years (median)
  • Mean patient age: 63.4 years
  • Percentage female: 20%

Other salient features/characteristics:

  • Diabetes: 33.5%
  • Prior myocardial infarction (MI): 47%
  • Left ventricular ejection fraction: 55%
  • Acute coronary syndrome presentation: 34%
  • Canadian Cardiovascular Society class III/IV 1 month prior to PCI: 30%
  • Two-vessel disease: 43%, three-vessel disease: 44%
  • Untreated chronic total occlusion (CTO): 33%, untreated small vessel or diffuse disease: 16%
  • Baseline SYNTAX: 17, residual SYNTAX: 10.5
  • Beta-blockers: 86%, calcium channel blockers: 25%, nitrates: 21%, total number of anti-ischemic drugs ≥2: 30%

Inclusion criteria:  

  • Post-PCI evidence of incomplete revascularization: ≥50% stenosis in one or more coronary artery with reference vessel diameter of ≥2.0 mm (visual assessment)
  • History of chronic angina: ≥2 anginal episodes 30 days to 1 year prior to PCI

Exclusion criteria:

  • Future planned revascularization
  • Unprotected left main ≥50% diameter stenosis
  • Major complications during the index PCI
  • New York Heart Association class III-IV heart failure
  • Stroke within 90 days or major disability
  • Estimated glomerular filtration rate <30 ml/min/1.73 m2
  • Cirrhosis
  • Previous ranolazine use for >7 days within 30 days
  • Hypersensitivity or intolerance to ranolazine
  • Use of class Ia, Ic, or class III antiarrhythmic (except amiodarone)
  • Strong CYP3A inhibitors, CYP3A4, or P-glycoprotein inducers
  • >20 mg simvastatin daily, >40 mg lovastatin daily, or >1000 mg metformin daily

Principal Findings:

  • Primary endpoint, time to first ischemia-driven revascularization or ischemia-driven hospitalization without revascularization for ranolazine vs. placebo: 26.2% vs. 28.3%, p = 0.48
  • Ischemia-driven revascularization: 15.3% vs. 15.5%, p = 0.91
  • Ischemia-driven hospitalization: 15.3% vs. 17.9%, p = 0.14

Secondary outcomes:

  • MI: 8.4% vs. 9.0%, p = 0.81
  • Sudden cardiac death: 0.5% vs. 0.9%, p = 0.4
  • Major adverse cardiac events: 10.7% vs. 11.1%, p = 0.99
  • Transient ischemic attack: 1% vs. 0.2%, p = 0.02

Quality-of-life assessments: There were significant improvements in the frequency of angina following PCI in both arms, with no differences between ranolazine vs. placebo at 1 month (86.6 vs. 85.8, p = 0.62) or 12 months (88.4 vs. 88.5, p = 0.6). Patients with diabetes appeared to have a benefit with ranolazine for angina frequency at 6 months (88.3 vs. 85.4, p = 0.033; p for interaction = 0.02). This difference, however, dissipated by 12 months (p = 0.18). Of note, ranolazine decreased hemoglobin A1c by 0.42% at 6 months and by 0.44% at 12 months in patients with diabetes mellitus and by 0.19% and 0.2% at 6 and 12 months, respectively, in patients without diabetes mellitus.


Overall, ischemia-driven events in patients with angina and incomplete revascularization following PCI are common (27% over 1.8 years), but the results of this trial indicate that ranolazine is not superior to placebo for this indication. There were also no benefits in angina frequency up to 1 year of follow-up, but modest improvements were observed in patients with diabetes mellitus. This is an important and significant subset of patients undergoing PCI. One limitation is that the trial included a mixed group of patients with residual disease, including untreated CTOs and diffuse distal disease. Similarly, the functional significance of untreated disease (stress, fractional flow reserve) is unknown.

Ranolazine has been studied before in patients with angina without PCI in the CARISA, MARISA, and TERISA trials, with a significant benefit in anginal symptoms among diabetic patients in the latter trial. This trial provides complementary information among patients undergoing PCI. Of note, no benefit was observed for the primary endpoint among the diabetic subset in this trial, but a modest benefit was observed in angina frequency in this patient subset.


Fanaroff AC, James SK, Weisz G, et al. Ranolazine After Incomplete Percutaneous Coronary Revascularization in Patients With Versus Without Diabetes Mellitus: RIVER-PCI Trial. J Am Coll Cardiol 2017;69:2304-13.

Alexander KP, Weisz G, Prather K, et al. Effects of Ranolazine on Angina and Quality of Life After Percutaneous Coronary Intervention With Incomplete Revascularization: Results From the Ranolazine for Incomplete Vessel Revascularization: (RIVER-PCI) Trial. Circulation 2016;133:39-47.

Presented by Dr. Karen P. Alexander at the American Heart Association Scientific Sessions, Orlando, FL, November 10, 2015.

Weisz G, Généreux P, Iñiguez A, et al. Ranolazine in patients with incomplete revascularization after percutaneous coronary intervention (RIVER-PCI): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2016;387:136-45.

Presented by Dr. Giora Weisz at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2015), San Francisco, CA, October 13, 2015.

Clinical Topics: Arrhythmias and Clinical EP, Invasive Cardiovascular Angiography and Intervention, SCD/Ventricular Arrhythmias

Keywords: Angina Pectoris, Death, Sudden, Cardiac, Constriction, Pathologic, Diabetes Mellitus, Myocardial Infarction, Myocardial Ischemia, Ischemic Attack, Transient, Percutaneous Coronary Intervention, Transcatheter Cardiovascular Therapeutics, AHA Annual Scientific Sessions

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