Abstract: We included 17 RCTs (9975 participants, mean age 63.3 years). We found very limited (or no) data to inform most planned comparisons. Summary data were used to inform comparison of ranolazine versus placebo. Overall, risk of bias was assessed as unclear. For add-on ranolazine compared to placebo, no data were available to estimate cardiovascular and non-cardiovascular mortality. We found uncertainty about the effect of ranolazine on: all-cause mortality (1000 mg twice daily, RR 0.83, 95% CI 0.26 to 2.71; 3 studies, 2053 participants; low quality evidence); quality of life (any dose, SMD 0.25, 95% CI -0.01 to 0.52; 4 studies, 1563 participants; I² = 73%; moderate quality evidence); and incidence of non-fatal acute myocardial infarction (AMI) (1000mg twice daily, RR 0.40, 95% CI 0.08 to 2.07; 2 studies, 1509 participants; low quality evidence). Add-on ranolazine 1000 mg twice daily reduced the fervour of angina episodes (MD -0.66, 95% CI -0.97 to -0.35; 3 studies, 2004 participants; I² = 39%; moderate quality evidence) but increased the risk of non-serious adverse events (RR 1.22, 95% CI 1.06 to 1.40; 3 studies, 2053 participants; moderate quality evidence). For ranolazine as monotherapy compared to placebo, we found uncertain effect on cardiovascular mortality (1000 mg twice daily, RR 1.03, 95% CI 0.56 to 1.88; 1 study, 2604 participants; low quality evidence). No data were available to estimate non-cardiovascular mortality. We also found an uncertain effect on all-cause mortality for ranolazine (1000 mg twice daily, RR 1.00, 95% CI 0.81 to 1.25; 3 studies, 6249 participants; low quality evidence), quality of life (1000 mg twice daily, MD 0.28, 95% CI -1.57 to 2.13; 3 studies, 2254 participants; moderate quality evidence), non-fatal AMI incidence (any dose, RR 0.88, 95% CI 0.69 to 1.12; 3 studies, 2983 participants; I² = 50%; low quality evidence), and frequency of angina episodes (any dose, MD 0.08, 95% CI -0.85 to 1.01; 2 studies, 402 participants; low quality evidence). We found an increased risk for non-serious adverse events associated with ranolazine (any dose, RR 1.50, 95% CI 1.12 to 2.00; 3 studies, 947 participants; very low quality evidence). We found very low quality evidence showing that people with stable angina who received ranolazine as monotherapy had increased risk of presenting non-serious adverse events compared to those given placebo. We found low quality evidence indicating that people with stable angina who received ranolazine showed uncertain effect on the risk of cardiovascular death (for ranolazine given as monotherapy), all-cause death and non-fatal AMI, and the frequency of angina episodes (for ranolazine given as monotherapy) compared to those given placebo. Moderate quality evidence indicated that people with stable angina who received ranolazine showed uncertain effect on quality of life compared with people who received placebo. Moderate quality evidence also indicated that people with stable angina who received ranolazine as add-on therapy had fewer angina episodes but increased risk of presenting non-serious adverse events compared to those given placebo.

Plain-language summary: We included 17 studies that involved a total of 9975 adult participants and lasted between 1 and 92 weeks. We only compared ranolazine and placebo because there were few data for other comparisons. The evidence was uncertain about the effect of ranolazine 1000 mg given alone twice daily to people with stable angina pectoris on the chance of dying from heart-related causes. There was no evidence about whether ranolazine changed the risk of dying from causes that were not heart-related. Although the evidence was uncertain about the effect of ranolazine 1000 mg twice daily on the chance of dying from any cause, quality of life, the possibility of heart attack or the frequency of angina attacks (for ranolazine taken alone), ranolazine did modestly reduce the numbers of angina attacks per week when given with other anti-angina drugs. Ranolazine 1000 mg twice daily increased the risk for experiencing dizziness, nausea and constipation from taking the drug (mild adverse events). Overall, evidence quality was assessed as very low for the chance of mild adverse events (for people who took ranolazine alone). Evidence was also low for estimating the chance of death from heart-related (when ranolazine is taken alone) or any causes, having a heart attack, and how often angina attacks occur (when ranolazine is taken alone). We found moderate quality evidence about quality of life, frequency of angina attacks and the chance of experiencing mild adverse events (for people who took ranolazine together with other anti-angina drugs), Low evidence quality related to problems and reporting of study methods and too few data to calculate precise estimates.