Ranolazine for people with stable angina pectoris

Review question

We wanted to find out if ranolazine (a drug to prevent angina) was more effective than a fake drug (placebo) or other drugs to treat stable angina.

Background

Angina pectoris is sudden chest pain caused when the heart does not get enough oxygen or from other stresses. People with stable angina have a predictable pattern of when they experience angina symptoms. Angina is made worse by physical effort and relieved by rest or some medications. Ranolazine is a relatively new drug for people with angina pectoris who are already taking other drugs to treat angina.

Search date

The evidence is current to February 2016.

Study funding sources

Most studies were either fully (9/17) or partly (3/17) funded by drug companies, two received no external funding, and three did not declare sources of funding.

Study characteristics

We included 17 studies that involved a total of 9975 adult participants and lasted between 1 and 92 weeks.

Key results

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).

Quality of evidence

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.

Authors' conclusions: 

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.

Read the full abstract...
Background: 

Stable angina pectoris is a chronic medical condition with significant impact on mortality and quality of life; it can be macrovascular or microvascular in origin. Ranolazine is a second-line anti-anginal drug approved for use in people with stable angina. However, the effects of ranolazine for people with angina are considered to be modest, with uncertain clinical relevance.

Objectives: 

To assess the effects of ranolazine on cardiovascular and non-cardiovascular mortality, all-cause mortality, quality of life, acute myocardial infarction incidence, angina episodes frequency and adverse events incidence in stable angina patients, used either as monotherapy or as add-on therapy, and compared to placebo or any other anti-anginal agent.

Search strategy: 

We searched CENTRAL, MEDLINE, Embase and the Conference Proceedings Citation Index - Science in February 2016, as well as regional databases and trials registers. We also screened reference lists.

Selection criteria: 

Randomised controlled trials (RCTs) which directly compared the effects of ranolazine versus placebo or other anti-anginals in people with stable angina pectoris were eligible for inclusion.

Data collection and analysis: 

Two authors independently selected studies, extracted data and assessed risk of bias. Estimates of treatment effects were calculated using risk ratios (RR), mean differences (MD) and standardised mean differences (SMD) with 95% confidence intervals (CI) using a fixed-effect model. Where we found statistically significant heterogeneity (Chi² P < 0.10), we used a random-effects model for pooling estimates. Meta-analysis was not performed where we found considerable heterogeneity (I² ≥ 75%). We used GRADE criteria to assess evidence quality and the GRADE profiler (GRADEpro GDT) to import data from Review Manager 5.3 to create 'Summary of findings' tables.

Main results: 

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).

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