ERICA 2006.

Methods	Study design: parallel‐group trial Total study duration: 9 weeks; recruitment from July 30, 2004 to February 16, 2005 Duration of follow‐up: no follow‐up beyond treatment phase Method of randomisation: randomisation in a 1:1 ratio, centralised and not stratified by centre Method of concealment of allocation: not mentioned Blinding: double‐blind, not described Power calculation: not mentioned Phases of the study: 2 (qualifying phase, treatment phase), treatment phase made up by 1‐week run‐in phase and 6‐week full‐dose treatment phase Number of patients randomised: 565 (284/281 for placebo/ranolazine group) Exclusions post‐randomisation: run‐in phase: 1 withdrawal before study drug treatment (placebo group), 3 exclusions from placebo group because not beginning full‐dose treatment phase, 4 exclusions from ranolazine group, 1 because not beginning full‐dose treatment phase, 3 because not having any diary data in the full‐dose treatment phase Withdrawals (and reasons): ranolazine group (3 adverse events, 1 death, 3 withdrew consent), placebo group (5 adverse events (4 according to the text), 1 death)
Participants	Total number: 564 Country of enrolment: Eastern Europe, United States, Canada Setting/location: not specified Diagnostic criteria (stable angina pectoris): history of chronic stable angina ≥3 months, documented history of CAD (macrovascular angina) Comorbidities: none Age (mean ± SD): 61.3±9.0 / 62.0±8.7 for placebo / ranolazine group Gender (male %): 73% / 72% for placebo / ranolazine group Inclusion criteria: Age ≥ 18 years Chronic stable angina ≥ 3 months, and ≥ 3 episodes of angina per week during a ≥2‐week qualification period despite treatment with 10 mg/day amlodipine Documented history of CAD (angiographic evidence of ≥ 60% stenosis of at least 1 major coronary artery, history of previous myocardial infarction and/or a stress‐induced reversible perfusion defect identified by radionuclide or echocardiographic imaging) Exclusion criteria: NYHA functional class IV congestive heart failure History of myocardial infarction or unstable angina within the previous 2 months Active acute myocarditis, pericarditis, hypertrophic cardiomyopathy, or uncontrolled hypertension History of torsades de pointes Receiving agents known to prolong the QTc interval QTc interval measurement > 500 ms at study entry Clinically significant hepatic disease, creatinine clearance < 30 mL/min, or chronic illness likely to interfere with protocol compliance
Interventions	Number of intervention groups: 2 Concomitant medications: amlodipine 10 mg/day; LANs and sublingual nitroglycerin as required Excluded medications: inhibitors of cytochrome P450‐3A4, digitalis preparation, perhexiline, trimetazidine, beta‐blockers, calcium cannel blockers other than amlodipine Placebo group Intervention: placebo Duration of intervention: 6 weeks (full‐dose treatment phase) Ranolazine group Intervention: ranolazine ER 1000 mg twice daily Duration of intervention: 6 weeks (full‐dose treatment phase)
Outcomes	Total number of outcomes: According to study protocol: no published protocol (registered data in clinicaltrials.gov is not available any more); according to the "Methods" section: 7 (average weekly frequency of self‐reported angina episodes, average weekly nitroglycerin consumption, change from baseline of the 5 dimensions of the Seattle Angina Questionnaire (SAQ), reported adverse events, haemodynamics, routine clinical laboratory measures, 12‐lead electrocardiograms) Reported: 7 All‐cause mortality Outcome definition: number of deaths Method and unit of measurement: absolute frequency Time points reported: 9 weeks Quality of life Outcome definition: change from baseline of the 5 dimensions of the Seattle Angina Questionnaire (SAQ), reported separately Upper and lower limits and whether a high or low score is good: each dimension (anginal frequency, physical limitation, anginal stability, disease perception, and treatment satisfaction) was scored on a scale of 0 to 100 Method and unit of measurement: score difference Time points reported: 6 weeks Acute myocardial infarction incidence (fatal and non‐fatal) Outcome definition: not described Method and unit of measurement: percentage Time points reported: 9 weeks Angina episodes frequency Outcome definition: average weekly angina episodes frequency Method and unit of measurement: number per week Time points reported: 6 weeks Adverse events incidence Outcome definition: number of patients that reported any adverse event Method and unit of measurement: percentage Time points reported: 9 weeks RESULTS All‐cause mortality Sample size: 565 (Intention‐to‐treat analysis) Missing participants: none Summary data: 1/284‐1/281 for placebo‐ranolazine group Subgroup analyses: not performed Quality of life Sample size: 558 (Intention‐to‐treat analysis) Missing participants: 7 (3 from placebo group, 4 from ranolazine group) Summary data: SAQ dimension 1 (anginal frequency) 22.5 ± 19.0/18.5 ± 18.8 for ranolazine/placebo group Subgroup analyses: significant improvement of SAQ anginal frequency only for patients with baseline angina frequency > 4.5 per week Acute myocardial infarction incidence (fatal and non‐fatal) Sample size: 565 (Intention‐to‐treat analysis) Missing participants: none Summary data: 0.7%/0.4% for placebo/ranolazine group Subgroup analyses: not performed Angina episodes frequency Sample size: 558 (intention‐to‐treat analysis) Missing participants: 7 (3 from placebo group, 4 from ranolazine group) Summary data: arithmetic means ± SE: 4.3 ± 0.64/3.29 ± 0.26 for placebo/ranolazine group; trimmed means ± SE: 3.31 ± 0.22/2.88 ± 0.19 for placebo/ranolazine group Subgroup analyses: significant reductions of angina frequency for patients with baseline angina frequency > 4.5 per week and for ≤ 4.5 per week Adverse events incidence Sample size: 565 (Intention‐to‐treat analysis) Missing participants: none Summary data: 35.3%/39.9% for placebo/ranolazine group. The most frequently reported adverse events in the ranolazine group were constipation (25/281), peripheral edema (16/281), dizziness (11/281), nausea (8/281) and headache (8/281); in the placebo group were peripheral edema (8/284), dizziness (7/284), headache (7/284), constipation (5/284) and nausea (2/284). Subgroup analyses: performed for the following variables: long acting nitrates (LAN) user state, gender, age
Notes	Relevant observations for the data provided before: given that 4 placebo patients and 3 ranolazine patients discontinued the study because of adverse events but 5 placebo patients are reported not to have terminated the trial because of adverse events and 3 more ranolazine patients are reported not to have terminated the trial because of withdrawing consent, it is not clear which patients were finally included in the efficacy analysis Source of funding: CV Therapeutics Notable conflicts of interest: all the authors have received some kind of reward or support for participating in this trial from several pharmaceutical companies
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation is stated but described only as "in a 1:1 ratio, centralized but not stratified"
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Treatment phase is declared to be double‐blinded, but not description is provided
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Treatment phase is declared to be double‐blinded, but not description is provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	Patients who did not complete the trial are described clearly, however, there is an inconsistency in the data provided for terminating patients in the placebo group for only one case and it is not clear which patients were finally included in the efficacy analysis
Selective reporting (reporting bias)	Unclear risk	There is no published protocol. Results for all the outcomes mentioned in the "Methods" section of the paper are reported
Other bias	High risk	The study was supported by CV Therapeutics Inc. All the authors have received some kind of reward or support for participating in this trial from several pharmaceutical companies