Shammas 2015.

Methods	Study design: cross‐over trial Total study duration: 16 weeks Duration of follow‐up: no follow‐up beyond treatment phase Method of randomisation: not described Method of concealment of allocation: not described Blinding: double‐blind, it is stated that the investigators and the patient remained blinded to the treatment until the completion of the trial, but no details are provided Power calculation: not performed (pilot study) Phases of the study: 1 (treatment phase) Number of patients randomised: 28 Exclusions post‐randomisation: 4 Withdrawals (and reasons): 5 (3 withdrew voluntarily, 1 lost to follow‐up, 1 withdrew involuntarily) (only 4 patients were excluded from the analysis)
Participants	Total number: 28 Country of enrolment: United States Setting/location: not specified Diagnostic criteria (stable angina pectoris): symptomatic (exertional angina or dyspnoea) ischaemic cardiomyopathy (ICM) with angiographic documentation of CAD (macrovascular angina) Comorbidities: none (not treatable by further revascularisation) Age (mean ± SD): 71.5 ± 8.4 years Gender (male %): 82.1% Inclusion criteria: ICM with continued symptoms on guideline‐directed medical treatment, where optimal medical treatment was defined as treatment with two anti‐ischaemic agents (amlodipine or long‐acting nitrates on top of beta blockers) as well as an ACEI/ARB unless contraindicated, and continued symptoms defined as significant exertional angina or dyspnoea, interfering with the patient’s daily activity Angiographic documentation of coronary artery disease that was not amenable to treatment by coronary intervention (already treated or non treatable) A recent ejection fraction (EF) of less than or equal to 40% within 6 months of enrolment, as assessed by echocardiography or isotope ventriculography Able to sign an informed consent before enrolment Exclusion criteria: Dyalisis patients There was no prespecified exclusion based on QTc or renal function
Interventions	Number of intervention groups: 2 Concomitant medications: angiotensin‐converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), a beta blocker, and at least one additional anti‐ischaemic drug (amlodipine or long‐acting nitrate) Excluded medications: none Placebo group Intervention: placebo Duration of intervention: 6 weeks (plus 2 weeks of washout) Ranolazine group Intervention: ranolazine (type of formulation not specified) 500 mg/1000 mg twice daily Duration of intervention: 6 weeks (plus 2 weeks of washout)
Outcomes	Total number of outcomes: According to study protocol: no published protocol; according to the "Methods" section: 2 (SAQ and Rose Dyspnea Scale (RDS) scores) Reported: 3 (including adverse events incidence) Quality of life 1. Seattle Angina Questionnaire (SAQ) Outcome definition: level of functioning scale, measured by the scores in the 5 sub scales, reported separately and as a mean score Upper and lower limits and whether a high or low score is good: higher scores are better, upper and lower limits are not described Method and unit of measurement: score Time points reported: 6 weeks 2. Rose Dyspnea Scale (RDS) Outcome definition: scale for dyspnoea with regular activities, measured by a total score Upper and lower limits and whether a high or low score is good: higher scores indicate dyspnoea leading to more physical limitation (worse) Method and unit of measurement: change from baseline, score Time points reported: 6 weeks Adverse events incidence Outcome definition: number of adverse events (serious and non serious) reported Method and unit of measurement: frequency Time points reported: 6 weeks RESULTS Quality of life 1. Seattle Angina Questionnaire (SAQ) Sample size: 24 (intention‐to‐treat analysis) Missing participants: 4 Summary data: baseline/post‐intervention score: i) physical limitation 62.35/58.02 ‐ 62.19/64.35, ii) anginal stability 50/63.89 ‐ 61.11/61.11, iii) anginal frequency 74.44/74.44 ‐ 71.11/86.67, iv) treatment satisfaction 89.58/87.5 ‐ 88.89/92.36, v) quality of life 68.52/66.67 ‐ 58.33/72.22 for placebo‐ranolazine group Subgroup analyses: not performed 2. Rose Dyspnea Scale (SAQ) Sample size: 20 (intention‐to‐treat analysis) Missing participants: 8 (4 because of not having dyspnoea) Summary data: ‐0.34/‐0.45 for placebo/ranolazine group Subgroup analyses: not performed Adverse events incidence Sample size: 24 (intention‐to‐treat analysis) Missing participants: 4 Summary data: neither the frequency of each adverse event nor the number of patients who report any adverse event were reported, but it is stated that the most common side effects reported in the ranolazine arm included nausea, dizziness, constipation, headache, hypotension and dyspepsia; while in the placebo patients, dizziness was reported. Subgroup analyses: not performed
Notes	Relevant observations for the data provided before: none Source of funding: research grant from Gilead Notable conflicts of interest: Dr Shammas is a speaker for and is on the advisory board of Gilead
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation is stated but not described
Allocation concealment (selection bias)	Unclear risk	It is stated that the investigators remained blinded to the treatment (allocation) until the completion of the trial, but no details are provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study declared to be double‐blinded, with blinding corresponding to investigators and patients
Blinding of outcome assessment (detection bias) All outcomes	Low risk	A core laboratory blinded to patient treatment determined the SAQ scores
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals and reasons are described; however, there is an inconsistency in the number of patients who did not complete the trial (5) and the number of patients excluded from the analysis (4)
Selective reporting (reporting bias)	Unclear risk	There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported
Other bias	High risk	The study was supported by a research grant from Gilead Science. Dr Shammas is a speaker for and is on the advisory board of Gilead.