| Methods |
Study design: parallel‐group trial
Total study duration: 12 weeks
Duration of follow‐up: no follow‐up beyond treatment phase
Method of randomisation: Interactive Voice/Web Response System (IVRS/IWRS)
Method of concealment of allocation: blinded study drug bottle assigned by the IVRS/IWRS
Blinding: double‐blind, participants and clinicians were blinded by using study drug bottles assigned by the IVRS/IWRS
Power calculation: 90% to show a relative reduction of 20% in weekly angina frequency
Phases of the study: 2 (qualifying phase, treatment phase)
Number of patients randomised: 949 (476/473 for placebo/ranolazine group)
Exclusions post‐randomisation: 22 (11 in the ranolazine arm, 11 in the placebo arm)
Withdrawals (and reasons): 20 (9 withdrawals, 3 deaths in the ranolazine group, 11 withdrawals, 2 deaths in the placebo group) |
| Participants |
Total number: 949
Country of enrolment: 14 (United States, Belarus, Bulgaria, Canada, Czech Republic, Georgia, Germany, Israel, Poland, Russian Federation, Serbia, Slovakia, Slovenia, Ukraine)
Setting/location: not specified
Diagnostic criteria (stable angina pectoris): at least a three‐month history of chronic stable angina that remain symptomatic despite treatment with 1 or 2 anti‐anginal, with documented history of CAD (macrovascular angina)
Comorbidities: type 2 diabetes mellitus
Age (mean ± SD): 64 ± 8.5 years
Gender (male %): 61%
Inclusion criteria:
Angiographic evidence of ≥ 50% stenosis of one or more major coronary arteries History of myocardial infarction (MI) documented by positive myocardial muscle creatine kinase (CK‐MB) enzymes, troponins, or electrocardiogram (ECG) changes Cardiac imaging study or exercise test diagnostic for CAD
Treatment with up to 2 anti‐anginal therapies at a stable dose for at least 2 weeks prior to the qualifying period. Documented history of T2DM Willing to maintain stable tobacco usage habits throughout the study Willing to maintain stable activity levels throughout the study Females of childbearing potential must agree to use highly effective contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug
Exclusion criteria:
New York Heart Association (NYHA) Class III and IV Acute coronary syndrome in the prior 2 months or planned coronary revascularisation during the study period Stroke or transient ischaemic attack within 6 months prior to screening QTc > 500 ms Uncontrolled hypertension (seated systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg) Systolic blood pressure < 100 mm Hg Clinically significant hepatic impairment Prior treatment with ranolazine, or known hypersensitivity or intolerance to ranolazine Females who are breastfeeding Positive serum pregnancy test Participation in another investigational drug or device study within 1 month prior to Screening Current treatment with trimetazidine, ivabradine, or nicorandil. Subjects will need to discontinue these medications 2 weeks prior to the qualifying period Current treatment with potent inhibitors of cytochrome (CYP)3A (e.g. ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir) Current treatment with CYP3A and P glycoprotein (Pgp) inducers (e.g. rifampicin/rifampin, carbamazepine, and St. John's wort [Hypericum perforatum]) Current treatment with CYP3A4 substrates with a narrow therapeutic range (e.g. cyclosporine, tacrolimus, and sirolimus) Subjects taking simvastatin who cannot reduce the dose to 20 mg once daily or who cannot switch to another statin Current treatment with Class I or III anti‐arrhythmic medications History of illicit drug use or alcohol abuse within 1 year of Screening Any other conditions that, in the opinion of the investigator, are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study
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| Interventions |
Number of intervention groups: 2
Concomitant medications: Anti‐anginal: beta blockers, calcium channel blockers, long‐acting nitrates; other cardiovascular medications: statins, antiplatelet agents, ACE‐I/ARB; antidiabetic medications: glucose‐lowering medications, insulin
Excluded medications: none (apart from those mentioned in the exclusion criteria)
Placebo group
Ranolazine group
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| Outcomes |
Total number of outcomes:
According to study protocol: 6 (angina episodes frequency, sublingual nitroglycerin use frequency, number of angina‐free days, proportion of subjects with ≥50% reduction in average weekly angina frequency, health‐related quality of life, adverse events incidence) Reported: 6
All‐cause mortality
Outcome definition: number of deaths Method and unit of measurement: absolute frequency Time points reported: 8 weeks
Quality of life
1. Medical Outcomes Short Form‐36 (SF‐36)
Outcome definition: health state scale, change from baseline in the Mental and Physical Components Upper and lower limits and whether a high or low score is good: the range of each health domain score is 0‐100, with 0 indicating a poorer health state and 100 indicating a better health state Method and unit of measurement: change from baseline, score Time points reported: 8 weeks
2. Patient’s Global Impression of Change (PGIC)
Outcome definition: change in overall status scale, total score Upper and lower limits and whether a high or low score is good: ranging from 1 (no change or worse) to 7 (very much improved) Method and unit of measurement: score Time points reported: 8 weeks
Acute myocardial infarction incidence (non‐fatal)
Outcome definition: number non‐fatal myocardial infarction cases Method and unit of measurement: absolute frequency Time points reported: 8 weeks
Angina episodes frequency
Outcome definition: average number of angina episodes per week from weeks 2 to 8 of treatment Method and unit of measurement: number of angina episodes per week Time points reported: 8 weeks
Adverse events incidence
Outcome definition: number of patients who report any non serious adverse event Method and unit of measurement: absolute frequency Time points reported: 8 weeks plus 30 days
RESULTS
All‐cause mortality
Sample size: 944 (intention‐to‐treat analysis) Missing participants: 5 Summary data: 2/474‐3/470 for placebo‐ranolazine group Subgroup analyses: not performed
Quality of life
1. Medical Outcomes Short Form‐36 (SF‐36)
Sample size: 927 (intention‐to‐treat analysis) Missing participants: 22 Summary data: Physical component: 1.9 (1.3‐2.5) / 2.9 (2.3‐3.5) for placebo/ranolazine group; mental component: 1.1 (0.28‐1.92) / 1.0 (0.18‐1.82) for placebo/ranolazine group Subgroup analyses: not performed
2. Patient’s Global Impression of Change (PGIC)
Sample size: 927 (intention‐to‐treat analysis) Missing participants: 22 Summary data: 3.9 (3.74‐4.10) / 4.0 (3.82‐4.19) for placebo/ranolazine group Subgroup analyses: not performed
Acute myocardial infarction incidence (non‐fatal)
Sample size: 944 (intention‐to‐treat analysis) Missing participants: 5 Summary data: 3/474 ‐ 1/470 for placebo‐ranolazine group Subgroup analyses: not performed
Angina episodes frequency
Sample size: 927 (intention‐to‐treat analysis) Missing participants: 22 Summary data: 4.3 (4.01‐4.52) / 3.8 (3.57‐4.05) for placebo/ranolazine group Subgroup analyses: several pre‐specified subset analyses, all are reported, significant interaction in the effect of ranolazine versus placebo was found only by the geographic region of enrolment (Russia, Ukraine, Belarus versus Other, pinteraction = 0.016). Russia, Ukraine and Belarus: 4.3 (4.1‐4.6) / 4.1 (3.9‐4.4) for placebo/ranolazine group; Other: 4.1 (3.7‐4.6) / 3.1 (2.8‐3.5) for placebo/ranolazine group
Adverse events incidence:
Sample size: 944 (intention‐to‐treat analysis) Missing participants: 5 Summary data: 85/474 ‐ 110/470 for placebo‐ranolazine group. The most common adverse events reported in the ranolazine group were dizziness (17/462), nausea (17/462), headache (7/462), constipation (8/462), hypoglycaemia (3/462); and in the placebo group were dizziness (6/465), nausea (2/465), headache (9/465) and constipation (2/465), hypoglycaemia = 0/465. Subgroup analyses: not performed
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| Notes |
Relevant observations for the data provided before: none
Source of funding: Gilead Sciences
Notable conflicts of interest: all the authors have financial relationships with Gilead Sciences |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Randomisation undertaken by the IVRS/IWRS |
| Allocation concealment (selection bias) |
Low risk |
Intervention was provided to personnel in blinded study drug bottles assigned by the IVRS/IWRS |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
Study declared to be double‐blinded, but no description is provided. Intervention was provided to personnel and patients in blinded drug bottles, so they were unaware of the treatment assigned |
| Blinding of outcome assessment (detection bias)
All outcomes |
Unclear risk |
Study declared to be double‐blinded, but no description about the blinding of data collectors/outcome adjudicators is provided |
| Incomplete outcome data (attrition bias)
All outcomes |
Unclear risk |
Withdrawals are reported, but no description is provided |
| Selective reporting (reporting bias) |
Low risk |
According to the protocol published in Clinicaltrials.gov, results for all the outcomes are reported |
| Other bias |
High risk |
The study was supported by Gilead Sciences. All the authors have financial relationships with Gilead Sciences |
