| Methods |
Study design: parallel RCT Duration of study: August 2002 to June 2009 Duration of follow‐up: mean follow‐up 4.0 ± 1.5 years |
| Participants |
Country: Brazil, Canada, USA Setting: 30 clinical sites Inclusion criteria: 6 months or more post kidney transplantation; aged 35 to 75 years; CrCl ≥ 30 mL/min for participants recruited prior to July 2005, thence ≥ 30 mL/min (men) or 25 mL/min (women); homocysteine level ≥ 12.0 μmol/L (men) or ≥11.0 μmol/L (women); provision of informed consent; cognitive function adequate for patient to give accurate information; adequate transportation facilities; geographic accessibility for follow‐up; within 120 days of screening Number: treatment group (2056); control group (2054) Mean age ± SD (years): treatment group (52 ± 9.4); control group (52 ± 9.5) Sex (M/F): treatment group (1289/767); control group (1293/761) Exclusion criteria: presence of cancer, end‐stage congestive heart failure, liver, or pulmonary disease, progressive human immunodeficiency virus or other chronic wasting illness, which in the opinion of the study physician would limit the life expectancy of the patient to less than 2 years or prevent evaluation of recurrent or de novo CVD; other conditions that prevent reliable participation in the study (refractory depression, severe cognitive impairment, or alcoholism or other substance abuse); history of solid organ transplant other than the kidney or pancreas; pregnant or lactating women or women of childbearing potential not practicing birth control; < 3 months post–acute MI or stroke, or < 3 months post–coronary artery, renal artery, or lower extremity artery percutaneous transluminal coronary angioplasty, or lower extremity amputation; less than 6 months post–coronary artery bypass graft surgery, abdominal aortic aneurysm; participation in another clinical study specifically involving CVD risk factor management |
| Interventions |
Treatment group
Control group
-
Low dose multivitamin
No folic acid 1.4 mg vitamin B6 2.0 μg vitamin B12
Other information
Both vitamin preparations contained 1.5 mg vitamin B1, 1.5 mg vitamin B2, 60 mg vitamin C, 30 μg d‐Biotin, 20 mg niacinamide and 10 mg pantothenic acid Participants continued on their intervention until study end or, in the case of those who developed dialysis‐dependent ESKD, until the occurrence of their first primary endpoint
|
| Outcomes |
Primary composite outcome: arteriosclerotic cardiovascular disease outcome (cardiovascular disease death, MI, resuscitated sudden death, stroke, coronary artery revascularization, lower extremity revascularization or, for severe arterial disease, amputation above the ankle, carotid endarterectomy or angioplasty, abdominal aortic aneurysm repair, or renal artery revascularization) -
Secondary outcomes
All‐cause mortality Dialysis‐dependent kidney failure Individual components of the primary outcome 'relevant' combinations of the components of the primary outcome
|
| Funding source |
Government funded support: National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health. The Office of Dietary Supplements, National Institutes of Health Commercial: Manufacture of multivitamin preparations |
| Presence or absence of grain fortification |
|
| Notes |
The study reports outcomes both according to intention‐to‐treat principles and outcomes censored 3 months after the return to dialysis. In this analysis, we have included the intention‐to‐treat outcomes. The study was concluded after an interim analysis when the Data Safety and Monitoring Board recommended the study be concluded as it had 'conclusively answered its original hypothesis'. |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
"Randomization by permuted block, stratified by clinical site". Two different block sizes were used. |
| Allocation concealment (selection bias) |
Low risk |
"Randomization ... was performed through the data management system. Because the need for emergency unblinding was expected to be low, unblinding codes were stored securely at the Data Coordinating Center, accessible only to authorized staff." |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
This was a placebo‐controlled RCT with both multivitamin preparations formulated to be similar in appearance and smell. Blinding was explicitly tested by survey of participants and study coordinators with 49% of each group providing incorrect guesses of intervention allocation.
"The trial was a .. double blind, randomised clinical trial". "Both multivitamins [standard and low dose] were formulated to be similar in appearance and odor to facilitate blinding" |
| Blinding of outcome assessment (detection bias)
All outcomes |
Low risk |
The first 4 components of the primary outcome (cardiovascular death, MI, resuscitated sudden death and stroke) were centrally reviewed and adjudicated. |
| Incomplete outcome data (attrition bias)
All outcomes |
Unclear risk |
Completeness of follow‐up: deceased (493); complete follow‐up to June 2009 (2788); incomplete follow‐up to June 2009 (822); no follow‐up (7)
Withdrawal of consent: treatment group (198/2056); control group (171/2054) |
| Selective reporting (reporting bias) |
Low risk |
Event data for all the primary and secondary outcomes according to intention‐to‐treat are reported. |
| Other bias |
Low risk |
No other biases detected |
