Randomized controlled trial

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POSITIVE: See Quality Criteria Checklist below.

To determine the efficacy of homocysteine-loweringtreatment with B vitamins for secondary prevention in patientswho had had an acute myocardial infarction (MI).

Men and women 30 to 85 years of age who had had an acute MI within seven days before randomization were eligible to participate.

• Presence of coexisting disease associated with a life expectancy of less than four years
• Prescribed treatment with B vitamins
• Untreated vitamin B deficiency
• Inability to follow the protocol, as judged by the investigator.

Recruitment

 

Unclear.

 

Design

 

RCT, multi-center, prospective, double-blind, 2x2 factorial design.

 

Dietary Intake/Dietary Assessment Methodology
 

Not applicable.

 

Blinding Used

 

Double blind.

 

Intervention

• Four groups: 
  • Group 1: Combination group: 0.8mg of folic acid, 0.4mg of vitamin B₁₂, and 40mg of vitamin B₆ per day
  • Group 2: 0.8mg of folic acid plus 0.4mg of vitamin B₁₂ per day
  • Group 3: 40mg of vitamin B₆ per day
  • Group 4: Placebo
• Study medication was given in a single capsule, taken once per day. For the first two weeks after enrollment, the combination-therapy group and the group given folic acid and vitamin B₁₂ received a loading dose of 5mg of folic acid per day, whereas the other two groups received placebo for the first two weeks. Capsule formulations were manufactured (Alpharma) to be indistinguishable by color, weight or their ability to dissolve in water
• Participants were given standard post–MI therapy and were seen at a follow-up visit at two months and at a final visit after 2.0 to 3.5 years
• Every six months after enrollment, study medication and a questionnaire were mailed to the participants. They were asked about study outcomes, compliance and adverse effects. Those who did not return the questionnaire were interviewed by telephone by study personnel or records were consulted to determine their vital status. Staff members at the coordinating center visited all participating hospitals to monitor data quality
• Smerud Medical Research, on behalf of the Norwegian Research Council, conducted an audit of the trial and approved it
• Blood samples were obtained from all available participants at baseline, at two months and at the final visit for the measurement of plasma total homocysteine, serum folate and serum cobalamin. Levels of these vitamins were determined with the use of published methods.

Statistical Analysis

 

• Sample size calculation was based on data from previous Scandinavian trials, assuming the three-year rate of the primary end point would be 25 percent in the placebo group
• The planned enrollment of 3,500 patients, with an average follow-up of 3.0 years, was expected to result in 750 primary events and give the study a statistical power of more than 90 percent to detect a 20 percent relative reduction in the rate of the primary end-point, given a two-sided alpha value of 0.05
• All analyses were conducted according to the intention-to-treat principle. The main focus was on comparison of treatment with folic acid and vitamin B₁₂ with control (the combination-therapy group and the group given folic acid and vitamin B₁₂ vs. the vitamin B₆ and placebo groups) and comparison of treatment with vitamin B₆ with control (the combination-therapy group and the group given vitamin B₆ vs. the group given folic acid and vitamin B₁₂ and the placebo group). The factorial design also allowed a comparison of the combination-therapy group with the placebo group
• Estimates of the hazard ratios and 95 percent confidence intervals were obtained with the use of Cox proportional-hazards models
• Interactions were identified by applying the likelihood ratio test to models with the interaction term and those without the interaction term and comparing the result
• Kaplan–Meier survival analysis was used to compare the cumulative incidence of the primary end-point in the four groups
• Differences between groups in baseline characteristics were tested with analysis of variance. Study center was included as a covariate in all analyses
• The reported P-values are two-sided and are not adjusted for multiple comparisons.

Timing of Measurements

 

 Baseline, follow-up at two months and at a final visit between 2.5-3.0 after baseline measurements.

 

Dependent Variables

Primary end-point:

• Composite of new non-fatal and fatal MI, non-fatal and fatal stroke and sudden death attributed to CHD
• Patients who were resuscitated after cardiac arrest were included in the analysis of the primary end-point, whereas those with a silent MI were not
• For each participant, only the first of all such events was included in the analysis of the primary end-point. If death occurred within 28 days after the onset of an event, the event was classified as fatal

Secondary end-points:

• Myocardial infarction, unstable angina pectoris requiring hospitalization, coronary revascularization with percutaneous coronary intervention or coronary-artery bypass grafting, stroke and death from any cause
• Incident cases of cancer were recorded as a measure of safety
• Acute coronary events were categorized according to symptoms, new changes on electrocardiography and levels of cardiac biomarkers
• An unequivocal global or focal neurologic deficit that occurred suddenly and lasted more than 24 hours was required for the diagnosis of stroke
• Blood samples for plasma total homocysteine, serum folate and serum cobalamin.

Independent Variables

 

Treatment group assignment.

 

Control Variables

 

• The baseline level of total homocysteine was a significant predictor of the primary end-point (RR associated with a 3-μmol difference in the total homocysteine level, 1.05; 95 percent confidence interval, 1.01 to 1.09; P=0.01) after adjustment for study center, age, sex, systolic blood pressure, total cholesterol level and smoking status
• After additional adjustment for the creatinine level, the RR was 1.03 (P=0.10). 

• Initial N: 3,749
• Attrition: Five withdrew after informed consent and did not receive assigned treatment, 404 (11%) stopped taking study medication during the trial but this was not different across groups
• Age: Mean age 63.6±11.9, 63.2±11.6, 62.5±11.7, 32.6±11.4 (P=0.11) for combination group, folic acid plus B₁₂, B₆ and the placebo group, respectively
• Ethnicity: Unclear
• Other relevant demographics: Group differences for "current smoker" and "warfarin"
• Anthropometrics: Yes
• Location: 35 Norwegian hospitals.
   
  

  	Folic Acid, B12 and B6 (N=937)	Foli Acid and B12 (N=935)	B6 (N=934)	Placebo (N=943)	P-value
  Age (year)	63.6±1.9	63.2±11.6	62.5±11.7	62.6±11.4	0.11
  Male sex (percent)	684±(73)	696 (74)	686 (73)	705 (75)	0.80
  BMI	26.5±4.0	26.2±3.5	26.3±3.8	26.3±3.8	0.66

 

• Mean follow-up was 36 months, compliance was between 93-99% and did not differ significantly between treatment groups
• Among those who received folic acid, the mean total homocysteine level was a mean of 4.2μmol per liter (0.57mg per liter) lower than the level in the group that did not receive folic acid after two months (a difference of 31%, P<0.001) and 3.8μmol per liter (0.51mg per liter) lower at the end of the intervention (a difference of 28%, P<0.001). The mean total homocysteine level did not change significantly in the group treated with vitamin B₆ alone. Treatment with folic acid and vitamin B₁₂ led to significant increases, by a factor of five to six, in the mean levels of plasma folate and increases in plasma vitamin B₁₂ by approximately 60 percent
• Treatment with folic acid in combination with vitamin B_12, with or without vitamin B₆, did not significantly reduce the risk of the primary end-point, as compared with placebo. Both treatment regimens were associated with a non-significant increase in risk, mainly driven by an event rate that was 22% higher in the combination-therapy group than in the placebo group (P=0.05)
• The cumulative hazard ratio for the combination-therapy group, as compared with the other three groups, was 1.20 (95% CI, 1.02 to 1.41; P=0.03). The result remained the same after adjusting for the use of warfarin at baseline, which differed among the four groups
• The risk of the secondary end-points was not significantly influenced by treatment with folic acid and vitamin B₁₂. Vitamin B₆ therapy was associated with a 17% increase in the risk of MI (P=0.05) and combination therapy was associated with a 30% increase in the risk of nonfatal MI (P=0.05)
• Sub-group analyses of the primary end-point indicated that treatment with B vitamins was not associated with a significant benefit in any sub-group. An increased risk associated with treatment was observed among patients with higher baseline levels of total homocysteine (more than 13μmol per liter, vs. 13μmol per liter or less) who received combination therapy (P=0.04) and among those with an MI without ST-segment elevation who received folic acid and vitamin B₁₂ (P=0.04).

The NORVIT trial demonstrated that intervention with folic acid, with or without high doses of vitamin B₆, did not lower the risk of recurrent cardiovascular disease or death after an acute MI. Such therapy may even be harmful after acute MI or coronary stenting and should therefore not be recommended.

• Although there was no significant difference between groups for the secondary end-point, the author's noted that the analyses were not adjusted for multiple comparisons and that apparent associations could readily be explained by chance
• Author's stated that non-compliance is not a likely explanation for the negative findings
• Power of the trial was slightly less than planned.