Multivitamins After Myocardial Infarction in Patients With Diabetes: A Randomized Clinical Trial

Abstract

Importance: In 2013, the Trial to Assess Chelation Therapy (TACT) reported that in 1708 patients with stable coronary disease and prior myocardial infarction (MI), oral multivitamins and multiminerals (OMVMs), in a factorial design with edetate disodium (EDTA) chelation therapy, did not reduce cardiovascular events relative to placebo OMVMs, but active EDTA combined with active OMVMs was superior to placebo OMVM/placebo EDTA.

Objective: To compare OMVM vs placebo in terms of efficacy for reducing major adverse cardiovascular events in patients with diabetes and prior MI.

Design, setting, and participants: The TACT2 randomized, multicenter double-masked 2 × 2 factorial clinical trial took place across 88 sites in the US and Canada. Participants were 50 years or older, had diabetes, and had an MI 6 weeks ago or more. TACT2 participants were enrolled between September 2016 and December 2020. Data were collected between October 2016 and June 2023.

Interventions: Six caplets daily of a 28 component OMVM or matching OMVM placebo, and 40 weekly infusions of an EDTA-based chelation solution or matching placebo, in a 1:1:1:1 allocation ratio.

Main outcomes and measures: The primary end point was the composite of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina.

Results: A total of 1000 participants were randomized (500 in the active OMVM group and 500 in the placebo group). The median (IQR) age was 67 (60-72) years, and 730 (73%) were male. Median (IQR) follow-up was 48 (34-58) months. The primary end point occurred in 175 participants (35%) in the active OMVM group and 175 (35%) in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.80-1.22]; P = .92). The 5-year event rate for the primary end point in the EDTA chelation + active OMVM group was 34.0%; in the EDTA chelation + placebo OMVM group, 35.7%; in the placebo infusion + active OMVM group, 36.0%; and in the placebo infusion + placebo OMVM group, 34.3%. The comparison of the active infusion + active OMVM with the placebo infusion + placebo OMVM was not significant (HR, 0.91 [95% CI, 0.67-1.23]; P = .54). Although nonsignificant, there was a numerically higher event rate of MI, stroke, mortality from cardiovascular causes in the active OMVM compared to placebo OMVM group.

Conclusions and relevance: The results of this randomized clinical trial demonstrated that, for participants with chronic coronary disease, diabetes, and a previous MI, high-dose OMVM alone or in conjunction with EDTA-based chelation did not reduce cardiovascular events.

Trial registration: ClinicalTrials.gov Identifier: NCT02733185.

Figure 1.. Screening, Randomization, and Follow-Up by 4 Treatment Groups

SI conversion factors: to convert creatine to μmol/L, multiply value by 76.25; to convert hemoglobin A_1c (HbA_1c) to proportion of total hemoglobin, multiply value by 0.01. MI indicates myocardial infarction. ^aHigh-dose oral multivitamins and multiminerals (OMVM). ^bRandomized participants who did not die, were not lost to follow-up, and did not withdraw consent are considered participants who completed the study. ^cParticipants who died before the end of study. ^dLost to follow-up is defined as no contact within 12 months of the end of study. End of study is defined as the 5-year informed consent expiration date or administrative end of study date (April 2024). Last contact is defined as the last known alive date. ^eAll randomized participants are included in the primary analysis population.

Figure 2.. Cumulative Incidence of Time to First Event

These values were derived from the primary analysis population. A, The primary outcome was a composite of myocardial infarction (MI), stroke, hospitalization for unstable angina, coronary revascularization, or death from any cause. B, A key secondary outcome was a composite of MI, stroke, or cardiovascular death. C, A key secondary end outcome was all-cause mortality. Beyond month 54, the sample size for the numbers at risk was lower than meaningful; therefore, the x-axis is displayed up to 54 months. The hazard ratios (HRs; active oral multivitamins and multiminerals [OMVM] group vs placebo OMVM group) and P value were derived from Cox proportional hazards regression with adjustment of edetate disodium chelation group, age, time-varying age, sex, and baseline insulin use. An HR of less than 1 indicates a benefit with active OMVM compared to placebo OMVM. Events occurring after withdrawal of consent or informed consent expiration were censored.