Therapeutics
High-dose oral multivitamins and minerals after MI did not reduce CV events
Lamas GA, Boineau R, Goertz C, et al. Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial. Ann Intern Med. 2013;159:797-805.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ Question
Main results
In patients with myocardial infarction (MI), do high-dose oral multivitamins and minerals reduce cardiovascular (CV) events?
The multivitamin and multimineral mixture did not differ from placebo for the primary or secondary composite outcomes (Table).
Methods Design: Randomized, placebo-controlled, factorial trial (Trial to Assess Chelation Therapy [TACT]). ClinicalTrials.gov NCT00044213. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, and outcome assessors). Follow-up period: Median 55 months. Setting: 134 sites in the USA and Canada. Patients: 1708 patients ≥ 50 years of age (median age 65 y, 82% men) who had MI ≥ 6 weeks before the start of the study and serum creatinine level ≤ 176.8 µmol/L (≤ 2.0 mg/dL). Intervention: Oral, 28-component, high-dose multivitamin and multimineral mixture, 3 caplets twice daily (n = 853), or placebo (n = 855). Patients were also randomized to 40 IV infusions of disodium EDTA-based chelation therapy or normal saline placebo; the results are not reported in this abstract. Outcomes: Primary outcome was a composite of time to allcause mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. The secondary outcome was a composite of time to CV mortality, recurrent MI, or stroke. 1700 patients {with a median follow-up of 4 y}† were required to detect a 25% relative reduction in the primary outcome with 85% power (α = 0.05), assuming a 2.5-year event rate of 20% in the placebo group. Patient follow-up: 289 patients (17%) withdrew from the trial, 43 met the primary endpoint before withdrawal, and an additional 9 patients died after they withdrew (death registry). 22 patients were lost to follow-up (intention-to-treat analysis). High-dose multivitamins and minerals vs placebo in patients with myocardial infarction‡ Outcomes
Event rates§ Multivitamin Placebo
At a median 55 mo RRR (95% CI)
Primary composite outcome||
27%
30%
9% (−6 to 22)
All-cause mortality
10%
11%
7% (−22 to 30)
Myocardial infarction
6.8%
7.1%
5% (−34 to 33)
Stroke
0.94%
1.8%
47% (−25 to 78)
Coronary revascularization Angina
15% 1.4%
Secondary composite outcome¶ Cardiovascular mortality
11% 5.3%
18% 2.2% 13% 6.5%
15% (−4 to 32) 37% (−29 to 70) 17% (−6 to 36) 19% (−17 to 45)
‡Abbreviations defined in Glossary. RRR and CI calculated from control event rates and hazard ratios in article. §Based on all events during follow-up (i.e., not just first events). ||First occurrence of all-cause mortality, myocardial infarction, stroke, coronary revascularization, or hospitalization for angina. ¶First occurrence of cardiovascular mortality, myocardial infarction, or stroke.
JC4
© 2014 American College of Physicians
Downloaded From: http://annals.org/ by a Fudan University User on 12/08/2016
Conclusion In patients with myocardial infarction, high-dose oral multivitamins and minerals did not reduce cardiovascular events. *See Glossary. †Lamas GA, Goertz C, Boineau R, et al. Design of the Trial to Assess Chelation Therapy (TACT). Am Heart J. 2012;163:7-12.
Sources of funding: National Heart, Lung, and Blood Institute and National Center for Complementary and Alternative Medicine. For correspondence: Dr. G. A. Lamas, Mount Sinai Medical Center, Miami Beach, FL, USA. E-mail [email protected]. ■
Commentary The well-designed randomized controlled trial by Lamas and colleagues tested the hypothesis that high-dose multivitamin therapy reduces CV events in patients with MI. The trial enrolled 1708 patients ≥ 50 years of age, most of who were receiving aspirin, statins, β-blockers, angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers. Strengths of the trial include the absence of industry funding; appropriate randomization; blinding of patients, providers, and endpoint assessors; and intention-to-treat analysis. The trial showed that the 28-component multivitamin mixture did not reduce the primary outcome (a composite of death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina). Failure to find an effect may result from a combination of the relatively low power of the trial (85%); high rate of discontinuation of the study medication—46% in both groups, possibly due to the large size of the caplets; or a true lack of efficacy. The results are consistent with the findings of the much larger Physicians’ Health Study, which found that a standard daily multivitamin did not reduce CV events or total mortality in > 14 000 men, 95% of whom had no history of CV disease (1). However the Physicians’ Health Study did find a small reduction in the incidence of cancer (2). In both trials, multivitamins were not associated with adverse events. As a clinician, I don’t routinely recommend supplements, but if a patient is taking them, I can at least confirm their safety and the possibility of a small benefit for cancer prevention. Hanna E. Bloomfield, MD, MPH VA Medical Center and University of Minnesota Minneapolis, Minnesota, USA References 1. Sesso HD, Christen WG, Bubes V, et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308:1751-60. 2. Gaziano JM, Sesso HD, Christen WG, et al. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308:1871-80.
20 May 2014 | ACP Journal Club | Volume 160 • Number 10
High-dose oral multivitamins and minerals after MI did not reduce CV events
Lamas GA, Boineau R, Goertz C, et al. Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial. Ann Intern Med. 2013;159:797-805.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ Question
Main results
In patients with myocardial infarction (MI), do high-dose oral multivitamins and minerals reduce cardiovascular (CV) events?
The multivitamin and multimineral mixture did not differ from placebo for the primary or secondary composite outcomes (Table).
Methods Design: Randomized, placebo-controlled, factorial trial (Trial to Assess Chelation Therapy [TACT]). ClinicalTrials.gov NCT00044213. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, and outcome assessors). Follow-up period: Median 55 months. Setting: 134 sites in the USA and Canada. Patients: 1708 patients ≥ 50 years of age (median age 65 y, 82% men) who had MI ≥ 6 weeks before the start of the study and serum creatinine level ≤ 176.8 µmol/L (≤ 2.0 mg/dL). Intervention: Oral, 28-component, high-dose multivitamin and multimineral mixture, 3 caplets twice daily (n = 853), or placebo (n = 855). Patients were also randomized to 40 IV infusions of disodium EDTA-based chelation therapy or normal saline placebo; the results are not reported in this abstract. Outcomes: Primary outcome was a composite of time to allcause mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. The secondary outcome was a composite of time to CV mortality, recurrent MI, or stroke. 1700 patients {with a median follow-up of 4 y}† were required to detect a 25% relative reduction in the primary outcome with 85% power (α = 0.05), assuming a 2.5-year event rate of 20% in the placebo group. Patient follow-up: 289 patients (17%) withdrew from the trial, 43 met the primary endpoint before withdrawal, and an additional 9 patients died after they withdrew (death registry). 22 patients were lost to follow-up (intention-to-treat analysis). High-dose multivitamins and minerals vs placebo in patients with myocardial infarction‡ Outcomes
Event rates§ Multivitamin Placebo
At a median 55 mo RRR (95% CI)
Primary composite outcome||
27%
30%
9% (−6 to 22)
All-cause mortality
10%
11%
7% (−22 to 30)
Myocardial infarction
6.8%
7.1%
5% (−34 to 33)
Stroke
0.94%
1.8%
47% (−25 to 78)
Coronary revascularization Angina
15% 1.4%
Secondary composite outcome¶ Cardiovascular mortality
11% 5.3%
18% 2.2% 13% 6.5%
15% (−4 to 32) 37% (−29 to 70) 17% (−6 to 36) 19% (−17 to 45)
‡Abbreviations defined in Glossary. RRR and CI calculated from control event rates and hazard ratios in article. §Based on all events during follow-up (i.e., not just first events). ||First occurrence of all-cause mortality, myocardial infarction, stroke, coronary revascularization, or hospitalization for angina. ¶First occurrence of cardiovascular mortality, myocardial infarction, or stroke.
JC4
© 2014 American College of Physicians
Downloaded From: http://annals.org/ by a Fudan University User on 12/08/2016
Conclusion In patients with myocardial infarction, high-dose oral multivitamins and minerals did not reduce cardiovascular events. *See Glossary. †Lamas GA, Goertz C, Boineau R, et al. Design of the Trial to Assess Chelation Therapy (TACT). Am Heart J. 2012;163:7-12.
Sources of funding: National Heart, Lung, and Blood Institute and National Center for Complementary and Alternative Medicine. For correspondence: Dr. G. A. Lamas, Mount Sinai Medical Center, Miami Beach, FL, USA. E-mail [email protected]. ■
Commentary The well-designed randomized controlled trial by Lamas and colleagues tested the hypothesis that high-dose multivitamin therapy reduces CV events in patients with MI. The trial enrolled 1708 patients ≥ 50 years of age, most of who were receiving aspirin, statins, β-blockers, angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers. Strengths of the trial include the absence of industry funding; appropriate randomization; blinding of patients, providers, and endpoint assessors; and intention-to-treat analysis. The trial showed that the 28-component multivitamin mixture did not reduce the primary outcome (a composite of death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina). Failure to find an effect may result from a combination of the relatively low power of the trial (85%); high rate of discontinuation of the study medication—46% in both groups, possibly due to the large size of the caplets; or a true lack of efficacy. The results are consistent with the findings of the much larger Physicians’ Health Study, which found that a standard daily multivitamin did not reduce CV events or total mortality in > 14 000 men, 95% of whom had no history of CV disease (1). However the Physicians’ Health Study did find a small reduction in the incidence of cancer (2). In both trials, multivitamins were not associated with adverse events. As a clinician, I don’t routinely recommend supplements, but if a patient is taking them, I can at least confirm their safety and the possibility of a small benefit for cancer prevention. Hanna E. Bloomfield, MD, MPH VA Medical Center and University of Minnesota Minneapolis, Minnesota, USA References 1. Sesso HD, Christen WG, Bubes V, et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308:1751-60. 2. Gaziano JM, Sesso HD, Christen WG, et al. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308:1871-80.
20 May 2014 | ACP Journal Club | Volume 160 • Number 10
