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Original Research |

Oral High-Dose Multivitamins and Minerals After Myocardial Infarction: A Randomized Trial

Gervasio A. Lamas, MD; Robin Boineau, MD, MA; Christine Goertz, DC, PhD; Daniel B. Mark, MD, MPH; Yves Rosenberg, MD; Mario Stylianou, PhD; Theodore Rozema, MD; Richard L. Nahin, PhD, MPH; Lauren Lindblad, MS; Eldrin F. Lewis, MD; Jeanne Drisko, MD; Kerry L. Lee, PhD, for the TACT (Trial to Assess Chelation Therapy) Investigators*
[+] Article and Author Information

* TACT Investigators are listed in the Appendix.


From Mount Sinai Medical Center, Miami Beach, Florida; National Heart, Lung, and Blood Institute and National Center for Complementary and Alternative Medicine, Bethesda, Maryland; Palmer Center for Chiropractic Research, Davenport, Iowa; Duke Clinical Research Institute, Durham, North Carolina; Biogenesis Medical Center, Landrum, South Carolina; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and University of Kansas Medical Center, Kansas City, Kansas.

Note: Dr. Lamas had full access to all of the data in the study and had final responsibility for the decision to submit this article for publication.

Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute; National Center for Complementary and Alternative Medicine; or National Institutes of Health.

Acknowledgment: The authors thank the TACT investigators (members are listed in the Appendix). They also thank Ana Mon, MPH, Project Leader at the Clinical Coordinating Center, for her organizational skills; Alyssa Cotler at the National Center for Complementary and Alternative Medicine, Susan Dambrauskas (formerly at the National Heart, Lung, and Blood Institute), and Vivian Thompson at the Duke Clinical Research Institute for their competent professional assistance; and the Florida Heart Research Institute for supporting the pilot study.

Grant Support: Grant U01HL092607 from the National Heart, Lung, and Blood Institute and grant U01AT001156 from the National Center for Complementary and Alternative Medicine of the National Institutes of Health.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1530.

Reproducible Research Statement: Study protocol, statistical code, and data set: Not available.

Requests for Single Reprints: Gervasio A. Lamas, MD, Columbia University Division of Cardiology, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140; e-mail, gervasio.lamas@msmc.com.

Current Author Addresses: Dr. Lamas: Columbia University Division of Cardiology, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140.

Drs. Boineau, Rosenberg, and Stylianou: National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, MSC 7956, Bethesda, MD 20892.

Dr. Goertz: Palmer Center for Chiropractic Research, 741 Brady Street, Davenport, IA 52804.

Drs. Mark and Lee and Ms. Lindblad: Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27705.

Dr. Rozema: Biogenesis Medical Center, 1000 East Rutherford Road, Landrum, SC 29356.

Dr. Nahin: National Center for Complementary and Alternative Medicine, 31 Center Drive, Room 2 B-11, Bethesda, MD 20892.

Dr. Lewis: Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115.

Dr. Drisko: Integrative Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 1017, Kansas City, KS 66160.

Author Contributions: Conception and design: G.A. Lamas, R. Boineau, C. Goertz, D.B. Mark, Y. Rosenberg, M. Stylianou, T. Rozema, R.L. Nahin, E.F. Lewis, J. Drisko, K.L. Lee.

Analysis and interpretation of the data: G.A. Lamas, R. Boineau, D.B. Mark, Y. Rosenberg, M. Stylianou, R.L. Nahin, L. Lindblad, E.F. Lewis, J. Drisko, K.L. Lee.

Drafting of the article: G.A. Lamas, R. Boineau, C. Goertz, M. Stylianou, L. Lindblad, J. Drisko, K.L. Lee.

Critical revision of the article for important intellectual content: G.A. Lamas, R. Boineau, D.B. Mark, Y. Rosenberg, M. Stylianou, R.L. Nahin, L. Lindblad, E.F. Lewis, J. Drisko, K.L. Lee.

Final approval of the article: G.A. Lamas, R. Boineau, C. Goertz, D.B. Mark, Y. Rosenberg, M. Stylianou, R.L. Nahin, L. Lindblad, E.F. Lewis, J. Drisko, K.L. Lee.

Provision of study materials or patients: G.A. Lamas, J. Drisko.

Statistical expertise: M. Stylianou, L. Lindblad, K.L. Lee.

Obtaining of funding: G.A. Lamas, R. Boineau, D.B. Mark.

Administrative, technical, or logistic support: G.A. Lamas, R. Boineau, Y. Rosenberg, T. Rozema.

Collection and assembly of data: D.B. Mark, E.F. Lewis, J. Drisko.


Ann Intern Med. 2013;159(12):797-805. doi:10.7326/0003-4819-159-12-201312170-00004
Text Size: A A A

Background: Whether high-dose multivitamins are effective for secondary prevention of atherosclerotic disease is unknown.

Objective: To assess whether oral multivitamins reduce cardiovascular events and are safe.

Design: Double-blind, placebo-controlled, 2 × 2 factorial, multicenter, randomized trial. (ClinicalTrials.gov: NCT00044213)

Setting: 134 U.S. and Canadian academic and clinical sites.

Patients: 1708 patients aged 50 years or older who had myocardial infarction (MI) at least 6 weeks earlier and had serum creatinine levels of 176.8 µmol/L (2.0 mg/dL) or less.

Intervention: Patients were randomly assigned to an oral, 28-component, high-dose multivitamin and multimineral mixture or placebo.

Measurements: The primary end point was time to total death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina.

Results: The median age was 65 years, and 18% of patients were women. The qualifying MI occurred a median of 4.6 years (interquartile range [IQR], 1.6 to 9.2 years) before enrollment. Median follow-up was 55 months (IQR, 26 to 60 months). Patients received vitamins for a median of 31 months (IQR, 13 to 59 months) in the vitamin group and 35 months (IQR, 13 to 60 months) in the placebo group (P = 0.65). Totals of 645 (76%) and 646 (76%) patients in the vitamin and placebo groups, respectively, completed at least 1 year of oral therapy (P = 0.98), and 400 (47%) and 426 (50%) patients, respectively, completed at least 3 years (P = 0.23). Totals of 394 (46%) and 390 (46%) patients in the vitamin and placebo groups, respectively, discontinued the vitamin regimen (P = 0.67), and 17% of patients withdrew from the study. The primary end point occurred in 230 (27%) patients in the vitamin group and 253 (30%) in the placebo group (hazard ratio, 0.89 [95% CI, 0.75 to 1.07]; P = 0.21). No evidence suggested harm from vitamin therapy in any category of adverse events.

Limitation: There was considerable nonadherence and withdrawal, limiting the ability to draw firm conclusions (particularly about safety).

Conclusion: High-dose oral multivitamins and multiminerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. However, this conclusion is tempered by the nonadherence rate.

Primary Funding Source: National Institutes of Health.

Figures

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Figure 1.

Study flow diagram.

* Includes 1 placebo recipient who died before starting the intervention.

† 297 high-dose vitamin recipients and 285 placebo recipients had follow-up after discontinuation and 97 high-dose vitamin recipients and 105 placebo recipients had no follow-up after discontinuation.

‡ 43 met the primary end point before withdrawal (16 in the high-dose vitamin group and 27 in the placebo group). Among the patients who had not had an event before withdrawal, 9 (5 in the high-dose vitamin group and 4 in the placebo group) were found through search of death registries to have died. All of these events were included in the primary end point analysis.

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Appendix Figure.

Kaplan–Meier estimates of discontinuation of vitamins: high-dose vitamins versus placebo.

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Figure 2.

Kaplan–Meier estimates of the primary composite end point (top) and CV death, MI, or stroke (bottom): high-dose vitamins versus placebo.

P values were calculated using the log-rank statistic. CV = cardiovascular; MI = myocardial infarction.

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Figure 3.

Subgroup analyses comparing high-dose vitamins with placebo.

CAM = complementary and alternative medicine; MI = myocardial infarction.

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Comments

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Remove intention-to-treat for hypothesis generation
Posted on December 18, 2013
David L. Keller, MD
None
Conflict of Interest: None Declared
The high levels of non-adherence to the study protocol could have obscured a small benefit due to the rigorous intention-to-treat analysis performed. I would suggest that the results be recalculated, eliminating subjects from the active arm who took less than 90% of their vitamins, as well as placebo subjects who took vitamins on their own, off-protocol. The results of that calculation would serve as follows: if there was still no benefit seen, it would tend to strengthen the conclusion of no benefit, and if a benefit became apparent, it would serve as hypothesis-generating data (although not statistically valid for drawing conclusions).
Comment
Posted on January 2, 2014
James H. Eychaner, MS
Retired
Conflict of Interest: None Declared
To the editor: Lamas and colleagues' article (1) evaluating a multivitamin regime after myocardial infarction was designed to detect a 25% reduction in the primary end-point event rate with a priori probabilities of less than 5% false positive result (Type I error, alpha < 0.05) and less than 15% false negative result (Type II error, beta<0.15). The data a posteriori showed a 21% likelihood of a false positive result (p=0.21), thus failing to confirm the study hypothesis with acceptable confidence. The probability of Type II error, however, varies inversely with the magnitude of the effect to be detected, and the data suggest an effect closer to 10% than 25%. For the study as implemented, what was the a priori false negative probability if there were a real effect of magnitude 10%?

References

1. Lamas G, Boineau R, Goertz C, Mark D, Rosenberg Y, Stylianou M, Rozema T, Nahin R, Lindblad L, Lewis E, Drosko J, Lee K. Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial. Ann Intern Med. 2013; 159:797-804.




As a 66-year-old male with no history of MI, the apparently high risk of false negative in this study dissuades me from accepting the editors' recommendation to stop taking a daily multivitamin.


James H. Eychaner, M.S.

Hydrologist (retired)

Carmichael, CA, USA

1cor1221@gmail.com

Submit a Comment

Summary for Patients

High-Dose Multivitamins and Minerals After a Heart Attack

The full report is titled “Oral High-Dose Multivitamins and Minerals After Myocardial Infarction. A Randomized Trial.” It is in the 17 December 2013 issue of Annals of Internal Medicine (volume 159, pages 797-804). The authors are G.A. Lamas, R. Boineau, C. Goertz, D.B. Mark, Y. Rosenberg, M. Stylianou, T. Rozema, R.L. Nahin, L. Lindblad, E.F. Lewis, J. Drisko, and K.L. Lee, for the TACT Investigators.

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