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HD Sesso, WC Christen, V Bubes, JP Smith, J MacFadyen, M Schvartz, JE Manson, RJ Glynn,
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Transcript of HD Sesso, WC Christen, V Bubes, JP Smith, J MacFadyen, M Schvartz, JE Manson, RJ Glynn,
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A Randomized Trial of a Multivitamin in the Prevention of Cardiovascular Disease in Men:
The Physicians’ Health Study IIHD Sesso, WC Christen, V Bubes, JP Smith,
J MacFadyen, M Schvartz, JE Manson, RJ Glynn,
JE Buring, JM Gaziano
Division of Preventive MedicineBrigham and Women’s Hospital
Boston, MA
Funding: NIH (NCI, NHLBI, NIA, and NEI) and an investigator-initiated grant from BASF Corporation. Pills and/or packaging were provided
by BASF, Pfizer and DSM Nutritional Products.
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Background
• More than half of US adults take vitamin supplements, with common multivitamins (MVM) the most widely used.
• Basic research suggests that some components of MVMs might reduce the risk of cardiovascular disease (CVD).
• Observational studies have not clearly demonstrated an association between MVMs and a lower risk of CVD.
• There are no large-scale, long-term randomized trials of a MVM in the prevention of CVD and other chronic diseases.
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Physicians’ Health Study (PHS)
1982 – 1996:
PHS I enrolled 22,071 male physicians in a trial by mail of aspirin and beta-carotene in the prevention of CVD and cancer.
1997 – present:
PHS II enrolled 7,641 PHS I participants and 7,000 new physicians in a new trial by mail.
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• Randomized, double-blind, placebo-controlled, factorial trial conducted by mail among 14,641 male physicians aged 50 years and older.
• Evaluated the long-term risks and benefits of vitamin E, vitamin C, and a multivitamin (Centrum Silver daily)
• Primary outcomes: CVD and cancer• Secondary outcomes: Eye disease and
cognitive function
Physicians’ Health Study II: Design
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Phase I: Mailed Invitations to 18,763 PHS I participants
Phase II: Mailed invitations to 254,597 new physicians
11,128 Enrolled in a Placebo Run-in
14,641 Randomized Participants
Active Vitamin E Vitamin E Placebo
Active Vitamin C Vitamin C Placebo
ActiveMulti-
Vitamin
Multi-VitaminPlacebo
ActiveMulti-
Vitamin
Multi- VitaminPlacebo
ActiveMulti-
Vitamin
Multi-VitaminPlacebo
ActiveMulti-
Vitamin
Multi-VitaminPlacebo
Active Vitamin C Vitamin C Placebo
PHYSICIANS’ HEALTH STUDY II RANDOMIZATION SCHEME
7,641 7,000
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Monthly Calendar Pack
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Physicians’ Health Study II: Follow-up
Mean follow-up was 11.2 years, with a total of more than 164,000 person-years of follow-up.
MVM compliance: 77% at 4 years, 72% at 8 years, and 67% at study end
Primary CVD Outcome: Major cardiovascular events (nonfatal myocardial infarction (MI), nonfatal stroke, and CVD death)
Other CVD Outcomes: Total and fatal MI, total and fatal stroke, ischemic and hemorrhagic stroke, CVD mortality, and total mortality
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Age, mean (SD) 64.2 (9.1) 64.3 (9.2)
BMI, mean (SD) 25.9 (3.4) 26.0 (3.4)
Current smoker, % 3.5 3.7
Exercise ≥1 time/wk, % 62.2 60.7
Current aspirin use, % 77.5 77.3
History of hypertension, % 41.8 42.7
History of high cholesterol, % 36.0 37.3
History of diabetes, % 6.5 5.9
Plasma TC, mean (SD) 203.5 (35.5) 203.7 (36.0)
Fruits & vegetables, servings/d (IQR) 4.26 (2.95-5.75) 4.19 (2.94-5.77)
Whole grains, servings/d (IQR) 1.13 (0.49-2.00) 1.07 (0.49-1.99)
Active(n = 7317)
Placebo(n = 7324)
JAMA 2012 In press
Baseline Characteristics by Multivitamin Treatment Assignment
P>.05 for all comparisons between multivitamin and placebo groups
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JAMA 2012 In press
Crude log-rank P = .69
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JAMA 2012 In press
Crude log-rank P = .44Crude log-rank P = .44
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Major cardiovascular events 876 856 1.01 (0.91-1.10) .91
Total MI 317 335 0.93 (0.80-1.09) .39
MI death 27 43 0.61 (0.38-0.995) .048
Total stroke 332 311 1.06 (0.91-1.23) .48
Stroke death 89 76 1.16 (0.85-1.58) .34
Ischemic stroke 277 250 1.10 (0.92-1.30) .29
Hemorrhagic stroke 49 45 1.08 (0.72-1.63) .69
Cardiovascular death 408 421 0.95 (0.83-1.09) .47
Total mortality 1345 1412 0.94 (0.88-1.02) .13
Cardiovascular Events by Multivitamin Treatment Assignment
Active(n = 7317)
Placebo(n = 7324) HR (95% CI)Outcome
JAMA 2012 In press
P
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JAMA 2012 In press
Crude log-rank P = .71 Crude log-rank P = .94
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Age, years .04
50-59 136 109 1.27 (0.99-1.63)
60-69 244 225 1.09 (0.91-1.31)
≥70 496 522 0.91 (0.81-1.03)
Smoking status .49
Never 412 414 0.95 (0.83-1.09)
Former 419 401 1.06 (0.92-1.21)
Current 45 41 1.11 (0.72-1.70)
Current aspirin use .07
No 199 169 1.20 (0.98-1.48)
Yes 654 663 0.96 (0.86-1.07)
History of high cholesterol .65
No 511 472 1.03 (0.91-1.16)
Yes 353 369 0.98 (0.85-1.13)
Effect Modification by Selected Baseline Characteristics on Major Cardiovascular Events
Active(n = 7317)
Placebo(n = 7324) HR (95% CI)Baseline Characteristic
JAMA 2012 In press
P int
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History of diabetes .33
No 765 740 1.02 (0.92-1.13)
Yes 109 116 0.89 (0.68-1.16)
History of CVD .62
No 745 728 1.02 (0.92-1.13)
Yes 131 128 0.96 (0.75-1.22)
Plasma TC ≥240 mg/dL .77
No 457 443 1.02 (0.89-1.16)
Yes 83 82 1.07 (0.79-1.46)
Fruit and vegetable intake .32
<4 servings/d 330 308 1.09 (0.93-1.27)
4 to <7 servings/d 318 300 0.99 (0.85-1.17)
≥7 servings/d 107 120 0.87 (0.67-1.13)
Effect Modification by Selected Baseline Characteristics on Major Cardiovascular Events
Active(n = 7317)
Placebo(n = 7324) HR (95% CI)Baseline Characteristic
JAMA 2012 In press
P int
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Total cancer 1290 1379 0.92 (0.86-0.998) .04
Total epithelial cell cancer 1158 1244 0.92 (0.85-0.997) .04
Prostate cancer 683 690 0.98 (0.88-1.09) .76
Total cancer minus prostate
641 715 0.88 (0.79-0.98) .02
Cancer mortality 403 456 0.88 (0.77-1.01) .07
Total mortality 1345 1412 0.94 (0.88-1.02) .13
By baseline history of cancer
Yes (n=1312) 95 126 0.73 (0.56-0.96) .02
No (n=13329) 1195 1253 0.94 (0.87-1.02) .15
Cancer Events by Multivitamin Treatment Assignment
Active(n = 7317)
Placebo(n = 7324) HR (95% CI)Outcome
JAMA 2012; Online October 17, 2012
P
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Conclusions• PHS II is the only large-scale randomized trial
testing long-term MVM use, finding no effect on major cardiovascular events in men.
• The main reason to take a daily MVM remains to prevent vitamin and mineral deficiency.
• The decision to take a MVM should also consider its modest beneficial effects on cancer.
• We will be providing additional trial results for the effects of a MVM on other important outcomes along with extending follow-up of the PHS II cohort.
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HD Sesso and coauthors
Multivitamins in the Prevention of Cardiovascular Disease in Men: The Physicians’ Health Study II Randomized Controlled Trial
Available at www.jama.com
jamanetwork.com