Nutraceuticals and Cardiovascular Disease: Are we fishing? ACC - PowerPoint PPT Presentation

Nutraceuticals and Cardiovascular Disease: Are we fishing? ACC Rockies 2013 March 20,2013 Sheri L. Koshman BScPharm, PharmD, ACPR Assistant Professor, Division of Cardiology, University of Alberta sheri.koshman@ualberta.ca

Conflicts of Interest • none

Overview • General supplement use • Impact of supplements in CV disease: – Multivitamins – Fish oils – Calcium

“Let food be thy medicine, and medicine be thy food” Hippocrates (460-377BC)

How many of your patients use supplement? 1. 10% 2. 20% 3. 50% 4. 80%

42% 53% $27 Billion NCHS Data Brief 2011: 61

Number of Supplement Bailey RL. J Nutr 2011;141(2):261-66

Types of supplements n = 1,055 Prasad K, et al. Am J Cardiol 2013;111:339-45

Supplements: Impact • Lack of evidence regarding safety and efficacy – Food vs drug classification • Beliefs about beneficial effects of supplements: – May be less likely to engage in other preventative health behaviors – May be less likely to engage in modern, proven medical therapies • Adherence – Pill burden – Financial burden

Multivitamins

Multivitamins 30% 39% NCHS Data Brief 2011: 61

Multivitamins • Observational data; sparse and inconsistent – Nurses’ Health Study • RR 0.76 (95% CI 0.65-0.90) – Swedish case-control • male RR 0.79 (0.63-0.98) • female RR 0.66 (0.48-0.91) – PHS I – no association – WHI – no association – Multiethnic cohort study – no association

JAMA 2012;308(17)1751-60

Methodology • Randomized, DB, PC, 2 x 2 x 2 x 2 factorial – Multivitamin (Centrum Silver) daily – Vitamin E 400IU q2d (ended 2007) – Vitamin C 500mg daily (ended 2007) – Beta-carotene 50mg q2d (ended 2003) • Outcomes: – Prevention of CV disease – Cancer – Eye disease – Cognitive decline JAMA 2012;308(17)1751-60

Methodology • n=14,641 • Male, physicians, > 50 years • 1999 thru August 2012 • Follow-up: >98%; median 11.2 years • Outcomes: – Primary: major CV events (non-fatal MI, non-fatal stroke, CVD mortality) – Other: total MI, total stroke, total mortality JAMA 2012;308(17)1751-60

Middle age Regular Exercise Regular ASA Few CVD risk factors Regular fruit/veg JAMA 2012;308(17)1751-60

Results JAMA 2012;308(17)1751-60

Conclusions • No effect of multivitamins on any CV outcome • Limited generalizability: – Male, caucasian, physicians – “healthy” – good nutritional status at baseline • Lack of incremental benefit • Small benefit in the prevention of cancer JAMA 2012;308(17)1751-60

Results: Cancer No difference in cancer mortality Effect the same for secondary prevention JAMA 2012;308(18):1871-80

Fish Oils

Fish oils: Biologic effects • Anti-inflammatory • Anti-atherogenic • Anti-thrombotic • Anti-arrhythmic • Lower BP • Lower TG

JAMA 2012;308(12):1024-33

Methodology • RCT • Omega-3 PUFA supplementation in adults • Diet or supplements – compared to another diet or placebo • Primary or secondary CVD • Treatment > 1 year • Result: 20 studies, 68,680 patients JAMA 2012;308(12):1024-33

JAMA 2012;308(12):1024-33

JAMA 2012;308(12):1024-33

Results No difference: mixed vs. secondary prevention vs. ICD, blinding status or dose JAMA 2012;308(12):1024-33

JAMA 2012;308(12):1024-33

Conclusions • No significant effect on major CV outcomes across patient populations at increase CV risk • Larger effects seen pre-statin era • Lack of incremental benefit on top of modern medical therapy • Similar results – Kwak et al. Arch Intern Med 20012;172:686-94 • limited to secondary prevention, placebo controlled only – Kotwal et al. Circ Cardiovasc Qual Outcomes 2012;5:808-18

Fish Oils Courtesy of Elizabeth Woo, RD

Calcium

Calcium NCHS Data Brief 2011: 61

Calcium • Calcium is essential for many biological actions • Historical data suggested that dietary calcium may be protective against CV disease • More recent data suggests that calcium supplementation may increase the risk of CV disease • No prospective RCTs to date have investigated the role of calcium supplementation of CV as a primary endpoint

Patient and trial level data RCT, PC, calcium > 500mg/d (without Vit D) n=11 trials (12,000) Median follow-up: 3.6 years BMJ 2010;341:c3691doi10.1136/bmj.c3691

BMJ 2010;341:c3691doi10.1136/bmj.c3691

BMJ 2011;342:d2040doi:10.1136/bmj.d2040

Methodology • WHI reanalysis (n=36,282): – Sub-group analysis of personal use versus no personal use • 54% of participant were taking personal calcium • 47% of participant were taking personal vitamin D – Hypothesis: frequent personal use obscured adverse CV outcomes • Meta-analysis – Calcium +/- vitamin D use – update previous analysis with WHI and non-users of personal calcium at randomization BMJ 2011;342:d2040doi:10.1136/bmj.d2040

Results: Reanalysis * * * Significant HR 1.22-1.13 HR 0.83-1.08 interaction with personal use, but not Vitamin D or dietary calcium BMJ 2011;342:d2040doi:10.1136/bmj.d2040

Calcium + Vitamin D vs. Placebo n=20,090 No significant effect on all cause mortality BMJ 2011;342:d2040doi:10.1136/bmj.d2040

Effect of supplementation (Calcium +/- Vit D): Patient-level data (n=24,869) NNH = 240 NNH = 178 NNH = 283 “Treating 1000 people with calcium or calcium + vitamin D x 5 years, would cause 6 additional MIs or stroke and prevent 3 fractures” BMJ 2011;342:d2040doi:10.1136/bmj.d2040

Effect of supplementation: trial-level data (n=28,072) BMJ 2011;342:d2040doi:10.1136/bmj.d2040

BMJ 2013;346:f228 doi:10.1136/bmj.f228

Methodology • Swedish mammography cohort, n=90,303 • Cohort 1987- 90 (n = 61,433) – 1997 (n=38,984) • Expanded dietary questionnaire • Supplement questionnaire • Categorized intake: – <600mg – 600-999mg – reference range, RDA in Sweden 800mg – 1000-1399mg – >1400mg • Follow-up (100%): – Median 19 yrs (1,094,880 person yrs) – Primary: death – Secondary: CV disease, IHD, and stroke BMJ 2013;346:f228 doi:10.1136/bmj.f228

<600mg HR 1.38 (1.27-1.51) >1400mg HR 1.40 (1.17-1.67) <600mg HR 1.63(1.42-1.87) >1400mg HR 1.49 (1.09-2.02) <600mg HR 1.65 (1.36-2.01) >1400mg HR 2.14 (1.48-3.09) <600mg HR 1.50 (1.14-1.97) >1400mg HR 0.73 (0.33-1.65) BMJ 2013;346:f228 doi:10.1136/bmj.f228

BMJ 2013;346:f228 doi:10.1136/bmj.f228

25% of cohort, 75% multivitamin (120mg calcium) (500mg) BMJ 2013;346:f228 doi:10.1136/bmj.f228

Conclusions • High dietary intake of calcium is associated with increase in mortality and CV events • High dietary intake + calcium tablets is associated with higher mortality • Limitations: – Cohort design – Questionnaire reliability – Healthy user bias BMJ 2013;346:f228 doi:10.1136/bmj.f228

JAMA Intern Med. doi:10.1001/jamainternmed.2013.3283

Methodology • NIH-AARP diet and Health Study, US 1995-96 • Age 50-71 – Men (n=219,059) – Women (n=169,170) • Baseline – Dietary intake (quintiles) – Frequency and dosage of calcium supplements – Multivitamin intake • An interaction by sex was found and therefore analysis was done separately • Follow-up: – 12 years – 3,549,364 person-years JAMA Intern Med. doi:10.1001/jamainternmed.2013.3283

Results • Calcium supplements: – Men 23% – Women 56% • Multivitamins containing calcium – Men 56% – Women 58% JAMA Intern Med. doi:10.1001/jamainternmed.2013.3283

Dietary Calcium

Supplements Consistent when limited to calcium supplements and not multivitamins

Total Calcium CVD mortality RR 1.12 (1.04-1.20) Men HD mortality RR 1.12 (1.04-1.21) No association Women

Conclusions • Supplementary calcium, but not dietary calcium is associated with increase CVD mortality in men, but not women. • Limitations: – Cohort design – Duration of supplement use – Calcium intake only measured at baseline

Key Points • Multivitamins – Limited data to support the routine use of multivitamins – RCT data from healthy males indicated no benefit to supplementation • Fish oils – Limited data to support routine use in prevention of CV disease, both primary and secondary prevention • Calcium – Data remains inconclusive – Minimal effect in fracture prevention unlikely to outweigh the potential risk of CV disease