Disclosures VITAL was supported by the U.S. National Institutes of Health: Vitamin D and Omega-3 Fatty Acids: • National Cancer Institute and National Heart, Lung and Do They Prevent Cardiovascular Disease and Cancer? Blood Institute (co-sponsors) • Additional NIH support: ODS, NINDS, and NCCIH (and JoAnn E. Manson, MD, DrPH, NCMP ancillary study support from multiple institutes) Chief, Division of Preventive Medicine Pharmavite of Northridge, CA (vitamin D) and Pronova BioPharma Brigham and Women's Hospital of Norway and BASF (Omacor fish oil, known as Lovaza in the U.S. ) Professor of Medicine and the donated study pills, matching placebos, and calendar packaging. Michael and Lee Bell Professor of Women's Health Harvard Medical School Quest Diagnostics (San Juan Capistrano, CA) measured serum 25OHD and other biomarkers at no cost. North American Menopause Society Annual Meeting Plenary Symposium #4 Chicago, Illinois; September 26, 2019 Objectives • Review the rationale and design of a large-scale randomized trial of vitamin D and marine omega-3 supplements in the primary prevention of CVD and cancer. • Describe the trial’s findings for each supplement in relation to CVD and cancer outcomes. • Discuss which patients are more or less likely to benefit from supplementation. 1
The VIT amin D and Omeg A -3 Tria L (VITAL): Design 25,871 Initially Healthy Men and Women *Primary Prevention* (Men >50 yrs; Women >55 yrs) Vitamin D 3 Placebo (2000 IU/d); N=12,927 N=12,944 EPA+DHA Placebo EPA+DHA Placebo (1 gm/d [1.3:1 ratio]) N=6464 (1 gm/d [1.3:1 ratio]) N=6474 N=6463 N=6470 Median Treatment Period = 5.3 years. 5,106 African Americans. Blood collection in ~16,953 at baseline, follow-up bloods in ~6000. Adapted from: Manson JE, Bassuk SS, Lee I-M, et al. Cont Clinical Trials, 2011. VITAL Specific Aims Mechanisms by Which Marine Omega-3 Fatty Acids May Lower CVD and Cancer Risk Primary Aims MARINE OMEGA-3 FATTY ACIDS 1) To test whether vitamin D 3 and/or omega-3 fatty acids reduce risk of (a) major CVD events (composite of MI, EPA-derived Arachidonic Acid- Other Pathways stroke, CVD death), (b) total invasive cancer. Eicosanoids derived Eicosanoids Secondary Aims Blood 1) To test whether these agents lower risk of the individual Inflammation Triglycerides Apoptosis Pressure endpoints of MI, stroke, CVD death. Cell Cardiac Proliferation Nitric Oxide- Arrhythmias 2) To test whether these agents lower risk of (a) site-specific Induced Endothelial Angiogenesis cancer, (b) total cancer mortality. Tumor Relaxation Endothelial Thrombosis 3) Assess key subgroups, including age, sex, race/ethnicity, Cell Adhesion nutrient status at baseline. CVD Prevention Cancer Prevention 2
Omega-3 Fatty Acids and Major Vascular Events: Fish Consumption and CVD: Meta-Analysis of RCTs in High Risk Populations (2018) Ecologic and Observational Studies Favors Favors Outcome Treatment Control Coronary Heart Disease Nonfatal MI 0.97 (0.87-1.08) • Ecologic studies (Greenland Inuits, Alaskan Eskimos, CHD death 0.93 (0.83-1.03) Any CHD 0.96 (0.90-1.01) other groups) P = 0.12 Stroke Ischemic 1.03 (0.88-1.21) • Meta-analysis of 13 cohort studies, intake >5 times/wk Hemorrhagic 1.07 (0.76-1.51) Any stroke 1.03 (0.93-1.13) vs <1/month: RR = 0.62 (0.46-0.82) for fatal CHD. P = 0.60 Revascularization • Meta-analysis of 9 cohort studies, intake >5 times/wk Coronary 1.00 (0.93-1.07) Noncoronary 0.92 (0.75-1.13) vs <1/month: RR = 0.69 (0.54-0.88) for total stroke. Any revascularization 0.99 (0.94-1.04) P = 0.60 Any Major Vascular Event 0.97 (0.93-1.01) P = 0.10 Source: He K, et al. Circulation 2004; 109:2705. He K, et al. JAMA 2002; 288:3130. Source: Aung T, et al. JAMA Cardiol 2018; 3(3):225-234. Omega-3 Fatty Acids and Major Vascular Events: Rationale for the Omega-3 Dose in VITAL Meta-Analysis of RCTs 1 gm/d (840 mg EPA+DHA, ratio of ~1.3:1.0 ) • Proposed dose appeared to represent the best balance Number Outcome Studies Events Participants RR (95% CI) of efficacy and safety in primary prevention. All-cause mortality 17 6295 63,279 0.96 (0.91-1.02) Cardiac death 13 3480 56,407 0.91 (0.85-0.98) • Current health recommendations: Sudden death 7 1030 41,751 0.87 (0.75-1.01) Myocardial infarction 13 1755 53,875 0.89 (0.76-1.04) 1 Prevention: 250-500 mg/d (~2 servings fish/wk) Stroke 9 1490 52,589 1.05 (0.93-1.18) 2 Prevention: 1 gm/d (AHA) Average intake in U.S. is 120-200 mg/d (dose is 5-8 times higher). Error bars indicate 95% CIs; PUFAs, polyunsaturated fatty acids; RR, relative risk. Source: Rizos EC, et al. JAMA 2012; 308(10):1024. 3
Hazard Ratios (HR) and 95% CIs of the CVD Outcomes by Baseline Characteristics of the 25,871 VITAL Participants Randomized Assignment to Omega-3 Fatty Acids N 25,871 Omega-3s Placebo Mean age ± SD, years 67.1 ± 7.1 (N=12,933) (N=12,938) HR (95% CI) No. of Events Sex, % female 13,085 (50.6) Cardiovascular disease Race/ethnicity, % (1 and 2 outcomes) Non-Hispanic White 18,046 (71.3) Major CVD events a 386 419 0.92 (0.80-1.06) African American 5,106 (20.2) Total MI 145 200 0.72 (0.59-0.90)* Total stroke 148 142 1.04 (0.83-1.31) Hispanic (not African American) 1,013 ( 4.0) CVD mortality 142 148 0.96 (0.76-1.21) Asian/Pacific Islander 388 ( 1.5) Major CVD + PCI/CABG b 527 567 0.93 (0.82-1.04) American Indian/Alaskan Native 228 ( 0.9) Other vascular outcomes c Mean body mass index (kg/m 2 ) ± SD 28.1 (5.7) PCI 162 208 0.78 (0.63-0.95)* CABG 85 86 0.99 (0.73-1.33) Current smoking, % 1,836 ( 7.2) Fatal MI 13 26 0.50 (0.26-0.97)* Hypertension, treated, % 12,791 (49.8) CHD death 37 49 0.76 (0.49-1.16) Total CHD d 308 370 0.83 (0.71-0.97)* High cholesterol, treated, % 9,524 (37.5) Diabetes, % 3,549 (13.7) a Primary outcome. A composite of MI, stroke and CVD mortality. b Expanded CVD composite c Not prespecified as primary or secondary outcomes. d A composite of MI, PCI/CABG, and CHD death. All analyses are intention-to-treat. *Nominal p-value <0.05. For MI, the nominal p-value was 0.003. Cumulative Incidence Rates of Major CVD Events and Total MI Follow-up Rates and Treatment Compliance by Year of Follow-up: Omega-3s vs. Placebo Major CVD Events Total MI • Mean follow-up rates over 5.3 yrs: Morbidity (>93%); mortality (>98%). • Study pill adherence: Mean of >83% over 5.3-yr follow-up. High adherence supported by biomarker studies at baseline and 1 year (n ~1,600): • Plasma omega-3 index: 54.7% with n-3s vs <2% with placebo. • Serum 25(OH)D: 40% with vitamin D vs ~2% with placebo. For major CVD events: p-value = 0.24 For total MI: nominal p-value = 0.003 and Bonferroni-adjusted p-value = 0.015. 4
Hazard Ratios of Major CVD Events by Baseline Fish Consumption, Hazard Ratios (HR) and 95% CIs of the Cancer Outcomes Comparing Omega-3 Fatty Acids and Placebo Groups and All-Cause Mortality (Omega-3s vs. Placebo) Omega-3s Placebo Subgroups Total Omega-3s Placebo HR (95% CI) Interaction Outcome (N=12,933) (N=12,938) HR (95% CI) No. of Events p-value No. of Events Fish Consumption 0.045 (servings/wk) 25,435 Total invasive cancer 820 797 1.03 (0.93-1.13) <median 13,514 189 232 0.81 Cancer death 168 173 0.97 (0.79-1.20) (1.5 servings/wk) (0.67-0.98) All-cause mortality 493 485 1.02 (0.90-1.15) >median 11,921 189 176 1.08 (1.5 servings/wk) (0.88-1.32) Excluding the first 2 years of follow up: 0.6 0.8 1 1.2 1.4 1.6 Total invasive cancer 536 476 1.13 (1.00-1.28) Hazard Ratios Cancer death 126 135 0.93 (0.73-1.19) n-3 fatty acids placebo better better All-cause mortality 371 381 0.97 (0.84-1.12) Source: Manson JE, Cook NR, Lee I-M, et al. NEJM 2018. Source: Manson JE, Cook NR, Lee I-M, et al. NEJM 2018. Updated Meta-Analysis of Marine Omega-3 Supplementation Hazard Ratios of Total MI by Subgroups, Comparing Omega-3 Fatty Acids and Placebo Groups and CVD in 13 Trials (127,477 participants) Interaction Subgroups Total Omega-3s Placebo HR (95% CI) p-value No. of Events Race 25,304 0.001 Non-Hispanic White 18,046 126 135 0.93 (0.73-1.18) African American 5,106 9 39 0.23 (0.11-0.47) Other 2,152 8 16 0.54 (0.23-1.26) Fish Consumption (servings/wk) 25,435 0.048 <median 13,514 74 121 0.60 (0.45-0.81) (1.5 servings/wk) >median 11,921 67 72 0.94 (0.67-1.31) (1.5 servings/wk) # of Cardiovascular Risk Factors 25,871 0.047 No risk factors 7,802 41 40 1.01 (0.65-1.56) 1 risk factor 8,948 53 70 0.75 (0.53-1.08) 0.57 (0.41-0.81 ) 2 or more risk factors 9,121 51 90 0.1 0.2 0.4 0.6 1 1.6 Hazard Ratios n-3 fatty acids placebo Source: Manson JE, Cook NR, Lee I-M, et al. NEJM 2018. Source: Hu Y, Hu FB, Manson JE. J Am Heart Assoc 2019. better better 5
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