8/9/2019 Today’s Outline • 8 articles to discuss SHOULD IT CHANGE YOUR PRACTICE? 10 minutes per article A DEEPER LOOK AT SOME OF THE PAST • Audience participation is essential YEAR’S MOST IMPORTANT PAPERS • Questions and comments can relate to: AUGUST 8, 2019 Overall topic Methods Clinical implications Michael G. Shlipak, MD MPH Practical experience Manuscript Review: Keeping up with the Literature Questions I Consider • Impossible task for busy clinicians • Does this study address an important question? • Nearly impossible task for academician • Can the study design answer the question? • My sources: • What were the results? Journal table of contents Overall conclusion Email newsletters (Journal Watch, specialty newsletters, AMA, etc.) Strength of the findings Popular press Generalizability of population Ethical or cost considerations • If the topic is interesting, then I go to the manuscript • Does this change my practice? 1
8/9/2019 A year of Surprising Trials 1. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease 2. Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer 3. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia 4. Acute Illness Associated With Cannabis Use, by Route of Exposure: An Observational Study 5. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy Vitamin D Supplements 6. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus 7. 8. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly SMG1 Why do we need RCTs of Vitamins? • Supplements heavily used • Nutritional epidemiology – observational studies seem to be overly optimistic very controversial, contradictory studies substantial confounding (activity, nutrition, socioeconomic status) • Large trials required to determine effect on clinically meaningful outcomes • 3 major supplements trials to discuss today 2
Slide 7 SMG1 Add the date, please Shlipak, Michael G., 7/22/2019
8/9/2019 Design: The VITAL Trial Why did VITAL study Vitamin D? • Setting : United States • Vitamin D is believed to have many beneficial properties • Age: Men ≥ 50; Women ≥ 55 • Enormous literature from cohort studies suggesting • Goal : 5,000 African Americans; 25,871 total beneficial effects • Intervention : 2000 IU vs. placebo • Anti-inflammation, anti-aging, prevention of atherosclerosis, prevention of cancer • Exclusions : cancer, CVD, ESRD, cirrhosis, hypercalcemia • Co-treatment : max of 800 IU of vitamin D • USPTF guidance on vitamin D (before VITAL) Screening: “I” indeterminant evidence • Outcomes : invasive cancer, CVD events Fracture prevention in men and women: “I” • Funding : NIH Effect of the Intervention on 25(OH) Participants in VITAL D levels Characteristic Total (N= 25,871) Mean Age 67±7 • Vitamin D: ↑40% (30 42) Female sex 51% Race • Placebo: 30 30 (no change) Non-Hispanic White 71% Black 20% Is that enough to change outcomes? Nonblack Hispanic 4% Asian or Pacific Islander 1% Body Mass Index 28±6 Current Smoking 7% Hypertension 50% 14% Diabetes Manson JE et al., N Eng J Med, 2019 3
8/9/2019 Vitamin D: No effect on CVD Risk Vitamin D: No effect on Cancer Manson JE et al., N Eng J Med, 2019 Manson JE et al., N Eng J Med, 2019 Vitamin D and Specific Cancers Vitamin D and Specific CVD Outcomes 4
8/9/2019 Conclusions of Vitamin D Trial No. of Subgroup Invasive Cancer Cardiovascular Events Participants • What are the major limitations? Baseline serum 25- Hazard Hazard hydroxyvitamin D 15,787 Vitamin D Placebo Ratio Vitamin D Placebo Ratio • Does it change your practice? category (95% CI) (95% CI) 0.94 1.02 <Median of 31 ng/ml 7,812 128 139 251 252 (0.74–1.20) (0.86–1.21) 1.09 0.95 ≥Median of 31 ng/ml 7,975 124 111 266 275 (0.84–1.41) (0.80–1.12) Manson JE et al., N Eng J Med, 2019 Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer 5
8/9/2019 Design of VITAL – Omega-3 Why did VITAL study Fish Oil/Omega 3 fatty acids? • Design : RCT, double-blind; 2x2 factorial design in combination with Vitamin D/placebo trial • Marine derived long-chain n-3 (omega-3) fatty acids may prevent CVD • Intervention: fish oil capsule vs. placebo 840mg of n-3 fatty acids • Mostly observational studies, small RCTs 460 EPA • Not definitive in the literature 380 DHA • Effect on cancer unknown • The chosen dose was AHA recommended • What is a 2x2 factorial design? Why did the • Donated by industry (BASF) investigators choose this design for VITAL? Omega 3’s and Cancer Risk Omega 3’s and CVD Risk 6
8/9/2019 Omega 3’s and More CVD Outcomes Omega 3’s and Specific CVD Outcomes § These events were not prespecified as primary or secondary end points. ¶ This end point was a composite of myocardial infarction, coronary revascularization (PCI or CABG), and death from coronary heart disease. Manson JE et al. New Eng J Med, 2019 Manson JE et al. New Eng J Med, 2019 Subgroups by Race and Fish Consumption on Omega-3’s and Cancer Risk Risk of Primary CVD outcome Manson JE et al. New Eng J Med, 2019 7
8/9/2019 Discussion • How do we reconcile the positive outcomes with all the negative outcomes? • Does it change your practice? Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia Why was this Fish Oil study done? • Is TG a modifiable risk factor for CVD? Most trials that lower TG’s have been null • Japan EPA Lipid Intervention Study (JELIS)- 19% lower CVD death • Icosapent-ethyl: highly purified and stable EPA ethyl ether • Hypothesized effects: anti-inflammatory, anti- oxidative, plaque-stabilizing • Can it decrease CVD events? 8
8/9/2019 Design of REDUCE-IT Trial REDUCE-IT • Icosapent-Ethyl: highly purified EPA ethyl • Icosapent-Ethyl: highly purified EPA ester vs. placebo ( mineral oil ) ethyl ester vs. placebo (mineral oil) • Intervention: 2g BID vs. placebo (>4x the 2g BID (>4x the VITAL dose) VITAL dose) • Is increased TG really a CVD risk • Design : RCT, double-blind, phase 3b factor? • Participants (High CVD Risk) : ≥ 45 years old with cardiovascular disease ≥ 50 years old with diabetes Manson JE et al. New Eng J Med, 2019 REDUCE-IT Design of REDUCE-IT Trial • N= 8,179; Mean age: 64 • TG fasting range: 150-499 • 71% CVD • LDL range: 41-100 • 29% diabetes without CVD • On statins for 4 weeks • 39% US • Outcomes: broad cardiovascular disease- • 29% female MI, CVA, unstable angina, cardiovascular • Mean LDL: 75 mg/dl death • Mean HDL: 40 mg/dl • Funding : Amarin Corporation • TG: 216 mg/dl 11 countries, 473 sites Bhatt DL et al., N Eng J Med, 2019 9
8/9/2019 Major CVD Primary Events Outcome (CVD death, MI, stroke) 17% vs. 22% at 5 years NNT= ?? 11% vs. 15% at 5 years NNT= 25 Bhatt DL et al., N Eng J Med, 2019 Bhatt DL et al., N Eng J Med, 2019 Effect by Key Subgroups on Major CVD Events Effect on Specific CVD Outcomes Hazard Ratio 95% CI) Bhatt DL et al., N Eng J Med, 2019 Bhatt DL et al., N Eng J Med, 2019 10
8/9/2019 Discussion of REDUCE-IT • Do you believe the results? • What might the mechanism be? • Could mineral oil block statin absorption? Acute Illness Associated with • Multiple trials in progress Cannabis Use, by Route of Exposure Background • Colorado: recreational cannabis approved in 2014 • Increase in ED visits • 40% of marijuana users (smoke only) • Only deaths in CO from cannabis were from edibles • Anecdotally, more toxic • Does the mode of cannabis use affect the risk of adverse events? 11
8/9/2019 Design Methods • Design : Retrospective observational; cases only • Urban hospital, ED • Setting : Academic ED; University of Colorado Hospital ~100,000 visits/year Emergency Department • 2012-2016 • Case ID: ICD-9 codes with screen for cannabis toxicity • Definition of “cannabis related”: Attributable to cannabis: 2,567 Identified cannabis as likely causing or 238 (9.3%) edible contributing • Compared with cannabis sales in CO Toxicity screen + for cannabinoids • Funding : Colorado Department of Public Health and Plausible association of symptoms with Environment cannabis use Reviewed by toxicologists Monte AA, Annals Int Med , 2019 Cannabis-related ED Visits Most Common Clinical Conditions Associated With N= 2,567 Cannabis-Attributable Visits ED Visits With Cannabis-Related Edible Inhalable ICD Code Condition Exposure Exposure (n=238; 9%) (n=2329; 91%) Age 30 years Gastrointestinal symptoms 15% 32% Men 65% Cannabinoid hyperemesis syndrome 8% 18% White 43% Intoxication 48% 28% Black 37% Psychiatric symptoms 26% 25% Acute psychiatric symptoms 18% 11% Hispanic 13% Acute exacerbation of chronic disease 0.4% 4% Admitted (no deaths) 32% Chronic psychiatric condition 0.4% 4% Cardiovascular symptoms 8% 3% Monte AA, Annals Int Med , 2019 12
Recommend
More recommend
