9/14/2019 DISCLOSURE Faculty: Erin Michos, MD Aspirin in Primary CVD Prevention: DISCLOSURE: I disclose that I have Is there any role in 2019? no relevant financial relationships with Erin D. Michos, MD, MHS, FACC, FAHA commercial interests Associate Professor of Medicine & Epidemiology Director of Women’s Cardiovascular Health Associate Director of Preventive Cardiology Ciccarone Center for the Prevention of Cardiovascular Disease Johns Hopkins University School of Medicine North American Menopause Conference, Sept 27, 2019 Aspirin for Major CV Events (MACE): Targets for Oral Antiplatelet Rx SECONDARY PREVENTION SECONDARY PREVENTION – 27% RRR in MACE ASPIRIN – Irreversible Inhibitor of COX-1 which halts production of Thromboxane A2 and thus platelet aggregation ** All high risk: Prior MI, acute MI, prior stroke/TIA, other high risk Antiplatelet Trialists Collaboration. BMJ. 1994;308:81-106. Bonaca MP, Creager MA. Circ Res. 2015;116:1579-1598. 1
9/14/2019 Aspirin for Primary Aspirin for Primary Prevention of CVD Prevention of CVD • Aspirin is widely accepted as effective in the secondary prevention of ASCVD • Based on older trials, prior US guidelines had recommended low dose aspirin for primary ASCVD prevention only in the setting of elevated 10-yr CVD risk CHD=Coronary heart disease Source: Pearson TA et al. Circulation 2002;106:388-391 Grundy SM et al. Circulation 1997; 95: 2329–2331 Aspirin for Primary Role of aspirin in primary Prevention of CVD prevention • Absolute risks of CVD Prevention vascular events are lower than in secondary prevention • Complication rates (bleeding) are Bleeding Risk comparable CVA=Cerebrovascular accident, MI=Myocardial infarction, RR=Relative risk Source: Ridker P et al. NEJM 2005;352:1293-1304 2
9/14/2019 2014 – the Japanese Primary Aspirin for Primary Prevention of ASCVD: Prevention Project (JPPP) 2014 Meta-analysis Ikeda et al. JAMA 2014 Patients aged 60–85 years ASCVD Events – 10% ↓ •Hypertension Eligible ✓ •Dyslipidemia RR 0.90 (95% CI 0.85, 0.95) •Diabetes mellitus (one or more condition) 1:1 randomization Major Bleeding – 55% ↑ . . . RR 1.55 (1.35, 1.78) . . . . . . .. . NNT to prevent 1 major . . . . . . Enteric-coated No . . ASCVD event over a mean f/u . . . . . . . . . aspirin 100 mg/day . . . aspirin .. . . . .. . . of 6.8 years = 284. . . . . . . . . .. . . . . . .. . .. . . . . . . . . . . . . . . . . .. . . . . .. . . . . NNH to cause 1 major .. . . .. .. . . . . .. Ongoing medications to control . . Xie M et al. PLoS ONE 2014; 9(10): e90286 . . . . bleeding = 299 ... underlying disease(s) . . Followup 6.5 years . . NNT = number needed to treat; NNH = number need to harm JPPP Primary endpoint: ARRIVE: Aspirin in Primary Prevention death from CV causes, nonfatal stroke and nonfatal MI Ikeda et al. JAMA 2014 • Enrolled 12,546 patients followed for mean of 60 months • Adults >55 y/o (men) or >60 y/o (women) with moderate estimated CV risk (10-yr ASCVD risk 17.4%) • However, observed event rates were lower (<10% 10- years ) • – Thus, population should be considered to have low to moderate risk • Excluded patients at high risk of bleeding or diabetes • Randomized enteric-coated aspirin (100 mg) or placebo daily Gaziano JM et al. The Lancet. 2018; 392 3
9/14/2019 ARRIVE: Primary Outcome ARRIVE: Bleeding Intention to Treat Intention to Treat Gaziano JM et al. The Lancet. 2018; 392 Gaziano JM et al. The Lancet. 2018; 392 ARRIVE: Overview of Efficacy ARRIVE: Subgroups (Intention to Treat) Intention to Treat *No difference in fatal events. No reduction in cancer. 16 Gaziano JM et al. The Lancet. 2018; 392 4
9/14/2019 ARRIVE ASPREE: Aspirin in Primary Prevention in Older Adults ( Per protocol, at least 60% compliant) • Adults in Australia (>70 y.o) & U.S. (>65 y.o among Blacks/Hispanics) • 19,114 participants – excluded those with CVD, dementia, disability - followed for mean of 4.7 yrs • Randomized to EC aspirin 100 mg daily vs. placebo • 50% were age ≥ 74 years, 56% women primary end point was a composite of death, dementia, or • persistent physical disability McNeil JJ et al. N Engl J Med 2018;379 Gaziano JM et al. The Lancet. 2018; 392 ASPREE: ASPREE: Death, Dementia, Disability CV outcomes and Bleeding • All Deaths • Cancer Deaths HR 1.14 (1.01-1.29 ) HR 1.14 (1.01-1.29) No benefit on Dementia or Persistent Physical Disability McNeil JJ et al. N Engl J Med 2018;379 5
9/14/2019 Diabetes – a Aspirin for Primary CVD Prevention in Patients with Diabetes prothrombotic disease Low dose ASA for primary prevention ASA and diabetes: 2008 JPAD RCT: among pts with type 2 diabetes: 2008 JPAD RCT Primary end point if 65 years or older Ogawa H et al. JAMA 2008 (300) 18; 2134 ‐ 2141 Ogawa H et al. JAMA 2008 (300) 18; 2134 ‐ 2141 6
9/14/2019 POPADAD: Asymptomatic “PAD” ASCEND: Aspirin in and diabetes: ASA ineffective Primary Prevention in DM •1276 adults age >40 with diabetes • Adults with diabetes, but no CVD and ABI <0.99, but no clinical CVD • 15,480 participants followed for mean of 7.4 yrs •RCT of ASA 100 • Randomized to aspirin 100 mg daily vs. placebo mg/d vs. placebo ±antioxidant in 2 x 2 factorial design • Mean age 63 years, 38% women •Median followup 6.7 yrs • Primary outcome – major vascular event (MI, stroke/TIA, vascular death) POPADAD Belch J et al. BMJ 2008 Bowman L et al. ASCEND Collaborative Group. N Engl J Med 2018;379:1529-39 . ASCEND ASCEND: Primary Outcome Effect of aspirin on major BLEED BENEFIT: Vascular Events Rate Ratio 1.29 (1.09-1.52) • Aspirin group [8.5%] vs. Placebo group [9.6%] HR 0.88 (0.79-0.97) Aspirin Placebo Absolute Type of Event (N=7740) (N=7740) Rate Ratio (95% CI) Difference (%) 12% RRR no. of participants with events (%) Major bleed Intracranial hemorrhage 55 (0.7) 45 (0.6) 0.1 Sight threatening eye bleed 57 (0.7) 64 (0.8) -0.1 Serious gastrointestinal hemorrhage 137 (1.8) 101 (1.3) 0.5 Other major bleed 74 (1.0) 43 (0.6) 0.4 Any major bleed 314 (4.1) 245 (3.2) 1.29 (1.09–1.52) 0.9 P = 0.003 0.5 0.7 1.0 1.0 1.5 2.0 Aspirin Better Placebo Better Bowman L et al. ASCEND Collaborative Group. N Engl J Med 2018;379:1529-39 . Bowman L et al. ASCEND Collaborative Group. N Engl J Med 2018;379:1529-39 . 7
9/14/2019 ASCEND: Aspirin and Mortality: Observed effects per 5000 person Meta-analysis primary prevention 2018 years of aspirin by vascular risk SVE/revasc Bleed SVE/revasc Bleed Less: 6 ± 4 More: 3 ± 3 Less: 11 ± 14 More: 10 ± 8 SVE/revasc Bleed Less: 13 ± 6 More: 9 ± 3 ± = Standard Error The absolute benefits from avoiding serious vascular events were largely 0.97 (0.93-1.01) counterbalanced by the increased risk of bleeding Ridker PM. N Engl J Med 2018; 379(16):1572-1574. Bowman L et al. N Engl J Med 2018;379:1529-39. Upda pdated 2019 re 19 recs cs for aspir for aspirin n in the in the 2019 Meta-Analysis: Aspirin Use for Primary Prevention With Cardiovascular prim primary prev prevention of ASCVD of ASCVD and Bleeding Events Recommendations for Aspirin Use COR LOE Recommendations 1. Low ‐ dose aspirin (75 ‐ 100 mg orally daily) might be considered for the primary prevention of ASCVD IIb A among select adults 40 to 70 years of age who are at higher ASCVD risk but not at increased bleeding risk. 2. Low ‐ dose aspirin (75 ‐ 100 mg orally daily) should not III: be administered on a routine basis for the primary B ‐ R Harm prevention of ASCVD among adults >70 years of age. 3. Low ‐ dose aspirin (75 ‐ 100 mg orally daily) should not CVD prevention: Number Needed to Treat: 265 III: be administered for the primary prevention of ASCVD C ‐ LD Major Bleeding: Number Needed to Harm: 210 Harm among adults of any age who are at increased risk of bleeding. Arnett DK, Blumenthal RS,…. Michos ED …et al. Circulation 2019 Zheng SL et al. JAMA. 2019;321(3):277-287. doi:10.1001/jama.2018.20578 8
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