SESSION 5 2:20 3:35 PM

SESSION 5 2:20 3:35 PM for the Primary Prevention of Cardiovascular Disease: A Personalized Approach SPEAKER Samia Mora MD, MHS Presenter Disclosure Information The following relationships exist related to this presentation: Samia Mora, MD, MHS: No financial relationships to disclose. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Objectives -Guide App www.aspiringuide.com 5. resistance? 7. -Guide app WHO: Impact of Chronic Diseases = "Global Emergency" 68% of all deaths world-wide are from chronic diseases Chronic disease epidemic is rapidly evolving Cardiovascular disease (CVD) Cancer Chronic respiratory diseases Diabetes 3 of 10 deaths are from CVD (heart attack and stroke) 17.5 million lives in 2012 World Health Organization

Causes of Chronic Diseases Atherosclerosis Begins in Childhood Bogalusa Heart Study World Health Organization Berenson GS et al. NEJM 1998;338:1650-6 The early history of aspirin The early history of aspirin Assyrians (Sumerian tablets): anti-inflammatory effects of the willow tree leaves Egyptians (Ebers papyrus): (Onion crushed with honey and taken with a beer) Jack DB, Lancet 1997; 350: 437-39. Jack DB, Lancet 1997; 350: 437-39. The early history of aspirin Assyrians (Sumerian tablets): anti-inflammatory effects of the willow tree leaves Egyptians (Ebers papyrus): : Mechanism of Action Membrane Phospholipids Arachadonic Acid COX-1 Prostaglandin H 2 Hippocrates subsequently recommended the extract of willow bark Jack DB, Lancet 1997; 350: 437-39. Thromboxane A 2 Platelet Aggregation Vasoconstriction Spite, Serhan Circulation 2010; 107:1170-1184 Prostacyclin Platelet Aggregation Vasodilation

: Mechanism of Action Thromboxane A 2 Platelet Aggregation Vasoconstriction Membrane Phospholipids Arachadonic Acid COX-1 Prostaglandin H 2 Prostacyclin Platelet Aggregation Vasodilation Objectives 5. resistance? 7. -Guide app Spite, Serhan Circulation 2010; 107:1170-1184 Evidence: Secondary Prevention of ASCVD Antithrombotic Trialists (ATT) Collaboration Meta-analysis of 16 randomized trials of aspirin (N=17,000 participants, 3306 serious vascular events) 31%, nonfatal MI 20%, major CHD events 19%, total stroke 19%, any serious vascular event (Results similar in men and women) Evidence: Dose and Efficacy Indirect comparisons of aspirin doses on vascular events in high-risk patients Dose No. of Trials (%) 500-1500 mg 34 19 160-325 mg 19 26 75-150 mg 12 32 <75 mg 3 13 Any aspirin 65 23 Odds Ratio for Vascular Events 0 0.5 1.0 1.5 2.0 Antiplatelet Better Antiplatelet Worse Antithrombotic Trialist Collaboration. Lancet 2009;373:1849 Antithrombotic Trialist Collaboration. BMJ 2002;324:71-86 Objectives 5. resistance? 7. -Guide app Evidence: Primary Prevention The role of aspirin in primary prevention is not clear, both for patients with or without diabetes The assessment of the benefits of aspirin in primary prevention is more complicated absolute risks of vascular events are lower than in secondary prevention complication rates (bleeding) are comparable nonsignificant reductions in vascular mortality Mora, Manson. JAMA Internal Med 2016; 176

Evidence: Primary Prevention Antithrombotic Trialists (ATT) Collaboration Meta-analysis of 95,456 low risk patients randomized to aspirin (100 mg every other day to 500 mg daily) vs. placebo for 4 to 10 years Number of Events ( vs. Control) Rate ratio (95% CI) ( vs. Control) Major coronary event 934 vs. 1115 0.82 (0.75-0.90) Non-fatal MI 596 vs. 756 0.77 (0.69-0.86) CHD mortality 372 vs. 393 0.95 (0.82-1.10) Stroke 655 vs 682 0.95 (0.85-1.06) Hemorrhagic 116 vs. 89 1.32 (1.00-1.75) Ischemic 317 vs. 367 0.86 (0.74-1.00) Unknown cause 222 vs. 226 0.97 (0.80-1.18) Vascular death 619 vs. 637 0.97 (0.87-1.09) Any serious vascular event 1671 vs. 1883 0.88 (0.82 vs 0.94) Major extracranial bleed 335 vs. 219 1.54 (1.30-1.82) reduces the risk of ischemic events, but with a higher rate of bleeding Lancet 2009;373:1849-60 Evidence: Primary Prevention among Diabetics Subgroup analyses show no differences in CVD effects of aspirin by diabetes status both in primary or secondary prevention Three trials only enrolled patients with diabetes Early Treatment Diabetic Retinopathy Study (T1D, T2D) POPADAD JPAD All three studies underpowered Evidence: Primary Prevention among Diabetics 3,711 asymptomatic patients with DM (30% T1D) to aspirin (650 mg/d) or placebo Early Treatment Diabetic Retinopathy Study (ETDRS) JPAD and POPADAD: No significant reduction in MI or stroke in diabetics Japanese Primary Prevention of Atherosclerosis with for Diabetes (JPAD) 1 The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) 2 Study Design Study Population Randomized, open-label controlled 2539 Japanese patients with well-controlled DM Randomized, double blind, placebo controlled 1276 Scottish patients with type 1 or 2 DM, asymptomatic PAD Total mortality 0.91 (95% CI 0.75-1.11) Fatal or nonfatal MI 0.83 (95% CI 0.66-1.04) ETDRS Investigators JAMA 1992; 268:1292 Dose 81 or 100 mg / d 100 mg / d Median Follow up 4.4 years 6.7 years 1 Ogawa H, Nakayama M, Morimoto T, et al. JAMA. 2008;200(18):2134 2141. 2 Belch J, MacCuish A, Campbell I. et al. BMJ 2008. 337:a1840. JPAD and POPADAD: No significant reduction in MI or stroke in diabetics ASA n=1262 JPAD Control n=1277 P ASA n=638 POPADAD Control n=638 P Evidence: Primary Prevention Among Diabetics Antithrombotic Trialists (ATT) Collaboration Similar results by diabetes status No. vascular events (% per yr) Composite End Point 68 86 0.16 116 117 0.86 Non-fatal MI 12 9 0.5 55 56 0.93 Non-fatal stroke 22 24 0.8 29 41 0.15 Control CVD mortality 1 10 0.0037 43 35 0.36 JPAD subgroup older than 65 years had 32% reduction in primary endpoint Ogawa et al. JAMA. 2008;200(18):2134 2141. Belch J et al. BMJ 2008. 337:a1840. Lancet 2009;373:1849

Evidence: Primary Prevention Bleeding risks with aspirin Non-fatal MI Stroke Vascular Mortality Effect of antiplatelet treatment on vascular events Major GI and extracranial bleeds Serious Vascular Events Antithrombotic Trialist Collaboration. Lancet 2009;373:1849 Rate Ratios for Vascular Events P=0.0001 0 0.5 1.0 1.5 2.0 Antiplatelet Better Antiplatelet Worse Risk factors for bleeding Age Male sex GI hospitalization Excess alcohol use Current smoking Hypertension Diabetes Liver / renal disease Concomitant meds (NSAIDs, anticoagulants) Whitlock E et al. 2015 www.uspreventiveservicestaskforce.org GI: Gastrointestinal Risk factors for bleeding Age Male sex GI hospitalization Excess alcohol use Current smoking Hypertension Diabetes Liver / renal disease Concomitant meds (NSAIDs, anticoagulants) Bleeding risks with aspirin Whitlock E et al. 2015 www.uspreventiveservicestaskforce.org Proton Pump Inhibitors (PPIs) may decrease risk of GI bleeding on aspirin Tran-Duy A. et al. 2015 Int J Clin Pract doi:10.1111/ijcp.12634 GI: Gastrointestinal PRECISION Trial: Bleeding and CVD risks with other NSAIDS? APTC outcome: CVD death, MI, stroke CAVEATS: - 68% of patients stopped the study drug - 27% discontinued f-u - Esomeprazole given to all patients Nissen et al. NEJM 2016;ePub ahead of print Nov 13 2016 100 mg po bid 600 mg po tid 375 mg po bid 2.7% Ibuprofen 2.5% Naproxen 2.3% Celecoxib PRECISION Trial: Bleeding and CVD risks with other NSAIDS? Outcome Composite serious GI event Clinically significant event Iron-deficiency anemia (GI) Celexocib (%) Serious GI Events Naproxen (%) Ibuprofen (%) C vs N Relative Risk 1.1 1.5 1.6 0.71 (0.54-0.93) 0.7 0.7 0.9 0.97 (0.67-1.40) 0.4 0.9 0.8 0.47 (0.31-0.71) C vs I Relative Risk 0.65 (0.50-0.85) 0.76 (0.53-1.08) 0.51 (0.33-0.77) No significant interactions with baseline aspirin use PRECISION Trial: Bleeding and CVD risks with other NSAIDS? Outcome Composite serious GI event Clinically significant event Iron-deficiency anemia (GI) Celexocib (%) Serious GI Events Naproxen (%) Ibuprofen (%) C vs N Relative Risk 1.1 1.5 1.6 0.71 (0.54-0.93) 0.7 0.7 0.9 0.97 (0.67-1.40) 0.4 0.9 0.8 0.47 (0.31-0.71) All-cause death 1.6 2.0 1.8 0.8 (0.63-1.00) P=0.052 C vs I Relative Risk 0.65 (0.50-0.85) 0.76 (0.53-1.08) 0.51 (0.33-0.77) 0.92 (0.73-1.17) P=0.49 No significant interactions with baseline aspirin use Nissen et al. NEJM 2016;ePub ahead of print Nov 13 2016 Nissen et al. NEJM 2016;ePub ahead of print Nov 13 2016

Evidence: Primary Prevention 2016 U.S. Preventive Task Force Services updated metaanalysis Outcome No. trials No. individuals Summary Relative Risk Nonfatal MI 10 114,734 0.78 (0.71-0.87) Nonfatal stroke 10 99,655 0.95 (0.85-1.06) CVD mortality 11 118,445 0.94 (0.86-1.03) Total mortality 11 118,445 0.94(0.89-0.99) Evidence: Primary Prevention 2016 U.S. Preventive Task Force Services updated metaanalysis Outcome No. trials No. individuals Summary Relative Risk Nonfatal MI 10 114,734 0.78 (0.71-0.87) 8 ( 100 mg) 87,524 0.83 (0.74-0.94) Nonfatal stroke 10 99,655 0.95 (0.85-1.06) 7 ( 100 mg) 68,734 0.86 (0.76-0.98) CVD mortality 11 118,445 0.94 (0.86-1.03) 8 ( 100 mg) 87,524 0.97 (0.85-1.10) Total mortality 11 118,445 0.94(0.89-0.99) 8 ( 100 mg) 87,524 0.95 (0.89-1.01) Guiruis-Blake JM et al. 2015 www.uspreventiveservicestaskforce.org Guiruis-Blake JM et al. 2015 www.uspreventiveservicestaskforce.org Longterm low-dose aspirin reduces cancer incidence and metastasis, in particular for gastrointestinal cancers (colorectal) Cancer incidence Cancer metastasis HR 0.88 (0.80-0.98), P=0.017 HR 0.81 (0.70-0.93), P=0.003 HR 0.88 (0.80-0.98), P=0.017 HR 0.81 (0.70-0.93), P=0.003 Years to Notification Years to Notification Years to Notification Years to Notification Rothwell PM. et al. 2012 Lancet 13:518 Rothwell PM. et al. 2012 Lancet 13:518 Wait it s not just about CVD prevention? and Cancer Prevention: Thrombosis Prevention Trial vs. aspirin vs. warfarin HR 0.78 (0.63-0.98), P=0.03 Warfarin HR 0.98 (0.78-1.22), P=0.83 Years to Notification Years to Notification Rothwell PM et al. Lancet. 2012;379:1602 1612.

Objectives in Primary Prevention: Sex differences? 5. resistance? 7. -Guide app Mora, Manson. JAMA Internal Med 2016; 176 Antithrombotic Trialist Collaboration. Lancet 2009;373:1849 Evidence: Primary Prevention in Men Physicians Health Study (PHS) 22,071 men randomized to aspirin (325 mg every other day) followed for an average of 5 years Evidence: Primary Prevention in Women The Women s Health Study 39,876 Initially healthy women Age 45 years and older (mean age 54.6) (100 mg po on alternate days) 19,934 on 19,942 on Mean Follow-Up Period of 10 years reduces the risk of MI among men in the PHS CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction, NS=Nonsignificant Physicians Health Study Research Group. NEJM 1989;321:129-35 Ridker P et al. N Engl J Med. 2005;352:1293-1304. for Primary Prevention in Women? Women s Health Study: Major Cardiovascular Events (Nonfatal Myocardial Infarction, Nonfatal Stroke, Cardiovascular Death) 39,876 women randomized to aspirin (100 mg every other day) or placebo for 10 years Cumulative Event Rate 0.00 0.01 0.02 0.03 RR = 0.91 95% CI 0.80 1.03 P = 0.13 9 percent Cumulative Event Rate Cumulative Event Rate 0.00 0.01 0.02 0.00 0.01 0.02 Women s Health Study Stroke and Myocardial Infarction Total Stroke RR = 0.83 (0.69-0.99) P = 0.04 0 2 4 6 8 10 Years of Follow-Up Ischemic Stroke RR = 0.76 (0.63-0.93) P = 0.009 Cumulative Event Rate Cumulative Event Rate 0.00 0.01 0.02 0.00 0.01 0.02 Myocardial Infarction RR = 1.02 (0.84-1.25) P = 0.83 0 2 4 6 8 10 Years of Follow-Up Hemorrhagic Stroke RR = 1.24 (0.82-1.87) P = 0.31 0 2 4 6 8 10 Ridker P et al. N Engl J Med. 2005;352:1293-1304. Years of Follow-Up 0 2 4 6 8 10 Years of Follow-Up 0 2 4 6 8 10 Years of Follow-Up

The Women s Health Study: Subgroup Analyses, Primary Endpoint of Major CV Event* RR 95%CI P (N=19,934) (N=19,942) Diabetes Yes 58 62 0.90 0.63-1.29 0.57 No 418 460 0.90 0.79-1.03 0.13 Age (years) 45 54 (24,025) 163 161 1.01 0.81-1.26 0.92 55 64 (11,754) 183 186 0.98 0.80-1.20 0.84 >65 (4,097) 131 175 0.74 0.59-0.92 0.008 *P for interaction by age = 0.05 for total CVD and 0.03 for MI Women s Health Study: Subgroup Analyses, Age >65 years Endpoint RR (95%CI) P Major CV Event 131 175 0.74 (0.59 0.92) 0.008 Total MI 41 62 0.66 (0.44 0.97) 0.04 Total Stroke 68 86 0.78 (0.57 1.08) 0.13 44 Fewer Major CV Events 16 Additional GI Hemorrhages Requiring Transfusion Major CV Event = nonfatal MI, nonfatal stroke, cardiovascular death Major CV Event* = Nonfatal MI, nonfatal stroke, cardiovascular death Ridker P et al. N Engl J Med. 2005;352:1293-1304. Objectives 5. resistance? 7. -Guide app Resistance? resistance (increased platelet aggregation) appears higher among diabetics Larsen et al., PLoS One 2015; 10(5):e0126767 In healthy volunteers, 325 mg immediate-release aspirin had no aspirin resistance, vs substantial aspirin resistance after enteric-coated aspirin (49% at 4 hours,17% at 8 hours) Grosser et al., Circulation 2013; 127:377-385. Objectives 1. mechanism of action 5. resistance? 7. -Guide app 2016 U.S. Preventive Services Task Force Recommendations for low dose aspirin Population Recommendation Grade Adults age 50-59 yrs For primary prevention of ASCVD and colorectal cancer if: - 10% ASCVD risk * - Not at increased risk of bleeding - Life expectancy of at least 10 yrs - Willing to take aspirin for at least 10 yrs B (Moderate) Adults age 60-69 yrs Individualize the decision if: - 10% ASCVD risk, - Not at increased risk of bleeding - Life expectancy of at least 10 yrs - Willing to take aspirin for at least 10 yrs Adults < 50 yrs Insufficient evidence I Adults 70 yrs Insufficient evidence I C *Pooled Cohort Equations available at http://my.americanheart.org/cvriskcalculator Guiruis-Blake JM et al. 2015 www.uspreventiveservicestaskforce.org

2016 ADA Recommendations for Patients with Diabetes 75 to 162 mg/day for primary ASCVD prevention in diabetic patients at increased ASCVD risk and not increased risk of bleeding Those at risk for ASCVD (10-year risk >10%) men >50 yrs, women >50 yrs, with >1 additional risk factor Family history of premature ASCVD HTN Smoking Dyslipidemia Albuminuria Not recommended for primary prevention in low risk groups (10-year risk <5%) Objectives 5. resistance? 7. -Guide app Clinical judgement for intermediate risk (5 to 10%) or <50 yrs and risk factors ADA Diabetes Care 2016;39:S1-S106 -Guide: A personalized approach and mobile app for shared decision making -Guide www.aspiringuide.com www. aspiringuide.com Mora, Ames, Manson, JAMA 2016; 316:709 Mora, Manson, JAMA Internal Med 2016; 176:1195 JAMA 2016; 316:709 JAMA Internal Med 2016; 176 -Guide: Practical Algorithm for Shared Decision Making -Guide: Practical Algorithm for Shared Decision Making Mora et al, JAMA 2016; 316:709 Mora et al, JAMA 2016; 316:709

-Guide: Practical Algorithm for Shared Decision Making Case 1: Tom 57 year old white man comes to see you in the clinic. He has no prior history of atherosclerotic cardiovascular disease (ASCVD), no major contraindications to aspirin, no prior gastrointestinal (GI) bleeding, no history of upper GI tract ulcer or other GI symptoms, no atrial fibrillation. He has never smoked cigarettes, but he has diet-controlled type 2 diabetes mellitus. He has hypertension and takes medications for his high blood pressure, which is now finally well-controlled on medications (BP 120/75 mm Hg on medications in his last clinic visit). He also has high cholesterol (on a statin medication his total cholesterol was 155 mg/dl, HDL cholesterol 40 mg/dl, LDL cholesterol 80 mg/dl, triglycerides 175 mg/dl). He does not take any other medications other than for his high blood pressure and cholesterol. Case 1 Questions: a.what is his calculated ASCVD risk score? b. What is his bleeding risk score? c. What is his Number Needed to Treat (NNT)? d. What is his Number Needed to Harm (NNH)? e. Would you recommend low-dose aspirin to Tom? Why or why not? Case 1 Questions: a.what is his calculated ASCVD risk score? 12% b. What is his bleeding risk score? 1.2% without asa, 1.9% with asa c. What is his Number Needed to Treat (NNT)? d. What is his Number Needed to Harm (NNH)? e. Would you recommend low-dose aspirin to Tom? Why or why not? Case 1 Questions: a.what is his calculated ASCVD risk score? 12% b. What is his bleeding risk score? 1.2% without asa, 1.9% with asa c. What is his Number Needed to Treat (NNT)? 56 d. What is his Number Needed to Harm (NNH)? 144 e. Would you recommend low-dose aspirin to Tom? Why or why not? asa estimated to reduce his ASCVD risk from 12% to 10% Case 2: Mary 68 year old black woman who is nondiabetic and nonsmoker. She has history of hypertension and takes medications for her high blood pressure (BP 155/82 mm Hg on medications). She also has high cholesterol (on a statin medication her total cholesterol recently was 164 mg/dl, HDL cholesterol 60 mg/dl, LDL cholesterol 70 mg/dl, triglycerides 170 mg/dl). She does not take any other medications other than for her high blood pressure and cholesterol. She does not have atrial fibrillation. When you talk to her more, you find out that she has a history of peptic ulcer disease (stomach ulcer) but has not had any recent bleeding, no prior serious GI bleeding, and no prior perforation of her ulcer. She currently denies any pain.

Case 2 Questions: a.what is her calculated ASCVD risk score? b. What is her bleeding risk score? c. What is her Number Needed to Treat (NNT)? d. What is her Number Needed to Harm (NNH)? e. Does Mary have any risk factors for GI bleeding? Case 2 Questions: a.what is her calculated ASCVD risk score? 13.2% b. What is her bleeding risk score? 7.8% without asa, 12% on asa c. What is her Number Needed to Treat (NNT)? 50 d. What is her Number Needed to Harm (NNH)? 23 e. Does Mary have any risk factors for GI bleeding? age>60 Prior peptic ulcer disease (hypertension) Case 2 Questions: f. Would you recommend low-dose aspirin to Mary? Why or why not? g. What if Mary had NO prior history of peptic ulcer disease. What would her NNT be? What would her NNH be? Would you recommend aspirin to her? Case 2 Questions: f. Would you recommend low-dose aspirin to Mary? Why or why not? g. What if Mary had NO prior history of peptic ulcer disease. What would her NNT be? What would her NNH be? Would you recommend aspirin to her? NNT 50, NNH 133 if no peptic ulcer disease adequate BP control before starting asa Women s Health Study: Subgroup Analyses, Age >65 years Ongoing aspirin trials Endpoint RR (95%CI) P Major CV Event 131 175 0.74 (0.59 0.92) 0.008 Total MI 41 62 0.66 (0.44 0.97) 0.04 Total Stroke 68 86 0.78 (0.57 1.08) 0.13 Major CV Event = nonfatal MI, nonfatal stroke, cardiovascular death Ridker P et al. N Engl J Med. 2005;352:1293-1304. Depta, Bhatt CCJM 2015;82:91-96

Topics Discussed 5. resistance? 7. -Guide app