Erica Crannage, Pharm.D., BCPS, BCACP Clinical Pharmacist/Associate - PowerPoint PPT Presentation

Erica Crannage, Pharm.D., BCPS, BCACP Clinical Pharmacist/Associate Professor Mercy Clinic-Family Medicine/St. Louis College of Pharmacy

1. Recognized the impact of the 2018 primary prevention trials to the body of literature regarding using aspirin (ASA) for primary prevention of cardiovascular disease (CVD) 2. Identify patients that qualify for ASA use for primary prevention of CVD 3. Recognize the changing role of ASA in the setting of secondary prevention of CVD

▪ 1897: first synthesized ▪ Commercialized in 1899 ▪ 1974: first trial showing trend of reduced mortality after acute myocardial infarction (MI) with ASA use ▪ 1985: FDA approves ASA for secondary prevention ▪ Based on meta-analysis data of individually inconclusive trials ▪ 1989: ISIS-2 ▪ First definitively positive secondary prevention trial with ASA Lancet 2019;393:2155-67. .

Circulation 2016;134 (23):1881- 1906.

Circulation 2016;134 (23):1881- 1906.

Aspirin Dose: < 100 mg/day *except BMD and PHS trials 1988 1989 1998 2001 2005 2008 2010 2018 2014 Lancet 2019;393:2155-67. .

1988 1989 1998 2001 2005 2008 2010 2018 2014 Lancet 2019;393:2155-67. .

1988 1989 1998 2001 2005 2008 2010 2018 2014 Lancet 2019;393:2155-67. .

Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) A Study of Cardiovascular Events iN Diabetes (ASCEND) ASpirin in Reducing Events in the Elderly (ASPREE) Lancet 2018;392:1036-46.; N Eng J Med 2018;370:1529-39.; N Eng J Med 2018;379:1509-18.

Randomized Multicenter Double-Blind Enteric-coated Aspirin 100 Placebo mg/day

ARRIVE ASCEND ASPREE Men aged > 55 years with Men and women Caucasians men and 2-4 CV risk factors*; aged > 40 years women aged > 70 Women aged > 60 years with diabetes years; with > 3 CV risk factors* Blacks/Hispanics aged > 65 years Germany, Italy, Ireland, UK Australia, USA Poland, Spain, UK, USA n =12,547 n = 15,480 n = 19,114 *CV risk factors: total cholesterol > 200 mg/dL (men) or > 240 mg/dL (women), LDL > 130 mg/dL (men) or > 160 mg/dL (women), HDL < 40 mg/dL, current smoker, systolic blood pressure > 140 mm Hg or on treatment for hypertension, and a family history of cardiovascular heart disease Lancet 2018;392:1036-46.; N Eng J Med 2018;370:1529-39.; N Eng J Med 2018;379:1509-18.

ARRIVE ASCEND ASPREE Age (years) Mean 64 Mean 63 Median 74 Male (%) 71 63 44 White Race (%) 98 97 95 Smoker (%) 29 8 4 Mean SBP (mm Hg) 145 136 139 PMH Hypertension (%) 65 62 75 PMH Hyperlipidemia (%) 58 - 66 Statin use (%) 43 75 34 Diabetes (%) 0 100 11 (94% T2DM) BMI (kg/m 2 ) 28.4 30.8 30 % had BMI > 30 Lancet 2018;392:1036-46.; N Eng J Med 2018;370:1529-39.; N Eng J Med 2018;379:1509-18.

ARRIVE ASCEND ASPREE Primary First composite CV First composite Death, dementia event CV event or persistent physical disability Key • Individual CV event • Individual CV • First components event composite CV Secondary • Cancer rates components event • Serious adverse • Major • Major effects (including bleeding bleeding bleeding) • GI cancer rates Lancet 2018;392:1036-46.; N Eng J Med 2018;370:1529-39.; N Eng J Med 2018;379:1509-18.

Lancet 2018;392:1036-46.

Lancet 2018;392:1036-46.

Aspirin Placebo (n=6270) (n=6276) Any GI bleed 61 (0.97%) 29 (0.46%) Severe 4 (0.06%) 2 (0.03%) Moderate 15 (0.24%) 5 (0.08%) p=0.0007 Mild 42 (0.67%) 22 (0.35%) Hemorrhagic 8 (0.13%) 11 (0.18%) stroke Lancet 2018;392:1036-46.

N Eng J Med 2018;370:1529-39.

N Eng J Med 2018;370:1529-39.

N Eng J Med 2018;370:1529-39.

N Eng J Med 2018;379:1509-18.

N Eng J Med 2018;379:1509-18.

N Eng J Med 2018;379:1509-18.

ARRIVE ASCEND ASPREE Hazard Ratio Rate Ratio 0.94 Hazard Ratio 0.99 (95% CI 0.85- 1.14 (95% CI 0.80- 1.04) (95% CI 1.01- 1.24; p=0.95) 1.29) Lancet 2018;392:1036-46.; N Eng J Med 2018;370:1529-39.; N Eng J Med 2018;379:1509-18.

▪ Lower event rate overall ▪ Adding to concerns that risk calculators developed with older data might overestimate risk ▪ Impact better overall blood pressure and cholesterol management ▪ Screening, detection and treatment of CV events ▪ Adherence ▪ Some differences between the intent-to-treat vs per protocol results for the ARRIVE trial ▪ Difficulty capturing outside of trial aspirin use ▪ Generalizability ▪ Reflective of current patient population and practice

Number Needed to Harm: 210 Number Needed to Treat: 265 JAMA 2019;321:277-87.

1989 2002 2003 2015 2019 2014 2016 2009 Lancet 2019;393:2155-67. .

Recommendations for Aspirin Use COR LOE Recommendations Low-dose aspirin (75-100 mg orally daily) might be considered for the primary prevention of ASCVD among select adults 40 to 70 IIb A years of age who are at higher ASCVD risk but not at increased bleeding risk Low-dose aspirin (75-100 mg orally daily) should not be III: administered on a routine basis for the primary prevention of B-R Harm ASCVD among adults > 70 years of age Low-dose aspirin (75-100 mg orally daily) should not be III: administered for the primary prevention of ASCV among adult of C-LD Harm any age who are at increased risk of bleeding JACC 2019;74:e177-232. COR = Class of Recommendation; LOE = Level of Evidence

▪ Optimal daily dose of ASA for long-term secondary prevention of CVD is unclear ▪ Evidence suggests that ASA doses between 75-100 mg/day have the same CVD benefit as higher ADA doses (i.e. >182 mg/day) but lower bleeding risk ▪ ASA nonresponse and resistance ▪ Obesity ▪ Diabetes ▪ Enteric-coating ▪ Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) trial ▪ N ~ 20,000 ▪ ASA 81 mg/day vs 325 mg/day for secondary prevention of CVD ▪ Scheduled to be completed at end of 2019 Circulation 2016;134:1881-1906.

▪ ASA has been the backbone of antiplatelet therapy for the past three decades ▪ Recent evidence has began to question if ASA should be the preferred long-term treatment for secondary prevention of CVD ▪ WOEST trial (duel therapy vs triple therapy) ▪ TWILIGHT trial ▪ Role of direct oral acting anticoagulant (DOAC) ▪ COMPASS trial Circulation 2016;134:1881-1906.

N Engl J Med September 26, 2019; published ahead of print.

Ticagrelor Monotherapy Ticagrelor + ASA (n=3555) (n=3564) Age (years) 65 65 Female (%) 24 24 BMI (kg/m 2 ) 28.6 28.5 Prior PCI (%) 29 29 Multivessel disease (%) 64 62 Indication for PCI (%) Asymptomatic 7 6 Stable angina 30 28 Unstable angina 35 35 NSTEMI 29 31 N Engl J Med September 26, 2019; published ahead of print.

▪ Primary Outcome ▪ Bleeding Academic Research Consortium (BARC) type 2,3, or 5 bleeding ▪ BARC types range from 0 (no bleeding) to 5 (fetal bleeding) ▪ Type 4 is excluded from this trial as it perioperative CABG-related bleeding N Engl J Med September 26, 2019; published ahead of print.

▪ Secondary Outcome ▪ Death for any cause, nonfatal MI, or nonfatal stroke ▪ Met pre-defined statistical non-inferiority N Engl J Med September 26, 2019; published ahead of print.

Randomized Multicenter Double-Blind Rivaroxaban + Aspirin Rivaroxaban Aspirin (2.5 mg BID + (5 mg BID) (100 mg/day) 100 mg/day) N Engl J Med 2017; 377:1319-30.

Rivaroxaban + Aspirin Rivaroxaban Alone Aspirin Alone (n = 9152) (n = 9117) (n = 9126) Age (years) 68 68 68 Female (%) 23 22 22 Smokers (%) 22 21 22 Hypertension (%) 76 75 75 Prior MI (%) 62 62 62 On lipid-lowering 90 90 89 medication (%) N Engl J Med 2017; 377:1319-30.

N Engl J Med 2017; 377:1319-30.

▪ Major Bleeding ▪ Rivaroxaban + ASA (n=9152): 228 (3.1%) ▪ Rivaroxaban alone (n=9126): 255 (2.8%) ▪ ASA alone (n=9126): 170 (1.9%) ▪ Rivaroxaban + ASA vs ASA alone: HR 1.70 (95% CI 1.40-2.05), p < 0.001 ▪ Rivaroxaban alone vs ASA alone: HR 1.51 (95% CI 1.25-1.84), p < 0.001 N Engl J Med 2017; 377:1319-30.

▪ Stop using aspirin for primary prevention for the majority of patients ▪ Target discontinuation of ASA in those over the age of 70 years ▪ Select patients with diabetes aged 40-70 years with a increased ASCVD (i.e. > 20% 10-year risk) could potentially benefit from aspirin for primary prevention ▪ A comprehensive approach to primary prevention of CVD is needed ▪ Diet and physical activity modifications ▪ Weight reduction ▪ Smoking cessation ▪ Blood pressure control ▪ Statin use ▪ Aspirin remains the cornerstone of secondary prevention of CVD

Erica Crannage, Pharm.D., BCPS, BCACP Clinical Pharmacist/Associate Professor Mercy Clinic-Family Medicine/St. Louis College of Pharmacy