ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events): A Study to Assess the Efficacy and Safety of Aspirin in Patients at Moderate Risk of Cardiovascular Disease J. Michael Gaziano, M.D., M.P.H. For the ARRIVE Executive Committee European Society of Cardiology August 26 th 2018 ARRIVE Executive Committee: JM. Gaziano, C. Brotons, R. Coppolecchia, C. Cricelli, H. Darius, PB. Gorelick, G. Howard, TA. Pearson, PM. Rothwell, LM. Ruilope, M. Tendera, G. Tognoni. 1
Declaration of Interest • Consulting/Royalties/Owner/Stockholder of a healthcare company (Consulting – Bayer) • All voting members of the ARRIVE Executive Committee (EC) received personal fees from Bayer during the conduct of the study. • R. Coppolecchia is an employee of Bayer Healthcare. • The following EC members report additional relationships: – PMR: personal fees from Bristol-Meyers Squibb – LMR: personal fees from Novartis, Sanofi, Medtronic, Daiichi-Sanyo and grants from Astra-Zeneca – MT: personal fees from Celyad, Janssen Cilag, Kowa, Perfuse Group, Servier • Role of the sponsor and executive committee are provided in detail in the paper in the Lancet.
ARRIVE Study Design • Design: Randomized, double-blind, placebo-controlled, multicenter trial to assess the efficacy and safety of aspirin among those at moderate estimated risk of a cardiovascular event. • Setting: Primary care offices in 7 countries: Germany, Poland, UK, Italy, Spain, Ireland, US • Study Population: Subjects had no known history of CVD or diabetes and were considered at moderate risk (estimated 10-year risk of major CHD events of 10-20% corresponding to a 10-year CVD risk of 20-30%) Men ≥55 years with 2 or more CV risk factors Women ≥60 years with 3 or more CV risk factors • Intervention: 100 mg enteric-coated aspirin daily versus placebo 3
ARRIVE Study Design • Primary Efficacy Endpoint: Time of first occurrence of composite endpoint: cardiovascular disease (CVD) death, myocardial infarction (MI), stroke, unstable angina (UA), transient ischemic attack (TIA) • Secondary Efficacy Endpoints: Composite of CVD death, Ml or stroke; all-cause death; and incidence of each of components of the primary endpoint • Safety Endpoints: Bleeding events and incidence of adverse events • Protocol amendments driven by lower than expected event rates: • Moved from event driven (1488 events) to common study end date (11/15/16) • Extended treatment and follow-up to 72 months to acquire 60,000 person-years • Addition of TIA and UA to primary composite endpoint 4
5 ARRIVE Study Design Year 0 1 2 3 4 5 6 12,546 N = 6276 subjects at moderate Aspirin 100 mg estimated risk of CVD N = 6270 Visit 1 Visit 2 Visit 4 Visit 8 Randomization Visit 3 Visit 5 Visit 6 Visit 7 Visit 9 Placebo Screening First subject July 5, 2007 / ~ 60,000 patient years LPLV November 15, 2016 1:1 R
Demographics (Intent-to-Treat Population) Placebo Arm (n= 6276) Aspirin Arm (n= 6270) Age at Randomization (year) Mean 63.9 63.9 SD 7.05 7.10 Median 63.0 63.0 Min – Max 50 - 97 50 - 91 Categorical Distribution of Age at Randomization, % <= 59 years old 25.75% 25.89% 60 to 69 years old 52.36% 52.70% >= 70 years old 21.89% 21.42% Gender, % Female 29.59% 29.52% Male 70.41% 70.48% Note: Percentages based on number of subjects randomized to the indicated treatment group 6
Demographics (Intent-to-Treat Population) Placebo Arm (n= 6276) Aspirin Arm (n= 6270) Weight at Randomization (kg) Median 82.0 82.0 Min – Max 43-177 35-163 BMI Mean 28.5 28.3 SD 4.3 4.3 White, % 97.9 97.8 Current antihypertensive medication, % 65.3 64.4 Elevated total cholesterol, % 58.3 58.2 Mean Framingham 10-year CHD risk score 14.1% 13.9% Mean ACC/AHA 10-year ASCVD risk score 17.4% 17.3% Note: Percentages based on number of subjects randomized to the indicated treatment group Observed ASCVD event rate normalized to 10 years 8.43% 8.80% 7
Primary Efficacy Endpoint: CVD Death, MI, UA, Stroke or TIA Time to First Occurrence of CV Death, MI, UA, Stroke or TIA (Intent-to-Treat population) HR (95% CI)* 0.96 (0.81;1.13) p-Value* 0.6038 *Comparison: Aspirin vs Placebo 8
Overview Efficacy Endpoints (Intent-to-Treat Population) Event Treatment Assignment Number of Events (%) † Hazard Ratio (95% CI) ‡ p-Value ¥ Aspirin 269 (4.29%) 0.96 MI, Stroke, CV Death, UA, or TIA 0.6038 (0.81;1.13) Placebo 281 (4.48%) Aspirin 208 (3.32%) 0.95 MI, Stroke or CV Death 0.6190 (0.79;1.15) Placebo 218 (3.47%) Aspirin 95 (1.52%) 0.85 Myocardial Infarction a 0.2325 Placebo 112 (1.78%) (0.64;1.11) Aspirin 88 (1.40%) 0.90 Non-Fatal Myocardial Infarction 0.4562 Placebo 98 (1.56%) (0.67;1.20) Aspirin 75 (1.20%) 1.12 Stroke b 0.5072 Placebo 67 (1.07%) (0.80;1.55) Aspirin 38 (0.61%) 0.97 CV Death 0.9010 (0.62;1.52) Placebo 39 (0.62%) Aspirin 20 (0.32%) 1.00 Unstable Angina 0.9979 (0.54;1.86) Placebo 20 (0.32%) Aspirin 42 (0.67%) 0.93 Transient Ischemic Attack 0.7455 (0.61;1.42) Placebo 45 (0.72%) Aspirin 160 (2.55%) 0.99 Any Death 0.9459 (0.80;1.24) Placebo 161 (2.57%) Aspirin 252 (4.02%) 1.07 Cancer Events c 0.4750 Placebo 236 (3.76%) (0.89;1.27) † Percentages based on number of subjects randomized to the indicated treatment group; ‡ Comparison: Aspirin vs Placebo; ¥ ( Log-Rank Test a Fatal or non-fatal myocardial infarction; b Fatal or non-fatal Stroke; c All cancers excluding non-melanoma skin cancer 9
Time to first occurrence of CV Death, MI, UA, Stroke, or TIA by Subgroups (Intent-to-Treat Population) 10
Cumulative Incidence Curve for Time to Fatal or Non-Fatal MI (Intent-to-Treat Population) Time to first occurrence of Fatal or Non-Fatal MI (Intent-to-Treat population) HR (95% CI)* 0.85 (0.64;11) p-Value* 0.2325 *Comparison: Aspirin vs Placebo 11
Cumulative Incidence Curve for Time to Fatal or Non-Fatal MI (Per-Protocol Population a ) Time to First Occurrence of Fatal or Non-Fatal MI (Per-Protocol Population) HR (95% CI)* 0-53 (0-36;0-79) p-Value* 0·0014 *Comparison: Aspirin vs Placebo a Per protocol: Correct number of risk factors at study entry, no concomitant anticoagulant therapy, and ≥60% compliant 12
Primary Efficacy Endpoints By Age Group (Intent-to-Treat and Per Protocol Populations) Intent-to-Treat Population Per Protocol Population Placebo Aspirin Hazard Hazard Age Placebo Aspirin Event Event Ratio* RRR † Ratio* RRR † Event Rate Event Rate Group Rate Rate (95% CI) (95% CI) 0.76 0.54 50-59 3.53% 2.71% 23.2% 3.32% 1.81% 45.5% (0.51, 1.13) (0.31,0.96) 0.95 0.85 60-69 4.02% 3.84% 4.5% 3.52% 3.00% 14.8% (0.60, 1.19) (0.60,1.19) 1.11 0.92 >=70 6.70% 7.30% 6.99% 6.44% 7.9% (0.83, 1.47) (0.63,1.34) Overall 0.96 0.81 4.48% 4.29% 4.2% 4.19% 3.40% 18.9% results (0.81, 1.13) (0.64,1.02) * Comparison: Aspirin vs Placebo † RRR: Relative Risk Reduction 13
Gastrointestinal Bleeding (Intent-to-Treat Population) Gastrointestinal Bleeding Adjudication Placebo Arm (n=6276) Aspirin Arm (n=6270) Time to First GI Bleeding Patients with events, n (%) 29 (0.46%) 61 (0.97%) 2.11 Hazard Ratio (95% CI)* [1.36;3.28] p-Value* 0.0007 Severity of adjudicated first GI Bleeding Mild, n (%) 22 (0.35%) 42 (0.67%) Moderate, n (%) 5 (0.08%) 15 (0.24%) Severe, n (%) 2 (0.03%) 4 (0.06%) *Comparison: Aspirin vs Placebo; p-Value from log-rank test of time to first event Note: Percentages based on number of subjects randomized to the indicated treatment group 14
Overview of Treatment Emergent Adverse Events (Intent-to-Treat Population) Event Placebo Arm (n=6276) Aspirin Arm (n=6270) Subjects with Adverse Events Any AEs 5129 (81.72%) 5142 (82.01%) Serious AEs 1311 (20.89%) 1266 (20.19%) Severe AEs 759 (12.09%) 724 (11.55%) AEs leading to death 78 ( 1.24%) 81 ( 1.29%) AEs leading to permanent discontinuation of 1238 (19.73%) 1277 (20.37%) study drug Subjects with Adverse Events Related to Treatment Any AEs 850 (13.54%) 1050 (16.75%) Serious AEs 49 ( 0.78%) 76 ( 1.21%) Severe AEs 30 ( 0.48%) 55 ( 0.88%) AEs leading to death 1 ( 0.02%) 4 ( 0.06%) AEs leading to permanent discontinuation of 325 ( 5.18%) 441 ( 7.03%) study drug Note: Percentages based on number of subjects randomized to the indicated treatment group 15
ARRIVE: Selected Endpoints (ITT Population) Compared to Other Primary Prevention Trials* 0.89 (0.82 – 0.97) Major CV Events PP trials 0.96 (0.81 – 1.13) ARRIVE CV Mortality 0.95 (0.84 – 1.07) PP trials 0.97 (0.62 – 1.52) ARRIVE MI 0.78 (0.65 – 0.94) PP trials 0.85 (0.64 – 1.11) ARRIVE Non fatal MI 0.80 (0.64 – 0.99) PP trials 0.90 (0.67 – 1.20) ARRIVE All-cause Stroke 0.94 (0.84 – 1.06) PP trials 1.12 (0.80 – 1.55) ARRIVE Hemorrhagic Stroke 1.43 (1.10 – 1.86) PP trials 0.73 (0.29 – 1.81) ARRIVE All-cause Mortality 0.94 (0.89 – 1.00) PP trials 0.99 (0.80 – 1.24) ARRIVE 4 Favors Intervention Favors Control *Raju et al. Updated Meta-Analysis of Aspirin in Primary Prevention of Cardiovascular Disease. Am J Med. 2016 May;129(5):e35-6. Trials: PHS, BDT, HOT, TPT, PPP, WHS, JPAD, POPADAD, AAA, JPPP
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