DECLARATION OF CONFLICT OF INTEREST

DECLARATION OF CONFLICT OF INTEREST

Is there a mortality risk associated with aspirin use in heart failure? Results from a large community based cohort Margaret Bermingham, Mary-Kate Shanahan, Saki Miwa, Ian Dawkins, Rory O Hanlon, Ken McDonald, Mark Ledwidge Heart Failure Unit, St Vincent s University Hospital, Dublin and School of Medicine and Medical Science, University College Dublin, Ireland

Background Aspirin use in heart failure is controversial Possible attenuation of ACE inhibitor benefits Dose Relationship between aspirin dose and adverse pharmacological effect (Juhlin et al, Eur J Heart Fail 2008;10:892-8) Adverse renal effects of aspirin evident from doses > 80mg NSAID Prospective clinical trials

Background WASH (Cleland et al, Am Heart J 2004;148:157 64) Prospective study Aspirin 300mg/d vs. Warfarin (INR 2.5) vs. no anti-thrombotic 279 patients with HF+LVSD over 27 months Pilot study, terminated early Trend to worse outcomes for aspirin patients especially for CV and HF hospitalisation

Background WATCH (Massie et al, Circulation 2009;119;1616-1624) Prospective study Aspirin 162mg/d vs. Clopidogrel 75mg/d vs. Warfarin (INR 2.5 3.0) 1587 patients with HF and EF 35% No difference in mortality between groups Aspirin patients more likely than warfarin to be hospitalized (22.2% vs. 16.5%, P = 0.02)

Background New Studies Optimize HF (Levy et al, Am Heart J 2010;159:222-30) Aspirin in ischaemic and non-ischaemic patients did not attenuate benefits of ACE inhibitor/arb in recently hospitalized HF and there was a trend (NS) towards mortality benefit with aspirin CHARM (Chang et al, Eur J Heart Fail 2010; 12:738 745) Aspirin use has no significant effect on outcomes in Candesartan or placebo groups in CHARM overall or sub-studies.

Methods Retrospective, cohort study Patients attend Heart Failure Disease Management Programme Chart review to confirm: Aspirin use at baseline Aspirin dose Duration of use Indication Primary endpoint: association with mortality of aspirin use vs. no aspirin use over long-term followup Unadjusted and adjusted Cox-proportional hazards modeling with Kaplan-Meier survival curves.

Results 1476 patients Mean follow-up 3 years Aspirin at baseline in 883 (60%) patients Average aspirin dose = 89mg (±52mg) Aspirin 75mg/d for 819 (92.8%) Aspirin prescribed for 100% follow-up in 687 (77.8%)

Results Demographics Characteristic Total population Aspirin No aspirin P-value (n = 1476) (n = 883) (n = 593) Age (years ) 70.4 ± 12.4 71.9 ± 11.2 68.2 ± 13.7 <0.001 Male 930 (63.0%) 566 (64.1%) 364 (61.4%) 0.289 Heart rate 75.8 ± 16.0 74.0 ± 15.8 76.7 ± 16.1 0.001 Systolic BP 128.8 ± 22.2 126.2 ± 22.9 125.6 ± 21.1 0.639 Diastolic BP 71.5 ± 13.5 71.6 ± 13.6 72.5 ± 13.3 0.224 BNP (n = 1363) 356 (164:693) 384 (187:734) 310 (140:635) 0.006 EF% (n = 1271) 40.2 ± 14.5 40.2 ± 14.2 40.7 ± 15.1 0.534 EF<45% (n = 1428) 926 (64.8%) 570 (66.4%) 356 (62.5%) 0.123 Abbreviations: BNP, b-type natriuretic peptide; EF%, ejection fraction; EF<45%, ejection fraction <45%. P-value is for comparison of aspirin vs. no aspirin

Results Co-morbidities Characteristic Total population Aspirin No aspirin P-value (n = 1476) (n = 883) (n = 593) Angina 269 (18.2%) 196 (22.2%) 73 (12.3%) <0.001 CAD 181 (12.3%) 141 (16.0%) 40 (6.7%) <0.001 MI 475 (32.2%) 367 (41.6%) 108 (18.2%) <0.001 Any IHD 665 (45.1%) 502 (56.8%) 163 (27.5%) <0.001 Hypertension 624 (42.3%) 399 (45.2%) 225 (37.9%) 0.006 Arrhythmia 552 (37.4%) 298 (33.7%) 254 (42.8%) <0.001 Asthma/COPD 236 (16.0%) 142 (16.1%) 94 (15.9%) 0.906 Dyslipidaemia 424 (28.7%) 295 (33.4%) 129 (21.8%) <0.001 Diabetes 318 (21.5%) 210 (23.8%) 108 (18.2%) 0.011 Abbreviations: CAD, coronary artery disease; MI, myocardial infarction; IHD, ischaemic heart disease; COPD, chronic obstructive pulmonary disease. P-value is for comparison of aspirin vs. no aspirin.

Results Medications Characteristic Total population (n = 1476) Aspirin (n = 883) No aspirin (n = 593) P-value Loop diuretic 1258 (85.2%) 755 (85.5%) 503 (84.8%) 0.718 ACE inhibitor 1128 (76.4%) 690 (78.1%) 438 (73.9%) 0.057 ARB 190 (12.9%) 105 (11.9%) 85 (14.3%) 0.170 Beta-blocker 979 (66.3%) 614 (69.5%) 365 (61.6%) <0.001 Cardiac glycoside 460 (31.2%) 212 (24.0%) 248 (41.8%) <0.001 Aldosterone antagonist 190 (12.9%) 103 (11.7%) 87 (14.7%) 0.091 Nitrate 561 (38.0%) 388 (43.9%) 173 (29.2%) <0.001 Calcium channel blocker 161 (10.9%) 108 (12.2%) 53 (8.9%) 0.050 Cholesterol lowering drug 202 (13.7%) 145 (16.4%) 57 (9.6%) <0.001 Warfarin 518 (35.1%) 172 (19.5%) 346 (58.3%) <0.001 Clopidogrel 206 (14.0%) 164 (18.6%) 42 (7.1%) <0.001 PPI 472 (32.0%) 286 (32.4%) 186 (31.4%) 0.679 Abbreviations: ARB, angiotensin II receptor blocker; H2A/PPI, histamine 2 antagonist/proton pump inhibitor. P-value is for comparison of aspirin vs. no aspirin.

Results indication for aspirin use 38.6% 34.3% 14.7% 6.0% 4.2% 2.2%

Results MORTALITY HF HOSPITALIZATION HR=0.62 (95% CI:0.48 0.79) HR=0.65 (95% CI:0.49-0.85) Adjusted Kaplan Meier survival curve for aspirin use (green line) vs. no aspirin use (blue line). When fully adjusted, aspirin use improved mortality by 38%. Adjusted Kaplan Meier curve for HF hospitalization for aspirin use (green line) vs. no aspirin use (blue line). When fully adjusted, aspirin users had 35% less HF hospitalization

Results ALL CAUSE HOSPITALIZATION AND MORTALITY HR = 0.75 (95% CI: 0.62 0.92) Adjusted Kaplan Meier curve for all cause hospitalization AND mortality for aspirin use (green line) vs. no aspirin use (blue line). When fully adjusted, aspirin users had 25% fewer events than patients with no aspirin at baseline

Conclusion This is the first large, retrospective, cohort study of aspirin in HF patients to show mortality benefits when adjusted for key population variables including BNP There appears to be an important relationship between aspirin dose and effectiveness in HF which is relevant in clinical practice More prospective randomised work is needed to understand the role of aspirin in heart failure