Conflict of interest statement

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1 Risk of stroke, systemic embolism or death according to heart failure and left ventricular function status in patients with atrial fibrillation: results of the ARISTOTLE trial J.J.V. McMurray 1, B. Lewis 2, J. Ezekowitz 3, B. Gersh 4, R.D. Lopes 5, D. Wojdyla 5, P. Mohan 6, L. Wallentin 7, J.H. Alexander 5, C.B. Granger 5, 1 University of Glasgow - Glasgow - United Kingdom, 2 Lady Davis Carmel Medical Center - Haifa - Israel, 3 University of Alberta - Edmonton - Canada, 4 Mayo Clinic - Rochester - United States of America, 5 Duke Clinical Research Institute, Duke University Medical Center - Durham - United States of America, 6 Bristol-Myers Squibb - Princeton - United States of America, 7 Uppsala University, UCR-Uppsala Clinical Research Center - Uppsala - Sweden, on behalf of the ARISTOTLE investigators

2 Conflict of interest statement My employer, Glasgow University, has been paid by BMS/Pfizer for my time spent as a member of the ARISTOTLE Executive Committee. I have received funding from BMS/Pfizer for travel and accommodation in relation to ARISTOTLE Executive Committee meetings.

3 Background: the relationship between atrial fibrillation and heart failure Patients with heart failure and atrial fibrillation have worse heart failure outcomes than heart failure patients in sinus rhythm Patients with atrial fibrillation and LV systolic dysfunction, heart failure or both are believed to have higher thromboembolism rates than AF patients without either LV systolic dysfunction or heart failure Comparison of apixaban and warfarin for prevention of stroke (and systemic embolism) in patients with atrial fibrillation AND heart failure, LV systolic dysfunction or both in the ARISTOTLE trial

4 ARISTOTLE trial

5 ARISTOTLE design: AF with at least one additional risk factor for stroke Inclusion risk factors Age 75 years Prior stroke, TIA, or SE HF or LVEF 40% Diabetes mellitus Hypertension Randomize double blind, double dummy (n = 18,201) Major exclusion criteria Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Warfarin (target INR 2-3) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

6 Current analysis: Outcomes according to LV function and HF status No HF or LVSD HF-PEF LVSD

7 ARISTOTLE: definition of heart failure and LV systolic dysfunction Patients: Only those with a report of both HF status and LV function were included in this analysis. Of the 18,201 patients randomized in ARISTOTLE, 14,671 (81%) had information on both HF status and LV systolic function Definition of HF: Inclusion criteria page ( symptomatic congestive heart failure within 3 months ) and the Cardiovascular disease history page ( Does the subject have symptomatic congestive heart failure? ) Definition of LVSD: was obtained from the Inclusion criteria page ( left ventricular dysfunction with an EF 40% by echocardiography, radionuclide study or contrast angiography ) and the Assessment of left ventricular function page, which recorded EF or LV dysfunction category (normal, mild, moderate or severe), if an evaluation LV function had been made

8 ARISTOTLE: analysis of outcomes according to HF status and LV systolic function Patients were divided into 3 categories: Patients with LV systolic dysfunction (LVSD), with or without HF; LVSD was defined as an EF 40% or a report of moderate or severe LV systolic dysfunction (n=2,736) Patients with HF and preserved EF (>40%), normal LV function or mild LV systolic dysfunction, collectively referred to as HF with preserved EF (HF-PEF) (n= 3,207) Patients with no HF and an EF >40% or normal LV function, i.e. with neither LVSD nor HF-PEF (n= 8,728) The effect of apixaban compared with warfarin was examined for the pre-specified efficacy and safety outcomes in each of these patient categories

9 Baseline characteristics No HF or LVSD HF-PEF LVSD

10 ARISTOTLE: Baseline characteristics according to LV systolic function and HF status No LVSD/no HF (n=8728) HF-PEF (n=3207) LVSD (n=2736) P value Age (yr) < Age 75 yr (%) < Female (%) < Systolic BP (mmhg) < Diabetes (%) Hypertension (%) < MI (%) < Stroke/TIA (%) < LBBB (%) < Type of AF (%) Paroxysmal Persistent/permanent < <0.0001

11 ARISTOTLE: Baseline characteristics according to LV systolic function and HF status NYHA Class (%) I II III IV No LVSD/no HF (n=8728) HF-PEF (n=3207) LVSD (n=2736) P value < LVEF (%) < Creatinine clearance (ml/min) > 80 > > CHADS < < Mean CHADS <0.0001

12 ARISTOTLE: Baseline characteristics according to LV systolic function and HF status No LVSD/no HF (n=8728) HF-PEF (n=3207) LVSD (n=2736) P value Diuretic < ACE inhibitor or ARB < Amiodarone < Beta-blocker < Aldosterone antagonist < Digoxin < CCB < Statin < Aspirin <0.0001

13 Outcomes (irrespective of treatment assignment) No HF or LVSD HF-PEF LVSD

14 ARISTOTLE: Efficacy outcomes according to LV systolic function and HF status No LVSD/no HF (N=8728) HF-PEF (N=3207) LVSD (N=2736) Rate* Rate* HR Rate* HR P value SSE (0.87,1.42) (0.77,1.33) SSE or death (1.34,1.77) (2.05,2.65) < SSE, MI or death (1.28,1.67) (2.00,2.56) < *per 100 patient years compared with no LVSD/no HF group

15 ARISTOTLE: Adjusted rates of SSE No LVSD/no HF HF-PEF LVSD P value (N=8728) (N=3207) (N=2736) Rate* Rate* HR Rate* HR SSE (0.89,1.48) (0.84,1.46) 0.52 * per 100 patient years adjusted for age, sex, HT, DM, Stroke/TIA, CHD, BMI, egfr compared with no LVSD/no HF group

16 ARISTOTLE: Heart failure hospitalization No LVSD/no HF (N=8728) HF-PEF (N=3207) LVSD (N=2736) P value Rate* Rate* HR Rate* HR SSE (0.87,1.42) (0.77,1.33) SSE or death (1.34,1.77) (2.05,2.65) < SSE, MI or death (1.28,1.67) (2.00,2.56) < HF hospitalization (2.26,3.40) (4.21,6.11) < *per 100 patient years compared with no LVSD/no HF group investigator reported

17 ARISTOTLE: Bleeding outcomes according to LV systolic function and HF status No LVSD/no HF (N=8728) HF-PEF (N=3207) LVSD (N=2736) P value Rate* Rate* HR Rate* HR Major bleeding (0.84,1.24) (1.01,1.50) SSE, major bleeding or death (1.22,1.54) (1.77,2.22) < *per 100 patient years compared with no LVSD/no HF group

18 Outcomes (according to treatment assignment) No HF or LVSD HF-PEF LVSD

19 Event rate ARISTOTLE: SSE or death according to LV systolic function and HF status 0.20 Warfarin Apixaban LVSD HF-PEF No LVSD/HF P for interaction = Months since randomization

20 Event rate ARISTOTLE: SSE, major bleeding or death according to LV systolic function and HF status LVSD HF-PEF No LVSD/no HF Warfarin Apixaban P for interaction = Months since randomization

21 ARISTOTLE: outcomes according to HF status and LV systolic function summary and conclusions Patients with atrial fibrillation and LV systolic dysfunction or HF-PEF have worse outcomes than AF patients without either LV systolic dysfunction or HF primarily because of their higher mortality rate Those with LVSD have a worse outcome than those with HF-PEF Overall, patients treated with apixaban had better outcomes than those treated with warfarin lower rates of SSE, SSE or death, death, major bleeding and SSE, major bleeding or death Baseline LVSD or HF-PEF did not modify the effect of apixaban