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
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.
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
ARISTOTLE trial
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
Current analysis: Outcomes according to LV function and HF status No HF or LVSD HF-PEF LVSD
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
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
Baseline characteristics No HF or LVSD HF-PEF LVSD
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) 71 69 68 <0.0001 Age 75 yr (%) 33.7 25.3 23.4 <0.0001 Female (%) 35.2 42.2 21.3 <0.0001 Systolic BP (mmhg) 130 130 126 <0.0001 Diabetes (%) 25.0 25.2 26.9 0.1313 Hypertension (%) 89.9 88.9 75.3 <0.0001 MI (%) 10.7 17.8 27.9 <0.0001 Stroke/TIA (%) 19.6 17.5 15.8 <0.0001 LBBB (%) 2.9 4.9 11.4 <0.0001 Type of AF (%) Paroxysmal Persistent/permanent 18.8 81.2 14.8 85.2 10.8 89.2 <0.0001 <0.0001
ARISTOTLE: Baseline characteristics according to LV systolic function and HF status NYHA Class (%) I II III IV No LVSD/no HF (n=8728) 73.2 24.4 2.3 0.1 HF-PEF (n=3207) 16.5 61.6 21.2 0.7 LVSD (n=2736) 26.7 50.2 21.9 1.2 P value <0.0001 LVEF (%) 60 56 35 <0.0001 Creatinine clearance (ml/min) > 80 > 50 80 > 30 50 30 CHADS 1 2 3 42.2 42.5 14.3 1.0 44.5 33.3 22.2 43.5 39.4 14.9 2.2 8.9 43.8 47.4 41.4 40.5 16.2 1.9 29.4 36.0 34.6 <0.0001 <0.0001 Mean CHADS 1.88 2.67 2.22 <0.0001
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 45.8 69.7 72.8 <0.0001 ACE inhibitor or ARB 66.5 77.1 80.6 <0.0001 Amiodarone 9.3 13.0 15.2 <0.0001 Beta-blocker 61.7 68.6 74.7 <0.0001 Aldosterone antagonist 0.5 1.4 2.3 <0.0001 Digoxin 24.1 39.2 47.5 <0.0001 CCB 37.2 26.4 15.7 <0.0001 Statin 46.2 37.5 43.3 <0.0001 Aspirin 30.0 32.0 34.3 <0.0001
Outcomes (irrespective of treatment assignment) No HF or LVSD HF-PEF LVSD
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 1.37 1.52 1.11 (0.87,1.42) 1.39 1.01 (0.77,1.33) 0.705 SSE or death 3.46 5.32 1.54 (1.34,1.77) 8.06 2.33 (2.05,2.65) <0.0001 SSE, MI or death 3.85 5.63 1.46 (1.28,1.67) 8.70 2.26 (2.00,2.56) <0.0001 *per 100 patient years compared with no LVSD/no HF group
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 1.38 1.58 1.15 (0.89,1.48) 1.53 1.10 (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
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 1.37 1.52 1.11 (0.87,1.42) 1.39 1.01 (0.77,1.33) 0.705 SSE or death 3.46 5.32 1.54 (1.34,1.77) 8.06 2.33 (2.05,2.65) <0.0001 SSE, MI or death 3.85 5.63 1.46 (1.28,1.67) 8.70 2.26 (2.00,2.56) <0.0001 HF hospitalization 1.12 3.24 2.77 (2.26,3.40) 5.99 5.07 (4.21,6.11) <0.0001 *per 100 patient years compared with no LVSD/no HF group investigator reported
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 2.50 2.55 1.02 (0.84,1.24) 3.09 1.23 (1.01,1.50) 0.114 SSE, major bleeding or death 5.27 7.24 1.37 (1.22,1.54) 10.46 1.98 (1.77,2.22) <0.0001 *per 100 patient years compared with no LVSD/no HF group
Outcomes (according to treatment assignment) No HF or LVSD HF-PEF LVSD
Event rate ARISTOTLE: SSE or death according to LV systolic function and HF status 0.20 Warfarin Apixaban 0.15 0.10 LVSD HF-PEF No LVSD/HF P for interaction = 0.63 0.05 0.00 0 6 12 18 24 Months since randomization
Event rate ARISTOTLE: SSE, major bleeding or death according to LV systolic function and HF status 0.20 0.15 LVSD HF-PEF No LVSD/no HF Warfarin Apixaban P for interaction = 0.59 0.10 0.05 0.00 0 6 12 18 24 Months since randomization
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