Aspirin not increasing heart failure events in heart failure patients – WARCEF trial

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AspirinAspirin does not increase heart failure events in heart failure patients, according to the 10-year Warfarin and Aspirin for Reduced Cardiac Ejection Fraction (WARCEF) trial, which is the largest randomised, double-blind comparison of aspirin and warfarin.

A study by researchers at NewYork-Presbyterian/Columbia University Medical Centre allays concerns among cardiologists that aspirin could increase the risk of hospitalisation and death related to heart failure for patients with heart failure who take one of the first-line therapies: angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).

The 10-year Warfarin and Aspirin for Reduced Cardiac Ejection Fraction (WARCEF) trial is the largest randomised, double-blind comparison of aspirin and warfarin (also known by its brand name Coumadin) for heart failure, following 2,305 heart failure patients whose heart muscle pumps less oxygen-rich blood into the body, known as reduced ejection fraction, at 168 study sites in 11 countries on three continents. The patients in WARCEF were in normal sinus rhythm (experiencing a normal heart beat) and were taking heart failure medications.

The researchers in this sub-study found that aspirin does not increase heart failure events in heart failure patients. Earlier heart failure studies, smaller than WARCEF, raised concern about a negative effect of aspirin with heart failure medications, due to a potential biochemical interaction.

“These findings allay concerns regarding the safety of aspirin for heart failure patients,” says senior author Shunichi Homma, Margaret Milliken Hatch professor of medicine at Columbia’s College of Physicians and Surgeons, and deputy chief of the cardiology division at New York-Presbyterian/Columbia.

“Up to 40% of Americans take aspirin, and in heart failure patients, this number may be even higher,” says co-author Susan Graham, a cardiologist and professor of medicine at the University of Buffalo. “It’s a great relief to learn that aspirin is safe for this population. One challenge in cardiology is that we may need to use many drugs, including two or three blood thinners. We always want to be sure we’re helping patients, not creating problems.

“Knowledge that aspirin is safe could have implications extending beyond the world of heart failure since ACE inhibitors are also used as a front-line therapy for hypertension and diabetes,” adds Graham.

The new study, a post-hoc analysis, follows the main WARCEF study published in 2012, finding neither aspirin nor warfarin superior for preventing a combined risk of death, stroke, and cerebral haemorrhage in heart failure patients with normal heart rhythm.

Abstract 1
Objectives: The aim of this study was to determine whether aspirin increases heart failure (HF) hospitalization or death in patients with HF with reduced ejection fraction receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).
Background: Because of its cyclooxygenase inhibiting properties, aspirin has been postulated to increase HF events in patients treated with ACE inhibitors or ARBs. However, no large randomized trial has addressed the clinical relevance of this issue.
Methods: We compared aspirin and warfarin for HF events (hospitalization, death, or both) in the 2,305 patients enrolled in the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial (98.6% on ACE inhibitor or ARB treatment), using conventional Cox models for time to first event (489 events). In addition, to examine multiple HF hospitalizations, we used 2 extended Cox models, a conditional model and a total time marginal model, in time to recurrent event analyses (1,078 events).
After adjustment for baseline covariates, aspirin- and warfarin-treated patients did not differ in time to first HF event (adjusted hazard ratio: 0.87; 95% confidence interval: 0.72 to 1.04; p = 0.117) or first hospitalization alone (adjusted hazard ratio: 0.88; 95% confidence interval: 0.73 to 1.06; p = 0.168). The extended Cox models also found no significant differences in all HF events or in HF hospitalizations alone after adjustment for covariates.
Conclusions: Among patients with HF with reduced ejection fraction in the WARCEF trial, there was no significant difference in risk of HF events between the aspirin and warfarin-treated patients.

John R Teerlink, Min Qian, Natalie A Bello, Ronald S Freudenberger, Bruce Levin, Marco R Di Tullio, Susan Graham, Douglas L Mann, Ralph L Sacco, JP Mohr, Gregory YH Lip, Arthur J Labovitz, Seitetz C Lee, Piotr Ponikowski, Dirk J Lok, Stefan D Anker, John LP Thompson, Shunichi Homma

Abstract 2
Background: It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm.
Methods: We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause.
Results: The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P=0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P=0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P=0.82).
Conclusions: Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.

Shunichi Homma, John LP Thompson, Patrick M Pullicino, Bruce Levin, Ronald S Freudenberger, John R Teerlink, Susan E Ammon, Susan Graham, Ralph L Sacco, Douglas L Mann, JP Mohr, Barry M Massie, Arthur J Labovitz, Stefan D Anker, Dirk J Lok, Piotr Ponikowski, Conrado J Estol, Gregory YH Lip, Marco R Di Tullio, Alexandra R Sanford, Vilma Mejia, Andre P Gabriel, Mirna L del Valle, Richard Buchsbaum

New York-Presbyterian Hospital material
JACC: Heart Failure abstract
New England Journal of Medicine abstract

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