Published online before print May 30, 2006, doi: 10.1161/CIRCULATIONAHA.105.602136
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(Circulation. 2006;113:2572-2578.)
© 2006 American Heart Association, Inc.
Heart Failure |
Aspirin Use and Outcomes in a Community-Based Cohort of 7352 Patients Discharged After First Hospitalization for Heart Failure
From the Division of General Internal Medicine (F.A.M.) and the Division of Cardiology (P.W.A.), University of Alberta, Edmonton, Canada; the Division of General Internal Medicine, University of Calgary, Calgary, Canada (W.A.G.); the Institute for Clinical Evaluative Sciences, University of Toronto, Toronto, Canada (Y.G., J.F.); and the Division of General Internal Medicine, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, Canada (J.V.T.).
Correspondence to Dr F. McAlister, 2E3.24 WMC, University of Alberta Hospital, 8440 112 Street, Edmonton, Alberta, Canada T6G 2R7. E-mail- Finlay.McAlister{at}ualberta.ca
Received November 16, 2005; revision received March 23, 2006; accepted March 24, 2006.
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Abstract |
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Background— The safety of aspirin in heart failure (HF) has been called into question, particularly in those patients (1) without coronary disease, (2) with renal dysfunction, or (3) treated with low-dose angiotensin-converting enzyme (ACE) inhibitors and high-dose aspirin.
Methods and Results— We examined prescription patterns and outcomes (all-cause mortality and/or HF readmission) in patients discharged from 103 Canadian hospitals between April 1999 and March 2001 after a first hospitalization for HF. Of 7352 patients with HF (mean age, 75 years; 44% without coronary disease and 29% with renal dysfunction), 2785 (38%) died or required HF readmission within the first year. Compared with nonusers, aspirin users were no more likely to die or require HF readmission (hazard ratio [HR], 1.02 [0.91 to 1.16]), even in patients without coronary disease (HR, 0.98 [0.78 to 1.22]) or patients with renal dysfunction (HR, 1.13 [0.94 to 1.36]). On the other hand, users of ACE inhibitors were less likely to die or require HF readmission (HR, 0.87 [0.79 to 0.96]), even if they were using aspirin (HR, 0.86 [0.77 to 0.95]). There were no dose-dependent interactions between aspirin and ACE inhibitors.
Conclusions— In this observational study, aspirin use was not associated with an increase in mortality rates or HF readmission rates, and aspirin did not attenuate the benefits of ACE inhibitors, even in patients without coronary disease, patients with renal dysfunction, or patients treated with high-dose aspirin and low-dose ACE inhibitors.
Key Words: aspirin • heart failure • outcomes
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Introduction |
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The role of aspirin in patients with heart failure (HF) is unclear. Although guidelines universally endorse aspirin for those patients with underlying coronary disease, its role in patients without coronary disease is under debate.1–4 Thus, it is not surprising that prescription patterns vary widely (between 31% and 70% of patients with HF with coronary disease were prescribed aspirin in different states participating in the National Heart Care Project).5 Although the Antiplatelet Trialists have clearly established that aspirin improves survival in patients with coronary disease without HF,6 those arguing against the use of aspirin in patients with HF point to a paucity of data evaluating its effects in these patients and the theoretical potential for aspirin to reduce the efficacy of angiotensin-converting enzyme (ACE) inhibitors.4 Recent reports from the Warfarin/Aspirin Study in Heart Failure (WASH)7 and Warfarin and Antiplatelet Therapy in Chronic Heart Failure Trial (WATCH)8 suggesting increased risk of HF hospitalizations in patients randomly assigned to aspirin have renewed concerns over the safety of aspirin in HF. However, HF hospitalization was a secondary outcome in both trials, and conclusions of excess risk were based on only 146 hospitalizations in 614 patients randomly assigned to aspirin in these two trials.
Editioral p 2566
Clinical Perspective p 2578
Numerous in vitro studies have shown that aspirin inhibits endothelial cyclooxygenase, thereby reducing vasodilatory prostaglandins, increasing vascular tone, and promoting renal salt and water retention.9 Six of 15 observational studies reported that aspirin use attenuated the prognostic benefits of ACE inhibitors.10–24 Although a meta-analysis of randomized trials of ACE inhibition did not find any interaction between aspirin and ACE inhibitors, very few patients in these trials had impaired renal function,25 an important prognostic factor in HF and the very subgroup in whom ACE inhibitor–aspirin interactions would most likely be seen.25,26 Indeed, all three studies that have examined for an ACE inhibitor–aspirin interaction in patients with moderate or severe renal insufficiency reported strong trends toward a negative interaction but were underpowered to definitively answer the question.
A recent report from the National Heart Care Project is the largest study to examine aspirin use and outcomes in HF.5 Although these authors found no evidence of harm from aspirin, their study had two important limitations: (1) Their cohort consisted entirely of patients with HF and coronary disease (yet most of the controversy surrounding aspirin is for patients without coronary disease), and (2) they did not have data on drug doses (yet any negative interaction would be most evident in patients treated with lower doses of ACE inhibitor and higher doses of aspirin).9
Although a 2x2 factorial trial would be the best way to evaluate the main effects of aspirin in HF and any interaction with ACE inhibitors, it would be unethical to conduct a trial randomly assigning patients with HF to "no ACE inhibitor." Accordingly, we analyzed data from a large prospective cohort study to examine the prognostic impact of aspirin and whether aspirin attenuates the benefits of ACE inhibitors, with particular attention to those patients in whom negative effects of aspirin would most likely be observed: (1) those with HF but without coronary artery disease, (2) those treated with low-dose ACE inhibitors and high-dose aspirin, and (3) those with HF with renal dysfunction. No previous studies, including the recent report from the National Heart Care Project, have examined the safety of aspirin in subgroups 1 and 2 above.
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Methods |
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As part of the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study, charts of a random sample of patients admitted to 103 hospitals (79 community hospitals, 11 small hospitals, and 13 teaching hospitals as defined by the Ontario Joint Policy and Planning Committee) in Ontario, Canada, with a new primary diagnosis of HF were reviewed by cardiology research nurses who were trained centrally but did chart reviews locally at each site. Patients with an admission for HF in the 3 years before the index hospitalization or who had development of HF as an inpatient complication were excluded. Full details about the EFFECT study hospitals and patients, as well as variable definitions and data collection procedures, are available at http://www.ccort.ca/EFFECT.asp.
For the purposes of this study, we included only those patients with a diagnosis of HF confirmed using modified Framingham criteria and excluded patients who died during the index hospitalization, patients with missing data, and patients with contraindications to ACE inhibitors (moderate or severe aortic stenosis, bilateral renal artery stenosis, documented allergy, systolic blood pressure 
90 mm Hg at hospital discharge, or serum potassium level >5.5 mmol/L) or who were prescribed an angiotensin receptor blocker.
We used discharge prescriptions to define medication use and a priori planned to examine whether there were dose-dependent interactions between ACE inhibitors and aspirin. In classifying ACE inhibitor dosage, we defined "high dose" as those doses that were at least 50% of the target doses in the trials proving the efficacy of that particular ACE inhibitor (as per previous health outcomes studies in HF).27 We defined aspirin dosage as high dose if it was 
325 mg/d.
We used the previously validated Modification of Diet in Renal Disease Equation (glomerular filtration rate [GFR] = 186x[serum creatinine]–1.154xage (years)–0.203x[0.742 if female]x[1.212 if black]) to divide the cohort into those with GFR 60 mL/min per 1.73 m2 and those with renal dysfunction (GFR <60 mL/min per 1.73 m2). These definitions were chosen on the basis of Kidney Disease Outcome Quality Initiative guidelines.28
Data Analysis
The baseline characteristics of those who were and were not prescribed ACE inhibitors and/or aspirin were compared by means of the 
2 test for dichotomous variables and Student t test for continuous variables.
We performed multivariate Cox proportional-hazards analysis with the backward stepwise selection technique to examine prognostic factors for mortality and the composite outcome of "mortality or HF readmission" within the first year after discharge. At the first step, we input all variables previously reported to predict the outcomes (age, respiratory rate, systolic blood pressure, serum sodium, hemoglobin, serum creatinine, history of cerebrovascular disease, dementia, chronic obstructive pulmonary disease, hepatic cirrhosis, cancer, diabetes mellitus)26,29,30 and any other baseline factors with P<0.20 on bivariate analyses and a prevalence of at least 1%, including gender and all prescribed medications (except ACE inhibitors and aspirin). We accepted statistical significance at a level of P<0.05.
We examined the associations between ACE inhibitors and aspirin and both outcomes of interest (mortality and "mortality or HF readmission") by including ACE inhibitors and aspirin along with all of the prognostic variables from the previous analysis in Cox proportional hazards models for (1) the entire cohort, (2) patients with coronary disease, and (3) patients without coronary disease (and ran further analyses for those patients in each of the above groups with GFR 60 mL/min per 1.73 m2 and GFR <60 mL/min per 1.73 m2). After calculating the main effects for each drug, we tested the ACE inhibitorxaspirin multiplicative interaction term in all 9 analyses to judge whether there was a statistically significant interaction. To present the data in a clinically meaningful way, we used the additive framework for interaction and calculated the effects of each ACE inhibitor–aspirin combination, using 3 dummy variables in the Cox proportional-hazards models (with patients taking neither ACE inhibitor nor aspirin being the referent category): patients taking ACE inhibitor and aspirin, patients taking ACE inhibitor without aspirin, and patients taking aspirin without ACE inhibitor. We repeated similar multiplicative and additive interaction testing for different dosing combinations of ACE inhibitor and aspirin (for example, high-dose aspirin plus low-dose ACE inhibitor).
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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Of the 9943 patients admitted to the 103 participating hospitals between April 1, 1999, and March 31, 2001, with HF, 782 (8%) died during the index hospitalization. Of those patients discharged alive, we excluded 516 (5%) patients without discharge prescription data, 503 (5%) patients with contraindications to ACE inhibitors, 484 (5%) patients receiving an angiotensin receptor blocker at hospital discharge, and 306 (3%) patients who did not have a serum creatinine, hemoglobin, or sodium recorded.
In our study sample of 7352 patients discharged alive (50% men; mean age, 75 years; 56% with ischemic pathology; 48% with systolic dysfunction), comorbidities were common (Table 1), and 29% had GFR <60 mL/min per 1.73 m2. The mean dose of aspirin prescribed in our cohort was 286 mg/d, and 77% of patients were prescribed 325 mg/d. Sixty-four percent of our cohort were prescribed an ACE inhibitor, and two thirds of those prescribed an ACE inhibitor were prescribed high doses (ie, 50% of trial target doses).
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In the first year after hospital discharge, 1943 (26%) patients died, 1320 (18%) were readmitted for HF, and 4403 (60%) were readmitted for any reason. Death or HF readmission occurred in 2785 (38%) patients: 39% of those with coronary disease and 37% of those without coronary disease. All outcomes were significantly more frequent in patients with GFR <60 mL/min per 1.73 m2 than in those with normal renal function: 35% versus 23% for mortality and 47% versus 34% for death or HF readmission (both P<0.0001).
Users of ACE inhibitors exhibited lower rates of death and "death or HF readmission" than did nonusers (Figure; both P<0.0001), whereas crude event rates were not significantly different in aspirin users than in nonusers (Figure; P=0.26 for death and P=0.23 for death or HF readmission). Several variables were independently associated with either mortality or the composite outcome of "death or HF readmission" (Table 2), with no appreciable difference in the multivariate predictors derived from models in the total cohort, models restricted to patients with/without coronary disease, and models restricted to those with GFR <60 or 60 mL/min per 1.73 m2.
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After adjustment for all covariates, ACE inhibitor use was associated with better outcomes overall and in all examined subgroups, and these associations did not differ according to whether the patient was or was not taking aspirin (Table 3). Aspirin use was not associated with higher rates of mortality or "death/HF readmission" overall or in any of the examined subgroups (Table 3). None of the multiplicative ACE inhibitor–aspirin interaction terms reached statistical significance for any subgroup (including those patients without coronary disease who had renal dysfunction; data available on request).
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Aspirin dose did not influence the outcome associations: Compared with patients not taking aspirin, those taking high-dose aspirin exhibited a hazard ratio (HR) of 0.95 [0.81 to 1.11] for mortality and 1.02 [0.89 to 1.16] for death or HF readmission, and HRs were 1.02 [0.80 to 1.31] for mortality and 0.995 [0.81 to 1.23] for death or HF readmission in those taking low-dose aspirin. Similarly, ACE inhibitor dose did not influence the outcome associations: For example, mortality HRs were 0.80 [0.69 to 0.94] for those taking high-dose ACE inhibitors and 0.78 [0.68 to 0.90] in those taking low-dose ACE inhibitors (with ACE inhibitor nonusers the referent group in both analyses). There were no statistically significant dose-dependent interactions; for example, the probability value for the interaction between low-dose ACE inhibitors and high-dose aspirin was 0.16 for mortality and 0.86 for mortality/HF readmission. Thus, patients taking low-dose ACE inhibitors with high-dose aspirin exhibited outcome associations (HR 0.93 [0.79 to 1.09] for death or HF readmission compared with patients not taking either agent) similar to those in patients taking high-dose ACE inhibitors with low-dose aspirin (HR 0.94 [0.78 to 1.14] for death or HF readmission compared with patients not taking either agent).
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Discussion |
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Data from this large prospective cohort of patients with newly diagnosed HF discharged from 103 hospitals provide new insights for several key questions in HF pharmacotherapy.
First, and perhaps most important, we have demonstrated that the benefits of ACE inhibition in patients with HF are present whether or not patients have underlying coronary disease and whether or not they are also taking aspirin (even in patients prescribed low-dose ACE inhibitor and high-dose aspirin). Although it had been hypothesized that the conflicting results from studies testing for ACE inhibitor–aspirin interactions may have arisen because the interaction is dose dependent (and thus more likely in patients treated with lower doses of ACE inhibitor and higher doses of aspirin) or is only present in patients with renal dysfunction (two claims that cannot be tested in trial databases given the rarity of renal dysfunction in trial participants and the high doses of ACE inhibitors commonly used in trials), we were able to examine these two issues in our cohort and provide evidence that is contrary to both claims.9,31,32
Second, we did not find an excess in the composite outcome of death or HF hospitalizations with aspirin treatment, even in patients without coronary disease—a finding contrary to the WASH and WATCH Trials7,8 but based on a much larger sample size (2785 of 7352 patients in our sample died or were hospitalized for HF during follow-up compared with 255 events in aspirin-treated patients in those two trials). Our study reinforces the findings from the National Heart Care Project analysis5 demonstrating that aspirin was not associated with increased mortality rates or HF hospitalizations in patients with HF with coronary disease; however, our study extends the evidence base by including data from patients without coronary disease and including drug dosing data (which permitted analyses for dose-dependent and renal-function–dependent interactions).
Third, we have confirmed that the use of ACE inhibitors is associated with improved survival and reduced HF hospitalizations in a heterogeneous sample of non–trial participants with ischemic or nonischemic HF, irrespective of renal function. The degree of benefit seen in our cohort is consistent with the results of randomized trials of ACE inhibition in HF.24
Although our study reports on a large, well-categorized, and heterogeneous cohort of patients after a first hospitalization for HF who are similar to HF cohorts recruited in other population-based studies,5,33 there are some limitations to our study. First, some may question whether our cohort consisted entirely of incident cases of HF; however, we excluded any patients with hospitalizations for HF in the 3 years before the index visit (the "washout" period), an established technique in HF health services research.27 An analysis of HF admissions in Ontario has confirmed that a 3-year washout is optimal for establishing incident cases of HF because very few patients with HF live beyond 3 years without at least one hospitalization (Dr Doug Lee, personal communication, February 1, 2006). Second, we only have prescribing data at time of hospital discharge; however, another study in this cohort has demonstrated that prescribing rates for cardiovascular medications are remarkably stable for at least the first year after hospital discharge (the time frame of our study); for example, the proportion of EFFECT cohort patients with left ventricular ejection fraction <0.40 prescribed an ACE inhibitor increased from 75% at discharge to 76% at 90 days and 77% at 12 months, and the proportion prescribed a ß-blocker increased from 34% at discharge to 36% at 90 days and 43% at 12 months.34 Furthermore, a study that used interviews to assess patient compliance with prescribed cardiovascular medications reported 12-month adherence rates of 82% for aspirin, 78% for ß-blockers, and 72% for ACE inhibitors.35 Nevertheless, we do acknowledge that any changes in medications or their dosing, patient noncompliance with prescribed therapy, or use of over-the-counter, nonsteroidal antiinflammatory drugs may have clouded associations between prescribed medications and outcomes and biased our study against finding harm with aspirin therapy. Finally, as with any observational study, it is important to highlight that this is not a randomized trial. Because we cannot fully adjust for potential unmeasured confounders, we cannot "prove" that particular therapies are beneficial or safe. However, the magnitude of the benefits associated with use of ACE inhibitors in this study are consistent with the benefits observed in clinical trials of these agents,24 and our study does provide important "real-world" data that suggest that the benefits of ACE inhibition are independent of aspirin in all important patient subgroups.
In conclusion, contrary to reports from the WASH and WATCH trials,7,8 we found that aspirin use was not associated with an increase in adverse outcomes in patients with HF in this observational study, even in those subgroups theorized to be most likely to exhibit harm with aspirin: patients without coronary disease, patients with renal dysfunction, and patients treated with low-dose ACE inhibitors but high-dose aspirin. We did find that patients with HF have better outcomes if they receive ACE inhibitors, irrespective of whether they have coronary disease and irrespective of whether aspirin is used. Although some may dismiss our findings as arising from an observational study rather than a randomized trial, it is worth repeating that a definitive randomized trial evaluating the efficacy and safety of aspirin in HF is unlikely to ever be successfully completed (given that the VA Cooperative Studies Program stopped the WATCH trial because of recruitment difficulties despite the best efforts of an internationally renowned group of investigators from 142 centers and that the ongoing Warfarin Versus Aspirin in Patients With Reduced Cardiac Ejection Fraction (WARCEF) trial is powered for stroke and mortality, not HF hospitalizations). We believe that our data do allay concerns about the safety of aspirin in HF, and we agree with Masoudi and colleagues5 that "withholding aspirin based on theoretical concerns about adverse effects appears to be unjustified."
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Acknowledgments |
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We thank Linda Donovan (coordinator of the EFFECT project) and the hospitals who participated in EFFECT; Dr Peter Austin for advice about data analysis; Dr Douglas Lee for providing unpublished data on the impact of different washout period definitions on heart failure rates in Ontario; and Dr Cynthia Jackevicius for providing insights into patient adherence rates.
Sources of Funding
The EFFECT study was supported by a grant to the Canadian Cardiovascular Outcomes Research Team from the Canadian Institutes of Health Research and the Heart and Stroke Foundation. F.A.M. is supported by the Alberta Heritage Foundation for Medical Research (AHFMR), the Canadian Institutes of Health Research, and the University of Alberta/Merck Frosst/Aventis Chair in Patient Health Management; W.A.G. is supported by the AHFMR and a Canada Research Chair; J.V.T. is supported by a Canada Research Chair.
Disclosures
None.
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CLINICAL PERSPECTIVE
As the safety of aspirin in heart failure (HF) has been called into question, this study was designed to examine aspirin use and outcomes in a prospective observational cohort of 7352 patients recently hospitalized with a new diagnosis of HF. In particular, the investigators focused on 3 patient subgroups that previous studies have been unable to examine and that would be most likely to exhibit any adverse effects of aspirin: (1) patients without coronary disease, (2) patients with renal dysfunction, and (3) patients treated with low-dose angiotensin-converting enzyme (ACE) inhibitors and high-dose aspirin. Of the entire cohort of 7352 patients, 2785 (38%) died or required HF readmission within the first year after discharge. Compared with nonusers, aspirin users were no more likely to die or require HF readmission (HR, 1.02 [0.91 to 1.16]), even in patients without coronary disease (HR, 0.98 [0.78 to 1.22]) and in patients with renal dysfunction (HR, 1.13 [0.94 to 1.36]). Moreover, users of ACE inhibitors were less likely to die or require HF readmission (HR, 0.87 [0.79 to 0.96]) than were nonusers, even if they were using aspirin (HR, 0.86 [0.77 to 0.95]), and there were no dose-dependent interactions between aspirin and ACE inhibitors. Although this is an observational study, the findings provide some reassurance that aspirin use does not attenuate the benefits of ACE inhibitors and is not associated with an increase in mortality rates or HF readmission rates, even in patients without coronary disease, patients with renal dysfunction, and patients treated with high-dose aspirin and low-dose ACE inhibitors.
Circulation 2006 113: 2565.
Circulation 2006 113: 2566-2568.
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  H.-C. Diener, H. Mattle, M. Böhm, and F. Ruschitzka CHAPTER 15a The Heart and the Brain ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text]
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 R. C. Becker, T. W. Meade, P. B. Berger, M. Ezekowitz, C. M. O'Connor, D. A. Vorchheimer, G. H. Guyatt, D. B. Mark, and R. A. Harrington The Primary and Secondary Prevention of Coronary Artery Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 776S - 814S. [Abstract] [Full Text] [PDF]
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