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Aspirin and the Treatment of Heart Failure in the Elderly
Harlan M. Krumholz, MD;
Ya-Ting Chen, PhD;
Martha J. Radford, MD
Arch Intern Med. 2001;161:577-582.
ABSTRACT
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Objectives We sought (1) to determine how often aspirin is prescribed as a discharge
medication among patients 65 years or older and hospitalized with both heart
failure and coronary artery disease; (2) to identify patient characteristics
associated with the decision to prescribe aspirin; and (3) to evaluate the
association between aspirin prescription at discharge and 1-year survival.
Methods We performed a retrospective cohort study of consecutive Medicare beneficiary
survivors of a hospitalization for heart failure at 18 Connecticut hospitals
(up to 200 hospitalizations per hospital) from 1994 to 1995.
Results Among the 1110 patients in the study sample who did not have a contraindication
to aspirin, aspirin therapy was prescribed for 456 (41%) at discharge. Patients
who were prescribed aspirin at discharge had a lower 1-year mortality after
discharge than patients who were not prescribed aspirin (odds ratio, 0.71;
95% confidence interval, 0.54-0.94), even after adjustment for baseline differences
in demographic, clinical, and treatment characteristics between the 2 groups.
Conclusions This study has identified a strong association between the use of aspirin
and lower mortality in older patients with both heart failure and coronary
artery disease. The benefit of aspirin is consistent with that expected from
randomized trials of other groups of patients with vascular disease.
INTRODUCTION
HEART FAILURE, the most common discharge diagnosis among Medicare beneficiaries,
is associated with a high mortality rate. Recent clinical practice guidelines
have defined the best strategies for the treatment of patients with heart
failure.1, 2, 3, 4
These guidelines, and the performance measures that have derived from them,
have focused on the use of angiotensin-converting enzyme (ACE) inhibitors,
digoxin, and, more recently, ß-blockers.
Notably, aspirin has received relatively little attention for the treatment
of patients with heart failure even though most of these patients have coronary
artery disease.5 Aspirin has great value for
patients with coronary artery disease because of its effectiveness, low cost,
safety profile, and lack of strong contraindications. Pooled analyses of more
than 18 000 patients with coronary artery disease show that aspirin significantly
reduces long-term vascular mortality by about 20%.6
The reluctance to endorse aspirin for patients with heart failure derives
from concerns about its effects as a prostaglandin inhibitor. Aspirin is reported
to attenuate the effect of antihypertensive therapy,7, 8, 9
reduce vasodilator reserve,10 antagonize the
action of ACE inhibitors,11 and decrease glomerular
filtration pressure.12 The clinical trials
have provided relatively little information about the effect of aspirin for
patients with heart failure.13 An analysis
of the Studies of Left Ventricular Dysfunction (SOLVD) trial14
suggested that the use of antiplatelet agents (more than 95% of which were
aspirin) is associated with improved survival. The most recent heart failure
guidelines warn about the combined use of antiplatelet agents and diuretics.3, 4
To address this issue, we examined the use of aspirin as a discharge
medication among Medicare beneficiaries who survived a hospitalization for
both heart failure and coronary artery disease. We identified patient characteristics
associated with the decision to prescribe aspirin and compared the 1-year
mortality of patients who were prescribed aspirin at discharge with those
who were not, adjusting for baseline differences between the groups. We also
evaluated the effect of aspirin among subgroups of patients by their clinical
characteristics (eg, baseline renal function) and treatments (eg, ACE inhibitors).
While observational studies of this type will not supplant randomized trials
for establishing efficacy, they allow for the rigorous study of patients in
actual clinical practice, including many patient groups that are not commonly
represented in the clinical trials.
METHODS
STUDY SAMPLE
Patients for the study were identified from Medicare's national claims
history file (1994-1995) as part of a collaborative quality improvement project
in Connecticut that was coordinated by Qualidigm (formerly the Connecticut
Peer Review Organization), Middletown, Conn, and VHA Inc, Irving, Tex. Patients
with a principal discharge diagnosis of heart failure (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 428-428.1, 402.01, 402.91,
404.01, 404.03, 404.11, 404.13, 404.91, 404.93) at 18 Connecticut hospitals
from 1994 to 1995 were selected for retrospective chart review. Initially,
200 hospitalizations from each hospital were reviewed. Institutions with fewer
than 200 hospitalizations had all cases reviewed. We restricted the sample
to patients who were aged 65 years or older with heart failure confirmed either
by symptoms of heart failure or radiographic findings consistent with the
diagnosis.
To decrease the heterogeneity of the sample, we excluded patients with
severe aortic stenosis, severe mitral valve stenosis, or heart failure secondary
to an acute medical illness (eg, sepsis). These exclusions resulted in an
initial study sample of 2445 patients. For the current analysis we also excluded
patients who died during hospitalization (n = 169), were transferred to another
institution (n = 78), or had a documented terminal illness at discharge (n
= 37). A terminal illness was considered present if (1) a patient was documented
as "terminally ill" or as having a life expectancy of less than 6 months;
(2) the admission orders indicated that the patient should be given palliative
care only; or (3) a "do not resuscitate" order was written. We further excluded
patients who did not have an indication for aspirin use, ie, patients without
coronary artery disease (n = 920). Patients who had the following contraindications
to long-term aspirin use were also excluded: documented allergy to aspirin
(n = 103), platelet count lower than 100 x 109/L (n = 35),
hematocrit level lower than 0.30 (n = 274), or bleeding (n = 19). The resulting
sample consisted of 1110 patients.
DATA SOURCE AND STUDY VARIABLES
Medical Record Review
Patient characteristics and clinical information (including the prescription
of aspirin at discharge) were obtained from medical record review using a
standardized data abstraction form. Trained nurses and medical record technicians
abstracted the hospital records. Strategies to decrease abstraction errors
and variability included training sessions and detailed data definitions for
each field.
Coronary artery disease was considered present before discharge if myocardial
infarction, angina, coronary artery disease, percutaneous transluminal coronary
angioplasty (PTCA), and/or coronary artery bypass graft surgery (CABG) were
documented in the medical record before or during the course of hospitalization.
Patients were also considered to have coronary artery disease if they were
hospitalized for ischemic heart disease (ICD-9-CM
codes 410-414) in the year before the index hospitalization.
Left ventricular ejection fractions (LVEFs) were obtained from medical
record review based on 1 of the following 3 methods: radionuclide ventriculography,
cardiac catheterization (contrast ventriculography), or echocardiography (prioritized
in that order for patients in whom LVEF was measured using more than 1 method).
Qualitative measures of left ventricular function were translated into quantitative
measures as follows: normal function was assigned a value of 55% or higher;
mild or mild-moderate depression, 40% to 54%; moderate or moderate-severe
depression, 20% to 39%; and severe depression, lower than 20%. Missing values
were indicated with a dummy variable.
Other study variables included demographic characteristics (sex, age,
and race); medical history (diabetes, hypertension, heart failure, myocardial
infarction, angina, PTCA, CABG, atrial fibrillation, and preadmission aspirin
and ß-blocker use); admission characteristics (blood pressure, rales,
pulmonary edema on chest radiograph, potassium level, creatinine level, and
albumin level); major complications during hospitalization (a composite variable
including cardiac arrest, myocardial infarction, and shock); major procedures
during hospitalization (a composite variable including CABG, PTCA, and cardiac
catheterization); and discharge characteristics (mobility, mental status,
creatinine level, ratio of serum urea nitrogen [SUN] level to creatinine level,
and the prescription of ß-blockers, calcium channel blockers, ACE inhibitors,
nitrates, nonsteroidal anti-inflammatory drugs [NSAIDs], and warfarin).
Administrative Data
Outcome variables (including death, all-cause readmission, heart failure–related
readmission, and death and readmission combined within 1 year after discharge)
were obtained from administrative data. Information about readmission was
derived from the Health Care Financing Administration's Medicare provider
analysis and review file (1994-1996). This file contains discharge abstracts
for all Medicare inpatients from Connecticut hospitals. Information about
mortality was obtained from the Medicare Enrollment Database.
STATISTICAL ANALYSIS
Initially, bivariate analyses were performed to examine the association
between aspirin prescription and patient demographic and clinical characteristics.
For presentation purposes, continuous variables were dichotomized or categorized
as given in the tables. Missing data for categorical variables were considered
as characteristics not present.  2 Statistics or the Fisher
exact test was used to compare proportions. Multivariate logistic regression
models and stepwise selection procedures with an entry level P value less than .20 and an exit level P
value greater than .10 were used to identify factors independently associated
with the prescription of aspirin at discharge. For these models we did not
include the prescription of aspirin at admission as a predictor variable.
Subsequently, associations between the prescription of aspirin and 1-year
mortality postdischarge were examined. Multivariate analyses were performed
using the Cox proportional hazards model, accounting for confounding effects.
Assumptions of proportionality were examined and satisfied for the factors
studied. Potential confounding factors were selected based on their significance
in the bivariate associations with aspirin prescription and clinical judgment.
The impact of aspirin use on 1-year mortality was also examined in the following
subgroups: sex, age (65-74 and  75 years), presence of diabetes, creatinine
level at admission (<176.80 µmol/L and 176.80 µmol/L),
the prescription of ACE inhibitors at discharge, the prescription of ß-blockers
at discharge, and measures of LVEF (<40%, 40%, and unknown). All analyses
were performed using PC-SAS version 6.12 (SAS Institute Inc, Cary, NC). All P values reported were 2-sided, and a P value less than .05 was considered to indicate statistical significance.
RESULTS
STUDY SAMPLE
A total of 1110 patients who had coronary artery disease, survived a
hospitalization for heart failure, and did not have a contraindication to
aspirin use were included in the analysis. The sample included more women
(55%) than men. The mean ±SD age was 78.3 ±7.3 years, and most
patients were white (89%). Comorbidity was common in the study sample: 68%
had prior heart failure; 60% had hypertension; 39% had diabetes; and 59% had
a myocardial infarction before admission. Aspirin was used in 38% of the patients
before the index hospitalization. The mortality at 1 year postdischarge was
24%. More than half (64%) of the patients were rehospitalized within 1 year
after discharge (Table 1).
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Table 1. Demographics, Clinical Characteristics, and the Prescription
of Aspirin at Discharge Among 1110 Patients With Both Heart Failure and Coronary
Artery Disease*
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PRESCRIBED USE OF ASPIRIN
Aspirin was prescribed at discharge for 456 (41%) of the patients. The
strongest bivariate associations (P<.01) were
found between aspirin prescription and hypertension; prior myocardial infarction;
prior atrial fibrillation; preadmission aspirin and ß-blocker use; and
the prescription of ß-blockers, digoxin, nitrates, and warfarin at discharge
(Table 1).
Patient and clinical characteristics independently associated with the
decision to prescribe aspirin at discharge were identified using logistic
regression models and stepwise selection procedures. Prior CABG; admission
with chest pain; SUN level at admission; and the prescription of ß-blockers,
calcium channel blockers, nitrates, ACE inhibitors, and warfarin at discharge
were significantly associated with aspirin prescription at discharge (Table 2). Patients with a SUN level greater
than 14.28 mmol/L at admission and patients who were prescribed warfarin at
discharge were less likely to be prescribed aspirin. Overall, the model showed
a good discriminant ability (c-statistic, 0.75) in differentiating those who
were and were not prescribed aspirin and did not indicate a lack of goodness
of fit (P = .87). The model excluding treatments
at discharge (with only demographic and clinical variables) had much less
discriminant value (c-statistic, 0.61).
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Table 2. Predictors of Aspirin Presciption at Discharge*
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ASPIRIN AND MORTALITY
Patients who were prescribed aspirin had a significantly lower mortality
at 1 year after discharge. The association between aspirin and long-term mortality
remained significant after adjusting for confounding factors including sex;
age; presence of diabetes, hypertension, or prior atrial fibrillation; albumin
level, SUN level, and chest pain at admission; LVEF; creatinine level and
SUN/creatinine ratio at discharge; and the prescription of ß-blockers,
calcium channel blockers, nitrates, warfarin, and ACE inhibitors at discharge
(Table 3). Patients who were prescribed
aspirin at discharge had a 29% lower mortality by 1 year after discharge compared
with those who were not prescribed aspirin at discharge (relative risk [RR],
0.71; 95% confidence interval [CI], 0.54-0.94). Aspirin was not associated
with rates of readmission or mortality and readmission combined at 1 year
after discharge (Table 1).
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Table 3. Prescription of Aspirin at Discharge and 1-Year Mortality*
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To examine the strength of the association between aspirin and mortality,
we performed subgroup analyses by sex, age, presence of diabetes, creatinine
level at admission, the prescription of ACE inhibitors and ß-blockers
at discharge, and LVEF (Table 3).
In general, the beneficial effect of aspirin on mortality persisted within
each subgroup, except for patients who did not receive a prescription of ACE
inhibitors at discharge and patients who had a normal LVEF (>40%). Not all
of the comparisons were statistically significant, but the effect sizes were
consistent. Prescriptions of other NSAIDs were found in 26 patients. An analysis
combining aspirin and NSAID prescriptions did not substantially change the
results.
COMMENT
The current American Heart Association guidelines for patients with
established coronary artery disease recommend the use of aspirin.15 This recommendation is based on the results of numerous
randomized controlled trials that have indicated the efficacy of aspirin and
other antiplatelet agents.6 Despite this recommendation,
the use of aspirin for patients with heart failure, many of whom have coronary
artery disease, has been controversial.13 The
randomized trials for the treatment effect of aspirin generally did not report
a subgroup analysis of patients with heart failure. The trials that presented
data for patients with heart failure did not provide definitive results.16, 17 An analysis of a randomized trial
population of patients with heart failure suggested that there is a benefit
in using the medication.14 Physiology-based
studies have provided a rationale for a potential harm of inhibiting prostaglandins
in these patients. As a result, guidelines do not endorse the use of aspirin
for patients with heart failure, even for those with coronary artery disease.
This uncertainty seems to have affected practice. In our study, among
the patients who had coronary artery disease and did not have a contraindication
to aspirin, only 41% were prescribed aspirin at discharge, which goes against
the recommendations of the American Heart Association's secondary prevention
guidelines.15 Patients who were less likely
to be prescribed aspirin included those with a history of atrial fibrillation
and a high SUN level at admission. However, demographic and clinical characteristics
provided relatively little information about the decision to prescribe aspirin,
suggesting that there is great variability in practice that is not dictated
by the patient's condition.
The benefit associated with aspirin in this study was substantial. Overall,
patients who were prescribed aspirin at discharge had a 29% lower risk of
mortality at 1 year than the other patients. This reduction of risk among
patients with heart failure is comparable to that reported in the randomized
trials of patients with vascular disease.6
The benefit demonstrated in our results is also remarkably close to that estimated
from the patients enrolled in the SOLVD trial.14
Given the high risk of mortality among patients with heart failure, this relative
reduction in mortality translates into a benefit of 60 lives saved per 1000
patients treated. This estimate compares with the results of the trials that
found antiplatelet therapy to be associated with about 40 vascular events
avoided for every 1000 patients treated.
In exploratory analyses, we examined potential interactions of aspirin
with other patient characteristics and treatments. In general, we found a
consistent effect across subgroups. In some cases, the effect was not statistically
significant, but the effect size was similar to other groups and the overall
result.
Studies have suggested that aspirin may interfere with the beneficial
effects of ACE inhibitors.18, 19, 20, 21
In patients with reduced LVEF, the SOLVD trial found that antiplatelet agents
reduced the benefit from enalapril in the treatment trial but not in the prevention
trial. The investigators concluded that antiplatelet agents were associated
with a persistent though reduced benefit from enalapril.14
We found that aspirin was associated with a greater survival advantage among
patients who were prescribed ACE inhibitors, as well as those with a reduced
LVEF. We did not specifically examine the influence of aspirin on the benefit
of ACE inhibitors because that would require restricting the sample to ideal
candidates for ACE inhibitors, which would markedly reduce the power of the
study. Future studies clearly need to address directly whether there are specific
groups that do not benefit from aspirin use or in which aspirin antagonizes
ACE inhibitors. We also were not able to assess the combined effect of aspirin
and warfarin because so few patients were treated with both medications.
The study has several limitations. First, treatment was not randomly
allocated. However, our methods minimized the problems in drawing inferences
from observational data.22 We defined a cohort
of patients who had coronary artery disease and were free of contraindications
to aspirin. We designated discharge as the reference time at which baseline
clinical status was determined and from which follow-up was ascertained. We
collected detailed information to adjust for differences between the treatment
groups in their risk of mortality. While we cannot exclude the possibility
of residual confounding factors, our results are very close to what was reported
from randomized trials of patients with cardiovascular disease.
Second, we focused on patients who were aged 65 years or older in Connecticut,
and the generalizability of our findings to younger patients is not known.
Nevertheless, our study is relevant to more than 80% of the patients hospitalized
in the United States with heart failure and who are Medicare beneficiaries.
Moreover, our sample was not selected and represents the patients who are
seen in practice. The study, however, was conducted solely in Connecticut,
which has a high rate of aspirin use among patients discharged after an acute
myocardial infarction compared with the rest of the country.23
Consequently, our estimates of the use of aspirin for patients with heart
failure may be higher than what might be found in other regions, and the opportunity
to improve care may be even greater elsewhere.
Third, we ascertained the use of aspirin at discharge through retrospective
chart review. It is possible that aspirin use may not have been properly recorded
or that treatment may not have continued after hospital discharge. These limitations,
however, would have tended to diminish the association between aspirin use
and improved survival.
Fourth, we determined the presence of coronary artery disease based
on information from medical records. This method may have led to some misclassification
of patients. The inclusion of patients in our cohort who did not have coronary
artery disease would have tended to dilute the effect of aspirin unless it
is effective for heart failure that is caused by nonischemic factors.
Finally, we are limited in our ability to suggest a mechanism of the
benefit. We did not find a difference in the all-cause readmission rate or
the heart failure readmission rate. The analysis from the SOLVD trial found
that the reduction in mortality from antiplatelet agents was due to a reduction
in sudden death and a reduction in fatal myocardial infarction. No association
was found between antiplatelet agents and death associated with worsening
heart failure.14
In conclusion, this study, undertaken as part of a local effort to improve
care for Medicare beneficiaries with heart failure, identified a strong association
between the use of aspirin and lower mortality among patients with both heart
failure and coronary artery disease. The benefit of aspirin is consistent
with what would be expected from randomized trials of other groups of patients
with vascular disease. None of the analyses suggested that aspirin was associated
with a significant harm. Thus, increasing the use of aspirin at discharge
may be an excellent opportunity to improve the care of elderly patients with
heart failure. Further studies need to determine the impact of aspirin on
the benefit of ACE inhibitors.
AUTHOR INFORMATION
Accepted for publication August 31, 2000.
From the Sections of Cardiovascular Medicine, Department of Medicine
(Drs Krumholz and Radford) and Chronic Disease Epidemiology, Department of
Epidemiology and Public Health (Dr Krumholz) and the Department of Medicine
(Dr Chen), Yale University School of Medicine, New Haven, Conn; Yale-New Haven
Hospital Center for Outcomes Research and Evaluation, New Haven (Drs Krumholz
and Radford); and Qualidigm (formerly the Connecticut Peer Review Organization),
Middletown, Conn (Drs Krumholz and Radford). Dr Chen's current affiliation
is Merck and Co, Inc, West Point, Pa.
Reprints: Harlan M. Krumholz, MD, Yale University School of Medicine,
333 Cedar St, PO Box 208025, New Haven, CT 06520-8025 (e-mail: harlan.krumholz{at}yale.edu).
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