Aspirin and Angiotensin-Converting Enzyme Inhibitors Among Elderly Survivors of Hospitalization for an Acute Myocardial Infarction FREE

ASPIRIN AND angiotensin-converting enzyme (ACE) inhibitors are commonly used medications for patients who have had an acute myocardial infarction (AMI). The American Heart Association–American College of Cardiology Guidelines for the management of patients with acute myocardial infarction recommend the use of both medications for secondary prevention.¹ Aspirin is considered beneficial for all patients, and ACE inhibitors are targeted for patients with left ventricular systolic dysfunction, although the International Study of Infarct Survival (ISIS) 4, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI)-3 trial, and the Chinese Captopril Study alone and in aggregate suggest the use of ACE inhibitors for all patients with AMI.²

However, recent studies including subgroup analyses of randomized trials have suggested the possibility of an adverse interaction between aspirin and ACE inhibitors.^3- 9 Aspirin blocks prostaglandin production, whereas ACE inhibitors tend to increase it. Animal experiments have shown that aspirin can block ACE inhibitor–induced vascular relaxation.¹⁰ Studies have also suggested that the combination of aspirin and ACE inhibitors may have an adverse effect on renal function.^1,6- 7 Previously reported clinical studies, mostly post hoc analyses of randomized trial populations, have shown inconsistent findings on an adverse interaction between these 2 medications.^8- 9 There is clearly a need for more information, and a randomized trial is unlikely to address this issue soon.

Accordingly, the main purpose of the study was to evaluate the effect and interaction of aspirin and ACE inhibitors on mortality among elderly patients who survived a hospitalization for AMI and were considered ideal candidates for treatment with both medications. To perform this study, we evaluated the medical records of more than 200 000 hospitalizations of Medicare beneficiaries nationwide from 1994 to 1995 with a principal discharge diagnosis of AMI, as part of the Cooperative Cardiovascular Project (CCP). The project, a Health Care Financing Administration collaboration with health care professionals and peer review organizations, was designed to examine patterns of care and stimulate improvements in the care and outcomes of Medicare beneficiaries with an AMI.

The study sample was obtained from patients in the CCP cohort. The CCP cohort was identified from hospital bills in the Medicare National Claims History File of claims submitted under fee-for-service plans.¹¹ Medicare patients from nongovernmental acute care hospitals in the United States and Puerto Rico with a principal discharge diagnosis of AMI (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]¹² code 410) were selected for the initial cohort, except those with codes indicating follow-up care (in which the fifth digit of the ICD-9-CM code is 2). Sampling for the CCP cohort was conducted during an approximately 8-month period (varying in each state) between February 1994 and June 1995, except for the states in the pilot study (Alabama, Connecticut, Iowa, and Wisconsin), in which sampling took place during a 4-month period from August through November 1995. The hospitalizations that were abstracted from the CCP pilot states occurred after a feedback intervention based on an initial data collection from admissions in 1992 and 1993.

The initial CCP cohort consisted of 234 769 patients. For the current study, we applied the exclusion criteria shown in Table 1. Patients were excluded if they were less than 65 years of age (n = 17 593) or without a confirmed AMI (n = 31 186). An AMI was defined as a creatine kinase –MB fraction higher than 0.05, elevation of lactate dehydrogenase level more than 1.5 times normal and lactate dehydrogenase 1 level higher than lactate dehydrogenase 2 level, or any 2 of the following: chest pain, a 2-fold elevation of the creatine kinase level, or evidence of AMI on the electrocardiogram. For patients who were hospitalized more than once in the sample period (n = 23 773), only the first AMI admission was included. We excluded patients who died during the index infarction (n = 33 508) and those who were transferred to another acute care institution (n = 39 028) because we were unable to determine their discharge medications. We also excluded patients who were considered to have a terminal illness or metastatic cancer (n = 4617), since the goals of their treatment may not have focused on a survival benefit.

To examine the effectiveness of ACE inhibitors and aspirin in a cohort of patients who would be expected to benefit from these therapies, we further restricted the sample to patients who had documented indications and no documented contraindications ("ideal" candidates) for ACE inhibitors and aspirin. This ideal cohort would be expected to be eligible for enrollment in a clinical trial of these agents, if one were to be performed, and was a group of patients for whom the current guidelines would recommend both medications. Thus, we excluded patients with a left ventricular ejection fraction (LVEF) of 40% or more (n = 100 065) or that was undocumented (n = 86 123). Patients who had 1 of the following contraindications to ACE inhibitor therapy were also excluded from the current analysis: aortic stenosis (n = 14 657), documented ACE inhibitor intolerance (n = 2063), and systolic blood pressure less than 100 mm Hg at discharge (n = 31 141). Also excluded were patients with 1 of the following contraindications to aspirin therapy: documented bleeding episode (current or past; n = 54 492), bleeding risk (n = 4554), and documented allergy to aspirin (n = 9839). These exclusion criteria resulted in a final study sample of 14 129 patients (Table 1).

To obtain detailed clinical information for the CCP from the medical records, the Health Care Financing Administration established 2 clinical data abstraction centers. Trained technicians abstracted predefined variables from copies of the hospital record and entered them directly into a computer database by means of interactive software. Data reliability was monitored by random reabstractions, with overall variable agreement averaging more than 90%.

Prescription of ACE inhibitors and aspirin at discharge was determined from medical records, abstracted as names of discharge medications (doses were not abstracted). All discharge medications were reviewed and ACE inhibitors and aspirin were identified.

The outcome variable of the study was mortality within 1 year of discharge. This information was ascertained from the Medicare Enrollment Database, derived from the Master Beneficiary Record from Social Security Administration data, a valid source of vital status.¹³

Potential confounding factors were examined, including demographics (sex, age, and race), medical history and comorbidity (hypertension, diabetes, smoking, dementia, AMI, heart failure, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, stroke, preadmission ACE inhibitor use, and preadmission aspirin use), admission characteristics (cardiac arrest, shock, cardiomegaly, atrial fibrillation or flutter, LVEF, systolic and diastolic blood pressure, heart rate, respiratory rate, hematocrit, and creatinine, serum urea nitrogen, sodium, glucose, and albumin levels), hospital course (percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, cardiac catheterization, receipt of ACE inhibitors, and receipt of aspirin), hospital complications (hypotension, shock, bradycardia, and heart failure or pulmonary edema), and discharge characteristics (discharge disposition, heart rate, blood pressure, and prescription of aspirin, β-blockers, calcium-channel blockers, and warfarin sodium).

We evaluated the independent effect and interaction of aspirin and ACE inhibitors on 1-year mortality after discharge. Patients were classified, according to their discharge medication prescription, into 4 groups: no aspirin and no ACE inhibitor; aspirin only; ACE inhibitor only; and both aspirin and ACE inhibitor. Bivariate associations of patient demographic and clinical characteristics with the 4 medication groups were described first. Multivariate analyses were performed subsequently with the use of Cox regression models to examine the effect of aspirin alone, ACE inhibitor alone, and both aspirin and ACE inhibitor on mortality compared with patients who received neither of the treatments, adjusting for confounding effects. We also repeated the analysis by using the combination therapy group as the referent group to specifically evaluate the effect of ACE inhibitors and aspirin together compared with either medication alone. Assumptions of proportionality were examined and satisfied for the study variables. Potential confounding factors were identified on the basis of clinical relevance and significance of bivariate associations with ACE inhibitor and aspirin prescription at discharge and with 1-year mortality after discharge. These factors were sex, age, hypertension, dementia, diabetes, cigarette smoking, previous AMI, previous heart failure or pulmonary edema, previous stroke, cardiomegaly at admission, atrial fibrillation or flutter at admission, LVEF, hypertension at admission (systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg), admission heart rate, creatinine level, serum urea nitrogen level, cardiac procedures during hospitalization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or catheterization), hospital complications (bradycardia, heart failure, or pulmonary edema), discharge disposition, discharge heart rate, and discharge prescription of β-blockers. We repeated the main analyses in the following subgroups: sex, age (<80 years or ≥80 years), presence of heart failure before discharge, discharge prescription of β-blockers, and creatinine level (≤176.8 µmol/L [≤2.0 mg/dL], >176.8 µmol/L [>2.0 mg/dL]). The potential interaction of aspirin and ACE inhibitor prescription at discharge was further examined in a Cox regression model accounting for main effects of both medication prescriptions and confounding effects mentioned above.

A total of 14 129 patients aged 65 years or older with a confirmed AMI and left ventricular dysfunction who survived a hospitalization for AMI and did not have a contraindication to ACE inhibitor and aspirin use were included in the analysis. The mean (SD) age of the patients was 76.3 (7.2) years, and 29% were aged 80 years or older. There were more men (56%) than women. The majority (89%) were white. About 40% of the patients had had a previous AMI. The most frequent comorbid condition was hypertension (63%), followed by diabetes (36%) and heart failure (29%). Mortality at 1 year after discharge was 28% (n = 3946).

At discharge, ACE inhibitors were prescribed to 58% (n = 8179) of the patients, and aspirin was prescribed to 64% (n = 9088). Of all patients, 26% (n = 3708) received aspirin only, 20% (n = 2799) received ACE inhibitor only, 38% (n = 5380) received both, and 16% (n = 2242) received neither at discharge. The most common ACE inhibitors were captopril (44%) and enalapril maleate (34%).

Bivariate analysis of associations between demographic and clinical characteristics and patients in the 4 medication groups is shown in Table 2. Compared with patients who were prescribed aspirin only, patients who received ACE inhibitors only or both ACE inhibitors and aspirin were more likely to be younger, female, hypertensive, diabetic, and current smokers, and to have heart failure or pulmonary edema, cardiomegaly, severe left ventricular systolic dysfunction, tachycardia, atrial fibrillation or flutter, and worse renal function. They were also less likely to have a cardiac procedure during hospitalization and to be prescribed a β-blocker or calcium-channel blocker at discharge. Characteristics that showed the most significant differences (χ²>100) across the 4 medication groups were previous heart failure, cardiomegaly at admission, atrial fibrillation or flutter, LVEF, heart rate at admission, respiratory rate at admission, use of ACE inhibitors before admission or during hospitalization, use of aspirin before admission or during hospitalization, creatinine level greater than 176.8 µmol/L (2.0 mg/dL), serum urea nitrogen level greater than 14.3 mmol/L (40 mg/dL), glucose level greater than 11.1 mmol/L (200 mg/dL), cardiac procedures during hospitalization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty), heart failure or pulmonary edema, discharge disposition other than home, prescription of calcium-channel blocker, and prescription of warfarin (Table 2).

In the multivariate analysis, patients who received both aspirin and ACE inhibitors alone had a significantly lower 1-year mortality (adjusted risk ratio[ARR], 0.86 [95% confidence interval [CI], 0.78-0.95] and 0.85 [95% CI, 0.77-0.93], respectively) compared with patients who received neither aspirin nor ACE inhibitors at discharge (Table 3). Prescribing aspirin and ACE inhibitors together was associated with further reduction of mortality (ARR, 0.81; 95% CI, 0.74-0.88) from that seen in aspirin-only or ACE inhibitor–only groups, but compared with the other treatment groups, the difference was not statistically significant. Subgroup analysis by sex, age, heart failure before discharge, prescription of β-blockers at discharge, and creatinine level showed similar estimates for the benefit of the treatments (Table 3). Survival curves for each of the 4 treatment groups adjusting for differences in demographic and clinical characteristics by means of Cox regression models showed consistent results (Figure 1). When the interactive effect of aspirin and ACE inhibitors on 1-year mortality was further examined in a multivariate Cox regression model as an interaction term accounting for the main effects of both medications and the effects of confounding factors, there was a trend toward an interaction (P = .10).

In this observational study of Medicare beneficiaries who survived an AMI, we could find no evidence of an adverse interaction between ACE inhibitors and aspirin. Both ACE inhibitors and aspirin were independently associated with a reduction in mortality at 1 year after discharge. In exploratory analyses, the estimate of benefit was similar across a spectrum of patient subgroups. Given together, the medications appeared to provide a slightly greater reduction than what they accomplished alone, but we could not exclude the possibility that this finding occurred by chance. Our results most strongly suggest that the combination of aspirin and ACE inhibitors is not harmful for patients. Whether greater benefit is achieved by the combination remains unresolved, although it seems unlikely that there is a great synergism of effect.

This large observational study has several notable features. First, it provides a comprehensive view of the use of ACE inhibitors and aspirin in "real-world" patients. In addition to the main finding, our study demonstrated substantial opportunities to improve the care of patients after an AMI. According to the American Heart Association–American College of Cardiology clinical practice guidelines, all of the patients in this study should be considered ideal candidates for ACE inhibitors and aspirin. We excluded patients without indications for these medications as well as those who had documented contraindications. Despite receiving the strongest endorsement by the guidelines, only about a third of the patients received both medications, and about 1 in 6 received neither therapy. National and local efforts are under way to remedy this deficiency in care, and the next Health Care Financing Administration national sample, performed in 1990, is expected to show improvements in these rates.

Second, this study takes advantage of the "natural experiments" that arise from variability in care, when patients with similar clinical characteristics are treated differently, to make inferences about therapeutic effectiveness of these medications alone and together. Observational studies lack the unique strength of randomization that is present in trials and are vulnerable to bias from the nonrandom allocation of therapy to patients. To eliminate or reduce this bias, it is necessary to specify an appropriate reference time to determine eligibility and adjust for baseline differences in prognostic risk, develop inclusion criteria so that all patients would be eligible to receive the intervention, and classify patients by suitable criteria to enable adjustment for inequalities in the susceptibility to the outcome.

Using this approach, we determined benefits of ACE inhibitors and aspirin that are consistent with what has been published in randomized trials.^14- 17 We found that aspirin alone was associated with a 14% relative reduction in 1-year mortality. This benefit was similar to the 15% mortality reduction reported by the Antiplatelet Trialists.¹⁴ We found that ACE inhibitors alone were associated with a relative reduction in the risk of 1-year mortality of 15%. This estimate was similar to the relative reduction reported by trials such as Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), and Trandolapril Cardiac Evaluation (TRACE).^15- 17 The use of ACE inhibitors and aspirin together produced an effect that was somewhat greater than that produced by either of the medications alone, but not significantly so.

Previous clinical studies of this topic have not provided consistent results. Several studies have suggested that there may be an important interaction between ACE inhibitors and aspirin. Investigators from the Cooperative Scandinavian Enalapril Survival Study (CONSENSUS) II stratified patients according to their use of aspirin and found that, among those treated with enalapril, the risk of death was higher for patients taking aspirin at baseline.⁸ Investigators using the Studies of Left Ventricular Dysfunction (SOLVD) database reported that patients taking aspirin at baseline did not appear to benefit from enalapril.⁹ The results of these randomized trial cohorts are intriguing, but their generalizability is not known.¹⁸ Also, in these studies, the trial cohorts were used in an observational study design: the nonrandom assignment of patients to aspirin means that unexplained confounders might be associated with aspirin administration. We addressed this concern by examining the effectiveness of the medications in "ideal" patients, and by adjusting as thoroughly as possible for potential confounders, including characteristics known to be associated with medication administration.¹⁹

This topic has great importance, since some physicians may be departing from the guidelines because of a concern about an adverse interaction between these medications. Moreover, with the recent publication of the Heart Outcomes Prevention Evaluation (HOPE) trial, more individuals may be recommended for ACE inhibitors.²⁰ Since the HOPE trial focused on patients with vascular disease, many of them will already be taking aspirin. Physicians need information to guide their current practice and cannot wait for a randomized trial that will specifically address the potential interaction. The results of this study suggest that the current guidelines need not be altered. Until more definitive data are available, the best practice appears to be to combine the use of these medications in appropriate patients.

The study has several limitations in addition to its observational design. We included only patients who were aged 65 years or older, and the generalizability of our findings to younger patients is not known. Nevertheless, older patients represent a large proportion of individuals hospitalized with an AMI and are often excluded from trials. Thus, the focus on this group may also be considered a strength. In addition, this study included patients who survived an AMI. The absence of an adverse interaction in this group may not be generalizable to other settings where aspirin and ACE inhibitors are indicated.

Also, we ascertained the use of ACE inhibitors and aspirin at discharge through medical chart review. It is possible that these medications may not have been continued after hospital discharge or, in the case of ACE inhibitors, that the dose was inadequate. These limitations, however, would have tended to diminish the association between these medications and survival.

Finally, we did not have the opportunity to assess a wider range of outcomes such as quality of life or functional status. These outcomes are important and deserve examination but are beyond the scope of this study.

In conclusion, this study, undertaken as part of a national effort to improve care for Medicare beneficiaries with an AMI, failed to identify an adverse interaction between ACE inhibitors and aspirin. The benefit of ACE inhibitors and aspirin is consistent with the finding that would be expected from randomized trials—and together the effect appears slightly greater than with either therapy alone, although the added benefit was not statistically significant. These findings support the current guidelines but suggest the need for further studies to determine the value of the combination therapy beyond what can be achieved by either one alone.

Accepted for publication August 31, 2000.

The analyses upon which this publication is based were performed under Contract Number 500-96-P549, entitled "Utilization and Quality Control Peer Review Organization for the State of Connecticut," sponsored by the Health Care Financing Administration, Department of Health and Human Services. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The author assumes full responsibility for the accuracy and completeness of the ideas presented. This article is a direct result of the Health Care Quality Improvement Program initiated by the Health Care Financing Administration, which has encouraged identification of quality improvement projects derived from analysis of patterns of care, and therefore required no special funding on the part of this Contractor. Ideas and contributions to the author concerning experience in engaging with issues presented are welcomed.

We are indebted to all the health care professionals, hospitals, and organizations that contributed to the development and implementation of the Cooperative Cardiovascular Project, and to Maria Johnson for her truly outstanding editorial assistance.

Corresponding author and 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@yale.edu)