Angiotensin-converting enzyme (ACE) inhibitor use in patients at high risk of coronary artery disease has been associated with a decrease in the risk of myocardial infarction (MI) and death. However, it is unclear whether chronic use of these agents modifies the course and outcome of an acute coronary syndrome (ACS). This study assessed the association between chronic use of ACE inhibitors and clinical outcomes in patients with ACS. From 1999 through 2008, 13,632 Canadian patients with ACS were identified in the Global Registry of Acute Coronary Events (GRACE), the expanded GRACE (GRACE 2 ), and the Canadian Registry of Acute Coronary Events (CANRACE). Patients were stratified by previous use of an ACE inhibitor. Clinical characteristics, in-hospital treatment, and outcomes were compared between the 2 groups. Multivariable logistic regression analysis adjusting for GRACE risk score and other clinical factors was performed. Patients receiving an ACE inhibitor before the ACS had a higher prevalence of diabetes (40.6% vs 21.2%, p <0.001), previous MI (51.8% vs 23.3%, p <0.001), heart failure (18.0% vs 6.9%), and higher GRACE scores at presentation (133 vs 124, p <0.001). Multivariable analysis demonstrated no significant association between previous ACE inhibitor use and death (adjusted odds ratio [OR] 1.15, confidence interval [CI] 0.90 to 1.49, p = 0.27), in-hospital re-MI (adjusted OR 0.99, CI 0.78 to 1.25, p = 0.91), or the composite end point of death/re-MI (adjusted OR 1.01, CI 0.84 to 1.20, p = 0.94). In conclusion, previous use of an ACE inhibitor is not independently associated with improved in-hospital outcomes after an ACS.
Pivotal trials have demonstrated a favorable effect of chronic angiotensin-converting enzyme (ACE) inhibitor use on the incidence of myocardial infarction (MI) and death in ambulatory patients at high risk for cardiovascular events. In addition, beneficial outcomes have been reported with early administration of these agents in patients who have developed an acute coronary syndrome (ACS). Although experimental animal models have suggested that ACE inhibitor use before an ACS may ameliorate the adverse consequences of ACS, it is less clear whether these observations translate into improved clinical outcomes when an ACS occurs. Therefore, we analyzed data from the Global Registry of Acute Coronary Events (GRACE), the expanded GRACE (GRACE 2 ), and the Canadian Registry of Acute Coronary Events (CANRACE) to determine the association between previous use of ACE inhibitor and the extent of myocardial injury and in-hospital outcomes in patients presenting with an ACS.
Methods
The study designs of the GRACE, GRACE 2 , and CANRACE have been previously described. In brief, the GRACE was a prospective multinational registry that enrolled patients with ACS from 1999 through 2007. The GRACE 2 was an expansion of the GRACE, which permitted additional hospitals to enroll patient with ACS from 2003 through 2007. In Canada, patient enrollment continued in 2008 as the CANRACE. Eligible patients were ≥18 years of age with a presumptive diagnosis of an ACS with ≥1 of the following findings: abnormal cardiac biomarkers, electrocardiographic changes consistent with an ACS, or previous coronary artery disease. Patients were excluded from the registry if the ACS was thought to be precipitated by a significant co-morbidity such as trauma, gastrointestinal bleeding, or operation or procedure or if the patient was already hospitalized when the patient developed the qualifying ACS. To recruit a less biased sample, hospitals were instructed to enroll their first consecutive 10 to 20 patients each month. Of note, only patients treated at Canadian hospitals were analyzed in the present study. The local hospital ethics review board approved the study, and where required, informed consent was obtained from participating patients.
Standardized reporting forms were completed by local study coordinators or physicians to record patient demographics, clinical history (cardiovascular risk factors, previous MI, stroke, and heart failure [HF]), presenting features (electrocardiogram, cardiac biomarkers, and clinical presentation including ST-segment elevation MI [STEMI], non-STEMI, presence of HF, shock, ventricular arrhythmias, and cardiac arrest), medication use (before and during hospitalization), in-hospital management (e.g., cardiac catheterization and coronary revascularization), and clinical events (myocardial re-infarction HF/shock, ventricular arrhythmias, and death).
STEMI was defined as ≥1-mm ST-segment elevation in 2 contiguous leads or a new left bundle branch block accompanied by ≥1 positive cardiac biomarker for necrosis. Non-STEMI was diagnosed when ≥1 positive cardiac biomarker was present without new ST-segment elevation on the index electrocardiogram. Unstable angina pectoris was diagnosed when cardiac biomarkers were within the reference range. Myocardial re-infarction was defined as a repeated increase of cardiac biomarkers >24 hours after admission.
Patients in the study cohort were categorized into 1 of 2 groups: patients with ACE inhibitor use before the ACS and those without ACE inhibitor use before the ACS. These groups were compared to assess for potential differences in baseline characteristics, treatment, and rates of in-hospital death and myocardial (re-)infarction.
Demographic and clinical features were reported for each group. Continuous variables were reported as medians with 25 th and 75 th percentiles. Categorical variables were described as percentages and frequencies. Comparisons of continuous and categorical variables were made with Mann–Whitney U and chi-square tests, respectively.
Multivariable logistic regression analysis adjusting for independent prognosticators in the validated GRACE risk score for in-hospital death and myocardial (re-)infarction was undertaken to determine the adjusted odds ratio (OR) and associated 95% confidence interval (CI) of myocardial necrosis (as determined by the presence of increased cardiac biomarkers), in-hospital death, and re-MI associated with previous ACE inhibitor use. Because previous MI, HF, diabetes, and concomitant medication use (i.e., previous aspirin, β blocker, angiotensin receptor blockade [ARB], and statin) are associated with ACE inhibitor use and may affect outcomes, these variables were included in the final model. The final multivariable regression model was evaluated for discrimination, and goodness of fit with the Hosmer–Lemeshow test with a p value >0.05 indicated an acceptable fit. We assessed for interaction between chronic ACE inhibitor use and ACS type (i.e., STEMI, NSTEMI, and UAP), and performed additional analyses after excluding patients with prior history of MI, HF, and ARB use. To confirm the robustness of our results, we also performed a propensity score analysis using stratification by quintiles. The propensity model included all baseline characteristics listed in Table 1 . Statistical analysis was performed using SPSS 15.0 (SPSS, Inc., Chicago, Illinois).
| Previous ACE Inhibitor Use | No Previous ACE Inhibitor Use | p Value | |
|---|---|---|---|
| (n = 4,308) | (n = 9,324) | ||
| Age (years) ⁎ | 69 (60–79) | 65 (55–76) | <0.001 |
| Men | 66.0% | 67.0% | 0.13 |
| Medical history | |||
| Current smoker | 21.1% | 29.5% | <0.001 |
| Diabetes mellitus | 40.6% | 21.2% | <0.001 |
| Hypertension | 82.2% | 50.2% | <0.001 |
| Angina | 60.8% | 34.3% | <0.001 |
| Dyslipidemia | 68.9% | 47.0% | <0.001 |
| Peripheral vascular disease | 13.1% | 6.6% | <0.001 |
| Transient ishemic attack/stroke | 13.6% | 7.0% | <0.001 |
| Myocardial infarction | 51.8% | 23.3% | <0.001 |
| Percutaneous coronary intervention | 29.0% | 12.3% | <0.001 |
| Coronary artery bypass graft surgery | 20.3% | 8.6% | <0.001 |
| Heart failure | 18.0% | 6.9% | <0.001 |
| Atrial fibrillation | 14.1% | 7.1% | <0.001 |
| Prehospital medication use | |||
| Aspirin | 64.8% | 33.1% | <0.001 |
| Clopidogrel | 21.6% | 7.2% | <0.001 |
| β Blocker | 58.4% | 23.6% | <0.001 |
| Statin | 65.3% | 28.2% | <0.001 |
| Angiotensin receptor blocker | 6.6% | 14.3% | <0.001 |
| Diuretics | 38.7% | 17.8% | <0.001 |
| Nitrates | 33.9% | 14.3% | <0.001 |
| Clinical presentation | |||
| Systolic blood pressure (mm Hg) ⁎ | 142 (124–162) | 144 (125–161) | 0.08 |
| Diastolic blood pressure (mm Hg) ⁎ | 78 (66–89) | 80 (70–92) | 0.08 |
| Heart rate (beats/min) ⁎ | 78 (66–94) | 78 (66–92) | 0.13 |
| Killip class | <0.001 | ||
| I | 78.9% | 86.3% | |
| II | 13.1% | 9.2% | |
| III or IV | 8.2% | 4.6% | |
| Cardiac arrest | 1.4% | 1.5% | 0.31 |
| ST-segment elevation | 16.7% | 28.3% | <0.001 |
| ST-segment depression | 29.5% | 29.8% | 0.36 |
| Positive initial cardiac biomarkers | 43.6% | 49.9% | <0.001 |
| Creatinine (μmol/L) ⁎ | 98 (81–122) | 90 (77–108) | <0.001 |
| Global Registry of Acute Coronary Events risk score ⁎ | 133 (107–164) | 124 (100–152) | <0.001 |
Results
From 1999 through 2008, 13,632 Canadian ACS patients from 55 hospitals without a documented contraindication to ACE inhibitor use and with complete data on previous ACE inhibitor use were included; 28% of the cohort developed a STEMI, 47% a non-STEMI, and 25% unstable angina pectoris.
Overall, 31.6% (n = 4,308) of the cohort received an ACE inhibitor before ACS presentation. Table 1 presents the relevant demographic and clinical features of the cohort at the time of the ACS. Table 2 lists the therapies received during the ACS hospitalization. Variations in use of evidence-based medications and coronary interventions were present between the 2 groups.
| Previous ACE Inhibitor Use | No Previous ACE Inhibitor Use | p Value | |
|---|---|---|---|
| (n = 4,308) | (n = 9,324) | ||
| Medication use within first 24 hours of admission | |||
| Aspirin | 90.3% | 92.9% | <0.001 |
| Clopidogrel | 62.9% | 66.9% | <0.001 |
| Warfarin | 7.5% | 4.1% | <0.001 |
| Any heparin | 85.2% | 88.3% | <0.001 |
| Glycoprotein IIb/IIIa inhibitor | 6.6% | 10.9% | <0.001 |
| Thrombolytics | 7.9% | 15.1% | <0.001 |
| Angiotensin-converting enzyme inhibitor | 77.6% | 47.3% | <0.001 |
| β Blocker | 78.2% | 77.8% | 0.61 |
| Angiotensin receptor blocker | 6.0% | 12.8% | <0.001 |
| Calcium channel blocker | 28.5% | 17.7% | <0.001 |
| Statin | 73.4% | 66.4% | <0.001 |
| Intravenous inotropic agent | 3.1% | 3.1% | 0.51 |
| In-hospital management | |||
| Cardiac catheterization | 53.9% | 63.8% | <0.001 |
| Percutaneous coronary intervention | 26.2% | 38.0% | <0.001 |
| Coronary artery bypass graft surgery | 3.3% | 3.2% | 0.48 |
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