Agents that block the renin-angiotensin system (RAS), including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, are of proven benefit in patients after ST-segment elevation myocardial infarction (STEMI). However, no studies have evaluated the benefit of pre-event use of RAS inhibitors before STEMI. A retrospective review was performed of patients admitted to a single hospital with the diagnosis of STEMI and without a history of coronary disease or the equivalent, including diabetes mellitus, peripheral vascular disease, or stroke. Patients were stratified according to the use of RAS inhibitors before STEMI. Compared to patients not taking RAS inhibitors, patients who were taking RAS inhibitors had a lower peak troponin I level (79 vs 120 ng/dl, p = 0.016). Of the patients who had medically treated hypertension, those receiving RAS inhibitors had a significantly lower peak troponin I compared to those receiving non-RAS agents (79 vs 130 ng/dl, p = 0.015), despite equivalent blood pressure across the 2 groups. The beneficial effect of RAS inhibitor pretreatment remained when concomitant aspirin and statin use were controlled for. In conclusion, in patients presenting with a first STEMI, pretreatment with RAS inhibitors conferred a cardioprotective effect. The mechanism of this benefit appears to be independent of an effect on blood pressure control and was not wholly due to the effect of concomitant use of other medicines known to be protective in patients with STEMI.
In the present study, we examined the protective effect of pretreatment with inhibitors of the renin-angiotensin system (RAS) on myocardial injury in the setting of a first ST-segment elevation myocardial infarction (STEMI) in patients without history of coronary artery disease (CAD) or the equivalent.
Methods
A retrospective review was performed using a computerized database of all patients admitted from January 2004 to April 2008 to Lehigh Valley Hospital (Allentown, Pennsylvania) with the diagnosis of STEMI. Patients included in the present review were those who had no history of coronary, cerebral, or peripheral vascular disease according to either clinical events or abnormal diagnostic test results. Additionally, the patients with a history of diabetes mellitus were not included in the present study. Patients with a pre-event history of angina were included if the diagnosis of CAD was not confirmed by diagnostic testing. All patients in the study underwent diagnostic cardiac catheterization within 4 hours of presentation or transfer to the study center. Data, including baseline characteristics, medical history, medicine use, admission laboratory study results, and hospital course, were extracted from an electronic medical record database.
The coronary anatomy and degree of stenosis were determined by the catheterizing physician with ≥2 views of each coronary artery. A coronary artery was defined as diseased if the major epicardial vessel or any major branches had >50% stenosis. The left ventricular ejection fraction was assessed qualitatively at cardiac catheterization by ventriculography in 2 planes. The serum lipid levels were assessed within 48 hours of admission, with the patient in a fasting state. The cardiac troponin I (TnI) levels were measured immediately on presentation and at 6 and 24 hours after admission. The patients were included in the RAS group if they had been treated with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers for ≥1 week before the index STEMI.
The baseline and end point analyses were performed with unpaired t tests for continuous data and chi-square tests for categorical data using the SigmaStat software (SYSTAT Software, San Jose, California). The institutional review board of the Lehigh Valley Health Network approved the study.
Results
A total of 511 patients met the criteria for inclusion in the present study. Of the total population, 266 were men (53%). The average patient age was 60 years (range 31 to 97). A total of 196 (36%) had a family history positive for premature CAD, and 267 (53%) were smokers. Of the 158 patients (31%) with a diagnosis of hypertension, 66 (13%) were taking RAS inhibitors (35 taking ACEIs and 31 taking angiotensin receptor blockers).
When the cohort was stratified by pretreatment with RAS inhibitors ( Table 1 ), the 2 groups were similar in terms of age, gender, and a family history of CAD. Fewer patients smoked in the RAS group than in the non-RAS group. In contrast, as would be expected, a significantly greater percentage of patients had hypertension in the RAS inhibitor group than the non-RAS inhibitor group. The use of both aspirin and statins was more common in patients receiving RAS inhibitors than in the remainder of the cohort. Compared to patients treated with non-RAS inhibitors, the patients receiving RAS inhibitors had lower systolic and diastolic blood pressures. However, neither of these reached statistical significance.
| Characteristic | RAS Use | p Value | |
|---|---|---|---|
| Yes (n = 66) | No (n = 445) | ||
| Men | 37 (56%) | 229 (52%) | 0.60 |
| Age (years) | 62.3 | 59.2 | 0.05 |
| Hypertension | 66 (100%) | 90 (20%) | <0.001 |
| Current smoker | 26 (39%) | 241 (54%) | 0.02 |
| Family history | 24 (36%) | 172 (38%) | 0.79 |
| Statin use | 17 (25%) | 68 (15%) | 0.028 |
| Aspirin use | 39 (59%) | 18 (4%) | <0.05 |
| Systolic blood pressure (mm Hg) | 124 | 130 | 0.22 |
| Diastolic blood pressure (mm Hg) | 69 | 77 | 0.32 |
| Total cholesterol (mg/dl) | 179.6 | 173.7 | 0.43 |
| Low-density lipoprotein (mg/dl) | 115.4 | 112.1 | 0.73 |
| High-density lipoprotein (mg/dl) | 37.9 | 37.2 | 0.60 |
| Triglycerides (mg/dl) | 173.0 | 149.5 | 0.10 |
| Serum creatinine (mg/dl) | 1.02 | 0.96 | 0.33 |
The geographic infarct location, coronary disease burden, and STEMI-related complications were compared between the RAS and non-RAS pretreated patients ( Table 2 ). Significantly more patients who had been pretreated with RAS inhibitors were found to have anterior myocardial infarction (54% vs 26%, p = 0.02); otherwise the number of diseased vessels, the incidence of left main CAD, the need for urgent coronary artery bypass grafting, and vasopressor use did not differ between the 2 groups. Likewise, the occurrence of ventricular tachycardia/fibrillation and death did not differ between the 2 groups.
| Variable | RAS Use | p Value | |
|---|---|---|---|
| Yes (n = 66) | No (n = 445) | ||
| Infarct location | |||
| Anterior | 36 (54%) | 117 (26%) | 0.02 |
| Lateral | 11 (16%) | 86 (19%) | 0.68 |
| Inferior | 28 (42%) | 247 (55%) | 0.07 |
| Posterior | 4 (6%) | 40 (9%) | 0.57 |
| No. of diseased vessels | |||
| 1 Vessel disease | 26 (39%) | 181 (41%) | 0.53 |
| 2 Vessel disease | 22 (33%) | 154 (34%) | |
| 3 Vessel disease | 19 (28%) | 106 (24%) | |
| Left main | 2 (3%) | 35 (8%) | 0.23 |
| Need for coronary artery bypass grafting | 5 (7%) | 45 (10%) | 0.58 |
| In-hospital death | 3 (4%) | 3 (1%) | 0.17 |
| Vasopressor use | 7 (10%) | 59 (13%) | 0.63 |
| Ventricular tachycardia/ventricular fibrillation | 12 (18%) | 91 (20%) | 0.37 |
The degree of myonecrosis due to the index STEMI was assessed for the RAS inhibitor pretreated and nonpretreated patients, as defined by the peak TnI ( Figure 1 ). The patients treated with RAS inhibitors had a significantly lower peak TnI compared to the those not treated with RAS inhibitors (79.8 vs 120.0 ng/dl, p = 0.016). This protective trend persisted but failed to reach clinical significance when we compared only those patients pretreated with ACEIs and nonpretreated patients (77.6 vs 120.0 ng/dl, p = 0.062, data not shown) or only those patients pretreated with angiotensin receptor blockers and nonpretreated patients (82.0 vs 120.0 ng/dl, p = 0.115, data not shown). The lack of significance in these subgroup analyses was likely due to the small size of the ACEI and angiotensin receptor blocker groups.
To determine whether the effect of RAS inhibitor pretreatment on the peak TnI level was wholly due to the attenuation of blood pressure by the RAS inhibitors and not specifically an effect due to modulation of the RAS system, we compared the peak TnI level between those patients pretreated with RAS inhibitors and those treated with other antihypertensive agents. Compared to patients treated with non-RAS antihypertensive agents, those treated with RAS inhibiting agents demonstrated a significantly lower peak TnI level (79.8 vs 146.2 ng/dl, p = 0.003; Figure 2 ).
