Long-Term Anti-Ischemic Effects of Angiotensin-Converting Enzyme Inhibition in Patients After Myocardial Infarction fn1

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MYOCARDIAL INFARCTION

Long-Term Anti-Ischemic Effects of Angiotensin-Converting Enzyme Inhibition in Patients After Myocardial Infarction AD F. M. VAN DEN HEUVEL, MD, WIEK H. VAN GILST, PHD, DIRK J. VAN VELDHUISEN, MD, FACC, ROB J. M. DE VRIES, MD, PETER H. J. M. DUNSELMAN, MD, PHD,* J. HERRE KINGMA, MD, PHD,† CAPTOPRIL AND THROMBOLYSIS STUDY (CATS) INVESTIGATORS‡

ON

BEHALF

OF THE

Groningen, Breda and Nieuwegein, The Netherlands

Objectives. This study was conducted to test the hypothesis that angiotensin-converting enzyme (ACE) inhibition reduces myocardial ischemia and related events after myocardial infarction (MI). Background. The oxygen demand/supply ratio of the myocardium is influenced by angiotensin II as a result of its arterial vasoconstrictive and inotropic effects and through its interaction with the sympathetic nervous system. Methods. We studied 244 patients who had been included in a double-blind, randomized, placebo-controlled, post-MI, ACE inhibition intervention study (Captopril and Thrombolysis Study [CATS]). All patients underwent exercise testing before and 3 and 12 months after hospital discharge. After 1-year double-blind treatment, all patients continued receiving single-blind placebo for 1 month. Results. Total exercise time increased in both groups after 3 months (placebo: 186 6 13 s; captopril: 169 6 12 s, p 5 0.8 between groups) and increased further after 1 year (placebo:

113 6 11 s; captopril: 133 6 13 s, p 5 0.7 between groups). There were also no differences in mean ST segment depression. During the 12 months, significantly fewer ischemia-related events occurred in the captopril group (82 vs. 52, p 5 0.015). This difference was found between 3 and 12 months but not during the first 3 months. After withdrawal from double-blind medication, nine ischemic events were reported in the captopril group compared with one in the placebo group (p 5 0.006 between groups). Conclusions. The present data show that captopril may reduce the incidence of ischemia-related events after MI, which becomes apparent after 3 months. However, no anti-ischemic effect was observed during exercise testing. After withdrawal from ACE inhibition, a high incidence of clinical events occurred, suggesting a rebound phenomenon. (J Am Coll Cardiol 1997;30:400 –5) ©1997 by the American College of Cardiology

The oxygen demand/supply ratio of the myocardium is influenced by angiotensin II as a result of its arterial vasoconstrictive and inotropic effects and through its interaction with the sympathetic nervous system. Angiotensin-converting enzyme (ACE) inhibitors have been shown (1– 4) to improve prognosis when administered after acute myocardial infarction (MI) and in patients with congestive heart failure (CHF). By a combination of hemodynamic and neurohumoral effects, ACE inhibitor therapy leads to improved left ventricular (LV) function. In addition, ACE inhibitors may possibly reduce the incidence

of recurrent myocardial ischemia (5,6). The latter phenomenon has not yet been fully elucidated because it is controversial whether ACE inhibition in patients has direct anti-ischemic effects (7–9). ACE inhibitors have been shown to inhibit platelet aggregation and thereby reduce the release of vasoconstrictors (thromboxane A2) (10) and stimulators of smooth muscle proliferation (platelet-derived growth factor) (11). Moreover, ACE inhibition inhibits the degradation of bradykinin, resulting in enhanced formation of prostacyclin and nitric oxide in the endothelium (12,13). The concept that ACE inhibitors may modify coronary vascular disease is supported by the recently published Trial on Reversing Endothelial Dysfunction (TREND) study (14), which showed beneficial effects of ACE inhibition on endothelial function. Most studies have shown that there is probably not a direct anti-ischemic effect but a long-term effect. We therefore investigated, in a post-MI, ACE inhibition intervention study (Captopril and Thrombolysis Study [CATS] [15]), the anti-ischemic effects of captopril. Patients in the CATS trial were not selected on the basis of left ventricular dysfunction, as in other, similar studies (Survival and Ventricular Enlargement study [SAVE] [6]). Assessments were performed at hospital discharge and 3 and

From the Departments of Cardiology/Thoraxcenter and Clinical Pharmacology, University Hospital Groningen, Groningen; *Department of Cardiology, Ignatius Hospital Breda, Breda; and †Department of Cardiology, Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands. ‡A complete list of the CATS Investigators appears in reference 15. This study was presented in part at the 46th Annual Scientific Session of the American College of Cardiology, Anaheim, California, March 1997 and was supported by a grant from Bristol Meyers Squibb, Woerden, The Netherlands. Manuscript received December 26, 1996; revised manuscript received April 14, 1997, accepted April 24, 1997. Address for correspondence: Dr. F. M. van den Heuvel, Department of Cardiology/Thoraxcenter, University Hospital Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. ©1997 by the American College of Cardiology Published by Elsevier Science Inc.

0735-1097/97/$17.00 PII S0735-1097(97)00183-6

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Abbreviations and Acronyms ACE 5 angiotensin-converting enzyme AP 5 angina pectoris CABG 5 coronary artery bypass graft surgery CATS 5 Captopril and Thombolysis Study LV 5 left ventricular MI 5 myocardial infarction PTCA 5 percutaneous transluminal coronary angioplasty SAVE 5 Survival and Ventricular Enlargement study SOLVD 5 Studies of Left Ventricular Dysfunction UAP 5 unstable angina pectoris

12 months after MI. Myocardial ischemia was evaluated by an exercise tolerance test and by assessment of ischemia-related events. Withdrawal effects, previously described in animal studies after discontinuation of ACE inhibitors in stroke and hypertension (16,17) but not been assessed after MI, were also studied. Accordingly, we also studied the influence of discontinuation of ACE inhibition after 12 months of treatment during a 1-month (month 13) single-blind, placebo treatment period.

Methods Study design. A detailed description of the rationale and design of the CATS trial has been published elsewhere (15). In brief, CATS was a double-blind, randomized study in 298 patients with a first MI, who were treated with captopril or placebo. The primary objective was to assess the effects of an ACE inhibitor on LV dilation, as assessed by echocardiography. Although very early treatment with captopril after MI did not reduce the occurrence of early dilation, it was associated with a reduced incidence of CHF. Patients who performed an exercise tolerance test at discharge, which was conducted according to the Bruce treadmill protocol, were included in this study. Written informed consent was obtained from each patient before entry into the study, and the protocol was approved by the institutional review boards at all participating hospitals. Study objective. The primary objective was to assess the efficacy of captopril versus placebo with regard to anti-ischemic effects during the first 3 months and during the period between 3 and 12 months. Treatment effects were assessed by changes in total exercise time and maximal ST segment depression during exercise tests at 3 months and 1 year after MI, with an exercise test at hospital discharge as baseline. Clinical ischemia-related events during follow-up were analyzed during the same periods. During the 1-month single-blind placebo period, after withdrawal from double-blind treatment (month 13), ischemia-related events were analyzed. Treatment protocol. Double-blind medication was initiated immediately on completion of the streptokinase infusion, provided that systolic blood pressure was stable and $100 mm Hg. The target maintenance dose of the double-

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blind study medication was 25 mg three times daily, administered from day 2 until 1 year after MI. Concomitant therapy with calcium antagonists or nitrates was instituted only for specific indications (e.g., angina pectoris [AP] and hypertension). The protocol did not prohibit the use of beta-adrenergic blocking agents for secondary prevention. The use of aspirin was also at the discretion of the local investigator. After 1 year, double-blind medication was stopped, and patients were treated with single-blind placebo for 1 month. Measurements. Exercise tolerance test. A symptom-limited Bruce treadmill exercise test was performed before and 3 and 12 months after hospital discharge. Exercise testing was conducted .8 h after the last dose of study medication. A three-lead electrocardiogram was recorded each minute during and until 6 min after completion of the exercise test. Standard criteria for ischemia were used (18). Ischemia-related events. Clinical ischemia-related events were scored during the first 3 months, during the period between 3 and 12 months and during the 1-month placebo period after withdrawal (month 13). These ischemia-related events were defined as unstable AP (UAP), recurrent MI, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft surgery (CABG) and death. UAP was defined as new-onset or worsening AP requiring hospital admission. The clinical adverse events were reviewed by the study directors and filed in the database. An independent data quality committee reviewed the data on clinical end points. In addition, the need for additional anti-ischemic medication was scored. Statistical analysis. According to the intention to treat principle, all outcome analyses were based on the treatment group to which the patients had been randomly assigned. In case of missing values, the last observation was carried forward. If not otherwise indicated, continuous variables were compared using analysis of variance for repeated measurements and categoric variables using Fisher exact test (twotailed). Results were considered statistically significant if p , 0.05, using the two-sided levels of significance. Statistical analyses were performed with SAS statistical software, version 6.08.

Results Baseline patient characteristics (Table 1, Fig. 1). During the enrollment period of the CATS trial, 298 patients were included, with 149 allocated to each treatment group. Of these 298, 244 (82%) were discharged with an exercise tolerance test (132 in the placebo group, 112 in the captopril group) (Fig. 1). Clinical and demographic characteristics of the 244 patients were similar to those of all 298 in the CATS cohort (15), and there were no statistically significant differences between the two groups (Table 1). Before hospital discharge, 15 patients in the placebo group and 16 in the captopril group underwent PTCA. Two patients underwent CABG in the placebo group and three in the captopril group (p 5 NS between groups).

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Table 1. Patient Characteristics

Age (yr) Men/women Pre-MI history of Hypertension Ischemic heart disease Diabetes mellitus Hyperlipidemia Smoking Beta-blockers Calcium antagonists Nitrates Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Killip class (%) I II LVESVI (ml/m2) LVEDVI (ml/m2) Cumu alpha-HBDH

Placebo Group (n 5 132)

Captopril Group (n 5 112)

59 6 1 108/24

59 6 1 83/29

22 (17%) 11 (8%) 10 (8%) 9 (7%) 78 (59%) 24 (18%) 20 (15%) 15 (11%) 126 6 10 77 6 7 80 6 8

27 (24%) 10 (9%) 10 (9%) 10 (9%) 78 (70%) 23 (21%) 12 (11%) 10 (9%) 129 6 9 78 6 6 83 6 8

76 24 29 6 11 60 6 14 1,403 6 1,089

80 20 27 6 12 59 6 16 1,219 6 879

Data presented are mean value 6 SD or number (%) of patients. Cumu alpha-HBDH 5 cumulative alpha-hydroxy butyrate in first 72 h; LVEDVI 5 left ventricular end-diastolic volume index; LVESVI 5 left ventricular end-systolic volume index; MI 5 myocardial infarction.

Exercise variables (Fig. 2). Total exercise time increased equally during the first 3 months in both groups (placebo: 186 6 13 s; captopril: 169 6 12 s [mean 6 SEM], p 5 0.8 Figure 1. Baseline patient characteristics. Numbers in parentheses 5 patients randomized to placebo and captopril groups, respectively. CABG 5 coronary artery bypass graft surgery; ETT 5 exercise treadmill test; PTCA 5 percutaneous transluminal coronary angioplasty; UAP 5 unstable angina pectoris.

Figure 2. Top, Change in total exercise time during Bruce treadmill protocol. *p , 0.05, baseline versus month 3 and month 3 versus 1 year. Middle, Change in maximal ST segment depression during Bruce treadmill protocol. *p , 0.05, baseline versus month 3 and month 3 versus 1 year. Bottom, Percent of exercise tests positive for ischemia ($0.1-mV ST segment depression) at baseline and 3 and 12 months. p 5 NS for all comparisons. Open bars 5 placebo; hatched bars 5 captopril.

between groups) and increased further after 1 year (placebo: 113 6 11 s; captopril: 133 6 13 s, p 5 0.7 between groups) (Fig. 2, top). During the first 3 months, there was a nonsignificant decrease in mean ST segment depression in both groups. After 1 year, changes in mean ST segment depression again did not show statistically significant differences between the groups (p 5 0.2) (Fig. 2, middle). The percent of exercise tests positive for myocardial ischemia ($0.1-mV ST segment depression) was also not different between groups at the three time points (Fig. 2, bottom). Ischemia-related events (Table 2). During the 12-month period, 82 events were observed in the placebo group versus 52 in the captopril group (p 5 0.015). These events occurred in 56 patients (42%) in the placebo group and 38 (34%) in the

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403

Table 2. Ischemia-Related Events 0 –3 mo

PTCA CABG MI AP/UAP Death Total No. (%) of patients

3–12 mo

Total (0 –12 mo)

Placebo

Captopril

Placebo

Captopril

Placebo

Captopril

12 2 1 21 1 37 36 (27%)

7 4 2 17 1 31 30 (27%)

5 5 1 32 2 45 42 (32%)

1 2 0 17 1 21* 20 (18%)‡

17 7 2 53 3 82 56 (42%)

8 6 2 34 2 52† 38 (34%)

*p 5 0.009, †p 5 0.015, ‡p 5 0.018 versus placebo. Data presented are number of events, unless otherwise indicated. AP 5 angina pectoris; CABG 5 coronary artery bypass graft surgery; MI 5 myocardial infarction; PTCA 5 percutaneous transluminal coronary angioplasty; UAP 5 unstable angina pectoris.

captopril group. This difference between the two groups was caused by fewer events after 3 months of treatment with captopril because the total number of ischemic events during the first 3 months was not significantly different between both groups (37 vs. 31, placebo vs. captopril, respectively [i.e., in 27% of patients in both groups]). In contrast, between 3 and 12 months, the total number of ischemia-related events was significantly higher in the placebo group (45 vs. 21, p 5 0.009, placebo vs. captopril, respectively). The number of patients who experienced these ischemia-related events was significantly higher in the placebo group than in the captopril group (placebo: n 5 42 [32%]; captopril: n 5 20 [18%], p 5 0.018). There were no differences in the use of anti-ischemic medication (Table 3). No significant correlation between LV dilation (and infarct size) and occurrence of ischemic events could be made. Withdrawal period (Table 4). In the month after withdrawal from double-blind study medication, nine ischemiarelated events occurred in the group that had previously been treated with captopril versus one ischemia-related event in the placebo group (p 5 0.006) (Table 4). Antianginal medication was prescribed in one patient in the placebo group (betablocker) and in 11 in the captopril group (p 5 0.005) (betablocker, n 5 2; calcium channel blocker, n 5 2; long-acting nitrate, n 5 6; beta-blocker and long-acting nitrate, n 5 1).

Discussion The main finding of the present study is that ACE inhibition, when started early after MI, reduces the incidence of ischemiarelated events within the first year. This effect does not become apparent until 3 months after MI and is not related to a reduction in exercise-induced ischemia. Furthermore, after withdrawal from ACE inhibition after 1 year treatment, a high incidence of ischemia-related events is observed. Reduction in ischemia-related events. The number of ischemia-related events in the present study was not significantly affected by captopril in the first 3 months but was significantly reduced compared with placebo in the following 9 months. These findings are in line with the results from earlier studies (5,6) that showed that long-term ACE inhibition in patients with depressed LV ejection fraction leads to a significant and substantial reduction in the incidence of major ischemic events. In the SAVE study (6), which studied the effect of captopril after MI in patients with depressed LV function (LV ejection fraction #0.40), the reduction in ischemic events became apparent after 12 months. In the Studies of Left Ventricular Dysfunction (SOLVD) trial (5), patients were required to have LV dysfunction (LV ejection fraction #0.35), and symptomatic CHF (SOLVD treatment arm) or asymptomatic LV dysfunction (SOLVD prevention arm). All

Table 3. Patients With Antianginal Medication 0 –3 mo

Beta-blocker Ca antagonist Nitrates Beta-blocker 1 Ca antagonist Beta-blocker 1 nitrate Ca antagonist 1 nitrate Triple therapy Total

3–12 mo

Placebo

Captopril

Placebo

Captopril

16 (12%) 5 (4%) 13 (10%) 4 (3%) 11 (8%) 11 (8%) 16 (12%) 76 (58%)

18 (16%) 10 (9%) 10 (9%) 2 (2%) 11 (10%) 2 (2%) 8 (7%) 61 (54%)

11 (8%) 11 (8%) 5 (4%) 3 (2%) 5 (4%) 4 (3%) 9 (7%) 48 (36%)

10 (9%) 11 (10%) 1 (1%) 3 (3%) 5 (4%) 1 (1%) 2 (2%) 33 (30%)

Data presented are number (%) of patients. Ca 5 calcium.

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VAN DEN HEUVEL ET AL. ANTI-ISCHEMIC EFFECT OF ACE INHIBITION AFTER MI

Table 4. Ischemia-Related Events During Withdrawal Period

PTCA CABG MI AP/UAP Death Total

Placebo

Captopril

0 0 0 0 1 1

0 0 3 5* 1 9†

*p 5 0.02, †p 5 0.006 versus placebo. Data presented are number of events. Abbreviations as in Table 2.

patients were enrolled at least 3 months after MI and were treated with enalapril. In these patients, the reduction in ischemic events also became apparent after an interval of 66 months. In contrast, the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Micardico (GISSI)-3 (19) and International Study of Infarct Survival (ISIS)-4 (20) trials showed no reduction in ischemic events despite a much larger number of events. This lack of effect on ischemic events may be explained by the short-term follow-up period (5 to 6 weeks). Taken together, these data may therefore suggest that the reduction of ischemic events by ACE inhibitors requires a longer exposure to the drug. In addition, the present data show that ACE inhibition is effective in preventing coronary ischemic events in a nonselected post-MI cohort, of which the majority had no CHF (21). The reduction in ischemic events may be due to multiple beneficial effects of ACE inhibition, but acute hemodynamic effects that include lowering of blood pressure (i.e., reduction in afterload) and coronary vasodilation are probably of lesser importance than long-term structural changes, such as an antiproliferative effect on vascular smooth muscle, prevention of atherosclerosis progression and myocardial hypertrophy and a favorable effect on endothelial function (10 –13,22–25). Most studies showed that there is probably not a direct anti-ischemic effect but a long-term effect, indicating that mechanisms such as platelet-derived growth factor are probably the most significant factors influenced by ACE inhibitors, which express their beneficial effects after long-term treatment. The present study shows that much of the beneficial effect of captopril was in reducing UAP or recurrent MI, probably related to plaque rupture. One possible mechanism of the beneficial effects seen in this study is that captopril reduced plaque instability (26). Such an effect would be compatible with the slow onset of the benefits observed in the present study and in the SAVE (6) and SOLVD (5) trials and with the observation that ACE inhibition has little if any effect on exertional AP (27). Absence of effect on ischemia during exercise. Captopril treatment in this study was not associated with an overall effect on exercise-induced ischemia. Moreover, after 3 months, placebo appeared to have a slightly more beneficial effect than captopril (p 5 0.3), but after 12 months the reverse was observed, again not statistically significant. These results may be compatible with previous short-term (7–9) trials that re-

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ported conflicting results on the effect of ACE inhibitors in patients with stable AP. These three previous studies lasted only 6 weeks to 3 months, which may correspond to the lack of a favorable effect during the first 3 months in the present study and may be related to the fact that ACE inhibitors induce no or minimal changes in rate–pressure product during exercise in normotensive patients, and the effect on myocardial oxygen demand appears to be modest (28). Daly et al. (27) showed that ACE inhibitors may improve exercise tolerance in patients with a high rate–pressure product by reducing it during exercise stress testing. In the present study, the exercise test was done .8 h after the last dose of medication, and only 25 mg of captopril three times daily was used; thus, there is a strong possibility that washout of captopril occurred during exercise stress testing. Had the exercise tests been performed during the active hemodynamic period, the effects of captopril might have been greater and may explain some of the results of the present study. It has been suggested (29) that when ischemia is observed in the presence of other conditions, such as CHF or increased neurohumoral activation, or both, the beneficial effects of ACE inhibitors on these modulating factors indirectly lead to a reduction in myocardial ischemia; again, this reduction may require long-term treatment. High incidence of ischemic events after withdrawal from ACE inhibition. During the 1-month placebo period, a higher incidence of ischemia-related events was reported, and more anti-anginal medication was prescribed in patients who had been previously been allocated to ACE inhibition. Although this finding is in line with previous observations (30), the number of events was small and is in contrast to the results of previous studies of other cardiovascular disease conditions. In a dog model of hypertension, Thybo et al. (16) showed that when higher doses of ACE inhibition were used, a less pronounced persistent effect after withdrawal from treatment was observed. ACE inhibition in rats was found (17) to cause long-lasting protection from stroke and mortality after the treatment period. An explanation for the present findings might be found in a substudy of the SOLVD (treatment arm) (30). Two weeks after withdrawal from that study, 13% of patients who had been withdrawn from enalapril developed ischemia-related events, whereas no patients previously randomized to placebo experienced an event. This result coincided with an increase in LV volumes to approximately the level observed before randomization, which might have led to higher oxygen demand. Another possible explanation might be the so-called rebound phenomenon that occurs after stopping ACE inhibition. It is known that under ACE inhibition, plasma renin activity increases, and in some organs, an elevation in mRNA in response to ACE may occur (31). Discontinuation of ACE inhibition results in a pronounced increase in angiotensin II and ACE activity, risk factors for MI (32). Another possibility is the decrease in bradykinin levels caused by an increase in ACE activity after stopping ACE inhibition (23). This decrease could have an adverse effect on the vascular wall (13). Because the ischemic events that occur during the withdrawal period (UAP and recurrent MI) are associated with plaque

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rupture, the clinical beneficial effects of ACE inhibitors may be linked to plaque stabilization, as discussed earlier. Limitations of the study. At the time of the design of the CATS study the beneficial effects of ACE inhibition had not yet been as well established as they are today. In the CATS trial, at the end of the study (month 12), echocardiography was performed and analyzed; depending on LV dimensions, it was decided whether treatment with captopril should be (re-) started. Up to then, all patients were treated with placebo for 1 month, which may be questionable today. Another limitation is that the present study was an analysis of secondary end points, which in general require more rigorous evaluation (33). However, these end points were predefined in the study protocol. Furthermore, the negative results of exercise testing do not exclude the possibility that ACE inhibition may have an effect on exercise-induced ischemia. It is therefore unclear whether other methods used to evaluate ischemia, in particular imaging techniques such as positron emission tomography, which are more sensitive than conventional exercise testing (34), would have detected an anti-ischemic effect, if present. Clinical implications. Because our data are based on patients with a previous MI and not on low ejection fraction or CHF, the observation of benefit in this cohort raises the possibility of a wider role for ACE inhibitors in preventing major ischemic events, possibly by plaque stabilization. This hypothesis should be tested in prospective studies in patients with ischemic heart disease (documented by positive exercise test results) and preserved LV function, with a long-term follow-up period.

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