Author + information
- Received July 28, 1998
- Revision received September 7, 1998
- Accepted September 15, 1998
- Published online January 1, 1999.
- John K French, MB, PhDa,* (, )
- David J Amos, MBa,
- Barbara F Williams, RNa,
- David B Cross, MBa,
- John M Elliott, MB, PhDa,
- Hamish H Hart, MBa,
- Miles G Williams, MBa,
- Robin M Norris, MDa,
- Noel G Ashton, BSc, LTha,
- Ralph M.L Whitlock, MBa,
- Stephanie C McLaughlin, PhDa and
- Harvey D White, MB, DSca
- ↵*Address for correspondence: Dr. John French, Department of Cardiology, Green Lane Hospital, Auckland 1003, New Zealand
Objectives. To determine whether early administration of captopril lessens infarct zone regional wall motion abnormalities when infarct artery blood flow is abnormal.
Background. The interaction between angiotensin-converting enzyme (ACE) inhibitor therapy, ventricular function and infarct artery blood flow has not been well described.
Methods. A total of 493 patients aged ≤75 years with first infarctions, presenting within 4 h of symptom onset, were randomized to receive 6.25 mg captopril, increasing to 50 mg t.d.s. or a matching placebo 2.1 ± 0.4 h after commencing intravenous streptokinase (1.5 × 106U over 30 to 60 min). Trial therapy was stopped 48 h prior to angiography at 3 weeks, to determine regional wall motion and infarct artery flow.
Results. There were no differences in ejection fractions or end-systolic volumes between patients randomized to receive captopril and those randomized to receive a placebo. Among patients with anterior infarction (n = 216), randomization to captopril resulted in fewer hypokinetic chords (40 ± 13; vs. 44 ± 13; p = 0.028) and a trend toward fewer chords >2 SD below normal (26 ± 17 vs. 30 ± 17; p = 0.052) in the infarct zone. In patients randomized to receive captopril who had anterior infarction and Thrombolysis in Myocardial Infarction (TIMI) 0–2, flow there were fewer hypokinetic chords (44 ± 12 vs. 50 ± 9; p = 0.043) and a trend toward fewer chords >2 SD below normal (33 ± 15 vs. 39 ± 13; p = 0.057). Patients receiving captopril who had anterior infarction and corrected TIMI frame counts >27 had fewer hypokinetic chords (42 ± 13 vs. 46 ± 12; p = 0.015) and fewer chords >2 SD below normal (27 ± 17 vs. 32 ± 17; p = 0.047). Captopril had no effect in patients with inferior infarction. There were 20 late cardiac deaths (median follow-up 4 years) in the captopril group and 35 in the placebo group (p = 0.036).
Conclusions. Randomization to receive captopril 2 h after streptokinase improved regional wall motion at 3 weeks. The greatest benefit was seen in patients with anterior infarction particularly when infarct artery blood flow is reduced.
Angiotensin-converting enzyme (ACE) inhibitor trials after myocardial infarction (MI) have randomized almost 100,000 patients within 24 h of symptom onset (1–4). At 5 weeks approximately five lives per 1,000 were saved in patients randomized to receive ACE inhibitors (1–3), with almost half the mortality benefit occurring on days 0 to 1 (5,6). Patients with anterior infarction have twice as much benefit (5,6).
Left ventricular dilatation (7)is a major determinant of increased mortality after acute MI, and is decreased by ACE inhibitors (8–11). Both left ventricular function and infarct-related artery patency independently influence long-term prognosis (12), with patency being a major determinant of left ventricular function and dilatation (12). However, there are limited data on the interaction of this relationship with ACE inhibition (13).
To examine the influence of early ACE inhibition on ventricular function and infarct artery blood flow, we randomized patients to receive captopril 2 h after streptokinase. We hypothesized that the major effect of captopril would occur in patients with anterior infarction and abnormal infarct artery flow.
From April 24, 1989, through December 7, 1994, patients aged ≤75 years presenting within 4 h of the onset of ≥30 min chest pain and with ≥1 mm of ST-segment elevation in two contiguous electrocardiographic leads, or ≥2 mm in leads V1–V3(14), were evaluated for enrollment. In addition to our previously reported contraindications against streptokinase (14,15), patients with prior MI who were receiving an ACE inhibitor and those with systolic blood pressure (BP) of <90 mm Hg 6 h after thrombolysis were excluded.
Patients were given oral aspirin (300 mg), intravenous streptokinase (1.5 × 106U over 30 to 60 min) and heparin (5,000 U were administered followed by a 48-h infusion of 1,000 U/h, adjusted to maintain the activated partial thromboplastin time between 90 and 110 s). Randomization to receive 6.25 mg captopril or matching placebo occurred 2 h after streptokinase was commenced if the systolic BP was ≥90 mm Hg. Dosing was increased, starting 2 h after randomization, as follows: 12.5 mg (3 doses), 25 mg (3 doses), then 50 mg 3 times daily for 3 weeks. Doses were lowered or omitted for hypotension. Trial therapy was stopped 48 h prior to angiography. Therapy, including ACE inhibitors, was at the physician’s discretion following angiography.
Beta-blocker therapy was continued or commenced on days 2 to 3 in patients without contraindications. Reinfarction was defined as 20 min of chest pain and elevation of creatine kinase above twice normal and/or the development of new Q waves (≥4 mV). Exercise testing (Bruce protocol) was performed at 3 weeks, unless contraindicated.
The primary end point was the effect of captopril on regional wall motion in the “area at risk” in the infarct zone in patients with anterior infarction. We also examined the interaction among therapy, infarct-related artery blood flow and ventricular function. Other secondary end points included the effects of captopril on inferior infarction, on ventricular volumes, on the ejection fraction, and on cardiac mortality (16). The adverse effects of captopril on blood pressure and renal function, and the occurrence of cardiogenic shock, were monitored.
Angiography was scheduled 3 weeks after infarction unless medically uncontrolled ischemia mandated earlier investigation (see Fig. 1). Revascularization was performed either for ischemia refractory to medical therapy or for ≥50% left main coronary stenosis.
Angiography was performed as previously described (15). Angiographic parameters were assessed blind to treatment allocation and patient outcome. The infarct-related artery was identified by either the site of electrocardiographic ST-segment changes, regional wall-motion abnormalities on ventriculography, or the presence of thrombus. Infarct-related artery flow was classified according to the Thrombolysis in Myocardial Infarction (TIMI) flow grade (17)and the corrected TIMI frame count, with normal described as ≤27 (mean ± 2 SD of individuals without infarction) (18). Ventricular volumes and the ejection fraction were calculated by an integration method, and regional wall motion was assessed by quantitative angiographic chord scores using a modification of the centerline method from the right anterior oblique ventriculogram (19). In this projection the “area at risk” or infarct zone for chord motion analysis was defined by the culprit lesion and the most distal landmark of the infarct-related artery (excluding nondominant left circumflex arteries, which were not profiled). Regional wall motion was analyzed with respect to the number of hypokinetic chords (below mean normal wall motion); the number of chords >1 SD and >2 SD below normal wall motion; the sum of hypokinetic chords (number of hypokinetic chords × SD from normal); and mean hyperkinetic chords in the noninfarct-zone (19).
To determine the effect of captopril in anterior infarction—the primary end point—the estimated sample size was 218 (α = 0.80, β = 0.05; two-tailed). A 20% difference between captopril and placebo in the number of hypokinetic chords >2 SD below normal mean motion in the infarct zone was hypothesized (19). Assuming that approximately 50% of patients had anterior infarction, and that 15% would not have ventriculograms suitable for analysis, the estimated total number of patients required was 510.
Analyses were performed on an intention-to-treat basis, with data expressed as mean ± SD. Kaplan-Meier survival curves were compared by log-rank tests. Continuous variables were compared by unpaired ttests. Multivariate logistic regression analyses were performed. For multiple comparisons, a one-way analysis of variance (ANOVA), with post hoc analysis by the Student-Newman-Keuls test, was performed.
Intravenous streptokinase was administered to 512 patients 3.1 ± 1.4 h after symptom onset (Fig. 1). Randomization was precluded in 13 patients because of persistent hypotension at 6 h; in 3 patients due to previous ACE inhibitor therapy, and in 3 because age and/or electrocardiographic (ECG) entry criteria were not fulfilled. Patients were administered either captopril (243 patients) or placebo (250 patients) 2.1 ± 0.4 h after commencing streptokinase (for baseline characteristics, see Table 1). Ventriculography was performed at 22 ± 6 days in 432 (88%) patients. The reasons for not performing ventriculography included 16 deaths, 6 previous MI (identified retrospectively), 9 coronary angiography only, and 30 patients declined (Fig. 1).
At 30 days, mortality (Table 2)was 2% in the captopril group and 4.8% in the placebo group (p = 0.078). Revascularization was performed in 18 patients (2 with left main stenosis) in the captopril group and 16 (3 with left main stenosis) in the placebo group. Reinfarction occurred in 13 and 17 patients randomized to receive captopril and placebo, respectively.
Over a median follow-up of 4 years (interquartile range 2.7 to 5.1 years) there were 20 cardiac deaths (11 with anterior MI) and 5 noncardiac deaths in the captopril group and 35 cardiac deaths (22 with anterior MI) and 10 noncardiac deaths in the placebo group (p = 0.036) (Fig. 2). The ACE inhibitors were prescribed to 32% of surviving patients in each group (Table 3).
Left ventricular function
Indices of left ventricular function including the ejection fraction, end-systolic volume and end-diastolic volume were similar in each group (Table 4). No differences existed between treatment groups whether arteries were patent (TIMI 2–3) or occluded (TIMI 0–1). Six patients had ventriculograms unsuitable for regional wall-motion analysis because of poor opacification or ventricular ectopy, and 18 patients had nondominant left circumflex infarct arteries (Fig. 1).
Regional wall motion and TIMI flow grades
Patients with anterior infarction in the captopril group had fewer hypokinetic chords, chords >1 SD and >2 SD below normal, and a smaller sum of hypokinetic chords compared with the placebo group (all p ≤ 0.05). Patients with anterior infarction and TIMI 0–2 flow in the captopril group had fewer hypokinetic chords (44 ± 12) compared with the placebo group (50 ± 9; p = 0.043), and a trend toward fewer chords >2 SD below normal (33 ± 15 vs. 39 ± 13; p = 0.057). The number of patients with either anterior or inferior infarction and occluded infarct arteries (TIMI 0–1 flow) was similar in each treatment group, and there were no significant treatment effects on regional wall motion (Table 5).
Regional wall motion and corrected TIMI frame counts
In patients with anterior infarction and corrected TIMI frame counts of >27, the number of hypokinetic chords in the captopril group was 42 ± 13 compared with 46 ± 12 in the placebo group (p = 0.015), and the number of chords >2 SD below normal was 27 ± 17 compared with 32 ± 17 in the placebo group (p = 0.047) (Table 6, Fig. 3). Captopril had no effect when corrected TIMI frame counts were <27.
In patients with patent infarct-related arteries there was a relationship between the corrected TIMI frame count examined as a continuous variable and both the number of hypokinetic chords (r = .19; p < 0.001) and the number of hypokinetic chords >2 SD below normal (r = .21; p < 0.001).
In the first 24 h, systolic blood pressure ≤90 mm Hg occurred in 87 patients in the captopril group and 58 in the placebo group (p = 0.003). No differences were seen in the frequency of death from cardiogenic shock (Table 2). Randomized therapy of 150 mg daily was not achieved in 17% of patients in the captopril group (mean dose 120 ± 53 mg) and in 11% of patients in the placebo group.
Predictors of late cardiac death
Univariate predictors of late cardiac death were: age (χ2= 19.2; p = 0.0001); ejection fraction (χ2= 14.1; p < 0.0001); end-systolic volume (χ2= 11.6; p = 0.0006); chords >2 SD below normal (χ2= 10.9; p = 0.001); exercise time (χ2= 8.69; p = 0.003); and randomization to receive captopril (χ2= 4.44; p = 0.035). Significant predictors on multivariate analysis were age and either the number of chords >2 SD below normal or the ejection fraction or the end-systolic volume (all p < 0.001).
We found that regional wall-motion abnormalities in the infarct zone were less in patients with anterior infarction who were randomized to receive captopril, compared with placebo, starting 2 h after the commencement of streptokinase therapy. The major benefit occurred in patients with anterior infarction and either TIMI 0–2 flow or a corrected TIMI frame count >27.
Randomized trials of early ACE inhibition after infarction (8–10,20–23)show that the mortality benefit appears within 24 h (5). This benefit on days 0 to 1 constituted 31% of the total survival benefit at 35 days in the Fourth International Studies of Infarct Survival (2)and 28% in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–3 (GISSI-3) (1).
Left ventricular function
The major predictor of survival after MI is left ventricular function (24,25), and end-systolic volume is a more powerful predictor than ejection fraction (7). Patency of the infarct-related artery has a major effect on left ventricular dilatation (23,26). Blood in patent infarct arteries and coronary veins helps provide a scaffold to limit dilatation (22,27,28). ACE inhibition after MI attenuates left ventricular dilatation, which commences within the first few hours after the onset of coronary occlusion (5,8,11,21,29–31).
Factors affecting the degree of ventricular remodeling and dilatation include the size and site of the infarct (anterior infarcts remodel more). Thrombolytic therapy reduces left ventricular dilatation (15), and the effect of ACE inhibitor therapy may be greater in patients who do not achieve normal infarct artery reperfusion and in those who do not fulfill criteria for reperfusion therapies.
The effects on left ventricular function of randomization to receive an ACE inhibitor therapy within 24 h of thrombolysis or angioplasty treatments for anterior MI have been examined in two randomized trials (32,33). In the Captopril and Thrombolysis Study (33)no changes in ventricular volumes, assessed by 2-D echocardiography, were found over 1 year in 298 patients receiving captopril (25 mg 3 times daily), compared with placebo, beginning 3.5 h after treatment with streptokinase (in comparison with 2.1 h in our study). The Healing and Early Afterload Reducing Therapy trial (32)performed 2-D echocardiography from days 1 to 14 following reperfusion therapy (77% thrombolysis, 23% primary angioplasty). Patients were randomized on day 1 (for 14 days) to receive 1) placebo (delayed) or 2) ramipril 0.625 mg daily (low) or 3) ramipril 1.25 mg increasing to 10 mg daily (early). Patients randomized to the highest ramipril dose showed the greatest improvement in ejection fraction compared with early, low, and delayed ramipril (4.9 ± 10.0% vs. 3.9 ± 8.2% vs. 2.4 ± 8.8%; p < 0.05). These studies (32,33)did not examine the effects of infarct artery blood flow on ventricular function.
Our study determined regional wall motion in the infarct zone, allowing examination of treatment effects with fewer ventriculograms (19), and was not powered to determine the effects of captopril on the ejection fraction, end-systolic, or end-diastolic volumes. The reduction of abnormal chord motion was approximately 15% at 3 weeks in patients with anterior infarction who were randomized to receive captopril. Because not all patients had ventriculograms, it is possible that the effects on ventricular function which we observed may have been greater in the initial hours and days after infarction affecting early survival.
Infarct-related artery flow
Patients with anterior infarction and TIMI 0–2 flow, or corrected TIMI frame counts of >27, who were randomized to receive captopril had fewer wall motion abnormalities compared with the patients randomized to placebo. There was a correlation between the corrected TIMI frame count, assessed as a continuous variable, and the number of hypokinetic chords >2 SD below normal (p < 0.001), albeit relatively weak (r = .21). Corrected TIMI frame counts have been shown to be a more reproducible measurement of infarct artery flow than TIMI flow grades (18). The differences in assessments of the effects of captopril on infarct zone regional wall motion with respect to infarct artery blood flow were modest when corrected TIMI frame counting was compared with TIMI flow grading (Tables 5 and 6).
One other study has examined the effect of infarct artery flow, ACE inhibition and outcome (13). The Survival and Ventricular Enlargement investigators (13)showed that patients (44% received thrombolysis) with occluded arteries who were randomized to receive captopril 3 to 16 days after MI had a reduction in a composite end point that included late mortality, decreased ventricular function and hospitalization. Captopril had no effect in patients with patent arteries.
The limitations of our study include the assessment of infarct artery coronary blood flow at 3 weeks, which represents the net effects of early and late reperfusion and reocclusion. The effect of captopril on anterior regional wall motion may have been different had it been examined with respect to 90-min infarct artery flow. Also, we did not have a prospective screening log.
We randomized a low-risk population and we cannot extrapolate our data to patients either ≥76 years or to those treated with other thrombolytic regimens. Late cardiac death was reduced (p = 0.036) in patients randomized to receive captopril, but our study was not powered for mortality and patients received randomized therapy for only 3 weeks. Late ACE inhibitor therapy was prescribed to 32% of patients in each group (Table 3), and was unlikely to have influenced differences in late survival.
Patients with anterior infarction benefit from very early administration of ACE inhibitor therapy, particularly when the infarct artery blood flow is abnormal. Whether long-term ACE inhibitor therapy is required when impaired infarct artery blood flow is improved by percutaneous or surgical revascularization is unknown.
The secretarial assistance of Clarissa Gould-Thorpe and the statistical advice of Heather Smith is gratefully acknowledged. Grant support was obtained from the Health Research Council of New Zealand and the National Heart Foundation of New Zealand.
- angiotensin-converting enzyme
- Thrombolysis in Myocardial Infarction
- myocardial infarction
- Received July 28, 1998.
- Revision received September 7, 1998.
- Accepted September 15, 1998.
- American College of Cardiology
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