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(Circulation. 1996;94:1503-1505.)
© 1996 American Heart Association, Inc.

Articles

Reduction of Transient Myocardial Ischemia With Pravastatin in Addition to the Conventional Treatment in Patients With Angina Pectoris

Ad J. van Boven, MD; J. Wouter Jukema, MD, PhD; Aeilko H. Zwinderman, PhD; Harry J.G.M. Crijns, MD, PhD; Kong I. Lie, MD, PhD; Albert V.G. Bruschke, MD, PhD; on behalf of the REGRESS Study Group

the Department of Cardiology, Thoraxcenter, University Hospital Groningen (A.J.v.B., H.J.G.M.C., K.I.L.); the Department of Medical Statistics, State University, Leiden (A.H.Z.); the Interuniversity Cardiology Institute, Utrecht (A.J.v.B., J.W.J., A.H.Z., H.J.G.M.C., K.I.L., A.V.G.B.); and the Department of Cardiology, University Hospital Leiden (J.W.J., A.V.G.B.), the Netherlands.

Correspondence to Ad J. van Boven, MD, Thoraxcenter, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, Netherlands.

	Abstract

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Background Lipid-lowering therapy reduces cardiac morbidity and mortality. Less is known about its potential anti-ischemic effect.

Methods and Results In a 2-year prospective randomized placebo-controlled study, the effect of pravastatin 40 mg on transient myocardial ischemia was assessed. Forty-eight–hour ambulatory ECGs with continuous ST-segment analysis were performed in 768 male patients with stable angina pectoris, documented coronary artery disease, and serum cholesterol between 4 and 8 mmol/L (155 and 310 mg/dL). During the trial, patients received routine antianginal treatment. In the patients randomized to pravastatin, transient myocardial ischemia was present at baseline in 28% and after treatment in 19%; in the placebo group, it was found in 20% and 23% of the patients, respectively (P=.021 for change in percentage between two treatment groups; odds ratio, 0.62; 95% CI, 0.41 to 0.93). Ischemic episodes decreased by 1.23±0.25 (SEM) episode with pravastatin and by 0.53±0.25 episode with placebo (P=.047). Under pravastatin, the duration of ischemia decreased from 80±12 minutes to 42±10 minutes (P=.017) and with placebo, from 60±13 minutes to 51±9 minutes (P=.56). The total ischemic burden decreased from 41±5 to 22±5 mm·min in the pravastatin group (P=.0058) and from 34±6 to 26±4 mm·min in the placebo group (P=.24). Adjusted for independent risk factors for the occurrence of ischemia, the effect of pravastatin on the reduction of risk for ischemia remained statistically significant (odds ratio, 0.45; 95% CI, 0.22 to 0.91; P=.026).

Conclusions In men with documented coronary artery disease and optimal antianginal therapy, pravastatin reduces transient myocardial ischemia. (Circulation. 1996;94:1503-1505.)

Key Words: drugs • cholesterol • electrocardiography • ischemia

	Introduction

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Transient myocardial ischemia can be detected by AECG monitoring.^{1 2} It is most frequent in patients with extensive coronary artery disease and unstable angina.³ In patients with coronary artery disease, transient myocardial ischemia has been demonstrated to be related to an impaired prognosis.^{4 5 6} Recent studies have reported the beneficial effects of cholesterol-lowering therapy on morbidity and mortality in persons at high risk as well as in patients with established coronary heart disease.^{7 8} Mechanisms through which lipid lowering might act include regression of atheromatous plaques⁹ and attenuation of coronary endothelial dysfunction.¹⁰ Little is known as to whether this therapy has anti-ischemic properties. In view of these considerations, we hypothesized that cholesterol-lowering therapy might reduce transient myocardial ischemia when used in addition to conventional anti-ischemic therapy.

	Methods

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Ambulatory ECG monitoring during 48 hours was performed in patients with stable angina pectoris and cholesterol values of 4 to 8 mmol/L (155 to 310 mg/dL) who participated in the Regression Growth Evaluation Statin Study (REGRESS). Inclusion and exclusion criteria, as well as criteria for clinical events, have been described.⁹ All patients were referred for coronary angiography because of anginal complaints and a positive stress test. Primary management was left to the discretion of the participating center. Either the patients underwent PTCA or CABG or they continued medical therapy. Randomization to either pravastatin 40 mg once daily or placebo was stratified according to this type of primary treatment. Patients, physicians, and Holter technicians were blinded to the results of randomization throughout the study. The attending physicians were unaware of the results of the AECG.

AECG monitoring was performed before randomization and after the intervention (PTCA or CABG). In the medical management group, the second recording was performed after 2 years. Not included in the AECG study were patients with initial ST-segment abnormalities, for example, due to intraventricular conduction delay or right bundle-branch block. For the recording and analysis of transient myocardial ischemia, a three-channel Marquette system was used. During the time of the AECG, anti-ischemic medication was continued. Transient myocardial ischemia was defined as the presence of episodes showing 0.1 mV horizontal or downsloping ST-segment depression, 80 ms after the J-point, lasting for 60 seconds and separated by 60 seconds from the next ischemic episode.¹¹ Ischemic burden was defined as the product of ischemic duration in minutes multiplied by ST-segment depression in millimeters. AECG recordings of bad technical quality were rejected, and recording periods in which the ST segment altered due to a change in body position (during sleep) were not included in the study.

Statistical Analysis
The probability of transient myocardial ischemia was assessed with a logistic regression model using random patient effects with randomized therapy (placebo/pravastatin), time since randomization (before trial/during trial), and their interaction as fixed covariates.¹² Evidence for a positive effect of pravastatin on the occurrence of transient myocardial ischemia was tested for significance by testing the interaction parameter between therapy and time being zero. The effects of baseline patient characteristics on the occurrence of transient myocardial ischemia were also assessed with this model. The effect of pravastatin on the duration of the ischemia and total ischemic burden was assessed by mixed-model ANOVA. Results were shown as mean±SEM. Our sample consisted of patients with one and patients with two or more 48-hour ECG recordings. Both the logistic regression model and the mixed-model ANOVA correctly adjust the estimated effects of medication and other covariates for the possible correlation of repeated measurements.¹³

	Results

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In the pravastatin group, total cholesterol was lowered from 6.02 mmol/L (232.79 mg/dL) to 4.90 mmol/L (189.48 mg/dL), LDL cholesterol dropped from 4.30 mmol/L (166.28 mg/dL) to 3.24 mmol/L (125.29 mg/dL), and triglycerides dropped from 1.77 mmol/L (156.77 mg/dL) to 1.46 mmol/L (129.31 mg/dL). HDL cholesterol increased significantly from 0.93 mmol/L (35.96 mg/dL) to 1.01 mmol/L (39.06 mg/dL, P<.001 for all). In the placebo group, the cholesterol values remained constant.

In 768 patients (age, 56±8 years; 87% of the total REGRESS sample), one or more 48-hour AECGs were made. Clinical characteristics revealed no differences between the placebo and pravastatin groups except for a higher incidence of hypertension in the placebo group (124 versus 101, P=.02). In total, 1352 AECGs were made. The distribution of AECGs and the corresponding percentages showing transient myocardial ischemia throughout the study are listed in Table 1. Mean time intervals between the two (available) AECGs were 364 days in the placebo and 353 days in the pravastatin group. The time between PTCA and CABG and second AECG was 34±31 days.

View this table: [in this window] [in a new window]   Table 1. Distribution of Ischemia in Patients With and Without Pravastatin

In the patients randomized to pravastatin, transient myocardial ischemia was present at baseline in 28% and after treatment in 19%; in the placebo group, these values were 20% and 23%, respectively (P=.021 for change in percentage between two treatment groups). The OR for recurrent ischemia with pravastatin treatment was 0.62, and the 95% CI was 0.41 to 0.93 (Table 1 and Fig 1).

View larger version (12K): [in this window] [in a new window]   Figure 1. ORs and 95% CIs of the pravastatin treatment for transient myocardial ischemia (TMI), raw and adjusted for age/prior myocardial infarction (MI), and CABG/PTCA.

At baseline, 1534 episodes of ischemia in total were observed, varying from 1 to 41 per AECG, with a mean of 5.15±5.99 and a median of 3 episodes. The number of ischemic episodes decreased by 1.23±0.25 episode in the pravastatin group and by 0.53±0.25 episode in the placebo group (P=.047). The total duration of transient myocardial ischemia decreased from, on average, 60±13 minutes at baseline to 51±9 minutes during the trial in the placebo group (P=.56) and from 80±12 minutes to 42±10 minutes in the pravastatin group (P=.017). The total ischemic burden decreased from, on average, 34±6 mm·min at baseline to 26±4 mm·min in the placebo group (P=.24) and from 41±5 to 22±5 mm·min in the pravastatin group (P=.0058, Fig 2). Adjusted for independent risk factors for the occurrence of ischemia, such as age, history of myocardial infarction, and time, the effect of pravastatin on the reduction of risk for ischemia remained statistically significant (OR, 0.45; 95% CI, 0.22 to 0.91; P=.026). The positive effect of pravastatin also remained intact when adjusted for the cardiac interventions during the trial (CABG/PTCA) (OR, 0.42; 95% CI, 0.21 to 0.86; P=.018; Fig 1). Clinical events occurred after 2 years in 11% of the patients with pravastatin and in 19% of the patients with placebo (Table 2, P=.0042). No differences were found in the numbers of events between patients with and without ischemia.

View larger version (30K): [in this window] [in a new window]   Figure 2. Diagram of the percentage reduction in components of transient myocardial ischemia during the study in placebo patients (plac, open bars) and in pravastatin patients (prava, hatched bars). *P=.017 and **P=.0058.

View this table: [in this window] [in a new window]   Table 2. Clinical Events

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
In patients with stable angina pectoris, documented coronary artery disease, and optimal antianginal therapy, 40 mg/d pravastatin reduced transient myocardial ischemia as detected by 48-hour AECG ST-segment monitoring. The effect of pravastatin resulted in fewer ischemic episodes, a reduction in duration of ischemia, and a diminution in total ischemic burden per patient compared with placebo.

This anti-ischemic action of pravastatin has not been reported before. The effect of 5 years' treatment with pravastatin on cardiac events and total mortality in asymptomatic high-risk persons was recently studied.⁷ Simvastatin, another 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been studied in this respect in patients with documented coronary artery disease.⁸ The mechanism behind the overall reduction of events by the "statins" has not been clarified. In the REGRESS trial, in which quantitative coronary angiography was used, we demonstrated that pravastatin reduced progression of coronary artery disease.⁹ These coronary-angiographic changes caused by lipid lowering might in part represent a stabilization of lipid-rich coronary lesions, but the exact relation between angiographic measures and the composition of the plaque has never been the subject of clinical study. Improvement of coronary endothelial function by lipid lowering, measured at the epicardial coronary artery with intracoronary acetylcholine, is another proposed mechanism.¹⁰ From these previous studies, however, it is unclear whether the study population had signs of ischemia and whether lipid-lowering therapy reduced its activity.

Because coronary artery lesions in extensive coronary artery disease tend to be fixed and calcified, the expected anti-ischemic effect of pravastatin in our study might also be mediated by a normalization of the coronary endothelial function. In this view, the contribution of the coronary microcirculation and the effect of lipid lowering should be considered, as reported by Gould et al,¹⁴ who used positron emission tomography. In contrast to static laboratory tests for ischemia, our study tested the effect of lipid lowering on ischemia in daily life. It studied patients to whom maximal effort was offered to reduce ischemia, including medication, PTCA, and CABG. Of note, pravastatin had a beneficial anti-ischemic effect in addition to all this.

	Appendix

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Participating Centers
University Hospitals of Amsterdam (Free University and Academic Medical Center), Groningen, Leiden, Maastricht, Nijmegen, and Utrecht. Nonuniversity Hospitals: St Antonius, Nieuwegein; Medisch Centrum, Alkmaar; Medisch Spectrum, Enschede; and Reinier de Graaf Gasthuis, Delft.

	Selected Abbreviations and Acronyms

 

AECG = ambulatory ECG CABG = coronary artery bypass graft surgery OR = odds ratio PTCA = percutaneous transluminal coronary angioplasty

	Acknowledgments

 
The REGRESS study was sponsored by the Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.

Received May 20, 1996; revision received July 17, 1996; accepted August 1, 1996.

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