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ACC/AHA 2008 Performance Measures for Adults With ST-Elevation and Non-ST-Elevation Myocardial Infarction

ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease
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J Am Coll Cardiol, 2003; 42:2049-2059, doi:10.1016/j.jacc.2003.07.027
© 2003 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CLINICAL TRIALS

Effects of angiotensin-converting enzyme inhibition on transient ischemia

The quinapril anti-ischemia and symptoms of angina reduction (QUASAR) trial

Carl J. Pepine, MD, MACC*,*, Jean-Lucien Rouleau, MD, FACC{dagger}, Karen Annis, MPH{ddagger}, Anique Ducharme, MD§, Patrick Ma, MD, FACC||, Jacques Lenis, MD, FACC, Richard Davies, MD, FACC#, Udho Thadani, MD, FACC**, Bernard Chaitman, MD, FACC{dagger}{dagger}, Harry E. Haber, MPH{ddagger}, S. Ben Freedman, MB, PhD, FACC{ddagger}{ddagger}, Milton L. Pressler, MD, FACC{ddagger}, Bertram Pitt, MD, FACC§§ QUASAR Study Group

* University of Florida College of Medicine, Division of Cardiovascular Medicine, Gainesville, Florida, USA
{dagger} University Health Network, Division of Cardiology, Toronto, Ontario, Canada
{ddagger} Pfizer, Inc., Ann Arbor, Michigan, USA
§ Montreal Heart Institute, Montreal, Quebec, Canada
|| Heart Health Institute, Research Center, Calgary, Alberta, Canada
Invascor Clinical Research, Quebec, Canada, Centre Hospitalier Pierre Boucher, Longueuil, Quebec Canada
# Ottawa Civic Hospital, Ottawa, Ontario, Canada
** University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Cardiology Section, Oklahoma City, Oklahoma, USA
{dagger}{dagger} St. Louis University ECG Core Laboratory, St. Louis, Missouri, USA
{ddagger}{ddagger} Concord Repatriation General Hospital, Department of Cardiology, University of Sydney, Sydney, Australia
§§ University of Michigan Medical Center, Department of Medicine, Ann Arbor, Michigan, USA

Manuscript received April 25, 2003; revised manuscript received July 9, 2003, accepted July 22, 2003.

* Reprint requests and correspondence: Dr. Carl J. Pepine, University of Florida College of Medicine, Division of Cardiovascular Medicine, P.O. Box 100277, Gainesville, Florida 32610-0277, USA
pepincj{at}medicine.ufl.edu


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 APPENDIX
 References
 
OBJECTIVES: We sought to determine whether angiotensin-converting enzyme inhibition (ACE-I) (i.e., quinapril) prevents transient ischemia (exertional and spontaneous) in patients with coronary artery disease (CAD).

BACKGROUND: It is known that ACE-I reduces the risk of death, myocardial infarction (MI), and other CAD-related outcomes in high-risk patients. Numerous studies have confirmed that ACE-I improves coronary flow and endothelial function. Whether ACE-I also decreases transient ischemia is unclear, because no studies have been adequately designed or sufficiently powered to evaluate this issue.

METHODS: Using a randomized, double-blinded, placebo-controlled, multicenter design, we enrolled 336 CAD patients with stable angina. None had uncontrolled hypertension, left ventricular (LV) dysfunction, or recent MI, and all developed electrocardiographic (ECG) evidence of ischemia during exercise. They were randomly assigned to one of two groups: 40 mg/day quinapril (n = 177) or placebo (n = 159) for 8 weeks. Patients then entered an additional eight-week treatment phase to examine the full dose range. Those assigned to 40 mg quinapril continued that dose and those assigned to placebo were titrated to 80 mg/day. Treadmill testing, the Seattle Angina Questionnaire, and ambulatory ECG monitoring were used to assess responses at baseline and at 8 and 16 weeks.

RESULTS: The groups did not differ significantly at entry or in terms of indexes assessing myocardial ischemia at 8 or 16 weeks of treatment. In this low-risk population, ACE-I was not associated with serious adverse events.

CONCLUSIONS: Our findings suggest short-term ACE-I in CAD patients without hypertension, LV dysfunction, or acute MI is not associated with significant effects on transient ischemia.

Abbreviations and Acronyms
  ACE-I = angiotensin-converting enzymeinhibition/inhibitor
  CAD = coronary artery disease
  ECG = electrocardiogram/electrocardiographic
  ETT = exercise treadmill test/testing
  LV = left ventricular
  MI = myocardial infarction
  QUASAR = Quinapril Anti-ischemia and Symptoms of Angina Reduction trial

Numerous trials have documented that angiotensin-converting enzyme inhibition (ACE-I) reduces the risk of death, myocardial infarction (MI), and other adverse outcomes in patients with or at high risk of coronary artery disease (CAD), acute MI, or left ventricular (LV) dysfunc-tion (1–8). Recent evidence also indicates ACE-I improves coronary flow and endothelial functional abnormalities that may limit blood flow in patients with ischemic heart disease (9–12). Other reports, when considered in aggregate, have suggested variability in the effects ACE-I in patients with signs or symptoms of myocardial ischemia (13–35). However, methodologic limitations related to a small sample size, confounding conditions, and other factors prevent definitive conclusions from these reports. Clearly, appropriately powered, randomized, placebo-controlled trials in lower risk chronic ischemic heart disease patients are necessary to better address whether ACE-I reduces the risk of adverse outcomes by preventing transient ischemia. Accordingly, we conducted a controlled trial in low-risk patients with chronic, stable ischemia to assess the effects of ACE-I (quinapril) on transient myocardial ischemia.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 APPENDIX
 References
 
The Quinapril Anti-ischemia and Symptoms of Angina Reduction (QUASAR) trial, a double-blinded, randomized, placebo-controlled, parallel-group trial involving 47 sites (Appendix), was designed to investigate whether ACE-I with quinapril lessens the frequency and severity of transient ischemia in low-risk patients with CAD. Transient ischemia was defined as ischemia occurring during exercise and ischemia occurring spontaneously. Quinapril was chosen because it has a high affinity for ACE in the vascular wall, slowly dissociates once bound (36), and improves coronary flow (11) and coronary endothelial function (9) in the patient population of interest.

The study was investigator-initiated and industry-sponsored. A steering committee was responsible for protocol development and direction of study conduct. The protocol was approved by local ethics committees, and all patients provided written, informed consent.

Patients.   Men or women (postmenopausal or nonpregnant using adequate contraception) were eligible if they had CAD documented by any of the following: ≥60% diameter stenosis of one or more major coronary artery, Q-wave MI, or an abnormal stress test by echocardiography or radionuclide imaging. Patients meeting these criteria were also required to have had an abnormal exercise treadmill test (ETT), using the Asymptomatic Cardiac Ischemia Pilot (ACIP) protocol (37), limited by angina pectoris occurring within 8 min and accompanied by an ischemic-type ST-segment response. This was defined as ≥1.0-mm ST-segment depression in two or more contiguous electrocardiographic (ECG) leads over at least three beats that was reversible. Medications included 80 mg/day aspirin or another antiplatelet agent and those required for angina pectoris (e.g., sublingual nitroglycerin, long-acting nitrates, calcium antagonists, beta-blockers), provided the drug and dose had been stable for at least two weeks before entering the baseline period.

Exclusions included conditions: 1) likely to confound the interpretation of response measures (e.g., severe bronchospastic lung disease, cor pulmonale, recent unstable angina, angina precipitated by correctable anemia or metabolic factors, significant uncorrected valvular or congenital heart disease, recent [6 months] revascularization, LV hypertrophy with ST-T-segment abnormalities, paced rhythm, uncontrolled ventricular or supraventricular arrhythmias, left or right bundle branch block, atrioventricular conduction defects and/or resting ST-segment depression [>0.9 mm], insulin-dependent or uncontrolled type 2 diabetes [HbA1C >9], and/or initiation or termination of hormone replacement therapy or lipid-lowering drugs within two months); 2) in which ACE-I might pose an increased risk of severe hypotension (e.g., renal artery stenosis, hypotension); and 3) where ACE-I was definitely indicated (e.g., recent MI, uncontrolled hypertension, heart failure). Patients with any exposure to ACE-I within two weeks of entering the baseline period also were excluded.

Study design.   The QUASAR design had three study periods (Fig. 1). After a two- to four-week, single-blinded, placebo-baseline period, patients were randomly assigned to a double-blinded treatment period with placebo (group 1) or 40 mg/day quinapril (group 2) for eight weeks. They then entered an extended double-blinded treatment period (additional eight weeks) during which group 1 was given 80 mg/day quinapril and group 2 continued 40 mg/day quinapril. Randomization was stratified by center and beta-blocker use within the previous 30 days (absent or present) to ensure a 1:1 distribution in each group. Patients performed an ETT at the end of the baseline period (single-blinded placebo, period 1) and at 8 weeks (double-blinded treatment, period 2) and 16 weeks (end of extended double-blinded treatment, period 3). A 48-h ambulatory ECG and responses to the Seattle Angina Questionnaire (38) were recorded at baseline and at 4, 8, and 16 weeks. Assessments included a monthly clinical evaluation, adverse event monitoring, and serum electrolyte and renal function tests at 4 and 12 weeks.



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  		Figure 1 Schematic of the QUASAR study design. Q = quinapril; R = randomize. After a 2- to 4-week single-blind placebo period (Period 1) patients were randomly assigned to two groups. Group 1 received double-blind placebo for 8 weeks (Period 2) and then double-blind Q 80 mg/day for 8 weeks (Period 3). In the latter, there was a 1 week dose titration from 40 to 80 mg/day. Group 2 received double-blind Q 40 mg/day for 8 weeks (Period 2) followed by double-blind Q 40 mg/day for an additional 8 weeks (Period 3).

 
The primary efficacy parameter was time to onset 1-mm ST-segment depression during ETT, comparing the treatment groups at eight weeks (end of period 2). Secondary efficacy parameters included time to onset of angina during exercise, exercise duration, number and duration of ischemic episodes during ambulatory ECG monitoring, ischemic burden (product of ischemic episode number, duration, and magnitude of ischemic ST-segment depression during ambulatory ECG monitoring), and severity of angina by the Seattle Angina Questionnaire (38). Other efficacy parameters included all these measures at 16 weeks (end of period 3).

Assessment of transient ischemia.   Ischemia during exercise stress was evaluated with treadmill testing using the ACIP protocol (37) for a ramp-like increase in work, avoiding the large step increases of the Bruce protocol (39). Treadmill tests were done in the morning, in the same laboratories at each site, and at trough plasma levels for background anti-anginal medications. Before and during ETT, 12-lead ECGs, blood pressure, and pertinent exercise-related symptom data were recorded on standardized forms for interpretation by the Core Exercise Laboratory (St. Louis University, St. Louis, Missouri), which was masked as to the clinical data and group assignment. Exercise-induced ECG ischemia was defined as the new development of ST-segment depression >1 mm over baseline. When baseline resting ST-segment depression (≤0.9 mm) was present, an additional 1-mm ST-segment depression was required. Exercise ECGs were analyzed using customized software, as previously described (40).

Ischemia occurring spontaneously during daily life was assessed by ambulatory ECG recordings for 48 h by a Rozinn (Glendale, New York) model 151 recorder (<0.1 Hz frequency response) with a C-120 cassette tape. After adequate skin preparation, leads were applied using V5 and either an "inferior-like" lead or a historically defined lead showing maximal ST-segment depression during ETT. Lead wires were stabilized; patient instruction was provided; and site personnel recorded approximately 8 min of 1-mV, 60-Hz, rectangular-caliber impulses at the beginning of each recording. Recordings were analyzed at the Ambulatory Electrocardiogram Core Laboratory (eResearchTechnology, Inc., Philadelphia, Pennsylvania), which was masked as to the clinical data and treatment group assignment.

ST-segment measurement.   The technician set one marker at the mid-point of the PR segment and a second marker 20 ms to the right of the J point (where the ST-segment measurement is made). A third marker was set 78 to 83 ms to the right of the second marker for slope determination. The vertical difference between where the first and second calipers intersect the ECG was taken as the ST-segment measurement for that beat; this measurement was made for all normally conducted beats. Each measurement was then compared with measurements for the three preceding normally conducted beats to determine whether it was contaminated by artifact. If not, the measurement was included in the subsequent evaluation.

Definitions of ischemic episodes and ischemic burden from ambulatory recordings.   The baseline ST-segment value was identified automatically as that value immediately preceding an episode of ischemic ST-segment deviation where the ST-segment value does not deviate more than 0.37 mm, compared with the preceding values. An ischemic episode was defined as additional ST-segment depression of ≥1 mm from baseline lasting ≥1 min. The onset of an episode was defined as that time when the ST-segment deviation first satisfied the ≥1-mm criterion, compared with baseline. The duration of an episode was the time during which the ST-segment values were depressed ≥1 mm, compared with baseline. A new episode of ischemia was defined when it was separated in time by ≥1 min from the previous episode and met the aforementioned criteria.

The product of the number of ischemic episodes and their duration per 24 h of analyzable recording was taken to represent ischemic burden. The integral of ST-segment depression over time was noted. For each patient and each variable, the rank of the variable among the entire evaluable population was obtained, and the two ranks were added for each patient to form a composite variable.

Hemodynamic findings.   Estimates of myocardial oxygen demand were assessed by measurement of heart rate, systolic blood pressure (brachial cuff), and rate-pressure product (systolic blood pressure x heart rate) in the standing position before and during each ETT.

Statistical considerations.   Statistical analyses
Analyses were performed on a modified intent-to-treat population that included all randomized patients with baseline values and at least one treatment period assessment. Randomized patients were considered evaluable for the protocol analyses if they had completed baseline and treatment period treadmill tests, complied with at least 80% of study medication, and had not violated the protocol regarding interim procedures or changes in medications.

The primary analysis, a priori, for treatment group comparisons was treadmill test parameters using log-rank tests based on Kaplan-Meier survival estimates at weeks 8 and 16. Mean and median values and standard deviations were also compared. Treatment group comparisons for ambulatory ECG parameters used an analysis of covariance model with treatment and center as effects and with baseline ambulatory ECG measurement and baseline low-density lipoprotein cholesterol levels as covariates. The center was included in the model as a fixed effect (41). Study centers were not chosen randomly and represent a specific type of facility. Randomization was also stratified by center. Treatment-by-center and treatment-by-covariate interactions also were examined. The O'Brien nonparametric rank-sum method was used to analyze "ischemic burden" (42).

Sample size considerations
The trial was initially planned for patients with ischemia during both ETT and daily-life ambulatory monitoring. However, on the basis of our experience with other trials in similar patients and the difficulty enrolling patients with both types of ischemia, an interim analysis was planned to reassess power and recruitment. Screening and recruitment results prompted a protocol modification to permit enrollment of patients with only ischemia on treadmill testing and a satisfactory ambulatory ECG study. For power estimates, time to onset 1-mm ST-segment depression on ETT at eight weeks was chosen, a priori, as the outcome of primary interest, and we assumed that it would be desirable to increase this time by 25% in those assigned to 40 mg quinapril over placebo to justify the cost and inconvenience of adding an additional anti-ischemic medication in this low-risk population. A sample size of 336 patients (168 per treatment group) was chosen to provide >95% power to detect a 25% increase in time to 1-mm ST-segment depression. This assumed a standard deviation of 2.1%. This sample would provide approximately 60% power to detect a 50% decrease from placebo in the number of ischemic episodes during ambulatory ECG monitoring, assuming a coefficient of variation of 160%. Power estimates used a two-sided significance of 0.05 and assumed a 25% withdrawal rate.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 APPENDIX
 References
 
Patient characteristics.   The demographic and clinical characteristics of the randomized patients by treatment groups are summarized in Table 1. Most patients were white men (mean age 64.5 years). Nearly one-half the patients had medically treated hypertension, a previous MI, or a remote revascularization procedure. Concomitant therapy included a beta-blocker, statin, and nitrates in approximately two-thirds of cases and calcium antagonists in approximately one-half. Group 1 comprised 159 patients, and group 2 comprised 177 patients. There were no significant differences in baseline characteristics between the groups.


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  		Table 1 Baseline Demographics and Clinical Characteristics

 
Exercise testing.   All exercise parameters are summarized for both treatment groups for each study period in Table 2 . Treatment groups were comparable at baseline in terms of the time to onset of 1-mm ST-segment depression, angina, and exercise duration. The times to 1-mm ST-segment depression and level 2 angina for each treatment group are displayed in a Kaplan-Meier fashion in Figures 2 and 3, respectively. The difference between treatment groups was not statistically significant (p = 0.4816), although a trend was noted for the time to level 2 angina (p = 0.074) (Fig. 3). Similar results were found after adjusting for gender, hyperlipidemia, and other baseline conditions.


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  		Table 2 Effects on Exercise Indexes of Transient Ischemia

 


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  		Figure 2 Time (min) to induce 1-mm ST-segment depression during exercise treadmill test at 8 weeks of therapy—evaluable population. The percentage of patients with ischemic-type ST-segment depression appears on the vertical axis, and time (min) is on the horizontal axis. There was no difference between treatment group 1 (placebo) and group 2 (40 mg/day quinapril) at 8 weeks.

 


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  		Figure 3 Time (min) to induce level 2 angina during exercise treadmill test at 8 weeks of therapy—evaluable population. The percentage of patients with level 2 angina appears on the vertical axis, and time (min) is on the horizontal axis. There was no difference between treatment group 1 (placebo) and group 2 (40 mg/day quinapril) at 8 weeks.

 
At baseline, the mean time to 1-mm ST-segment depression (ischemia) was 4.2 ± 0.1 min versus 4.3 ± 0.1 min (group 1 vs. group 2, p = 0.639). After eight weeks, the times to ischemia increased to 4.7 ± 0.2 min and 4.8 ± 0.2 min in the placebo and quinapril groups, respectively (p = NS). The time to ischemia after an additional eight weeks of treatment with 40 mg quinapril (Group 2) was 5.2 ± 0.2 min and after 80 mg quinapril (Group 1), 5.0 ± 0.2 min (p = NS). The mean time to angina was 5.4 ± 0.1 min for group 1 and 5.5 ± 0.1 min for group 2. After eight weeks of treatment, the mean time to angina was 6.1 ± 0.2 min for group 1 (placebo) and 6.6 ± 0.2 min for group 2 (40 mg quinapril). The mean time to angina after 16 weeks was 6.6 ± 0.2 min for group 1 (80 mg quinapril) and 7.1 ± 0.3 min for group 2 (40 mg quinapril). This difference was not statistically significant. At baseline, the total exercise duration was 6.1 ± 0.2 min and 6.4 ± 0.2 min with placebo and 40 mg quinapril groups, respectively (p = NS). After eight weeks of treatment, values increased to 6.4 ± 0.2 min in the placebo group and 6.7 ± 0.2 min in the 40-mg quinapril group (mean change 0.23 min; 95% confidence interval [CI] –0.09 to 0.54). Treatment with 80 mg quinapril was not superior to treatment with 40 mg quinapril (mean change –0.03 min; 95% CI –0.37 to 0.31). Although each of these measures increased in both groups compared with the preceding study period, the increases appeared related to training or time effects, as no significant intergroup differences were detected (Table 2, Fig. 4) .



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  		Figure 4 Summary of the three exercise (Ex) parameters for treatment groups 1 and 2. All exercise times increased over the study period (baseline to 8 weeks and 8 to 16 weeks). The increases were not associated with whether patients had received active drug, nor were they dose-dependent; thus, they are likely to be training-related. ST SD = ST-segment depression.

 
There were no significant changes in heart rate (Fig. 5), systolic blood pressure (Fig. 6), or rate-pressure product (data not shown) when comparing group 1 versus 2 at rest or during exercise.



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  		Figure 5 Heart rate (beats/min) at peak exercise at baseline and at 8 and 16 weeks of therapy. There was no significant difference between treatment group 1 (open bars) and group 2 (solid bars).

 


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  		Figure 6 Systolic blood pressure (mm Hg) at peak exercise at baseline and at 8 and 16 weeks of therapy. There was no significant difference between treatment group 1 (open bars) and group 2 (solid bars).

 
Ambulatory ECG monitoring.   Distributions of the number of ischemic episodes per 24 h at baseline were similar when comparing treatment groups, with 29.1% (37/127) of patients in each group having no ischemic episodes (Table 3). Although fewer ischemic episodes occurred at week 8, distributions of the number of ischemic episodes per 24 h were similar for both groups, and no significant differences between the groups were observed. The same was true for week 16 data.


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  		Table 3 Effects on Indexes of Spontaneous Ischemia/24 h

 
Seattle Angina Questionnaire.   The mean values for the five scores were very similar between the two groups at baseline and at weeks 8 and 16 (data not shown). The score for treatment satisfaction remained relatively constant for both groups from baseline to weeks 8 and 16. Slight improvements were seen at weeks 8 and 16 in the other variables, compared with baseline. However, these changes were similar in both groups.

Safety.   Overall, quinapril at 40 and 80 mg was well tolerated in this population, as the frequency of adverse events was similar when comparing treatment groups. Two cardiovascular deaths occurred, both in the 40-mg quinapril group. The investigator treating the patients considered both unrelated to the study medication. Three patients experienced nonfatal MIs: two in the 40-mg quinapril group and one in the placebo group. Investigators considered all MIs to be unrelated to the study treatment.

There were no reports of significant changes in serum electrolytes or renal function during the study. One week after completing two weeks of treatment with 40 mg quinapril, one patient withdrew from the study during hospitalization for MI and was diagnosed with renal failure at discharge. The study investigator considered the renal failure to be probably related to quinapril treatment.

Thirty-six patients withdrew from the study because of adverse events. Of the adverse events that led to withdrawal, four were reported by more than two patients within a treatment group. These included increased cough, rash, increased angina, and chest pain. The only trend observed was that cough occurred most often with 40 mg quinapril. No patients withdrew from the study because of cardiac adverse events during treatment with 80 mg quinapril. However, two patients on this treatment withdrew because of rash and one withdrew because of angioedema.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
APPENDIX
 References
 
Recent studies have clearly shown ACE-I reduces adverse cardiovascular outcomes in patients with CAD and those at high risk of developing CAD (1–8). Whether a reduction of transient ischemia potentially contributes to this benefit, however, remains unclear, because previous studies had small numbers of subjects with various confounding conditions (e.g., heart failure, hypertension, syndrome X) and treatment durations. Hence, the data available from previous studies (13–35), summarized in Table 4, are limited when addressing this question. The QUASAR trial was the first definitive study to assess ACE-I, per se, for improving symptoms and signs of transient ischemia in patients with CAD who did not have other indications (e.g., heart failure, acute MI, uncontrolled hypertension) for ACE-I.


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  		Table 4 Characteristics of Studies Evaluating the Effect of Angiotensin-Converting Enzyme Inhibition in Patients With Myocardial Ischemia

 
Episodes of transient ischemia might be precipitated by increased myocardial oxygen demand in patients with flow-limiting stenoses. Coronary constriction and/or a lack of appropriate dilation as myocardial demand is increased also may play a role in regions with (9,43,44) and without (45–50) flow-limiting stenoses. Such abnormalities in coronary vasomotion have been documented as related, at least in part, to endothelial dysfunction (51). Lastly, quinapril restores coronary endothelial function (9) and improves coronary flow (11) in patients with CAD. Therefore, we hypothesized that the ACE-inhibitory action of quinapril might reduce transient ischemia in patients with stable angina. However, although our results affirmed safety of quinapril in medically treated, clinically stable CAD patients, we did not observe a significant reduction in transient ischemia recorded during exercise or daily life.

The benefits of ACE-I for reducing the frequency of clinical events in chronic heart failure, post-infarction, post-coronary bypass patients, and even those with stable atherosclerosis or at high risk of atherosclerosis, are documented (1–3,6–8,35,52,53). Our findings indicate that a reduction of exercise-induced or daily-life ischemia is not likely to be prominent among the possible mechanism(s) responsible for decreasing adverse events. Quinapril at doses of 40 or 80 mg/day had no significant effect on heart rate or systolic blood pressure during exercise. For patients whose heart rates and blood pressure responses were well controlled by background anti-anginal agents, little additional change was detected from the addition of ACE-I over an 8- to 16-week period. These observations support the notion that ischemia occurring in stable angina patients receiving anti-anginal drugs is very dependent on the severity of relatively "fixed stenoses," rather than vasomotor dysfunction at a distance from or in the neighborhood of flow-limiting stenoses. Another possibility is that when high-risk patients are excluded, a great many patients who could have benefited were eliminated.

An additional factor that likely plays an important role in these results is that the flow-limiting effects of vasomotor changes on exertional and spontaneous ischemia are likely to already have been modified by aggressive previous management of risk factor conditions (e.g., hyperlipidemia, hypertension). So, adding an ACE-I conferred little additional benefit.

For example, baseline low-density lipoprotein C was 106 and 108 mg/dl among the two groups in this study. We have previously found that an improvement in endothelial function after six months of quinapril therapy is more striking at higher levels of low-density lipoprotein C, >130 mg/dl (54).

It is also likely that vascular mechanisms leading to clinical events known to be prevented by ACE-I (death, MI, and hospitalization) differ from those leading to transient ischemia occurring during exercise or daily life. Thus, the actions of chronic ACE-I to reduce these events may depend more on increasing plaque stability and reducing local thrombogenicity and less on modifying the vascular motor dysfunction known to occur in chronic angina patients. Increased ACE activity has been observed in the "shoulder region" of atherosclerotic plaque, which could play a role in plaque rupture, thrombus formation, and rapid progression of obstructive CAD (55). There is an improve-ment of endothelial function with ACE-I in patients with CAD and/or atherosclerotic risk factors (9,12,56). The observation that the prognostic benefits of ACE-I have been consistently shown to be independent of and additive to those of beta-blockers is consistent with this concept, as the latter have profound effects on the incidence of exercise-induced and daily-life ischemia.

Study limitations.   By design, ETT was not repeated several times before entry, as in some anti-anginal treatment studies, to eliminate patients with variable exercise ischemic thresholds. We reasoned that this practice may help select for a population with relatively fixed, fibrotic, or calcific stenoses. We hypothesized that variability of time to ischemic ST-segment depression and moderate angina on ETT might be influenced by endothelial-mediated vasomotion, and selecting those with highly reproducible exercise times might, a priori, exclude those most likely to derive benefit from ACE-I. Second, exercise results in those randomized to placebo demonstrate the well-known placebo and/or training effect, with an increase of ~30-s observed when comparing baseline and eight-week ETTs. It is possible the effect of ACE-I on ischemia, if present, is so modest it cannot be detected with ETT and a 30-s placebo and/or training effect. Third, the duration of quinapril treatment may not have been adequate to permit its full effects to become manifest. We chose 8- and 16-week periods because this duration was sufficient to demonstrate vascular effects in other studies using similar patients (12,57). Another recent study found no improvement in ETT or ambulatory ECG findings after one year with a beneficial effect on cardiovascular adverse outcomes (58). Furthermore, the benefits observed in other studies required several years to become manifest, and the potential vascular effects of ACE-I that lead to anti-anginal effects may require more time to become manifest (1,2,7). More recent trials in patients similar to those in QUASAR have extended their duration of treatment (59,60). Ongoing studies in this area may help clarify the role of ACE-I and provide a rationale, other than a reduction of transient ischemia, for using ACE-I in those with CAD but without hypertension, heart failure, or additional high-risk features.


   APPENDIX
Top
 Abstract
 Methods
 Results
 Discussion
 APPENDIX
References
 
For a list of the Steering Committee Members, Investigators, and Study Conduct, please see the December 17, 2003, issue of JACC at http://www.cardiosource.com/jacc.html.


   Acknowledgments
 
The authors thank Melanie Fridl Ross, MSJ, ELS, for her editing assistance.


   Footnotes
 
This study was sponsored by grants provided by Pfizer/Parke-Davis, Inc.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 APPENDIX
 References
 

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