Tissue ACE trials in patients with CAD and preserved LV function Content Points: A series of clinical trials for improving endothelial function and reducing cardiac risk through tissue ACE inhibition have been conducted in patients with CAD and preserved left ventricular function: – Trial on Reversing ENdothelial Dysfunction (TREND) enrolled 129 patients – Brachial Artery Normalizatoin of Forearm Function (BANFF) conducted in 80 patients – QUinapril Ischemic Events Trial (QUIET) conducted in 1750 post-revascularization patients – Effects of QUinapril On Vascular ACE and Determinants of ISchemia (QUO VADIS) conducted in 149 post-corononary artery bypass grafting (CABG) patients – Angiotensinn-converting enzyme inhibition Post REvascularization Study (APRES), conducted in 159 post-revascularization (coronary angioplasty or CABG) patients – Heart Outcomes Prevention Evaluation (HOPE) study, conducted in 9297 patients

TREND: Endothelial function and ACE inhibition Content Points: TREND was a 6-month randomized, double-blind, placebo-controlled study in 129 normotensive adults with CAD. The effects of quinapril on endothelial function in the epicardial coronary artery was studied using serial intracoronary acetylcholine and quantitative coronary angiography.91 This slide summarizes the results for the primary end point of the study, the net change in mean diameter of the target segment after 6 months of treatment. Target segment was defined as the segment with the greatest initial constriction in response to acetylcholine challenge. Subjects randomized to quinapril treatment showed a net increase in the main diameter of the target segments. Diameters were initially 4.5 ± 3.0% for the 10-6 mol/L acetylcholine infusion and 12.1 ± 3.0 for the 10-4 acetylcholine infusion after 6 months of treatment. The placebo group showed no improvement. The difference between the placebo and quinapril groups in the effect on endothelial function was highly significant with the higher dose of acetylcholine (P < .0003).

TREND: Influence of smoking status on progression of endothelial dysfunction Content Points: A TREND substudy demonstrated the influence of smoking on coronary endothelial function in normotensive patients with CAD, but without LV dysfunction, severe hypercholesterolemia, or insulin-dependent diabetes mellitus.92 Placebo-treated patients (N = 54) from the larger study were classified at baseline as smokers or nonsmokers for this subgroup analysis. Patients underwent coronary angiography at baseline and again after 6-months. At baseline, there was a trend for a greater decrease in target segment diameter in smokers compared with nonsmokers (-17.2 ± 5.3% vs -8.0 ± 2.5%, acetylcholine 10-4 mol/L). All measured coronary artery segments (N = 202) showed similar responses (-7.3 ± 2.7% vs -3.8 ± 1.3%, acetylcholine 10-4 mmol/L, for smokers vs. nonsmokers, respectively). After 6 months, smokers showed an even greater vasoconstrictor response to acetylcholine whereas nonsmokers did not. The next slide will describe the impact of treatment on smokers.

TREND: Effect of smoking and ACE-I on coronary artery segment diameter Content Points: This retrospective analysis of data from TREND studied the influence of smoking status on ACE inhibition and its ability to improve endothelial function. At the outset, patients were classified as either smokers (N = 23) or nonsmokers (N = 82).93 The primary outcome was the change in acetylcholine response in target coronary artery segments between baseline and 6-month follow-up angiograms. At baseline, coronary artery vasomotor responses were similar in smokers and nonsmokers in the placebo and quinapril groups. At 6-months, nonsmokers in the quinapril-treated group showed significantly less vasoconstriction (2.7% vs 13.2%, P =.003). Nonsmokers in the placebo group showed no significant change in vasoconstriction. At 6 months, vasoconstriction decreased substantially in the smokers who were treated with quinapril (.5% vs 17.9%, P = .002). Smokers in the placebo group had a slight increase in vasoconstriction (21.7% vs 17.2%), but the change was not statistically significant. These results indicate that ACE inhibition improves the coronary vasomotor response in both smokers and nonsmokers, but that smokers apparently derive even greater benefit than nonsmokers. Moreover, whereas endothelial function declines slightly in smokers over the course of 6 months, endothelial function improves in smokers who are taking quinapril.

BANFF: Effect of ACE inhibitors vs other cardiovascular agents on FMD Content Points: BANFF was an open-label, randomized, crossover study to determine the effects on the endothelium of four antihypertensive agents each given in 8-week treatment periods with 2-week washout periods. The agents included the ACE inhibitors quinapril 20 mg/day (N = 56), enalapril 10 mg/day (N = 55), the ARB losartan 50 mg/day (N = 38), and the calcium channel blocker amlodipine 5 mg/day (N = 45).94 Patients in the study had documented coronary artery disease and preserved LV function. Patients with previous CABG, LV ejection fraction < 40%, total cholesterol > 6.0 mmol/L, uncontrolled hypertension, cigarette smoking, or lipid-lowering therapy were excluded. Endothelial function was assessed by measuring reactive hyperemia to determine FMD of the brachial artery. The quinapril group had significantly improved FMD. None of the other groups showed significant improvement, although some improvement was seen with losartan.

BANFF: Results by ACE genotype Content Points: This slide shows the absolute change in percent FMD from baseline following therapy and compares the pretreatment baseline values for quinapril and enalapril according to ACE genotype in the BANFF study.94 In response to 8 weeks of therapy there was no improvement in brachial responses noted in the DD genotype with any of the four agents. The DD genotype is a characteristic known to increase ACE activity. It has been associated with increased risk of coronary stenosis and MI in some but not all studies. Significant improvement was related only to quinapril in the ID and II genotypes.This suggest that the response to quinapril is related to ACE genotype and that ACE inhibitors, and other vasodilators, differ in their ability to improve endothelial function.

Trials of ACE inhibition effects on outcomes following revascularization Content Points: The two trials that are next discussed both studied the use of long-term tissue-selective ACE inhibition in patients who underwent revascularization to determine their effects on outcomes. QUO VADIS was a randomized trial that assessed the effect of long-term ACE inhibition with quinapril (40 mg/day) on ischemic events following coronary artery bypass grafting (CABG) in 148 patients with, follow-up of 1 year.96 APRES was a randomized trial assessing the effect of ACE inhibition with ramipril (20 mg/day) on cardiac events following revascularization with percutaneous transluminal coronary angioplasty (PTCA) or CABG in 159 patients, with follow-up of 3 years.95

APRES: Effect of ramipril on cardiac outcomes Content Points: In the APRES study, after PTCA or CABG, 159 patients with preoperative chronic stable angina pectoris, left ventricular ejection fraction between 30% and 50%, and no clinical heart failure were randomly assigned to receive double-blind treatment with either ramipril or placebo and followed for a median of 33 months.95 Ramipril reduced the incidence of the triple-composite end point of cardiac death, acute MI, or clinical heart failure (risk reduction 58%; 95% confidence interval 7% to 80%, P = .03). Treatment with ramipril did not alter the incidence of the quadruple-composite end point of cardiac death, acute MI, clinical heart failure, or recurrent angina pectoris. These findings were consistent across subgroups, that is, those with left ventricular ejection fractions below or above 40%, and whether CABG or PTCA was performed. For single events, the risk of cardiac death was lowered by 86% with ramipril (P = .03). The reductions in clinical heart failure and MI were not statistically significant.

QUO VADIS: Effects of quinapril on ischemia Content Points: In the QUO VADIS study, 148 patients scheduled for CABG were randomized 27 days prior to surgery to treatment with quinapril or placebo. The study medication was taken for up to 1 year.96 One year following revascularization, total exercise duration was comparable between the quinapril and placebo groups. There was an increase of 77 seconds in total exercise duration and an improvement in ST segment changes in patients who were taking quinapril. Whereas all patients showed ST segment changes at baseline, only 33% showed ST- segment changes at 1year. There was a significant difference between the quinapril and placebo groups in the number of clinical events at one year. In the placebo group, 18% of the patients experienced a clinical event, either angina, MI, ischemic stroke, or transient ischemic attack, compared with 4% of the patients in the group that took quinapril (P = .03). This meant an 80% reduction in clinical events in the group that took quinapril. These results suggest that ACE inhibition may improve vascular disease outcomes after patients undergo CABG.

QUO VADIS: Chronic ACE inhibition and Ang II formation in internal mammary artery segments Content Points: The investigators in QUO VADIS also evaluated the effects of long-term ACE inhibition on Ang II formation in the human vasculature. Patients (N = 187) scheduled for CABG were randomly assigned to either quinapril (40 mg) or captopril (3 x 50 mg) 27 days before surgery.97 Both drugs decreased blood pressure to a similar extent. Segments of internal mammary arteries obtained from patients were exposed to increasing doses of Ang I and Ang II in organ baths. There was a small but statistically significant reduction in local Ang II formation with quinapril compared with placebo (P = .01). Ang II formation was decreased to a lesser extent with captopril and the difference not statistically different from placebo (P = .3). This is the first randomized study to demonstrate that long-term oral treatment with an ACE inhibitor reduces vascular Ang II formation in humans.

New tissue ACE trials: Differences in scope Content Points: The next two trials to be discussed, QUIET and HOPE, are conceptually related but differ significantly in scope. QUIET was a smaller, randomized trial to investigate the effects of tissue-selective ACE inhibition on ischemic events and angiographic progression of CAD in low-risk patients.98 HOPE was a large randomized trial, powered to evaluate the effects of a tissue-selective ACE inhibitor on morbidity and mortality in high-risk patients.99

QUIET: Design and methods Content Points: QUIET (QUinapril Ischemic Events Trial) included patients from 38 centers in North and South America and Europe. A total of 1750 men and women were enrolled.98,100 All eligible patients had undergone successful percutanous coronary intervention (PCI) within 12 to 72 hours prior to randomization. Inclusion criteria included: Age under 75 years Left ventricular ejection fraction > 40% LDL-C <165 mg/dL BP < 160/95 mm Hg Patients were excluded if they had a history of CABG, MI, or PTCA other than the index procedure within the past 3 months. Patients were randomized immediately after the index procedure to receive quinapril 20 mg daily or placebo for 3 years.

QUIET: Cardiac death, nonfatal MI, or VT/VF Content Points: There was no significant difference in the primary clinical end point of the study of combined ischemic events, but 80% of the events were repeat PTCA or CABG. The high incidence of repeat events coupled with a low incidence of other events (only .5% deaths/year and 1.5 MI/year) precluded a definitive conclusion.101 However, the survival curves in QUIET demonstrate an interesting trend. As shown on the slide, there was an early separation between the groups in combined cardiac death, nonfatal MI, and resuscitated cardiac arrest (ventricular tachycardia or ventricular fibrillation). This separation persisted and increased throughout the course of the study. As will be seen in later slides, this finding would be confirmed and extended in the much larger HOPE study.

QUIET: Effect of quinapril on CAD progression according to LDL-C level Content Points: A QUIET subgroup underwent quantitative angiography and revealed that similar numbers of patients in the placebo and quinapril groups had progression in CAD (49% vs 47%, respectively). However, further analysis of the group by LDL-C level above and below the median level at entry revealed an interesting finding. As shown on the slide, in patients with LDL-C levels <130 mg/dL, quinapril had only a slight effect on progression of CAD. By contrast, in patients with LDL-C >130 mg/dL, there was significantly less progression of CAD in the group that received quinapril compared with those who took placebo (P = .08).102 Thus, the rapid disease progression seen in patients who took placebo did not occur in patients who took quinapril. Moreover, there was a prominent effect of ACE inhibition in the patients who had higher LDL-C levels at entry.

HOPE: Design and methods Content Points: HOPE included 267 research centers in 19 countries in North and South America and Europe.99 A total of 9297 patients were randomized using the following inclusion criteria – Age > 55 years – Left ventricular ejection fraction > 40% – Confirmed CAD, peripheral vascular disease, or stroke – Diagnosed diabetes plus 1 other risk factor Patients were excluded from the study if they had an ejection fraction of less than 40%, heart failure, or stroke or MI within the past month. Study subjects were randomized to receive ramipril 10 mg daily, vitamin E 400 IU daily, or placebo by a 2-by-2 factorial design. There was a 4.5 year follow-up.

HOPE: Primary outcome (MI, stroke, CV death) Content Points: The data from the HOPE study that are shown represent the outcomes for the 9297 patients in the study.99 There was a 22% risk reduction in the primary outcome, the combined incidence of MI, stroke, and cardiovascular death in the group that received the ACE inhibitor as compared with the group given placebo. There was a 14.1% rate of events in the active treatment group versus 17.7% in the placebo group. The difference between the two groups was significant at P < .001. The rapid response to ACE inhibition and the continuing divergence of results between the treatment and placebo groups indicate that longer-term treatment may have yielded even greater risk reduction.

HOPE: Risk reduction with ACE inhibition Content Points: In the HOPE study, ACE inhibition was associated with significant risk reductions when each of the outcomes was analyzed separately.99 Risk reductions included: – Cardiovascular death 25% (P < .001) – Nonfatal MI 20% (P < .001) – Stroke 31% (P < .001) – Revascularization (CABG or PTCA) 16%(P < .001) – New onset diabetes 32% (P < .002) It was postulated that the beneficial effects with regard to new onset diabetes may have been mediated by improved insulin sensitivity, a decrease in hepatic clearance of insulin, an anti-inflammatory effect, improved blood flow to the pancreas, or an effect on abdominal fat. The HOPE investigators comment that treatment of 1000 patients for 4 years prevents about 150 events in approximately 70 patients.

HOPE: Risk reduction in diabetic cohort Content Points: The HOPE study included 3577 patients with diabetes, aged 55 or older. Ramipril lowered the risk of the primary outcome of combined death, MI, stroke, and cardiovascular death by 25% in this group of patients (P = .0004).103 As shown on this slide, ramipril lowered cardiovascular death by 37% (P = .0001), nonfatal MI by 22% (P = .01), stroke by 33% (P = .0074), and total mortality by 24% (P = .004). The need for revascularization was reduced by 17%, and overt nephropathy was reduced by 24%. Overall, treatment with the tissue-avid ACE inhibitor ramipril significantly lowered the risk of major cardiovascular outcomes by 25% to 30% in a broad range of high-risk middle-aged and elderly people with diabetes.

HOPE: Baseline SBP vs global endpoint Content Points: This subanalysis of the HOPE data shows the decrease in absolute risk of an event relative to baseline systolic blood pressure quartile. The lowest average baseline systolic blood pressure quartile was 124 mm Hg and the highest was 158 mm Hg. The global endpoint refers to the combined rate of death, MI, and stroke, plus chronic heart failure and the need for revascularization. There were 4355 patients with hypertension and 4952 patients without hypertension in the HOPE study. As shown on the bottom of the slide, as a whole, those patients who received ramipril had about a 3-mm reduction in systolic blood pressure and about a 2-mm reduction in diastolic blood pressure, regardless of their baseline blood pressure.99 As the graph shows, the absolute risk of an event was strongly related to baseline blood pressure level in the placebo group. In contrast, in the group that received ramipril, the absolute risk for an event was the same for all blood pressure quartiles. The most striking reduction in risk of an event occurred in patients with the highest baseline systolic blood pressure (P < .0001). The difference was less striking for the groups with normal blood pressure. Although the HOPE investigators suggested that only a small part of the benefit of treatment could be attributed to the decline in blood pressure, the effects were strongly dependent on the initial blood pressure. Hypertensive patients had a greater relative risk reduction from treatment than did nonhypertensive patients.

Tissue ACE trials in patients with CAD and preserved LV function: Benefits observed Content Points: The HOPE findings confirm and extend those of the TREND, BANFF, APRES, QUO VADIS, and QUIET trials. Together, these trials demonstrate that ACE inhibitors with high tissue affinity may be of particular benefit in enhancing vascular function and improving cardiovascular outcomes. BANFF and TREND showed that quinapril at doses of 20 to 40 mg daily significantly improved endothelial function. BANFF further showed that all vasoactive agents are not alike in their effects on endothelial function. Thus, these trials suggest that inhibition of tissue ACE may be an important mechanism favorably modifying vascular pathobiology. QUIET, conducted in post-revascularization patients, showed a trend toward decreased cardiac death, nonfatal MI, and cardiac arrest in the group receiving quinapril 20 mg daily for 3 years. QUO VADIS, conducted in post-CABG patients, showed that a higher dose of quinapril was associated with a significant 80% reduction in ischemic events at 1 year (4% vs 18% with placebo). The recent APRES study, conducted in post-revascularization patients, showed that ramipril reduced the combined outcome of cardiac death, myocardial infarction, and heart failure by 58% after nearly 3 years of treatment. Finally, the HOPE study, a morbidity and mortality study, confirmed and extended the results of the tissue ACE trials, showing that ramipril 10 mg daily, significantly reduces cardiovascular morbidity and mortality in patients with coronary artery disease and preserved left ventricular function.

Tissue ACE trials in patients with CAD and preserved LV function: Implications for clinical practice Content Points: In summary, the accumulated data from TREND, BANFF, QUIET, APRES, QUO VADIS, and HOPE indicate that effectively inhibiting tissue ACE reduces cardiovascular risk. Further, a likely mechanism may be improvement of endothelial function.

EUROPA: An upcoming tissue ACE trial Content Points: The purpose of the EUROPA (European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease) study is to assess the effect of perindopril, a tissue-avid ACE inhibitor in patients with coronary artery disease but no clinical heart failure.104 EUROPA is a large, double-blind, placebo-controlled, multicenter study. Recruitment was targeted at 10 500 patients from 350 to 500 centers in 24 European countries. Enrollment began in October 1997 and recruitment was completed in 1998. The study will continue for 3 to 5 years. Preliminary results of the EUROPA trial may be announced within the next few months. These findings should add to the information about the effects of ACE inhibition that has been provided by the tissue ACE trials. Patients randomized to perindopril will receive 8 mg daily in addition to their usual treatment. The daily dose may be reduced to 4 mg if the patient’s systolic BP falls to less than 110 mm Hg. Patients will continue treatment until the last patient enrolled completes the 3-year follow-up. The primary end point is a combined effect on total mortality, nonfatal acute MI, unstable angina pectoris, and cardiac arrest with successful resuscitation. Secondary end points of the study include the individual effect of treatment on a wide variety of cardiac events.

EUROPA substudies: Confirmation of pathophysiologic concepts Content Points: A series of substudies will be conducted as part of the EUROPA program. These substudies will assess the effect of ACE inhibition on endothelial function and atherosclerosis, determine the impact of genotype on outcomes, as well as determine the effect of perindopril in the subset of patients with diabetes.105 PERFECT is an acronym for PERindopril—Function of the Endothelium in Coronary artery disease Trial. In this substudy, the effect of perindopril on endothelial function in the brachial artery will be assessed in approximately 300 patients. Measurements will be compared at the start of treatment and 6, 12, 24, and 36 months after enrollment. The primary endpoint is the percentage of change in FMD in the brachial artery between baseline and 36 months. PERSPECTIVE is an acronym for (PERindopril’S Prospective Effect on Coronary aTherosclerois by angiographical and intraVascular ultrasound Evaluation). Angiographic and intravascular ultrasound of coronary vessels will be performed in approximately 400 patients before and after 3 years of treatment with either perindopril or placebo to assess the progression and possible regression of coronary athersclerotic lesions. Genetic characterization will be performed in all participants in EUROPA to assess whether specific genotypes respond more or less favorably to perindopril. The effect of perindopril will be investigated in patients with type 2 diabetes. The results of EUROPA and of the EUROPA substudies, in particular, should complement and augment the findings in HOPE, as well as the findings in TREND, BANFF, QUO VADIS, and APRES.