The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function.

Angiotensin-converting enzyme inhibitors improve endothelial function, inhibit experimental atherogenesis, and decrease ischemic events. The Quinapril Ischemic Event Trial was designed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events (the occurrence of cardiac death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or hospitalization for angina pectoris) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction. A total of 1,750 patients were randomized to quinapril 20 mg/day or placebo and followed a mean of 27 +/- 0.3 months. The 38% incidence of ischemic events was similar for both groups (RR 1.04; 95% confidence interval 0.89 to 1.22; p = 0.6). There was also no significant difference in the incidence of patients having angiographic progression of coronary disease (p = 0.71). The rate of development of new coronary lesions was also similar in both groups (p = 0.35). However, there was a difference in the incidence of angioplasty for new (previously unintervened) vessels (p = 0.018). Quinapril was well tolerated in patients after angioplasty with normal left ventricular function. Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis. However, the absence of the demonstrable effect of quinapril may be due to several limitations in study design.

Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction.

The goal of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is to determine whether early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute myocardial infarction. Within 1 to 4 days of hospitalization for one of these conditions, 2,100 patients will be randomly assigned to receive atorvastatin, 80 mg/day, or placebo in a double-blind design. Both groups receive dietary counseling. Over a 16-week follow-up period, the primary outcome measure is the time to occurrence of an ischemic event, defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Secondary outcome measures are the time to occurrence and incidence of each of the primary outcome components, as well as nonfatal stroke, worsening angina, congestive heart failure requiring hospitalization, and need for coronary revascularization not anticipated before randomization. The sample size of 1,050 patients in each group is expected to provide 95% power to detect a 30% reduction in the primary outcome measure with a 5% level of significance. The results of the MIRACL study will determine the utility of profound cholesterol lowering as an early intervention in acute coronary syndromes.

Quinapril hydrochloride effects on renal function in patients with renal dysfunction and hypertension: a drug-withdrawal study.

Patients with mild to moderate hypertension (diastolic blood pressure > or = 95 and < or = 115 mmHg) and renal dysfunction entered one of two studies to assess the safety of efficacious daily doses of quinapril on renal function and blood pressure. Twenty-four patients with moderate renal impairment (MRI) (creatinine clearance > 30 and < or = 60 ml/min) entered 24 weeks of open-label quinapril treatment; 31 patients with chronic renal failure (CRF) (creatinine clearance < 30 ml/min) entered 16 weeks of open-label quinapril treatment. Patients with MRI initially received quinapril 5 mg once daily (qd) followed by titration to a maximum dosage of 40 mg/day (furosemide optional at 40 mg only). Patients with CRF initially received quinapril 2.5 mg qd and were titrated up to 20 mg/day (furosemide optional). Open-label quinapril treatment resulted in significant decreases in mean systolic (SBP) and diastolic (DBP) blood pressure. The 20 patients with MRI and the 28 with CRF who completed the open-label phase were then randomly assigned to continue active drug or to receive placebo in a 4-week, double-blind, drug-withdrawal phase. During the double-blind withdrawal phase, placebo-treated patients had significant increases in mean SBP and DBP from the end of open label. Creatinine clearance was essentially unchanged following open-label quinapril treatment or quinapril withdrawal. In conclusion, in patients with mild to moderate hypertension and renal dysfunction, quinapril in dosages of 5-40 mg qd for patients with MRI and 2.5 to 20 mg qd for patients with CRF significantly reduces blood pressure without adversely affecting renal function.

Quinapril and hydrochlorothiazide combination for control of hypertension: assessment by factorial design. Quinapril Investigator Group.

A factorial design method was applied in this multicentre trial of the angiotensin-converting enzyme inhibitor quinapril hydrochloride (Accupril) in combination with the diuretic hydrochlorothiazide (HCTZ) to assess the additive effects of the combination versus monotherapy, to characterise the dose-response relationship of each drug in the presence of the other and to determine if quinapril would attenuate the hypokalemic effect of HCTZ. Following a two to four week placebo-baseline period, 460 qualifying patients with a DBP > or = 100 mmHg and < or = 115 mmHg were randomised to an eight week double-blind phase with one of 16 parallel treatments: placebo, one of three doses of quinapril monotherapy, one of three doses of HCTZ monotherapy or one of nine possible corresponding combinations of quinapril and HCTZ. Mean reductions in sitting SBP/DBP at trough with combination therapy ranged from 7.8 mmHg/7.2 mmHg to 19.6 mmHg/15.1 mmHg (n = 458). Results of the response surface analyses indicate that the effects of the two drugs were additive and that the maximum antihypertensive effect of quinapril in combination with HCTZ within the doses studied is achieved approximately at a dose of 26 mg quinapril and 25 mg HCTZ. The degree of attenuation of the hypokalemic effect of HCTZ was directly related to the dose of quinapril. At 40 mg quinapril, the HCTZ dose-related decreases of serum potassium were not apparent and overall hypokalemic effects were attenuated by quinapril. Thus, the combination of quinapril and HCTZ given once daily provided additive antihypertensive effects of predictable degrees and the addition of quinapril attenuated the hypokalemic effect of HCTZ.

Ambulatory blood pressure monitoring can play an integral role in patient selection, dosage adjustment and efficacy assessment in clinical trials of antihypertensive agents.

OBJECTIVE: To evaluate the efficacy and duration of action of the angiotensin converting enzyme inhibitor quinapril hydrochloride by using ambulatory blood pressure monitoring. DESIGN: Eleven centers in the USA and Canada entered 155 patients with previously diagnosed hypertension into a 4-week placebo-baseline phase. Twenty patients (13%) with elevated diastolic blood pressure (DBP) only by cuff measurement were excluded from entry into a double-blind test based on ambulatory blood pressure monitoring, and 135 patients with a mean waking blood pressure of 155/100 mmHg were assigned randomly to receive either quinapril or placebo once a day for 8 weeks, with optional titration to a higher dose after 4 weeks, based on the DBP response assessed by repeat ambulatory blood pressure monitoring only. RESULTS: Quinapril therapy produced highly significant decrease in mean daytime DBP compared with placebo. The antihypertensive effect of quinapril was evident over 24 h, with 50% of the peak effect remaining at the trough. After 4 weeks of treatment 49% of the patients in the quinapril group were titrated to the higher dose compared with 86% of the patients who had been receiving placebo. More than 70% of the patients in the quinapril group who remained at the low dose would have been titrated to the higher dose based solely on the clinic DBP measurements. CONCLUSIONS: The use of ambulatory blood pressure monitoring in the present study reduced the false-positive response to placebo and lessened the likelihood of titrating patients to the higher dose of quinapril in comparison with the number that would have been so treated based on clinic blood pressure measurements alone. More importantly, our results suggest that the convenience, ease and relatively low cost of traditional cuff blood pressure measurement should be weighed against the potential shortcomings of the method.

The QUinapril Ischemic Event Trial (QUIET) design and methods: evaluation of chronic ACE inhibitor therapy after coronary artery intervention.

The rationale, trial design, and statistical aspects of QUIET, the QUinapril Ischemic Event Trial, are described. QUIET is a prospective, double-blind placebo-controlled study that will assess the ability of the angiotensin-converting enzyme (ACE) inhibitor quinapril to reduce the rate of cardiac ischemic events and to slow or prevent the development of coronary artery atherosclerosis as assessed by serial angiography in a normolipidemic population without left ventricular dysfunction. The study began in September 1991 and has completed recruitment with 1740 patients across 38 centers (28 U.S., 4 Canada, 6 Europe) by the end of 1992. Patients are randomized to 20 mg of quinapril or placebo once daily and continue in the study for 3 years. Study completion is projected for 1995.