Vasomotor Dysfunction in Patients With Coronary Artery Disease: The TREND (Trial on Reversing ENdothelial Dysfunction) Study - TREND

Description:

TREND was a double-blind, placebo-controlled, randomized trial to evaluate whether angiotensin-converting enzyme (ACE) inhibition with quinapril would ameliorate endothelial dysfunction in normotensive patients with coronary artery disease who were free of left ventricular dysfunction and severe dyslipidemia.

Hypothesis:

ACE inhibition may ameliorate endothelial dysfunction in normotensive patients with coronary artery disase.

Study Design

Study Design:

Patients Enrolled: 129

Patient Populations:

Single or double coronary artery disease (>50% diameter stenoses) that required a nonsurgical revascularization procedure (percutaneous transluminal coronary angioplasty, atherectomy, stent, or laser) and one adjacent main coronary artery with <40% stenoses that had never been revascularized. This adjacent artery was designated as the target artery and exhibited endothelial dysfunction, defined as either a definite constrictive response (5% reduction in mean lumen diameter) or no response to acetylcholine (<5% change in mean lumen diameter).

Exclusions:

Vasodilation was seen in response to both acetylcholine challenges; a dominant right coronary artery was the only eligible target artery (because of possible induction of complete AV block by acetylcholine); age was >75 years; low-density lipoprotein cholesterol was >4.3 mmol/l; systolic blood pressure was >160 mm Hg and diastolic blood pressure was >90 mm Hg; history of coronary artery bypass grafting or coronary spasm; previous mechanical revascularization procedures within the previous three months; myocardial infarction within seven days of randomization; left ventricular ejection fraction of <40%; type I diabetes mellitus; clinically significant hepatic or renal dysfunction; valvular heart disease; second- or third-degree AV block; or treatment with lipid-lowering agents within the previous six months

Primary Endpoints:

Net change in the acetylcholine-provoked constriction of target segments between the baseline (prerandomization) and six-month follow-up angiograms

Drug/Procedures Used:

Patients with documented coronary atherosclerosis were randomized to receive six months of oral quinapril (Accupril) 40 mg (n=64) or placebo (n=65) once daily after baseline assessment of endothelial dysfunction. Patients discontinued all vasoactive medications except beta-blockers and sublingual nitrates at least 12 hours before the study.

During the initial (baseline) catheterization, the target artery was identified and a baseline angiogram was taken, followed by two stepwise intracoronary infusions of acetylcholine of 10-6 mol/l and 10-4 mol/l delivered at 0.8 ml/min for two minutes through the guide or diagnostic catheters. Angiography was repeated after each infusion. A nitroglycerin bolus was then administered, followed by an angiogram. The patient then underwent the clinically indicated nonsurgical revascularization procedure and was randomized to receive the first dose of study medication or placebo within 12 to 72 hours. After six months, coronary angiography was repeated by use of identical baseline acetylcholine challenge procedures.

Principal Findings:

Baseline characteristics were similar except systolic blood pressure, which was slightly lower in the quinapril group, but was within the normotensive range (mean 119-127 mm Hg). At baseline, the degree of acetylcholine-induced vasoconstriction in the target artery segment was similar in the placebo and quinapril groups.

After six months, the placebo group had no change in responses, whereas the quinapril group showed significantly less constrictor response (1.6% and 2.3%) compared with the prerandomization response (6.1% and 14.3%; p<0.014). In the quinapril group, responses expressed as net change from baseline (primary endpoint) improved by 4.5 ± 3.0% and 12.1 ± 3.0% at each acetylcholine dose, whereas the placebo group responses did not change (-0.1 ± 2.8 and -0.8 ± 2.9 at each acetylcholine dose) (p<0.002). These results remained significant even when baseline constrictive response at each dose level was used as a covariate (p=0.003).

At six months, the extreme response to acetylcholine infusion of abrupt and total occlusion was rare, but there was a trend for this response to be seen more frequently in the placebo group compared with the quinapril group (9.3% vs. 2.0%; p=0.131). A 5% improvement in response was significantly more common in the quinapril group in the target segments (53% vs. 28%; p=0.008) and nearly significant in all segments (37% vs. 27%; p=0.056).

Interpretation:

Among normotensive patients with coronary artery disease, preserved left ventricular function, and minimal or mild dyslipidemia, treatment with quinapril, an ACE inhibitor with high tissue-binding affinity, for six months was associated with an attenuation of impaired endothelial vasomotor function compared with placebo.

References:

Mancini GB, Henry GC, Macaya C, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation 1996;94:258-65.

Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Heart Failure, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Coronary Artery Disease, Atherectomy, Tetrahydroisoquinolines, Blood Pressure, Constriction, Pathologic, Vasoconstriction, Angioplasty, Balloon, Coronary, Stents, Dyslipidemias, Coronary Angiography, Nitrates, Catheterization, Ventricular Dysfunction, Left, Nitroglycerin


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