A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.

BACKGROUND: Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces mortality among survivors of acute myocardial infarction, but whether to use ACE inhibitors in all patients or only in selected patients is uncertain. METHODS: We screened 6676 consecutive patients with 7001 myocardial infarctions confirmed by enzyme studies. A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction, < or = 35 percent). On days 3 to 7 after infarction, 1749 patients were randomly assigned to receive oral trandolapril (876 patients) or placebo (873 patients). The duration of follow-up was 24 to 50 months. RESULTS: During the study period, 304 patients (34.7 percent) in the trandolapril group died, as compared with 369 (42.3 percent) in the placebo group (P = 0.001). The relative risk of death in the trandolapril group, as compared with the placebo group, was 0.78 (95 percent confidence interval, 0.67 to 0.91). Trandolapril also reduced the risk of death from cardiovascular causes (relative risk, 0.75; 95 percent confidence interval, 0.63 to 0.89; P = 0.001) and sudden death (relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98; P = 0.03). Progression to severe heart failure was less frequent in the trandolapril group (relative risk, 0.71; 95 percent confidence interval, 0.56 to 0.89; P = 0.003). In contrast, the risk of recurrent myocardial infarction (fatal or nonfatal) was not significantly reduced (relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.13; P = 0.29). CONCLUSIONS: Long-term treatment with trandolapril in patients with reduced left ventricular function soon after myocardial infarction significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death, and the development of severe heart failure. That mortality was reduced in a randomized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infarction.

Efficacy and tolerance of trandolapril (0.5-2 mg) administered for 4 weeks in patients with mild-to-moderate hypertension. Investigator Study Group.

This double-blind, placebo-controlled, dose-ranging study recruited 170 patients with mild-to-moderate hypertension from nine centers. After a 4-week, single-blind, placebo run-in phase, patients were randomized in a double-blind fashion to four parallel groups that received either placebo or 0.5, 1, or 2 mg trandolapril for 4 weeks. Treatment was administered as a once-daily dose in the morning and blood pressure was measured 24 h after drug intake. The primary criterion of efficacy was a decrease in supine diastolic blood pressure. At the end of the study, the lowest dose of trandolapril that consistently produced a significant difference from placebo in reducing blood pressure was 1 mg (-6.6 mm Hg for supine diastolic blood pressure). It was effective from around 2 weeks onward; the 2-mg dose differed significantly from placebo from around 1 week onward. At the end of the study, the 1- and 2-mg doses were equally effective. The lowest dose tested, 0.5 mg, showed some evidence of an effect on systolic blood pressure and may well prove to be a useful dose in patients who are highly sensitive to the effect of ACE inhibition. Tolerance throughout the study was good for all doses tested.

Comparison of the efficacy and safety of trandolapril and captopril for 16 weeks in mild-to-moderate essential hypertension. Investigator Study Group.

This multicenter international trial recruited 180 patients from 27 investigators. After a 4-week, single-blind placebo run-in, patients were randomized double-blind to 16 weeks of trandolapril 4 mg o.d. or captopril 50 mg b.i.d. If blood pressure was not normalized at 8 weeks, hydrochlorothiazide (HCTZ) 25 mg was added. Morning predosing supine diastolic blood pressure (DBP) was the primary efficacy measurement. At 8 weeks, the intention-to-treat analysis showed a significant difference for supine DBP (mean +/- SEM) between the two groups: trandolapril -13.5 +/- 0.9 mm Hg; captopril -10.1 +/- 1.0 mm Hg (p = 0.007). The proportion of patients whose blood pressure was normalized was 61% for trandolapril and 44% for captopril (p = 0.02). At 8 weeks, 26% of the trandolapril group received HCTZ compared with 38% taking captopril. The addition of HCTZ further increased the antihypertensive effect in patients who had shown only moderate reductions in blood pressure after drug monotherapy. Both treatments were well tolerated clinically and biochemically. Withdrawals owing to adverse events were three from trandolapril and eight from the captopril group. Trandolapril given once daily is an effective and well-tolerated antihypertensive agent that, in this study, exhibited better efficacy compared with captopril. When blood pressure is not sufficiently controlled with monotherapy, the combination of trandolapril and HCTZ enhances the antihypertensive effect.

Comparison of the efficacy and safety of trandolapril and nifedipine SR in mild-to-moderate hypertension. Investigator Study Group.

After a single-blind, 4-week placebo run-in period, 161 patients were randomized to trandolapril 2 mg once daily (n = 54), nifedipine slow-release (SR) 20 mg twice daily (n = 55), or a combination of both drugs (n = 52) for 16 weeks. Morning predosing supine diastolic blood pressure (DBP) was the primary efficacy measurement. After 16 weeks the intention-to-treat analysis showed no significant difference in supine DBP (mean +/- SEM) between trandolapril (-12.4 +/- 1.5 mm Hg) and nifedipine SR (-15.3 +/- 1.4 mm Hg; p = 0.1). However, the combination therapy was more effective (-18.9 +/- 1.3 mm Hg). Normalized blood pressure at 16 weeks was seen with 54% on trandolapril, 63% on nifedipine SR, and 77% on the combination. Adverse events, possibly related to drug, were more common with nifedipine SR (34%) than with trandolapril (17%; p < 0.05), and in comparison with the combination (21%). Drug-related treatment emergent events, reported by more than 3% of patients (fatigue, palpitations, edema, migraine), were seen only in the nifedipine SR and combination groups. Trandolapril 2 mg proved a well-tolerated and effective antihypertensive agent, comparable to nifedipine SR 40 mg. Furthermore, the combination of the two drugs was shown to enhance the antihypertensive effect of the two compounds alone. Adverse events were less common with trandolapril and the combination than with nifedipine SR alone.

Double-blind comparison of the efficacy and safety of trandolapril 2 mg and hydrochlorothiazide 25 mg in patients with mild-to-moderate essential hypertension. Investigator Study Group.

This multicenter international trial recruited 205 patients from 16 investigators. After a 4-week, single-blind placebo run-in, patients were randomized to receive 16 weeks of trandolapril 2 mg/day (68 patients), hydrochlorothiazide (HCTZ) 25 mg/day (68 patients), or the combination (69 patients). Morning predosing supine diastolic blood pressure (DBP) was the primary efficacy measurement. Intention-to-treat analysis showed significant decreases in all three groups in mean (+/- SEM) supine DBP throughout the study, with no significant differences at week 16 between trandolapril (-10.6 +/- 1.3 mm Hg) and HCTZ (-10.9 +/- 1.3 mm Hg). The combination gave a significantly greater reduction than either drug alone (-15.1 +/- 1.13 mm Hg). Blood pressure was normalized in the combination group in 67% of patients, a significantly higher proportion than either trandolapril (63%) or HCTZ (60%; p = 0.04). Each treatment was well tolerated. The incidence of adverse events was similar in all three groups. Trandolapril 2 mg once daily is an effective antihypertensive agent, comparable to HCTZ. Furthermore, the combination of the two drugs was shown to enhance the antihypertensive effect of the two compounds alone.

Long-term therapy with trandolapril, a new nonsulfhydryl ACE inhibitor, in hypertension: a multicenter international trial. Investigator Study Group.

An international trial recruited 1,049 patients from 122 investigators. After a 2- to 4-week, single-blind placebo run-in, patients were treated unblinded for 1 year. Therapy was started with trandolapril 2 mg once daily. The dose was increased to 4 mg/day if, after 1 month, blood pressure was not normalized, and then was combined with diuretics and/or calcium antagonists in increasing doses if necessary. At the cutoff point for this interim analysis. 481 patients had been treated for over 12 months and 960 for 3 months. At end point, trandolapril produced a significant decrease in blood pressure (-14 mm Hg for mean supine diastolic blood pressure). Blood pressure was normalized in 60% of the population with monotherapy. Trandolapril, alone or in combination with diuretics or calcium antagonists, was well tolerated clinically and biochemically. Only 3.9% patients reported dry cough. Withdrawals of patients from the study for treatment related reasons were 3.8%. Trandolapril had also an excellent antihypertensive effect and was well tolerated in elderly patients, in patients with glucose intolerance, and in patients with renal dysfunction.

Converting enzyme inhibition: dissociation between antihypertensive and arterial effects.

In this study the dose-response curves reflecting the arterial and the antihypertensive effects of converting enzyme inhibition were analysed. The BP measurement (using a random zero sphygmomanometer) and its decrease following converting enzyme inhibition were used as a marker of the arteriolar effect of the drug. The effect on conduit arteries was evaluated through determination of carotid-femoral pulse wave velocity used as an index of arterial distensibility. We compared the dose-response curves of these two parameters in a double-blind study carried out in 24 patients with essential hypertension, who were randomised between placebo and 2, 4 and 8 mg of the converting enzyme inhibitor trandolapril given for 8 days. The antihypertensive effect was observed from 2 mg, at which dose the plateau of BP reduction was already achieved. No significant correlation was found between dose and BP reduction (r = -0.34), whereas the dose was significantly related to the change in pulse wave velocity (r = -0.56, P < 0.01). No significant correlation was found between changes in BP and change of pulse wave velocity. The study provides evidence that the effect on the conduit artery was obtained for higher doses than the BP effect in patients treated for hypertension by the converting enzyme inhibitor trandolapril.