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.

[Pharmacokinetics and pharmacodynamics of a new 80 mg oral delayed-action isosorbide dinitrate preparation]. / Pharmacocinétique et pharmacodynamique d'une nouvelle forme orale retard de dinitrate d'isosorbide dosée à 80 mg.

A new galenic form of isosorbide dinitrate (consisting of a hydrophilic matrix which allows very slow release of the active drug) was studied from the pharmacokinetic and pharmacodynamic view points in 11 patients with stable angina pectoris under betablocker therapy. After testing their sensitivity to nitrates with a sublingual trinitrin test causing a fall greater than or equal to 20 mmHg in systolic and greater than or equal to 10 mmHg in diastolic blood pressure, the patients were given a single tablet of Risordan LP 80 daily for 7 days. The equilibrium plasma concentrations of isosorbide dinitrate and its mononitrate metabolites (2-isosorbide mononitrate and 5-isosorbide mononitrate) over 24 hours were measured on the 6th treatment day. A method of measuring these nitrate derivatives has been developed and validated. The concentrations measured enabled the study of the pharmacokinetics of this new form, showing an average minimal concentration of 5-isosorbide mononitrate (principal metabolite) of 85 +/- 41 micrograms/l and an amplitude of fluctuation over the 24 hours period of 296 +/- 102 micrograms/l. From the pharmacodynamic point of view, the evaluation of the sensitivity to a single dose of 0.75 mg of trinitrin 24 hours after the first dose of Risordan LP 80, just before the second dose and 24 hours after the seventh dose, showed a significant difference (average decrease of 40 +/- 19 mmHg in systolic blood pressure) with respect to the values observed during the selection phase.(ABSTRACT TRUNCATED AT 250 WORDS)

[Nycthemeral changes in plasma concentrations of active nitrate derivatives. Comparison of a single dose of LP 60mg isosobide dinitrate and LP 20mg isosobide dinitrate administered 3 times daily]. / Les variations nycthémérales des concentrations plasmatiques de nitrés actifs. Comparaison du dinitrate d'isosorbide LP 60 mg en monoprise et du dinitrate d'isosorbide LP 20 mg en 3 prises.

The daily plasma level fluctuation is critical in the prevention of tolerance during long-term nitrate therapy. Two dosage regimens of sustained-release isosorbide dinitrate (ISDN) (60 mg tablet once daily vs 20 mg three times daily) were compared at steady state. Comparative bioavailability data of the two forms after single administration in 12 healthy subjects enabled calculation of the steady state blood levels of ISDN, IS-2MN and IS-5MN by simultation of the two regimens. Both achieved the required trough concentration to restore sensitivity to nitrates (100 micrograms/l for IS-5MN), but greater plasma level increases were observed (greater than 200 micrograms/l for IS-5MN), with 60 mg once daily. A parallel, randomised, double-blind, double placebo study involved 126 patients with stable angina, concomitantly receiving beta-blockers and/or calcium inhibitors. Ergometric parameters 4 hours after drug administration and clinical symptoms were compared at inclusion under 20 mg three times daily, and after a 4 week treatment with either dosage. Compared with 20 mg three times daily, the once daily regimen: improved equally the symptoms and ergometric parameters of stable angina in combination therapy; had a similar side-effect profile; enhanced the sensitivity to nitrate 4 hours after administration with regard to the hypotensive effect; the latter may clinically reflect the pharmacokinetic differences between the two regimens. Sixty milligrammes sustained release ISDN once daily may thus avoid nitrate tolerance and improve patient compliance.

[Evaluation of tolerance during intravenous administration of low dose of isosorbide dinitrate in the treatment of unstable angina]. / Evaluation du phénomène d'échappement lors de l'administration intraveineuse du dinitrate d'isosorbide à posologie modérée dans le traitement de l'angor instable.

The eventuality of tolerance was assessed in 19 patients with unstable angina treated by continuous intravenous infusion of 50 micrograms/min of isosorbide trinitrate (ISDN) in association with heparin and betablocker therapy. The tolerance phenomenon was evaluated by the hypotension produced by the ISDN infusion and by the amplitude of fall in blood pressure produced by an intravenous bolus of 1 mg of glyceryl trinitrate (GTN) according to the principle of crossed tolerance to the two nitrate derivatives. Under these conditions of administration, the authors observed partial attenuation of the blood pressure response to continuous ISDN infusion and absence of cross tolerance between ISDN and intravenous GTN. The co-prescription of intravenous N-acetylcysteine at a dosage of 10 g/24 hours in 10 of the 19 patients did not affect the blood pressure or the response to the GTN bolus compared with the 9 other patients who had received placebo after double-blind randomisation. The results of this study do not indicate if the maintenance of vascular sensitivity to nitrate derivatives at least for 72 hours, was related to the choice of a relatively low dose and/or the use of ISDN rather than another nitrate derivative, in particular glyceryl trinitrate. The use of intravenous ISDN at a low dose over a 3 day period in the usual conditions of prescription for unstable angina does not seem to induce a quantitatively significant phenomenon of tolerance.