[Antihypertensive action and predictive factors of efficacy of benazepril in mild-to-moderate hypertension: clinical trial in general medical practice on 16,987 patients]. / Activité antihypertensive et facteurs prédictifs d'efficacité du bénazépril dans l'hypertension artérielle légère à modérée: Etude clinique pragmatique conduite en médecine générale chez 16,987 patients.

UNLABELLED: The aim of the study was to evaluate in general practice, in a large and unselected population of patients, the efficacy and safety of benazepril associated or not with hydrochlorothiazide (HCTZ) and to identify clinical and demographic predictive factors of antihypertensive efficacy. In this open uncontrolled study, 16,987 patients with mild to moderate hypertension were included by 5350 GPs. They received benazepril (BNZ) 10 mg once daily for 8 weeks. If sitting DBP remained > 90 mmHg after 4 weeks, HCTZ 12.5 mg once a day was then added for the last 4 weeks. RESULTS: In the intent to treat analysis, 54.5% of patients, after 4 weeks, and 80.6% of patients after 8 weeks, were controlled (DBP < 90 mmHg). Mean sitting DBP decreased from 100.5 +/- 5.5 mmHg (baseline) to 86.7 +/- 7.5 mmHg after 4 weeks and to 82.5 +/- 6.5 mmHg after 8 weeks. Mean SBP decreased from 169.5 +/- 13.1 mmHg to 150.5 +/- 12.5 mmHg after 4 weeks and to 145.0 +/- 10.9 mmHg after 8 weeks. Of the 16,900 patients included in the safety analysis, 853 (5.0%) dropped out of the study, 504 (3.0%) for adverse events (AE). The most frequent AE were: cough (3.5%), headache (0.9%), dizziness (0.8%), asthenia (0.6%) and nausea (0.5%). 13 deaths were observed during the study, mainly due to stroke or cancer. Six cases of raised serum creatinine level, 3 cases of angio-oedema and 2 cases of hepatitis were also reported. After 8 weeks of treatment, the main predictors of therapeutic response (DBP) were: recently discovered hypertension (86.3% of controlled DBP), regular exercise (85.5%) and age < 50 years (84.6%). Conversely: obesity, diabetes mellitus (77.9%), previously treated with several drugs (75.2%) and initial DBP > or = 105 mmHg (74.5%) were not predictive. Predictive factors emerging from logistic regression were : baseline DBP (< 105 mmHg), history of hypertension, body mass index, initial treatment of hypertension (no treatment--one drug--several drugs) and age. CONCLUSION: This large-scale study confirms, the antihypertensive efficacy and good tolerability of benazepril alone or associated with hydrochlorothiazide in general practice.

[Efficacy of benazepril after failure of the first antihypertensive treatment]. / Efficacité du bénazépril après échec d'un premier traitement antihypertenseur.

The aim of the study was to evaluate efficacy of benazepril prescribed as replacement therapy in patients with mild to moderate hypertension, according to the pharmacological class of the previous unsuccessful drug. After wash-out of the ineffective or badly tolerated medication, 814 patients were randomly and blindly assigned to receive either benazepril 10 mg (group 1), benazepril 20 mg (group 2) or benazepril 10 mg plus hydrocholorothiazide 12.5 mg (group 3) once daily. The mean DBP changes from baseline were highly significant in each group (p < 0.001), and greater in groups 2 and 3 versus group 1 (p = 0.003). There was a non-significant trend for a greater efficacy of benazepril when the previous therapy was a diuretic or a calcium inhibitor. In this study, benazepril appears to be efficient as replacement therapy in moderate hypertension, but no link was demonstrated between the quality of the result and the nature of the previous drug.

Prophylactic efficacy of maprotiline on unipolar depression relapse.

BACKGROUND: Although antidepressant medications have been in use for about 30 years, the question remains about their utility in the prophylaxis of recurrent depression. The purpose of this study was to evaluate the efficacy of maprotiline, a tetracyclic antidepressant, for depression prophylaxis. METHOD: We conducted a vast, prospective, multicenter, double-blind, placebo-controlled study of 1141 outpatients suffering from depression and treated with maprotiline or placebo for 1 year. The very large size of the study population allowed for the testing of two drug doses. The study design included a pre-inclusion treatment phase that assured that all study patients had recently suffered from a depressive episode and were in remission at the time they were randomized into two treatment groups (1 and 1/2 tablet of maprotiline 75 mg) and two control groups (1/2 and 1 tablet of placebo). RESULTS: The actuarial relapse rate at 1 year was 16% for maprotiline 75 mg, 1 tablet; 23.8% for maprotiline 75 mg, 1/2 tablet; 31.5% for 1 tablet placebo, and 37.5% for 1/2 tablet placebo. The difference between each group is statistically significant, except for the difference between the two placebo groups. The actuarial incidence of adverse drug reactions during the year was not statistically significant between the treatment and control groups. CONCLUSIONS: This study demonstrates maprotiline's prophylactic effectiveness for depressive relapses, the 75-mg dose being more effective than the 37.5-mg dose. The patients' tolerance of maprotiline therapy was satisfactory at both doses with prolonged prescription.

Effectiveness of oral diclofenac in the acute treatment of common migraine attacks: a double-blind study versus placebo.

In a multicentre double-blind cross-over trial, oral diclofenac at a dose of 50 mg to 100 mg was compared to placebo in the acute treatment of migraine attacks. A hundred and seven patients suffering from migraine without aura were included, and 91 were analysed for efficacy; they had to treat four successive attacks--two with diclofenac and two with placebo. Diclofenac was significantly more effective than placebo (p less than 0.05) on the main judgement parameter, which was the number of attacks aborted within 2 h of drug intake, as well as on the following secondary parameters: the necessity for an escape medication and the evaluation of global efficacy. Diclofenac was well tolerated. This trial demonstrates the efficacy of diclofenac in the acute treatment of migraine attacks. It confirms the good clinical relevance of the main judgement parameter chosen, which is the one recommended by the International Headache Society, but appears to be a severe one in terms of successes.

From the parallel group design to the crossover design, and from the group approach to the individual approach.

The consequences of heterogeneity in response to antihypertensive drugs for the clinical development programs of new antihypertensive drugs and for the care of the individual hypertensive patient have not previously been sufficiently recognized. They play a role in the inappropriate choice of too-high daily doses of some antihypertensive drugs at the end of extensive international development programs. They are also implicated in the insufficient control of blood pressure observed in the long-term multicenter trials in hypertension, where some patients have been treated for several years with drugs that were not the most appropriate for their disease and which did not adequately control their blood pressure. In addition to the parallel group studies, the use of double-blind two-period or multiple period crossover designs can provide valid data for the dose-finding of new antihypertensive drugs and their comparative evaluation. At the end of the trial, these designs also offer each patient the opportunity to be treated with the right dose of the drug most appropriate for his or her disease.

Use of crossover trials to obtain antihypertensive dose-response curves and to study combination therapy during the development of benazepril.

When a new drug is developed, one of the first requirements is to establish the correct dose. Unfortunately, in dose-determination studies, not enough lessons have been learned from the past. Pilot studies are often planned without sufficient statistical power, due to an insufficient number of patients and highly variable blood pressure measurements. In the development of the new angiotensin converting enzyme (ACE) inhibitor benazepril, crossover trials were used to obtain useful information. At the end of phase II of the benazepril development, a double-blind crossover study was carried out with 25 patients, and the results made it possible to redefine the 12- and 24-h effects of benazepril in comparison with placebo. Moreover, the crossover trial allowed an investigation of the biological effects of the treatment. In further work, the efficacy of 10 mg benazepril, administered once a day, was confirmed in comparison with captopril and enalapril, with a beta-risk of less than 20%. Since this crossover study yielded reliable data, and there was no carryover effect, a similar crossover design was used to study the interaction between benazepril and nifedipine. In the past, mistakes were made and many antihypertensive drugs were administered in high doses, with no further beneficial effect on blood pressure and an increased risk of side effects. Work described in this paper shows that fewer but better designed and implemented studies can improve the efficiency and value of dose-finding studies for antihypertensive drugs.

Crossover design for the dose determination of an angiotensin converting enzyme inhibitor in hypertension.

In order to determine the dose regimen of new antihypertensive compounds, between-patient trials are usually performed. However, the combined use of a crossover design and a precise methodology to measure blood pressure (BP) and biological effects can provide relevant data with a minimal number of patients, if there is no carryover effect which invalidates the experiment. Such goals were successfully achieved with just 25 hypertensive patients who were randomly allocated in double-blind fashion every 2 weeks to a new angiotensin converting enzyme (ACE) inhibitor, benazepril [10 mg once a day (o.d.), 20 mg o.d., 10 mg twice a day (b.i.d.) and 20 mg b.i.d.], or a placebo. The mean BP fall [systolic (SBP)/diastolic (DBP), measured in mmHg] just before drug intake was significantly greater with benazepril: -14/-9 (10 mg o.d.); -15/-8.5 (20 mg o.d.); -22.5/-14 (10 mg b.i.d.), and -21/-13 (20 mg b.i.d.) in comparison with placebo (-3/-3). Mean active plasma renin (measured in pg/ml), assessed by an immunoradiometric assay based on two monoclonal antibodies, increased significantly in a dose-dependent manner, by +0.7 (placebo), +15.0 (10 mg o.d.), +23.4 (20 mg o.d.), +44.4 (10 mg b.i.d.) and +78.8 (20 mg b.i.d.), whereas plasma ACE decreased (by 67 and 78% after 10 and 20 mg o.d., respectively, and by 91-92% after 10 and 20 mg b.i.d.). In the clinical development of an antihypertensive drug, the earlier use of such within-patient studies, with the random insertion of one placebo period between the active periods, should help in the dose-response curve search.(ABSTRACT TRUNCATED AT 250 WORDS)

[Recurrence of unipolar depression and efficacy of maprotiline]. / Rechutes de dépression unipolaire et efficacité de la maprotiline.

Although antidepressive treatments have been used for about thirty years, the question of their duration remains controverted. In fact, among the large number of therapeutic trials, only about fifteen control studies versus placebo, have evaluated the prophylactic advantage of a long-term antidepressive treatment. In order to complete the small number of products evaluated for this indication (imipramine, amitriptyline, zimelidine, nomifensine, fluoxetine), we have undertaken a vast multicenter study (130 psychiatrists), including 1,141 patients suffering from depression and treated with maprotiline, double-blind versus placebo, in ambulatory, for 1 year. The controlled trial was preceded with a pre-inclusion period in which 1,339 patients suffering from depression were treated, in an open study, with maprotiline at a dose of 75 to 150 mg. Only patients who were clinically improved during this preliminary study (MADRS less than 10), were included in the prophylactic evaluation phase, and divided into four groups: maprotiline 75 mg, maprotiline 1/2 tablet of 75 mg, placebo 1 tablet or placebo 1/2 tablet. The relapse was defined by a score exceeding 27 on the MADRS or exceeding 25 during two separate work-ups of 8 days or according to the experimenter's judgment. The actuarial relapse rate at 1 year was: 16% with 75 mg of maprotiline, 23.8% with 37.5 mg of maprotiline, 31.5% with one placebo tablet and 37.5% with 1/2 tablet of placebo, the difference being statistically significant between the 4 groups except for the "placebo" groups between them. In addition, the tolerance of maprotiline was satisfactory with prolonged prescription.

[Blood concentrations of maprotiline in depressive patients]. / Etude des concentrations sanguines de maprotiline chez des patients déprimés.

Blood levels of Maprotiline were analysed and their relationship to the clinical response was examined in 89 depressed inpatients, according DSM III criteria for Major Depressive Episode, given the drug treatment for 3 weeks. Maprotiline produced marked decreases in mean MADRS and COVI scale scores by the end of treatment. On day 21, no correlation between blood levels of Maprotiline and MADRS or COVI scores were found when all patients were considered. Nevertheless, significant correlations were observed on day 14 (r = .22; p less than .05 for MADRS and r = .23; p less than .05 for COVI scale). In addition, a significant correlation between MADRS or COVI scale scores and Maprotiline blood levels were observed on days 14 and 21 in subgroups of young patients, severe depression (high scores to clinical global investigations), during of at least 3 months, treated without other drug than Maprotiline and good responders.

Crossover design to test antihypertensive drugs with self-recorded blood pressure.

In a double-blind, within-patient study, blood pressure was measured at regular intervals at the clinic by the physician and each day at home by the patient. Both methods of blood pressure measurement demonstrated an antihypertensive effect of the diuretics chlorthalidone (25 mg) and triamterene (50 mg) and the beta-blocker oxprenolol (160 mg) and the greater efficacy of the combination of the two therapies. During placebo, as well as during active treatment, blood pressure values were higher at the clinic than at home, except when the patients were taking the beta-blocker, which minimized the arousal response during blood pressure measurements in the clinic. With 2-week treatment periods, separated by 2 weeks of placebo administration, blood pressure returned toward its initial level after each of the three treatments and none of the carryover effects was significant at the 5% level. This methodology was intended to make it possible to demonstrate in 27 patients at the clinic and in 20 patients with measurements made at home, at the usual statistical risks (alpha = 5%, beta = 10%), a fall of 5 mm Hg in diastolic blood pressure in comparison with a placebo. Moreover, at the end of this 3-month follow-up, each patient could continue to receive the treatment that was the most effective and the best tolerated. In conclusion, the use of a within-patient trial design, with a 15-day washout period between active treatments and careful recording of blood pressure values, can minimize the number of patients included in hypertension trials and offer to each patient the possibility of individualization of treatment.