Impact of presentation of research results on likelihood of prescribing medications to patients with left ventricular dysfunction.

This study was conducted to evaluate willingness to prescribe medication based on identical data presented in different outcome terms to health professionals of varied discipline, geographic location, and level of training. Cross-sectional survey using a self-administered questionnaire was performed in 400 health professionals (physicians, pharmacists, physicians-in-training, and pharmacy students) in the United States and Europe. Data reflecting a clinical trial were presented in 6 outcome terms: 3 terms describing identical mortality (relative risk reduction, absolute risk reduction, and number of patients needed to be treated to prevent 1 death); and 3 distractors (increased life expectancy, decreased hospitalization rate, and decreased cost). Willingness to prescribe and rank order of medication preference assuming willingness to prescribe were measured. The results of the study showed that willingness to prescribe and first choice preference were significantly greater when study results were presented as relative risk reduction than when identical mortality data were presented as absolute risk reduction or number of patients needed to be treated to avoid 1 death (p <0.001). Increase in life expectancy was the most influential distractor. In conclusion, this study, performed in the era of "evidence-based medicine," demonstrates that the method of reporting research trial results has significant influence on health professionals' willingness to prescribe. The high numerical value of relative risk reduction and the concrete and tangible quality of increased life expectancy exert greater influence on health professionals than other standard outcome terms.

Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor.

BACKGROUND: The increased prostaglandin synthesis that might follow stimulation of the arachidonic acid cascade by angiotensin-converting-enzyme inhibition (ACE-I) has been suggested to underlie the appearance of cough on ACE-I treatment. We investigated whether the prostanoid thromboxane was involved. METHODS: Nine patients with essential hypertension who had cough after enalapril 20 mg once a day (coughers) were treated, while continuing the enalapril, in a double-blind crossover study with placebo or picotamide, 600 mg twice daily. Picotamide is a platelet antiaggregant that acts through both inhibition of thromboxane synthase and thromboxane-receptor antagonism. Thirteen hypertensive patients with no history of ACE-I-induced cough were also treated with enalapril and served as controls. Cough frequency was measured by a visual analogue scale and by a daily cough diary. 24 h urinary recovery of 11-dehydro-thromboxane-B2 and 6-keto-PGF1 alpha were measured to assess any changes in endoperoxide metabolism during the study periods. FINDINGS: 11-dehydro-thromboxane-B2 (TXB2) recovery was significantly reduced by picotamide, which led to the disappearance of cough in eight patients within 72 h. Picotamide urinary recovery data suggested incomplete absorption in the non-responder. At baseline and after rechallenge with enalapril, 11-dehydro-TXB2 excretion was in the same range in the controls and in the coughers, but the latter showed significantly lower excretion of 6-keto-PGF1 alpha, and their ratio of 11-dehydroTXB2 to 6-keto-PGF1 alpha was twice that of the controls (1.40 [95% CI 0.86-1.95] vs 0.61 [0.37-0.84]). INTERPRETATION: A thromboxane antagonist is effective in ACE-I-induced cough. An imbalance between thromboxane and prostacyclin may represent a marker of patients susceptible to ACE-I-induced cough.

[Treatment of hypertension with indapamide 1.5 mg sustained-release form: synthesis of results]. / Traitement de l'hypertension artérielle par l'indapamide 1,5 mg comprimé enrobé à libération prolongée: synthèse des résultats.

In accordance with international recommendations on the need to decrease doses of antihypertensive drugs, a low-dose (1.5 mg) sustained-release form of indapamide was developed so as to optimize the safety/efficacy ratio, while maintaining a once-daily administration. The new formulation ensures that the active ingredient release occurs in a sustained manner over 24 hours, with mean concentrations close to the maximal concentration over a prolonged period, while avoiding peak plasma concentrations. Clinical data were obtained mainly through two European multicenter, randomized, double-blind trials, totalling 690 patients. Firstly, the antihypertensive efficacy' of the new indapamide 1.5 mg form was demonstrated by measuring blood pressure 24 hours after the last drug intake, using a mercury sphygmomanometer; the equivalence of its antihypertensive efficacy with the immediate-release form of indapamide 2.5 mg was then verified. Biochemical safety data showed better acceptability with indapamide 1.5 mg with in particular a reduction of more than 50% of the number of patients with kalemia < 3.4 mmol/l; clinical safety data confirmed the good acceptability observed with the 2.5 mg immediate-release form of indapamide since many years, especially regarding glucose and lipid neutrality. In conclusion, the 1.5 mg sustained-release form of indapamide has an improved antihypertensive efficacy/safety ratio which is in accordance with international recommendations for the usage of low doses of antihypertensive drugs and diuretics in the first-line treatment of hypertension.

Cardiac glycosides. Drug interactions of clinical significance.

Several commonly coadministered drugs interfere significantly with the pharmacokinetics or pharmacodynamics of cardiac glycosides. Only a few of these interactions (e.g. amiodarone, propafenone, quinidine) take place consistently, and although their extent may vary in individual patients, digitalis dosage adjustments should be made to avoid underdigitalization or toxicity. In other instances the appearance of clinically significant interactions depends on individual pharmacokinetic/metabolic characteristics (e.g. erythromycin, tetracycline), and the result cannot be anticipated on clinical grounds. Some interactions are controversial, having not been confirmed by all studies; others have been shown only in healthy volunteers but lack the definition of their relevance in the context of disease states. In view of the possible impact on the individual patient, close clinical monitoring (which may be supplemented with evaluation of digitalis plasma concentration) is recommended when prescribing cardiac glycosides with other therapeutic agents for which the possibility of an interaction has been reported.

Efficacy and tolerability of simvastatin 20 mg vs pravastatin 20 mg in patients with primary hypercholesterolemia. European Study Group.

The safety, tolerability, and efficacy of 20 mg daily doses of simvastatin and pravastatin were compared in this double-blind, randomized trial of 210 patients with primary hypercholesterolemia. Simvastatin was found to produce significantly greater mean percent reductions from baseline in total cholesterol (28% versus 21%), LDL cholesterol (38% versus 29%), and apolipoprotein B concentrations (25% versus 17%) than did pravastatin, and a greater percentage of patients receiving simvastatin (94% versus 80%) had at least a 20% reduction in LDL cholesterol. Both simvastatin and pravastatin produced similar significant mean percent reductions from baseline in triglyceride concentrations (14% and 11%) and significant mean percent increases in the concentrations of HDL cholesterol (7% for both) and apolipoprotein A-I (4% for both). Resulting reductions in the ratios of total cholesterol: HDL cholesterol, LDL cholesterol: HDL cholesterol, and apolipoprotein B: apolipoprotein A-I were significantly greater in the simvastatin group. Both simvastatin and pravastatin were well tolerated. The incidence and severity of clinical and laboratory adverse experiences were similar in both groups, and none were classified as serious. The results of this study confirm the results of prior studies that have found simvastatin to produce lipid-lowering effects superior to those of pravastatin when administered at equivalent mg doses, while demonstrating similar safety profiles.

ACE inhibition in diabetic patients: effect on pressor responsiveness to noradrenaline.

The pressor responsiveness to noradrenaline was assessed before and after four weeks of treatment with enalapril (20 mg/day) in eight mild-to-moderate essential hypertensives, in eight normotensive type II diabetics and in eight mild-to-moderate hypertensive type II diabetic patients. The ACE inhibitor interfered to the same extent with the renin-angiotensin system and did not alter noradrenaline kinetics in the three groups of patients, but significantly reduced the arterial responsiveness only in non-diabetic subjects. It is suggested that factors, such as an exaggerated sodium retention, might determine the lack of effect of enalapril in diabetic patients.

Simvastatin versus pravastatin: efficacy and tolerability in patients with primary hypercholesterolemia.

One hundred patients with primary hypercholesterolemia (total plasma cholesterol greater than or equal to 6.2 mmol/L [240 mg/dl]) were enrolled in an open, randomized, parallel comparative study of simvastatin and pravastatin. All patients started or continued a standard lipid-lowering diet for at least six weeks prior to entry into the four-week placebo baseline period. Fifty patients received simvastatin and 50 patients received pravastatin, both at the recommended starting dose of 10 mg/day, for a treatment period of six weeks. Total cholesterol levels were reduced by 24% (from 7.59 mmol/L to 5.80 mmol/L) with simvastatin, and by 15% (from 7.48 mmol/L to 6.35 mmol/L) with pravastatin. Low-density-lipoprotein cholesterol levels were reduced by 33% and 22% and high-density-lipoprotein cholesterol levels were increased by 10% and 7% with simvastatin and pravastatin, respectively. Plasma total triglyceride levels were reduced by 12% with simvastatin and by 6% with pravastatin. Adverse experiences were similar between treatment groups and both drugs were well tolerated. No patients were withdrawn from the study due to clinical adverse experiences; one patient in the pravastatin group required a reduction in dose to 5 mg/day due to insomnia. At the recommended starting dose, simvastatin had a significantly greater lipid-lowering effect than pravastatin. These results may have implications for the appropriate lipid-reduction therapy for patients at risk of coronary heart disease.

The effect of ace inhibition on peripheral hemodynamics in normotensive and hypertensive patients with type II diabetes.

The effect of treatment with enalapril (10 days at 10 mg/d followed by 4 weeks at 20 mg/d) on forearm hemodynamics was assessed in eight normotensive patients and eight patients with hypertension affected by Type II diabetes as well as in eight patients with essential hypertension and normal glucose tolerance. The ACE inhibitor decreased regional vascular resistances and increased the maximum arteriolar-vasodilating capacity and venous distensibility in the three groups of patients. Thus, this study shows that ACE inhibition by enalapril improves regional hemodynamics in patients with Type II diabetes.

Angiotensin converting enzyme inhibitors, thiazide diuretics and magnesium balance. A preliminary study.

Serum and mononuclear cell magnesium content were determined in a cross-sectional study performed in four groups of hypertensive patients on chronic treatment with atenolol (n = 11), enalapril (n = 10), thiazide diuretics (n = 12), or enalapril + thiazides (n = 11). Our study shows that in patients treated with the thiazides alone, in spite of normal serum potassium and magnesium levels, mononuclear cell magnesium was decreased. To the extent that mononuclear Mg content mirrors the body ion stores, our results indicate that thiazides induce a Mg depletion not detectable by monitoring serum levels.

ACE inhibition and pressor responsiveness to norepinephrine in hypertensive patients.

The pressor response to norepinephrine (NE) was assessed in normal renin essential hypertensive patients before and after they were randomly assigned to receive in parallel groups of treatment a single dose of an angiotensin converting enzyme (ACE) inhibitor (captopril or lisinopril) or a prolonged therapy with lisinopril (30-45 days) or with hydrochlorothiazide (9 days). Blood pressure was significantly reduced by all treatments. The pressor response to NE was unchanged after the single administration of the ACE inhibitors, while it was blunted after chronic administration of lisinopril and after the diuretic. On the basis of these results, it is suggested that the attenuation of the sympathetically mediated vasoconstriction may represent an additional mechanism contributing to the antihypertensive effect of ACE inhibitors administered chronically.

Evaluation of the efficacy and safety of enalapril plus hydrochlorothiazide plus methyldopa vs standard triple therapy in the treatment of moderate to severe hypertension: results from a multicentre study.

We report the results of a randomized, double-blind, parallel group multicentre study in 120 patients with moderate to severe hypertension, comparing two different types of antihypertensive treatment: a) the standard 'triple therapy' with hydrochlorothiazide, propranolol and hydralazine, and b) the combination of an ACE inhibitor, enalapril with hydrochlorothiazide (HCTZ) and methyldopa. The two regimens caused similar degrees of blood pressure reductions. The only significant difference between the two groups was heart rate due to the bradycardiac effect of propranolol in the group treated with the standard 'triple therapy'. Only 3.4% of patients receiving the regimen of enalapril, HCTZ and methyldopa were withdrawn from the study for adverse reactions, against 10% of patients on HCTZ, propranolol and hydralazine. Four cases of hypokalaemia in the enalapril group and 19 in the propranolol group were reported: so enalapril seemed to ameliorate the hypokalaemic effect of HCTZ. The overall analysis of the study results shows that the treatment based on enalapril, HCTZ and methyldopa is as efficient and better tolerated than the established regimen of HCTZ, propranolol and hydralazine.

Interaction study of fenoldopam--digoxin in congestive heart failure.

The potential interaction between fenoldopam, a DA1 selective agonist, and digoxin has been studied in 10 patients with heart failure (NYHA Class II or III) on chronic digoxin treatment. Plasma levels and urinary recovery of the glycoside were monitored for 24 h before and after 9 days of treatment with fenoldopam 100 mg tid. Fenoldopam caused a small, non-significant decrease in the mean steady state plasma concentration and area under the plasma concentration curve of digoxin. As the clearance of digoxin was unchanged there does not appear to be an interaction between fenoldopam and digoxin at the level of the renal tubule.

The metabolic effects of enalapril.

The metabolic effects of Enalapril (EN) were compared in a cross over study with those of Propranolol (PPL). Long term treatment with the ACEI did not modify the lipid and glucose profile and increased urate excretion, while PPL increased triglycerides and decreased urate clearance.

[Plasma levels of anti-arrhythmic drugs and clinical effectiveness in the treatment of ventricular arrhythmias]. / Livelli plasmatici dei farmaci antiaritmici ed efficacia clinica nel trattamento delle aritmie ventricolari.

In spite of the ratio between plasmatic concentration and antiarrhythmic effects of a drug many factors can be influenced by many factors, the plasma level monitoring plays an important clinical role. The efficacy of the antiarrhythmic therapy should be evaluated not only by means of ECG-Holter monitoring and/or electrophysiological study but also by the means of determination of plasmatic and tissular concentration of a drug and metabolites. This latter is indispensable in the evaluation of new antiarrhythmic drugs and of a dose/effect relationship during acute and chronic therapy.