Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators.

BACKGROUND: Drugs that improve symptoms in patients with heart failure must also be assessed for their effects on survival. Ibopamine stimulates DA-1 and DA-2 receptors and causes peripheral and renal vasodilatation; the drug improves symptoms of heart failure. We assessed the effect of ibopamine on survival in patients with advanced heart failure in a multicentre, randomised placebo-controlled study. METHODS: Patients with advanced severe heart failure (New York Heart Association classes III and IV) and evidence of severe left-ventricular disease, who were already receiving optimum treatment for heart failure, were randomly allocated oral ibopamine 100 mg three times daily or placebo. The primary endpoint was all-cause mortality. The study was designed to recruit 2200 patients, and the minimum duration of treatment would be 6 months. We did intention-to-treat and on-treatment analyses; a post-hoc subgroup analysis was also done. FINDINGS: After we had recruited 1906 patients the trial was stopped early, because of an excess of deaths among patients in the ibopamine group. 232 (25%) of 953 patients in the ibopamine group died, compared with 193 (20%) of 953 patients in the placebo group (relative risk 1.26 [95% CI 1.04-1.53], p = 0.017). The average length of follow-up was 347 days in the ibopamine group and 363 days in the placebo group. In multivariate analysis, only the use of antiarrhythmic drugs at baseline was a significant independent predictor of increased fatality in ibopamine-treated patients. INTERPRETATION: Ibopamine seems to increase the risk of death among patients with advanced heart failure who are already receiving optimum therapy, but the reasons for this increase are not clear. Our finding that antiarrhythmic treatment was a significant predictor of increased mortality in ibopamine-treated patients may be important, but exploratory analyses must be interpreted with caution.

[Drug evaluation methods in lower limb arteriopathy]. / Méthodes d'évaluation des médicaments dans l'artériopathie des membres inférieurs.

The prevalence and severity of chronic vascular leg disease explains the necessity to clarify methods for assessing it. Today the methods are both clinical and paraclinical. Clinically, they are based on the Fontaine and Leriche classification and appearance of ischaemic pain. Paraclinically, they are measuring distal blood pressure, artery output, micro-circulation, rheology, and tissular metabolism. But this approach must be also global, assessing coronary and carotid disease. Trials methodology includes a first step of explanatory studies by paraclinical ways and lastly pragmatic efficacy and tolerability studies. We recommend an accurate selection of patients and a stratification. The disease must be stable and the treatment and diet too. The trials should be randomised vs placebo. In conclusion we propose a multiparametric classification of the disease.

[Rehabilitation of patients with chronic cardiac insufficiency. Immediate and midterm effects]. / Réadaptation des malades en insuffisance cardiaque chronique. Effets immédiats et à moyen terme.

OBJECTIVES: While physical training is known to improve cardiac performance in patients with chronic congestive heart failure, we conducted this study to evaluate the effect of such training programmes. METHODS: The study group included 48 untrained patients with stable chronic heart failure controlled with the same daily oral regimen including 0.25 mg digitoxin, 40 mg furosemide and 50 mg captopril. Halt of the patients (n = 24) entered a physical rehabilitation programme for a 3-week period. Each daily session included passive mobilization of the limbs (10 min), respiratory exercises (10 min) and endurance exercise on an ergometric cycle with a maximum work load of 50, 60 and 70% of the theoretical maximal load for weeks 1, 2 and 3 respectively. The other 24 patients did not change their physical activity level and served as controls. The immediate and medium term effects (3 months after the end of the training programme) were assessed using exercise tests, left ventricular isotopic ejection fraction and plethysmography of the lower limbs. The quality of life was compared using the NYHA functional classification and the Goldsman questionnaire. RESULTS: At the end of the 3-week training period, and compared with the control group, there was a moderate improvement of VO2max (p < 0.02) and a 10% improvement in the ejection fraction (p < 0.05) in the trained patients. There was a clearly significant improvement in the anaerobic threshold and arterial blood flow rate (p < 0.001) and lowered vascular resistance (p < 0.001) and venous tone (p < 0.001). The quality of life was also improved in the training group. However, 3 weeks after the end of the training period, these differences disappeared. CONCLUSION: Patients with chronic heart failure can benefit from physical training showing functional improvement and no deleterious effect on left ventricular function. This beneficial effect is nonetheless temporary and would appear to be due to improved skeletal muscle oxidative capacity and peripheral haemodynamics.

Multicentre study of the determination of peak oxygen uptake and ventilatory threshold during bicycle exercise in chronic heart failure. Comparison of graphical methods, interobserver variability and influence of the exercise protocol. The VO2 French Study Group.

Assessment of the ventilatory threshold (VT) has been proposed to assess exercise tolerance more objectively, particularly in clinical trials, but reproducibility, interobserver variability and feasibility of the graphical methods for determination of VT have not been properly studied in patients with chronic heart failure (CHF). Fifty-one patients with mild to moderate CHF (mean peak oxygen uptake (VO2): 20.5 ml.min-1.kg-1) were assessed during two consecutive bicycle exercise tests within 8 days. Two graded exercise protocols were compared with stages of 30 W every 3 min (22 patients) or 10 W/min (29 patients). VT was determined separately by five trained physicians using five different graphical methods. The 'crossing method' (first crossing of the VCO2 and VO2 curves) yielded the highest rate of determination (88%) but tended to overestimate the mean VT. The VE method (disproportionate increase of ventilation relative to VO2) produced the best interobserver agreement (coefficient of variation = 78%). Peak VO2 was very highly reproducible in both exercise protocols (relative difference 2-test 1/test 1 = -0.32% for the 30 W 3 min protocol; +2.18% for the 10 W.min-1 protocol). The reproducibility of VT was slightly lower regardless of the graphical method used to determine it (relative differences varied from -3.3% to +7.3%). Therefore, peak VO2 appears more suitable than VT for assessment of exercise tolerance in CHF.

Changes in exercise tolerance and resting haemodynamics during long-term treatment of heart failure with xamoterol.

The long-term efficacy of xamoterol in improving effort capacity and haemodynamics was investigated in a study lasting 1 year in heart failure patients. Following a 3 month, double-blind period of treatment with xamoterol, patients continued therapy for a further 9 months. Exercise duration rose by 27% at 3 months and this improvement was maintained at 12 months. Similarly, the statistically significant increase in cardiac index and reduction in pulmonary wedge pressure and exercise heart rate persisted for 12 months.

[The syndrome of "muscle deconditioning" in chronic cardiac insufficiency]. / Le syndrome de "déconditionnement musculaire" de l'insuffisance cardiaque chronique.

Fatigue, that cardinal symptom of heart failure, expresses muscle deconditioning and is becoming the main complaint of our patients. Dyspnoea also is, at least partially, a consequence of muscle deconditioning; however, the wide use of diuretics which reduce water and salt retention has improved the "pump" function an therefore dyspnoea. The "muscle deconditioning" syndrome in heart failure has two causes: reduction of the nutritive blood flow in skeletal muscle, and specific alteration of mitochondrial oxidative metabolism. The syndrome appears only after a lasting reduction of physical activities. Its anatomical substrate is a mild muscular fibrosis and, mainly, reduced area of oxidative mitochondrial cristae. It remains for approximately three months, which accounts for the delayed improvement of exercise tolerance under vasodilatator treatment with angiotensin-converting enzyme inhibitors. This syndrome explains the success of retraining techniques which, in ou opinion, should become part of our therapeutic armamentarium.

[Effects of xamoterol in moderate cardiac insufficiency]. / Effets du xamotérol dans l'insuffisance cardiaque modérée.

Xamoterol, a partial agonist of beta 1-adrenoceptors, was tested as a cardiotonic drug in 10 patients with moderate chronic heart failure. The trial was double-blind drug versus placebo for 3 months and open for one year. At 3 months the patients were clinically improved with downgrading by one NYHA class, and there was a significant increase in response to a 36-second exercise, as compared with the placebo group. Haemodynamic index, a 14 per cent fall in pulmonary wedge pressure and a 7 per cent increase in left ventricular stroke work as compared with the placebo group. This clinical and haemodynamic improvement was paralleled by a reduction of the double product on exercise. In long term use, xamoterol did not seem to induce tachyphylaxis, and few side-effects were recorded during this trial.

[Abnormalities of the peripheral circulation and tolerance to exertion of patients with heart failure]. / Anomalies de la circulation périphérique et tolérance à l'effort chez l'insuffisant cardiaque.

Chronic heart failure is attended by a number of abnormalities of peripheral circulation. To a great extent, these abnormalities determine the patients' functional symptoms, their tolerance to exercise and their response to treatment, at least in the short term. The response to exercise of heart failure patients depends on their maximal oxygen consumption which is determined by their maximal cardiac output and by various peripheral adjustments, such as distribution of regional blood flow and peripheral oxygen extraction. Abnormalities of peripheral arteriolar and capillary dilatation are determined by hyperstimulation of neurohormonal systems. An increase in maximal muscular blood flow, which determines the patients' capacity of exercise, can be obtained with drugs which increase the muscular perfusion pressure (inotropic drugs) or which decrease muscular resistances without lowering the perfusion pressure (venous or balanced vasodilators, diuretics). Physical rehabilitation may improve maximal oxygen consumption by improving the peripheral use of oxygen. Thus, a better understanding of the physiopathology of heart failure will in the future improve the functional symptoms of these patients and prolong their survival, which has not always been the case with conventional therapies.

[Multiparameter correlative study of respiratory gas exchange during exercise]. / Etude corrélative multiparamétrique des échanges gazeux respiratoires à l'effort.

Patients with chronic heart failure were evaluated simultaneously by conventional methods and by heart-lung exploration during exercise with the purpose of validating the latter method. Only 50 patients were evaluated on two occasions and therefore included in the correlative statistical study. In this study such data as NYHA classification, cardiothoracic ratio, ejection fraction, echocardiographic fibre shortening fraction and biochemical values (venous lactate, plasma noradrenaline levels) were compared with data obtained from evaluation during exercise, i.e. VO2 max, VO2 peak, anaerobic threshold, oxygen pulse, VCO2, O2 equivalent and respiratory quotient, alveolar ventilation per minute, duration and load of exercise. Very good correlation was found with the indices obtained from VO2 and in particular with the O2 pulse and the VO2 max percentage. Good correlation was also found with VCO2 and the O2 equivalent as well as with alveolar ventilation per minute. In contrast, the anaerobic threshold and respiratory quotient correlated poorly with the first set of data and therefore were disappointing. It appears from this study that the indices obtained from VO2 are highly representative of the heart-lung unit in patients with heart failure. It seems, however, that the muscular status of the patients plays a considerable role in their exercise capacity. We suggest that these indices should be used in clinical pharmacology studies.

Comparative study of once-daily administration of captopril 50 mg, hydrochlorothiazide 25 mg and their combination in mild to moderate hypertension.

Two hundred and eleven patients with mild or moderate hypertension, mean age 53.5 +/- 9.5 years (range 24-70) were randomised double-blind to treatment with either captopril 50 mg (C50), hydrochlorothiazide 25 mg (HCTZ 25), the fixed combination of captopril 50 mg and hydrochlorothiazide 25 mg (C50/HCTZ 25) or placebo. Blood pressure, heart rate, body weight and side effects were assessed at the end of the run-in period on placebo and after 4, 6, 8 weeks treatment at the same time, 20-24 h after the last dosing. Routine biochemical examinations were carried out on all patients after the placebo period as well as after 4 and 8 weeks. Blood pressure significantly decreased in all groups, but the mean percentage change from baseline was highly statistically significant at 8 weeks, for C50 and C50/HCTZ 25 groups. The incidence of clinical side effects was low and not statistically different for the four groups with few specific adverse effects (one transient alteration of taste in captopril group). No patient was withdrawn from the study due to side effects. A better anti-hypertensive efficacy was obtained with the fixed combination captopril 50 mg/hydrochlorothiazide 25 mg once daily compared to placebo or each component alone, and without any difference in side effects.

[Effect of captopril in left ventricular failure during the acute stage of myocardial infarction]. / Effet du captopril dans l'insuffisance ventriculaire gauche au stade aigu de l'infarctus du myocarde.

The oral inhibitor of the converting enzyme of angiotensin has previously been used successfully in the treatment of chronic cardiac failure. Its action as an arterial and venous vasodilator and in significantly reducing the heart rate which we have previously reported, led us to assess its effects in left ventricular failure during acute myocardial infarction. The effects of captopril were compared with those of isosorbide dinitrate in 10 patients with left ventricular failure during acute myocardial infarction. An arterial and venous vasodilatation was obtained with both drugs. Captopril induced a greater fall in left ventricular filling pressures and significantly reduced the heart rate, leading to a slight increase in left ventricular systolic work index. Pulmonary arterial resistances decreased more significantly with captopril whilst systemic arterial resistances fell equally. The left ventricular function curve was shifted to the left by both captopril and isosorbide dinitrate, but only captopril induced an upward shift and only captopril caused very significant reductions in the rate-pressure product. The plasma renin activity of these patients was high but the correlation with the vasodilator effect was poor. There was little change in medium-term survival (50% mortality). These results indicate that captopril may be a valuable drug in the treatment of left ventricular failure in acute myocardial infarction. However, its oral presentation makes it difficult to determine the optimal dose.

[Side effects induced by captopril. Comparison of a series of hypertensive patients with renal failure and a series with cardiac failure]. / Les effets secondaires induits par le captopril. Comparaison d'une série d'hypertendus insuffisants rénaux avec une série d'insuffisants cardiaques.

The first oral converting enzyme inhibitor, Captopril, has been used to treat hypertension and cardiac failure since 1978. Based on this two year experience, we studied the side-effects of this drug in 64 patients, a privileged series as it included 32 hypertensive patients with chronic renal failure and 32 patients with cardiac failure and normal renal function. After 16 months of treatment, we observed 19 p. 100 of skin complaints, 17 p. 100 disturbance of taste, 6 p. 100 oral problems, and one case of orthostatic hypotension. From the biological point of view: 20 p. 100 eosinophilia, 10 p. 100 hyperkalemia, 5 p. 100 antinuclear antibodies, 2 p. 100 renal failure, and one case of agranulocytosis. The group with renal failure had many more side effects due to a relative dosage (corrected for weight and renal function) which was three times as great. It would therefore appear to be essential to adapt the dosage in each individual case, a task which we have attempted using a formula which considerably reduced the incidence of side effects in our series: (formula; see text)

[Isosorbide dinitrate in the treatment of threatening myocardial infarction (author's transl)]. / Le dinitrate d'isosorbide dans le traitement du syndrome de menace (author's transl)]

Thirty patients with threatening myocardial infarction were treated with intravenous isosorbide trinitrate. Eight patients had increasingly severe angina, 6 had de novo crescendo angina, 3 had Prinzmetal angina and 13 had signs of impending extension of a previous infarct. In all cases the anginal attacks occurred spontaneously. The drug was administered in association with a beta-blocker or a calcium antagonist. The initial dosage was 33 mcg/min and dosage adjustments ranged from 16 to 130 mcg/min. the main duration of treatment was 3.6 days. Pain was controlled in all patients. Anginal attacks ceased completely and permanently in 24, but the remaining 6 became isosorbide dinitrate-dependent and could only be weaned by aortocoronary bypass. The effects on the drug on heart rate and blood pressure remained moderate and never interfered with dosage adjustments. Coronary artery angiography was performed without any trouble in 25 patients, 21 of whom underwent myocardial revascularization by venous grafts.

["Slowing" right bundle-branch block in reciprocating tachycardia from a latent right lateral Kent bundle]. / Bloc de branche droit "ralentisseur" dans une tachycardia réciproque empruntant un faisceau de Kent latéral droit inapparent.

The authors report the case of a 56 year old man with paroxysmal reciprocating tachycardia. The participation of a right lateral Kent bundle, latent in sinus rhythm and with retrograde atrioventricular conduction during tachycardia was proved by : 1) the slowing of the tachycardia rhythm and lengthening of the ventriculo-atrial conduction time by 50 ms during right bundle branch block ; 2) atrial mapping during tachycardia showing right lateral atrial pre excitation ; 3) the spontaneous termination of some attacks after a blocked Hisian depolarisation. Analysis of the mechanisms of spontaneous termination of tachycardia showed a block in the accessory pathway in 80% of cases, leading to the successful use of Amiodarone. The particular electrophysiological mechanism of functional bundle branch block makes it the most reliable positive diagnostic criterion in reciprocating tachycardia. A review of previously reported series shows participation of right lateral and septal accessory pathways to be uncommon during reciprocating tachycardia. Functional bundle branch block does not necessarily lengthen the ventriculo-atrial interval with septal accessory pathways. Left lateral Kent bundles are much more common. These points are analysed together with the mechanism of functional bundle branch block in the discussion.

[Clinical, haemodynamic and biochemical effects of angiotensin-converting enzyme inhibition in chronic refractory cardiac failure (author's transl)]. / Effets cliniques, hémodynamiques, biologiques de l'inhibition de l'enzyme de conversion dans l'insuffisance cardiaque chronique réfractaire.

Twenty patients with chronic congestive heart failure resistant to conventional treatment with digitalis, diuretics and vasodilators received captopril, an oral inhibitor of the angiotensin-converting enzyme, in daily doses of 200 mg and were followed up for 2 months or more. At 2 months, there was a significant reduction in functional symptoms (NYHA classification), bodyweight and left ventricular filling pressure, with an equally significant rise in cardiac output and sodium urinary excretion. There was no fall in systemic blood pressure, nor tachycardia. These effects were sustained in 8 patients followed up for 6 months. They seem to indicate that captopril is both effective and well tolerated in chronic congestive heart failure.