Systematic versus sentinel-lymph-node-driven axillary-lymph-node dissection in clinically node-negative patients with operable breast cancer. Results of the GF-GS01 randomized trial.

PURPOSE: Sentinel-lymph-node (SLN) resection seems to minimize systematic axillary-lymph-node dissection (sALND) side effects in operated breast cancer patients. We explored whether SLN resection achieves similar therapeutic outcomes as sALND but with fewer side effects. METHODS: A randomized, controlled, open-label trial with parallel-group design compared sALND restricted to cases with positive SLN biopsy (test arm, n = 774) versus SLN biopsy followed by sALND (control arm, n = 770). RESULTS: The five-year overall survivals in control and test arms were 96.42 and 95.64% (P = 0.2925). The estimated difference was nearly zero (precisely, - 0.79%, one-tailed 95% confidence interval (CI) limit - 2.44%). In a multivariate Cox model, the adjusted hazard ratio in the test arm was HR 0.81 (upper 95% CI limit 1.17). Advanced age (HR 1.05 per additional year, CI [1.03-1.08]), negative progesterone receptor (HR 2.17 [1.35-3.45]), SLN metastasis (HR 1.69 [1.03-2.79]), and only one SLN identification technique (HR 4.14 [1.21-14.18]) were associated with lower survival. Patients with ≥ 1 severe side effect at 1 month in control and test arms were 173/703 = 24.6% [21.5-28.0%] and 91/693 = 13.1% [10.7-15.9%] (P < 0.001). The estimated sensitivity of SLN biopsy (control arm) was 145/178 = 81.5% [74.8-86.7%]. CONCLUSIONS: Restricting ALND to cases with positive SLN biopsy does not affect the overall survival but reduces by 11.5% [7.5-15.6%] (P < 0.001) the risk of severe short-time side effects of sALND.

Value of a planned compression ultrasonography after an isolated superficial vein thrombosis: results from a prospective multicentre study.

OBJECTIVES: To assess the efficiency of a systematically planned compression ultrasonography (SP-CUS) to detect venous thrombotic complications (VTCs) in patients with symptomatic isolated superficial vein thrombosis (SVT). DESIGN: Post hoc analysis of a prospective, multicentre, cohort study (POST). PATIENTS: As many as 537 patients with CUS-confirmed isolated SVT undergoing an SP-CUS 8-15 days after the initial CUS. OUTCOMES: Asymptomatic VTC (extension or recurrence of SVT, deep-vein thrombosis (DVT) of the lower limbs) diagnosed by the SP-CUS and symptomatic thromboembolic complications (VTC and pulmonary embolism (PE)) up to 3 months. RESULTS: VTC was suspected before or on the day of the SP-CUS in 18 patients (3.0%). Among the 519 asymptomatic patients (97%) undergoing SP-CUS, this revealed asymptomatic VTC in 12 patients (2.3%; 4 DVT, 4 SVT recurrences, 4 SVT extensions), none of whom subsequently experienced symptomatic thromboembolic events up to 3 months. Among the 507 patients with a normal SP-CUS, 29 (5.7%) presented symptomatic thromboembolic events during follow-up: 2 PE, 7 DVT, 9 SVT recurrences and 11 SVT extensions. CONCLUSIONS: In this study, the SP-CUS detected a few asymptomatic VTC, but failed to identify patients at risk of thromboembolic events during follow-up. Use of an SP-CUS was therefore neither efficient nor cost effective.

Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

Oral buflomedil in the prevention of cardiovascular events in patients with peripheral arterial obstructive disease: a randomized, placebo-controlled, 4-year study.

BACKGROUND: Cardiovascular-related morbidity and mortality in patients with peripheral arterial obstructive disease remain high. We performed an international, multicenter, randomized, double-blind, placebo-controlled trial to investigate whether long-term administration of oral buflomedil could reduce the rate of cardiovascular events in patients with intermittent claudication. METHODS AND RESULTS: Patients >40 years of age with documented peripheral arterial obstructive disease, intermittent claudication, and an ankle-brachial index between 0.30 and 0.80 were eligible for inclusion and were randomized to receive orally either buflomedil or placebo for 2 to 4 years. Aspirin was recommended for all patients (unless they were receiving other antithrombotic treatments at inclusion). The primary efficacy outcome was critical cardiovascular events, defined as the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, symptomatic deterioration of peripheral arterial obstructive disease, or leg amputation. A total of 2078 patients were recruited. Mean treatment duration was 33 months. The rate of critical cardiovascular events was significantly lower in buflomedil-randomized patients than in placebo-randomized patients (9.1% versus 12.4%; hazard ratio, 0.742; 95% confidence interval, 0.603 to 0.915; P=0.0163). Ankle-brachial index increased by 9.2% in buflomedil-randomized patients and decreased by 3.6% in placebo-randomized patients (P<0.001). Tolerance of buflomedil and placebo was comparable. CONCLUSIONS: Compared with placebo, buflomedil administered for 3 years reduced the occurrence of symptomatic cardiovascular events by 26%. The main contributor to the difference in the composite outcome was the reduction in symptomatic deterioration of peripheral arterial disease. The use of buflomedil should be considered in addition to an antiplatelet agent in patients with peripheral arterial obstructive disease and intermittent claudication.

Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial.

BACKGROUND: beta-Blockade-induced benefit in heart failure (HF) could be related to baseline heart rate and treatment-induced heart rate reduction, but no such relationships have been demonstrated. METHODS AND RESULTS: In CIBIS II, we studied the relationships between baseline heart rate (BHR), heart rate changes at 2 months (HRC), nature of cardiac rhythm (sinus rhythm or atrial fibrillation), and outcomes (mortality and hospitalization for HF). Multivariate analysis of CIBIS II showed that in addition to beta-blocker treatment, BHR and HRC were both significantly related to survival and hospitalization for worsening HF, the lowest BHR and the greatest HRC being associated with best survival and reduction of hospital admissions. No interaction between the 3 variables was observed, meaning that on one hand, HRC-related improvement in survival was similar at all levels of BHR, and on the other hand, bisoprolol-induced benefit over placebo for survival was observed to a similar extent at any level of both BHR and HRC. Bisoprolol reduced mortality in patients with sinus rhythm (relative risk 0.58, P:<0.001) but not in patients with atrial fibrillation (relative risk 1.16, P:=NS). A similar result was observed for cardiovascular mortality and hospitalization for HF worsening. CONCLUSIONS: BHR and HRC are significantly related to prognosis in heart failure. beta-Blockade with bisoprolol further improves survival at any level of BHR and HRC and to a similar extent. The benefit of bisoprolol is questionable, however, in patients with atrial fibrillation.

A prospective placebo-controlled double-blind multicenter trial of intravenous streptokinase in acute myocardial infarction (ISAM): long-term mortality and morbidity.

Long-term mortality and morbidity of 1,741 patients with acute myocardial infarction, treated with intravenous streptokinase (1.5 million IU/h) or placebo, was assessed in a double-blind placebo-controlled trial (ISAM). At the 7 month follow-up, 94 (10.9%) of the 859 patients in the streptokinase group and 98 (11.1%) of the 882 patients in the placebo group had died; at an average follow-up of 21 months, 14.4% of the streptokinase group and 16.1% of the placebo group had died. The differences were not statistically significant. Long-term mortality was slightly higher in patients with anterior myocardial infarction and streptokinase treatment (20.1 versus 18.4%) and lower in patients with inferior myocardial infarction (10.2 versus 14.2%). Patients with previous myocardial infarction had a higher long-term mortality rate with streptokinase (34.9 versus 21.5% with placebo, p = 0.03). At 7 months, there were significantly more cases of reinfarction in the streptokinase group (7.2 versus 4.5%, p = 0.02). It is concluded that despite a significant limitation of infarct size by intravenous streptokinase, long-term mortality is only slightly reduced and reinfarction is significantly more frequent. Both findings suggest the need for complementary therapy such as revascularization procedures after thrombolysis.

Epidemiology of venous thromboembolism in Asian patients undergoing major orthopedic surgery without thromboprophylaxis. The SMART study.

BACKGROUND: In Asian patients undergoing surgery, the incidence of venous thromboembolism (VTE) is thought to be low relative to Western patients, and the routine use of thromboprophylaxis is controversial. OBJECTIVES: The aim of this work was to study the epidemiology of VTE in Asian patients undergoing orthopedic surgery without thromboprophylaxis. PATIENTS AND METHODS: We performed a prospective observational study of a cohort of consecutive Asian patients hospitalized for total hip or knee replacement or hip fracture surgery without thromboprophylaxis. The primary study outcome was the incidence of the composite of symptomatic VTE or sudden death at hospital discharge. This outcome was also assessed at 1 month's follow-up. RESULTS: Between April 2001 and July 2002, 2420 patients were enrolled. Median age was 68 years and the median duration of hospital stay was 13 days. The rate of symptomatic VTE or sudden death as notified by investigators was 2.3%[55 patients, 99% confidence interval (CI) 1.6, 3.2] and 1.2% (28 patients, 99% CI 0.7, 1.8) after adjudication by an independent committee. Chronic heart failure, varicose veins and a history of VTE were independent risk factors (P < 0.05) for the occurrence of the primary endpoint. At 1 month's follow-up, the incidence of adjudicated symptomatic VTE or sudden death was 1.5% (35/2264 patients). CONCLUSION: In Asian patients, the incidence of symptomatic VTE after major orthopedic surgery is not low, consistent with the rates observed in Western countries. The use of thromboprophylaxis should be considered in Asian patients undergoing such high-risk surgical procedures.

[Risk factors management in 5708 ambulatory patients suffering from peripheral vascular disease followed in urban practices]. / Contrôle des facteurs de risque dans une population de 5 708 artériopathes des membres inférieurs vus en médecine de ville.

STUDY OBJECTIVE: we examined the management of risk factors in patients suffering from obliterating peripheral arterial disease (OPAD), in urban medical practice. METHODS: PRISMA, ECLAT1 and APRES are surveys based on urban medicine in France. These 3 studies have allowed a compilation of data pertaining to the control of risk factors in patients suffering from one or more clinical manifestations of atherothrombosis, including cerebral vascular accident, coronary insufficiency or OPAD. The study population was divided among patients with isolated OPAD, versus OPAD associated with coronary artery disease (CAD), versus OPAD associated with cerebral vascular disease. RESULTS: a total of 5 708 patients with stable OPAD were included among the 3 studies. Risk factors were not managed in the majority of patients, including 62.6% of hypercholesterolemic patients, 71.1% of diabetics, and 77.4% of hypertensive patients. Overall, the control of risk factors was less satisfactory in patients with OPAD than in patients with CAD. Smoking (70.6% current or past smokers) remains a major risk factor in OPAD. The proportion of current smokers was significantly higher is the group with isolated OPAD than in the other 2 groups of patients (p < 0.0001). CONCLUSIONS: The control of risk factors in patients with OPAD is suboptimal, mainly because of failure to reach the therapeutic goals, rather than because of poor medical management. It is important that recent recommendations be implemented in medical practice. Awareness of the primary physicians will be key in the optimisation of treatment prescriptions and, above all, in the achievement of a higher level of clinical performance.

Drugs effect on platelet survival time: comparison of two pyrimido-pyrimidine derivatives in patients with aortic or mitral replacement.

A prospective randomized trial of the effects of 2 antiplatelet aggregating drugs, dipyridamole (375 mg/d), a related substance RA 233 (1500 mg/d) and placebo, concomitantly with oral anticoagulants, was carried out in patients with prior valvular replacement. The study was aimed to determine effect on platelet survival time (PST) of these 2 agents. The trial sample consisted of 40 males and 15 females aged 40-70 years (average 53 years). 32 received Björk-Shiley valve in aortic position, 23 underwent mitral valve replacement: 3 with Cooley-Cutter, 11 with Lillehei-Kaster 500 and 9 with Starr-Edwards 6120 prostheses; 28 patients had aortic stenosis, 21 aortic insufficiency. All the PST measured after 3 months of treatment were within normal ranges and not different between placebo, dipyridamole or RA 233 treated subjects: averages in days were, respectively, 7.49, 7.11 and 6.88. The present study did not support the claim that modern valve prosthesis could lead to a shortened PST.

Persistent reduction of mortality for five years after one year of acebutolol treatment initiated during acute myocardial infarction. The APSI Investigators. Acebutolol et Prévention Secondaire de l'Infarctus.

The APSI trial was a randomized placebo-controlled trial designed to assess the efficacy of 1 year of treatment by acebutolol in high-risk patients who had survived an acute myocardial infarction. At 1 year there was a statistically significant 48% relative reduction in total mortality (p = 0.019) in favor of acebutolol. In 1995 a long-term mortality survey was undertaken through an administrative inquiry and contacts with investigators. The vital status of 586 of the 607 (96.5%) patients enrolled was known at the cutoff date and all these patients were followed up for at least 5 years. During follow-up (in-trial and post-trial period), 74 deaths (24.8%) occurred in the acebutolol group and 96 (31.1%) in the placebo group (p = 0.10). No difference between the 2 groups was observed for the number of deaths that occurred after the end of the trial: 55 deaths (19.6%) among the 281 survivors in the acebutolol group and 59 deaths (21.7%) (p = 0.70) among the 272 survivors in the placebo group. The annual hazard rate (annual death rate), calculated year by year using the actuarial method, was significantly different (p < 0.01) only for the first year and was not significantly different thereafter. Thus, the initial benefit obtained in 1 year of treatment by acebutolol lasts for 5 years.

Secondary prevention after high-risk acute myocardial infarction with low-dose acebutolol.

Acebutolol et Prévention Secondaire de l'Infarctus (APSI), a randomized, placebo-controlled trial, was designed to test long-term acebutolol, 200 mg twice daily, a beta blocker with mild intrinsic sympathomimetic activity, in the prevention of late death in high-risk postacute myocardial infarction (AMI) patients. APSI was planned because patients with a death rate greater than 20% have not been enrolled in significant numbers in previous trials and in such high-risk patients, it remained to be proven that beta blockers have a beneficial effect. Patients with an expected average risk of greater than 20% were to be selected based on clinical criteria. At the time of the second interim analysis, the placebo group 1-year mortality was much lower than expected (12%). The ethical board recommended to stop the trial: 309 patients had been allocated to placebo, 298 to acebutolol. The average delay between onset of symptoms and inclusion was 10.5 days. The average follow-up was 318 days after inclusion. About the same number of patients were discontinued from study treatment in both groups. All patients were included in the analysis. There were 17 deaths in the acebutolol group and 34 in the placebo group, a 48% decrease (p = 0.019). The vascular mortality decreased by 58% (p = 0.006), the highest ever observed with a beta blocker. All cardiovascular causes of death, including congestive heart failure, were less frequent in the acebutolol group. Although the objective was not achieved, APSI patients were at a higher risk than the average of the 9 previous trials with beta blockers (12% instead of 7%). In addition, the total mortality reduction did not decrease in 9 subgroups with increasing mortality risk from 2 to 23%. APSI shows that moderately severe postAMI patients can benefit from a beta-blocking treatment and a beta-blocker with mild intrinsic sympathomimetic activity can be effective.

Efficacy of acebutolol after acute myocardial infarction (the APSI trial). The APSI Investigators.

A randomized, placebo-controlled trial was carried out to determine the effectiveness of acebutolol in preventing late death in high-risk patients surviving an acute myocardial infarction (MI). The average 1-year mortality rate in placebo groups of 9 trials of beta blockers in post-MI patients was 7.2% compared with 17% in a nonselected cohort of patients who had survived at least 7 days after an MI. The mandate for this trial was based on the fact that high-risk patients whose mortality rate exceeds 20% have not been enrolled in significant numbers in previous trials. It remains to be proved whether beta-blocking therapy in this patient population is beneficial. Selection of high-risk patients for inclusion in the trial was based on an algorithm set up from the Essai de Prevention Secondaire de l'Infarctus du Myocarde Registry. At the time of the second interim analysis, the mortality rate in the placebo group was 12%, lower than expected (greater than or equal to 20%). The trial was stopped; at that time, 309 patients had been allocated to placebo and 298 patients to acebutolol therapy. After 318 days, there were 17 deaths in the acebutolol-treated group and 34 in the placebo group, a reduction in total mortality of 48% (p = 0.019). There were 30 vascular deaths in the placebo group and 12 in the acebutolol group. Thus, cardiovascular mortality with acebutolol was reduced by 58% (p = 0.006). The incidence of all cardiovascular-related deaths was lower in the acebutolol-treated group. The total reduction in mortality did not appear to be correlated with secondary risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the efficacy and safety of low molecular weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis. An updated meta-analysis.

The aim of this study was to determine whether treatment with low molecular weight heparin (LMWH) reduces the incidence of recurrent thromboembolic events, death, haemorrhages, and extension of thrombus more than treatment with unfractionated heparin (UFH) in patients with established deep vein thrombosis (DVT). The study design was an updated meta-analysis of results from 20 randomised controlled clinical studies comparing LMWH with UFH. The main outcomes measured included i) the incidence of thromboembolic events (DVT and/or pulmonary embolism): ii) the incidence of major haemorrhages; iii) total mortality; and iv) extension of thrombus. Statistically significant reductions in favour of LMWH were observed for mortality [common odds ratio (OR) 0.70, 95% confidence interval (CI) 0.50 to 0.98; p = 0.035]. major haemorrhage (common OR 0.59, 95% CI 0.35 to 0.98; p = 0.042) and thrombus extension (common OR 0.65, 95% CI 0.44 to 0.96; p = 0.03). A nonsignificant trend, also in favour of LMWH, was observed for the recurrence of venous thromboembolic events (common OR 0.77, 95% CI 0.55 to 1.08; p = 0.13). The results from the meta-analysis showed that LMWHs seem to have a higher benefit/risk ratio than UFH in the treatment of venous thrombosis.

A randomised placebo-controlled pilot dose-response study with anisoylated plasminogen streptokinase activator complex in acute coronary artery occlusions.

The aim of this study was to determine the dose-response relationship of anisoylated plasminogen streptokinase activator complex (APSAC) by means of a between group double-blind comparison of the new agent and placebo. 50 patients with symptoms of acute myocardial infarction of less than 6 hours duration and whose coronary artery occlusion had been confirmed by coronary angiography were randomly allocated to 5 treatment groups (15, 20, 25 or 30U of APSAC, or placebo) and treatment was given as an intravenous injection over 2 minutes. Angiography was performed again at 15, 30, 45, 60 and 90 minutes and the films were assessed centrally by 2 independent cardiologists. Six patients were excluded from the angiographic analysis, 4 because their angiograms revealed patent arteries before APSAC was administered, 1 patient was excluded because streptokinase had been infused just after randomisation because of cardiogenic shock and 1 because the angiogram was not available due to problems in the film development. Clinical and laboratory examinations carried out for 72 hours after treatment showed that the drug was well tolerated. The reperfusion rates were as follows: placebo, 0/9; APSAC 15U, 5/8; APSAC 20U, 5/9; APSAC 25U, 6/9; APSAC 30U, 5/9. Reperfusion was achieved in 60% of treated patients but no dose relationship was revealed.

Correlation between anti-Xa and occurrence of thrombosis and haemorrhage in post-surgical patients treated with either Logiparin (LMWH) or unfractionated heparin. Post-surgery Logiparin Study Group.

A total of 1290 patients (Pts) undergoing general surgery were enrolled in a randomized, multicentre double-blind study in order to investigate the efficacy and safety of two different doses of a low molecular weight heparin (LMWH) (Logiparin) for the prevention of deep vein thrombosis. Patients were randomized to either 5,000 IU unfractionated heparin twice daily, 2,500 anti-Xa or 3,500 anti-Xa units of Logiparin once daily. Each treatment was given subcutaneously two hours before surgery and continued for seven to ten days. All coagulation tests were performed blindly in a core laboratory. Blood samples were collected before surgery and then 3 hours after injection on Day 3 and 5 after surgery. Anti-Xa amidolytic activities were significantly higher in the two LMW Heparin groups than in the unfractionated heparin group (mean peak levels +/- s.e.m. on Day 3: 0.097 +/- 0.004; 0.152 +/- 0.004 and 0.034 +/- 0.003 IU respectively). As expected a significant correlation was observed between anti-Xa activity and the dose of LMW Heparin injected. The correlation coefficient was higher when the doses were expressed in anti-Xa units/kg body weight. However, the body weight accounts for only 16% of the interindividual variability of anti-Xa activity. Therefore, there is no clear evidence to suggest that weight-adjusted doses should be recommended when this LMW Heparin is used as prophylactic treatment in general surgery. A weak negative correlation was found between anti-Xa activity and thrombosis as demonstrated by a positive radiolabelled fibrinogen uptake test and confirmed by positive phlebography. No significant correlation was demonstrated between anti-Xa activity and the occurrence of postoperative bleeding.

Relationship between plasma mexiletine levels at steady-state. Presence of ventricular arrhythmias and side effects.

The relationships between plasma mexiletine levels and the presence of ventricular arrhythmias and side effects were studied on patients from IMPACT (International Mexiletine and Placebo Antiarrhythmic Coronary Trial). 630 patients who had suffered a myocardial infarction were randomized between placebo and mexiletine. Plasma levels were measured 1 month after the beginning of treatment. Arrhythmia findings (presence or absence of premature ventricular contractions (PVCs), couplets, runs, bigeminy, trigeminy, multiformity and various combinations) were assessed from 24-h ambulatory ECG recordings. The empirical logistic transform was used for modeling the relationships. For all these variables, except the presence of PVCs, trigeminy and runs, the association with plasma level was significant: the higher the plasma level, the lower the rate of occurrence of the particular arrhythmia. This was true whether or not the patient had the arrhythmia at baseline. Analyses based on the same model showed a significant correlation between plasma level and tremor, constipation, sexual problems and the presence of at least one side effect. As the levels of mexiletine at which side effects become frequent are in the same range as those necessary to suppress arrhythmias, the therapeutic range is narrow and individual dose adjustment should preferably be made.

EasyMA: a program for the meta-analysis of clinical trials.

Meta-analysis of clinical trial data is an increasingly important method in clinical research, particularly in the field of therapeutic evaluation. This method uses some specific statistical techniques which are not all available on standard packages and therefore require specific developments. This paper describes a program designed to help medical researchers perform meta-analyses of clinical trial data with dichotomous outcomes. This program includes the various statistical methods of meta-analysis and enables cumulative meta-analysis and sub-groups to be performed. A robustness index can be determined and the results obtained in table and graphic formats. Data-editing and data-manipulating facilities are also possible. Much care has been taken to make the user interface as user-friendly as possible, so that the program is within the reach of all medical researchers.

[Circadian changes of myocardial infarction]. / Variations circadiennes de l'infarctus du myocarde.

Several studies have demonstrated a circadian rhythm in the onset of myocardial infarction. Most show a peak rate between 8 and 12 o'clock in the morning. The frequency of infarction in this time period is one and a half to two times that observed during the rest of the day. This phenomenon has been observed in different countries and does not seem to be influenced by the characteristics of the population (sex, previous infarction). However, this circadian rhythm seems less pronounced in younger subjects. The prescription of calcium antagonists before infarction does not change the circadian rhythm whereas aspirin and betablocker therapy decrease the frequency of matinal infarction. The mechanism underlying the circadian rhythm is hypothetical: many factors could play a triggering role and circadian variations in coagulation, platelet aggregation, catecholamine levels and blood pressure may also be important. Recent studies have shown that the morning peak in onset of infarction could be related to the times of waking and getting up. Suppression of the morning peak of infarction (and also of episodes of myocardial ischaemia and sudden death) with betablocker therapy, suggests a direct or indirect role of circulating catecholamines in the induction of the phenomena leading to infarction. When using betablockers, the authors suggest prescribing the doses so as to obtain therapeutic efficacy in the morning.

[Economic evaluation of treatments of cardiac insufficiency]. / Evaluation économique des traitements de l'insuffisance cardiaque.

The objective of classical treatments of cardiac failure (diuretics, digitalis) was to relieve patients' symptoms. Vasodilators and ACE inhibitors also improve morbidity and mortality. The introduction of the latter class of drugs for cardiac failure will, however, lead to a significant increase in the cost of medication at national level. These costs may increase even further in theory due to a predictable increase in the number of patients with cardiac failure (ageing of the general population, improved survival of cardiac patients) and due to the extension of prescription of these drugs to populations of subjects with cardiac failure hitherto relatively undertreated. On the other hand, economies may be realised in the management of cardiac failure related to fewer and shorter hospital admissions and reduced indirect costs or to the suppression of previous, less useful drugs (calcium antagonists, digitalis). Cost-effective analyses with ACE inhibitors carried out in different countries (Canada, netherlands) tend to show that the costs induced by prescription of these drugs are more than compensated by the economies realised by the reduction in hospital admissions. This is even more marked in the treatment of patients with severe cardiac failure. In subjects at low risk, the prescription of ACE inhibitors would not seem to be justified from both the clinical and economic points of view. It is up to each physician to decide the threshold of basic risk below which this treatment becomes "economically" acceptable.

[Intermediary and substitution criteria in the development of anti-arrhythmia agents]. / Critères intermédiaires et critères de substitution dans le développement des antiarythmiques.

The traditional view that the suppression of arrhythmias (risk factor) after myocardial infarction can only be beneficial, has been queried by the results of the Cardiac Arrhythmia Suppression Trial (CAST) which showed increased mortality in two treatment groups. The methodology of trials of secondary prevention of myocardial infarction by antiarrhythmic agents partially explains why the reduction of anti-arrhythmias has come to be considered as a substitute for mortality in the assessment of drug efficacy. The authors define substitutive criteria and describe their three advantages (facility, correspondence, estimation). A meta-analysis of 6 trials of secondary prevention of myocardial infarction by Class I antiarrhythmics, in which the antiarrhythmic effect was evaluated (Holter monitoring) in parallel with mortality, shows that anti-arrhythmias were significantly reduced by nearly 60% (p = 10-8) whereas mortality remained unchanged (p = 0.41). A special graphic presentation of the results of these 6 trials shows that, even before the results of the CAST, it was clear that the suppression of antiarrhythmics was not a suitable substitutive end point for mortality.