Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

[Clinical evolution of patients following investigation of atrial vulnerability after a first cerebral ischaemic accident]. / Evolution clinique des patients ayant eu une recherche de vulnérabilité atriale après un premier accident ischémique cérébral.

Atrial vulnerability reflects the ability of the atrium to fibrillate. ISAV (Ischemic stroke and atrial vulnerability) is a French epidemiological registry whose main goal is to assess the evolution modalities of patients in whom an electrophysiological study of the atrium has been performed. A group of 269 patients with a history of non elucidated ischemic stroke and an electrophysiological study of the atrium performed in a mean delay of 3 months after the stroke has been included. Their mean age at the time of the stroke was 55 +/- 15.8 years. The electrophysiological study has measured the effective refractory period of the atrium, the locoregional right intra-atrial conduction time, the index of latent atrial vulnerability and assessed the inductibility. The mean delay between the date of the stroke and the date of the last news was 4.4 +/- 2.8 years. We observed 12 deaths and 11 patients presented during the follow up a spontaneous atrial arrhythmia and 17 a recurrence of stroke. If we consider the occurrence of the 28 combined events (atrial arrhythmia and/or stroke), it is not correlated with the presence of an atrial septal defect nor with the existence of an atrial vulnerability. On the contrary this occurrence is correlated with tobacco consumption and/or arterial hypertension; 82% of patients have these risk factors versus 54% of patients without events (p = 0.004). This association is not significant in patients younger than 55 years.

[Flecainide acetate utilisation review among general practitioners and hospital or office-based cardiologists in France. Obepine: observational study of flecainide]. / Etude de l'usage de l'acétate de flécainide auprès des médecins généralistes et des cardiologues hospitaliers ou libéraux en France. OBEPINE: etude observationnelle des prescriptions de flécaïnide.

A pharmacoepidemiological cross-sectional observational study was performed among a representative sample of French general practitioners and cardiologists. The aim of this study was to describe the prescription modalities of flecainide acetate, an Ic class antiarrhythmic, and how these modalities match the marketing authorization and the current summary of product characteristics. A total of 941 physicians participated in the study, 496 GPs and 445 cardiologists, and 1116 patients treated with flecainide for more than one month were included. On average, the patients were 68.7-years-old and 54% of them were women. Most of the initial flecainide prescriptions came from cardiologists (96%) and the check-up included an electrocardiogram (98%), a Holter monitoring (56%) and/or an echocardiography (71%). The preferred indication was supraventricular rhythm disorders (95%) and mostly atrial fibrillation (63%). A small proportion of coronary patients (7%) and of patient suffering from cardiac insufficiency (4%) was found. Flecainide was prescribed with a median posology of 150 mg per day, mostly as LP form (64%). Overall, the indications specified in the summary of product characteristics were respected in 90% of the cases, the contraindications in 91% of the cases and the patient follow-up was appropriate in 99% of the cases. In conclusion, the study showed that the prescription's conditions of flecainide in France complied with the summary of product characteristics data for most of the prescribing physicians with a respect of the indications, contraindications and management recommendations in 84% of the cases.

[1/1 nodo-ventricular conduction atrial flutter with amiodarone]. / Flutter atrial à conduction nodovenhiculaire 1/1 sous amiodarone.

1/1 atrial flutter is a regularly described complication of class I anti-arrhythmics. It is, however, very rarely encountered with class III anti-arrhythmics because prolongation of the atrio-ventricular node refractory period prevents 1/1 nodo-ventricular conduction. There have only been seven cases of 1/1 atrial flutter with amiodarone reported in the literature. Here we describe a new case of 1/1 atrial flutter with amiodarone. Our case clearly illustrates not only the different pro-arrhythmic effects of amiodarone (prolongation of the flutter cycle, and infra-Hissian block) but also the pathophysiological mechanisms possible with 1/1 conduction (prolongation of the flutter cycle, considerable permeability of the AV node). It demonstrates the difficulties of diagnosing such a rhythm disturbance, and that it is sometimes poorly tolerated, as well as underlining the importance of early diagnosis (in this case by oesophageal recording). Preventive treatment of 1/1 flutter can include amiodarone, digitalis, a betablocker or a bradycardic calcium inhibitor.

[New energy sources for ablative methods]. / Nouvelles sources d'énergie dans les méthodes ablatives.

Radiofrequency current is the reference energy source for endocavitary ablation of arrhythmias. It is particularly well adapted for the ablation of focal arrhythmogenic substrates such as accessory pathways or foyers of automatism. Technological advances have made the lesions larger but the extension of the indications of percutaneous ablation to more complex substrates such as atrial fibrillation have justified the evaluation of alternative energies. The production of linear transmural lesions or deeper lesions which respect the parietal myocardial architecture and endocardial structure are a challenge for these energies. The capacity of functional mapping specific to cryogenics has provided this energy source with a clinical application for ablation of high risk structures whereas other energies, despite the chronicity of their experimental evaluation, are still at the stage of preliminary clinical trials with the sophisticated catheters in special indications.

[Long-term evaluation of endocavitary cryoablation of nodal reentry]. / Evaluation à long terme de la cryoablation endocavitaire dans le traitement des réentrées nodales.

Radiofrequency ablation is the reference treatment of refractory nodal reentry. Cryoablation has the advantage of having more modulable effects and minimises the risk of permanent atrioventricular block (AVB). Its immediate efficacy seems comparable to that of radiofrequency ablation but the long-term results are not well known. Endocavitary cryoablation of the slow pathway was undertaken in 26 patients (18 women) with an average age of 47.7 +/- 72.8 years with re-entrant nodal tachycardia refractory to medical therapy. The primary success rate was 92% (24 out of 26). On average, 2.6 +/- 2.2 (1 to 10) cryoablations at - 70 degrees C were delivered and were preceded by 6.4 +/- 4.5 (1 to 16) cryomappings to locate the site of the slow pathway. During cryomapping, 8 episodes of AVB were observed in 6 patients (6 second or third degree), all of which were revertible on rewarming. No cases of permanent AVB were observed. An oesophageal stimulation test of inducibility was performed on the 4th day in 21 patients, 16 of which were not reinducible. During follow-up of 355 +/- 194 days, 22 of the 26 patients (85%) had no recurrence of the arrhythmia. Two of the 24 primary successes had a recurrence, in addition to the two primary failures. Two of the four recurrences occurred in a non-sustained form which was less disabilitating for the patient and the recurrences were controlled in the 4 patients by antiarrhythmic therapy. These results suggest that cryoablation may be a reliable and effective long-term treatment of re-entrant nodal tachycardias. If confirmed in larger series in terms of efficacy and safety, cryoablation could become the treatment of choice of re-entrant nodal tachycardia.

[Automobile driving and implantable defibrillators]. / Conduite automobile et défibrillateur implantable.

The consequences of implanting an automatic cardioverter defibrillator (ICD) on vehicle driving in France are poorly known. This retrospective study examined the behaviour at the wheel of ICD recipients who were recommended to abstain from driving for 3 to 6 months after device implantation. The study population included 98 patients (mean age = 59.5 +/- 14.8 years) followed for a mean of 24. +/- 23.9 months, who underwent ICD implant for ventricular tachycardia (65% of patients ventricular fibrillation (15%), syncope (8%), as part of a research protocol of myocardial cell transplantation 6%, or for primary prevention (5%). The underlying heart disease was ischemic in 59% of patients dilated cardiomyopathy in 11%,hypertrophic cardiomyopathy in 8%, valvular in 6%. Brugada syndrome in 4%, right ventricular arrhythmogenic cardiomyopathy in 2%, and miscellaneous disorders in 9% of patients. Five patients died without post mortem interrogation of the ICD. Only 28% of drivers remembered, and 13% observed, the recommended driving limitations. However, 45% (the oldest) claimed to drive prudently. During follow-up, 47% of patients received an ICD shock. Their mean it ventricular ejection fraction was 34 +/- 14%, versus 43 +/- 18% in patients who received no ICD therapy (p = 0.015). Syncope occurred in 16% who received ICD shocks. Shocks were delivered during driving in 6 patients, without consequent accident. Despite their non-observance of recommended driving limitations. ICD recipients suffered few traffic accidents. Legislation in France should reproduce the guidelines issued by European professional societies and enacted by the British laws.

[AFFIRM: what we have learned ... and pending issues]. / AFFIRM: ce que nous avons appris ... et les questions en suspens.

During these last years, several therapeutic strategies trials have been performed in atrial fibrillation: the goal was to compare the rhythm control strategy (restoration and maintenance of sinus rhythm) to the rate control strategy (slowing of heart rate in atrial fibrillation). The most important of these different trials is the AFFIRM study. The main conclusion of this trial is that rate control can be chosen in first intention and not only in case of failure of the rhythm control strategy. These results can not be applied to 2 categories of patients: on one hand patients with heart failure and on the other hand young patients without cardiopathy in whom the strategy of rhythm control and sinus rhythm maintenance, mainly by class I antiarrhythmic drugs, remains the better choice.

Intra-SA-nodal pacemaker shift: indirect evaluation in the open chest dog.

Thirteen open chest dogs with normal sinus node function were studied by premature stimulations with a constant relative prematurity--50% of the preceding sinus cycle length. These premature beats were induced in the lower part of the crista terminalis of the right atrium and to the roof of the left atrium. Significant linear correlations were found between the return cycle (A2A3) and the spontaneous cycle (A1A1) lengths, with a slope of +0.75 in the right atrium, +1.36 in the left atrium. The evaluation of sinus node function is disturbed by pacemaker shifts, both spontaneous and induced. Sinus node organisation may be assessed by stimulating standardised sites, by measuring intra-atrial conduction time, and by comparing A2A3 with A1A1 at constant relative prematurity during significant variations in A1A1 obtained with changes in vago-sympathetic tone.

Intracellular and extracellular recordings of sinus node activity: comparison with estimated sinoatrial conduction times during pacemaker shifts in rabbit heart.

Sinoatrial conduction times, estimated by premature atrial stimulation, were compared with direct measurement of the sinoatrial conduction time in 15 isolated rabbit sinus node preparations before and after intrasinusal pacemaker shifts induced by cooling. Transmembrane potentials and surface electrograms were recorded from the sinus node and crista terminalis. Extracellular sinus node activity was recorded in five preparations. Mapping was performed at 38 degrees C and 35 degrees C to determine the site of the dominant pacemaker. The sinus cycle was significantly longer at 35 degrees C (319.4 ms vs 258.1 ms). Intracellular measured conduction time was significantly shorter (63.8 ms vs 70.4 ms) because of caudal shift of the dominant pacemaker. Estimated sinoatrial conduction time was significantly longer (110.3 ms vs 85.4 ms) owing to the depression of automaticity by the extrastimulus. Extracellular measured conduction time did not differ significantly from intracellular measured conduction time. These results suggest that intrasinusal pacemaker shift may explain inaccuracies in indirect estimations of sinoatrial conduction time by atrial pacing techniques. Extracellular recordings appear to be a better method of evaluating sinoatrial conduction times.

Cellular electrophysiological effects of flecainide on human atrial fibres.

STUDY OBJECTIVE: The aim of the study was to examine the electrophysiological characteristics of human atrial specimens collected during heart surgery and to investigate the effects of the class I antiarrhythmic agent flecainide on their electrical activity. DESIGN: Atrial specimens were studied using standard microelectrode techniques, with and without superfused flecainide (5 x 10(-7) M) or the transient outward current inhibitor 4-aminopyridine (0.5 mM). EXPERIMENTAL MATERIAL: Atrial fragments 0.5-1.0 cm2 were obtained at operation from 34 patients, mean age 30 years. There was no history of previous atrial arrhythmia in any patient and drug therapy was stopped 24 h before surgery. MEASUREMENTS AND MAIN RESULTS: Two types of transmembrane action potential were identified: (1) triangular shaped potentials (group A, classically found in animal models); (2) potentials with a large plateau preceded by a notch (group B). The effect of flecainide was compared on the the two types of action potential. In both, flecainide lessened the depolarisation rate. In group B, but not in group A, it increased the action potential duration at 50% and 90% repolarisation (APD50, APD90) and the effective refractory period. The notch in group B action potentials is generated by transient outward currents (Ito). Inhibition of these currents, either by increasing the pacing rate or by adding 4-aminopyridine, limited the increase in APD50, APD90, and effective refractory period generated by the presence of flecainide. CONCLUSIONS: The effects of flecainide on the atrial repolarisation process depend on the shape of the action potential. These effects are more marked in cells with a plateau, where Ito is activated.

Cardiac prognosis in hypertensive patients. Incidence of sudden death and ventricular arrhythmias.

The cardiac prognosis of hypertensive patients has been able to be precisely determined over the last 20 years as a result of large-scale epidemiologic surveys. The incidence of ischemic heart disease and the importance of left ventricular hypertrophy have been clearly defined in the literature. In contrast, the incidence of sudden death and ventricular arrhythmias has been poorly taken into account, although hypertension increases the risk of sudden death to the same degree as coronary artery disease. The relative risk increases progressively as a function of the quintiles of distribution of blood pressure, reaching a value of 3.2 for the highest quintile. There is also a significant correlation between hypertension and ventricular arrhythmias. Hypertensive subjects with other cardiovascular risk factors such as hypercholesterolemia or smoking and with ventricular extrasystoles, reflecting the presence of silent ischemia, can be considered to be at high risk of cardiac death.

Effects of bisoprolol on heart rate variability in heart failure.

Analysis of heart rate variability (HRV) provides a non-invasive index of autonomic nervous system activity. HRV has been shown to be reduced in heart failure. Preliminary data indicate that beta blockers improve clinical status in patients with heart failure, but HRV improvement remains to be demonstrated. Fifty-four patients from the randomized double-blind, placebo-controlled Cardiac Insufficiency Bisoprolol Study were included in the HRV study. The bisoprolol daily dose was 5 mg once daily. We assessed HRV during 24-hour Holter recordings before randomization and after 2 months of treatment. HRV as measured in the time domain by root-mean-square successive differences (rMSSD), the percentage of adjacent RR differences >50 ms (pNN50), and the SD of RR intervals (SDNN), and in the frequency domain by high-frequency (0.16 to 0.40 Hz) and low-frequency (0.04 to 0.15 Hz) power. Most patients were in New York Heart Association functional class III. The mean left ventricular ejection fraction was 27 +/- 7%, and heart failure was idiopathic or ischemic. After 2 months, the patients receiving bisoprolol had a reduced mean heart rate compared with that in placebo patients (p=0.0004). Bisoprolol increased 24-hour rMSSD (p=0.04) and 24-hour pNN50 (p=0.04), daytime SDNN (p=0.05), and daytime high-frequency power (p=0.03) power. Bisoprolol induced a significant increase in HRV parameters related to parasympathetic activity in heart failure. Increased vagal tone may contribute to the protective effect of beta blockers and may have prognostic implications.

Parasympathetic activity in Friedrich's ataxia.

We compared 19 patients with Friedreich's ataxia, a progressive hereditary neuromuscular disorder, with 19 healthy age-matched subjects. During nighttime, patients had shorter mean RR and decreased heart rate variability parameters related to parasympathetic activity than healthy subjects, whereas no difference occurred during daytime.

Pro-arrhythmic effect of nicorandil in isolated rabbit atria and its suppression by tolbutamide and quinidine.

Nicorandil, a potent vasodilator substance which exerts its effects through complex mechanisms including KATP channel activation, has so far been reported to exert antiarrhythmic but not pro-arrhythmic cardiac activity. We now examined the effects of 10(-4) M nicorandil on spontaneously active or electrically driven isolated rabbit atria. Nicorandil (a) significantly reduced the action potential duration at both 50% (by approximately 45%) and 80% (by approximately 30%) repolarization and the effective refractory period (by approximately 25%) and (b) reproducibly induced short periods of tachycardia either in normal Tyrode solution after a single extra-stimulus or in low-potassium media in the absence of extra-stimulation. Quinidine (10(-5) M) or the KATP channel inhibitor, tolbutamide (10(-5) M), suppressed the nicorandil-induced arrhythmias. It is suggested that the pro-arrhythmic effect of nicorandil results from its KATP channel opener activity and occurs essentially when the underlying conditions facilitate re-entry.

Efficacy of very low dose perindopril 2 mg/indapamide 0.625 mg combination on left ventricular hypertrophy in hypertensive patients: the P.I.C.X.E.L. study rationale and design.

The PICXEL study is designed to evaluate the effects of long-term administration of very low-dose combination perindopril 2 mg/indapamide 0.625 mg (Per/Ind) vs enalapril in reducing left ventricular hypertrophy (LVH) in hypertensive patients. This multicentre, controlled, randomised, double-blind, parallel group study is carried-out to assess the variation of left ventricular mass index (LVMI) after treatment, using a centralised control of M-mode echocardiography determinations, and a dedicated software for semi-automatic measurement. Following a 4-week placebo run-in period, hypertensive outpatients aged >/=18 years, with LVH (LVMI >120 and 100 g/m(2) for men and women, respectively), are randomised to receive once daily, over 52 weeks, either Per/Ind or enalapril. According to blood pressure levels, the dose may be adjusted. In addition to clinical examinations, ECG, blood pressure, heart rate and laboratory assessments echocardiographic determinations are performed for selection, at baseline, after 24 weeks and at the end of the study. The main outcome criteria is the change from baseline in LVMI which is considered the primary efficacy criterion; changes in blood pressure and echo-Doppler parameters constitute secondary criteria. Two-sided Student's t-test for independent samples will be used to differentiate the effects of the treatment between groups with alpha = 5%, and the inter-group difference of LVMI variation will be analysed with a power of 90%. A sample size of 500 patients is required making it necessary to randomise at least 550 patients, based on a 10% proportion of potentially non-assessable patients. The results of this study, obtained after applying strict methodological procedures and requirements, are expected to provide valuable and reliable information on the effects of long-term administration of Per/Ind on LVH, and on its potential superiority over enalapril.

[Sinus variability: value of rhythmology]. / La variabilité sinusale: intérêt en rythmologie.

The study of heart rate variability is a mean of assessing the influence of the autonomic nervous system on the normal and pathological heart. It may be performed by temporal or spectral analysis over 24 hours or shorter periods. It is possible to define for each temporal or spectral analysis the components of the autonomic nervous system which influence these parameters. After myocardial infarction a decrease in heart rate variability indicates a poor prognosis. This post-infarction risk factor is relatively reliable compared with the other prognostic factors. A decreased heart rate variability is also observed in cardiac failure but the significance of this finding has not been established. Many other fields of application of the study of heart rate variability may be envisaged, in other cardiovascular pathologies, in the evaluation of cardiovascular therapeutic interventions or in the assessment of patients with non-cardiac pathology in which the autonomic nervous system plays an important role. A lot of research on heart rate variability is currently under way and many developments are expected in the next few years.