Steen Pehrson

Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure

BACKGROUND The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). METHODS In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. RESULTS After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). CONCLUSIONS In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation.

BACKGROUND There are limited data comparing radiofrequency catheter ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation. METHODS We randomly assigned 294 patients with paroxysmal atrial fibrillation and no history of antiarrhythmic drug use to an initial treatment strategy of either radiofrequency catheter ablation (146 patients) or therapy with class IC or class III antiarrhythmic agents (148 patients). Follow-up included 7-day Holter-monitor recording at 3, 6, 12, 18, and 24 months. Primary end points were the cumulative and per-visit burden of atrial fibrillation (i.e., percentage of time in atrial fibrillation on Holter-monitor recordings). Analyses were performed on an intention-to-treat basis. RESULTS There was no significant difference between the ablation and drug-therapy groups in the cumulative burden of atrial fibrillation (90th percentile of arrhythmia burden, 13% and 19%, respectively; P=0.10) or the burden at 3, 6, 12, or 18 months. At 24 months, the burden of atrial fibrillation was significantly lower in the ablation group than in the drug-therapy group (90th percentile, 9% vs. 18%; P=0.007), and more patients in the ablation group were free from any atrial fibrillation (85% vs. 71%, P=0.004) and from symptomatic atrial fibrillation (93% vs. 84%, P=0.01). One death in the ablation group was due to a procedure-related stroke; there were three cases of cardiac tamponade in the ablation group. In the drug-therapy group, 54 patients (36%) underwent supplementary ablation. CONCLUSIONS In comparing radiofrequency ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation, we found no significant difference between the treatment groups in the cumulative burden of atrial fibrillation over a period of 2 years. (Funded by the Danish Heart Foundation and others; MANTRA-PAF ClinicalTrials.gov number, NCT00133211.).

Antidepressant Use and Risk of Out-of-Hospital Cardiac Arrest: A Nationwide Case–Time–Control Study

Treatment with some types of antidepressants has been associated with sudden cardiac death. It is unknown whether the increased risk is due to a class effect or related to specific antidepressants within drug classes. All patients in Denmark with an out‐of‐hospital cardiac arrest (OHCA) were identified (2001–2007). Association between treatment with specific antidepressants and OHCA was examined by conditional logistic regression in case–time–control models. We identified 19,110 patients with an OHCA; 2,913 (15.2%) were receiving antidepressant treatment at the time of OHCA, with citalopram being the most frequently used type of antidepressant (50.8%). Tricyclic antidepressants (TCAs; odds ratio (OR) = 1.69, confidence interval (CI): 1.14–2.50) and selective serotonin reuptake inhibitors (SSRIs; OR = 1.21, CI: 1.00–1.47) were both associated with comparable increases in risk of OHCA, whereas no association was found for serotonin–norepinephrine reuptake inhibitors/noradrenergic and specific serotonergic antidepressants (SNRIs/NaSSAs; OR = 1.06, CI: 0.81–1.39). The increased risks were primarily driven by: citalopram (OR = 1.29, CI: 1.02–1.63) and nortriptyline (OR = 5.14, CI: 2.17–12.2). An association between cardiac arrest and antidepressant use could be documented in both the SSRI and TCA classes of drugs.

Recurrence of arrhythmia following short-term oral AMIOdarone after CATheter ablation for atrial fibrillation: a double-blind, randomized, placebo-controlled study (AMIO-CAT trial)

AIMS Patients undergoing catheter ablation for atrial fibrillation (AF) often experience recurrent arrhythmias within the first few months post-ablation. We aimed to investigate whether short-term use of amiodarone to prevent early arrhythmias following radiofrequency ablation for AF could reduce later recurrence. METHODS AND RESULTS In a two-centre, randomized, double-blind, placebo-controlled study, we randomized a total of 212 patients undergoing AF ablation. Patients were stratified according to type of AF (paroxysmal/persistent) and history of previous AF ablation and randomly assigned to 8 weeks of oral amiodarone therapy or matched placebo following catheter ablation. Patients were followed for 6 months. Analyses were performed according to the intention-to-treat principle. Of 212 enrolled patients [median age 61 (inter-quartile range 54-66), 83% male, 50% paroxysmal, 29% with history of previous ablation], 206 patients were available for analysis of the primary end-point which was any documented atrial tachyarrhythmia lasting >30 s following a blanking period of 3 months. This was observed in 42/107 (39%) in the amiodarone group vs. 48/99 (48%) in the placebo group (P = 0.18). Among the secondary end-points, the amiodarone group showed significantly lower rate of atrial tachyarrhythmia-related hospitalizations [rate ratio = 0.43; 95% confidence interval (CI) = 0.23-0.77, P = 0.006] and cardioversions (rate ratio = 0.36; 95% CI = 0.20-0.62, P = 0.0004) within the blanking period. CONCLUSION Short-term oral amiodarone treatment following ablation for paroxysmal or persistent AF did not significantly reduce recurrence of atrial tachyarrhythmias at the 6-month follow-up, but it more than halved atrial arrhythmia related hospitalization and cardioversion rates during the blanking period.

Risk of arrhythmia induced by psychotropic medications: a proposal for clinical management

Several drugs used in the treatment of mental diseases are associated with an increased risk of sudden cardiac death (SCD). A general cause-relationship between the intake of these drugs and SCD is unattainable, but numerous case reports of drug-induced malignant arrhythmia and epidemiological studies, associating the use of specific drugs with SCD, strongly support the presence of an increased risk. Whereas the absolute risk of drug-induced life-threatening arrhythmia may be relatively low, even small increments in risk of SCD may have a major health impact considering that millions of patients are treated with psychotropics. In subgroups of pre-disposed patients, e.g. patients with cardiac diseases or other co-morbidities, the elderly or patients treated with other negatively interacting drugs, the absolute risk of drug-induced arrhythmia may be considerable. On the other hand, several of the major mental disorders are associated with a large risk of suicide if untreated. The observed risk of malignant arrhythmia associated with treatment with psychotropic drugs calls for clinical guidelines integrating the risk of the individual drug and other potentially interacting risk factors. In this review, data from various authorities on the risk of arrhythmia associated with psychotropic medications were weighted and categorized into three risk categories. Additionally, we suggest a clinically applicable algorithm to reduce the risk of malignant arrhythmia in patients to be treated with psychotropic medications. The algorithm integrates the risk categories of the individual drugs and pre-disposing risk factors and suggests a prudent follow-up for patients with an increased risk. We believe this clinically manageable guideline might improve safety in the many and rapidly increasing number of patients on psychotropic drugs.

Does Conversion and Prevention of Atrial Fibrillation Enhance Survival in Patients with Left Ventricular Dysfunction? Evidence from the Danish Investigations of Arrhythmia and Mortality ON Dofetilide/(DIAMOND) Study

BACKGROUND Atrial fibrillation is a common arrhythmia in patients with left ventricular dysfunction associated with increased morbidity and mortality. The present study investigated the potential of dofetilide to restore and maintain sinus rhythm in patients with left ventricular dysfunction, which might reduce mortality and hospitalizations. METHODS AND RESULTS In the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies, 506 patients were in atrial fibrillation (AF) or atrial flutter (AFl) at baseline. Over the course of study, cardioversion occurred in 148 (59%) dofetilide- and 86 (34%) placebo-treated patients. In these patients, the probability of maintaining sinus rhythm for 1 year was 79% with dofetilide versus 42% with placebo ( P < 0.001). Dofetilide had no effect on all-cause mortality, but restoration and maintenance of sinusrhythm (independent of study treatment) was associated with a significant reduction in mortality (risk ratio [RR], 0.44; 95% CI, 0.30 to 0.64; P < 0.0001). In addition, dofetilide therapy was associated with a significantly lower risk ratio versus placebo for either all-cause (RR, 0.70; 95% CI, 0.56 to 0.89; P < or = 0.005) or congestive heart failure (RR, 0.69; 95% CI, 0.51 to 0.93; P < or = 0.02) rehospitalization. CONCLUSIONS Dofetilide is safe and increases the probability of obtaining and maintaining sinus rhythm in patients with structural heart disease. The present study suggests that restoration of sinus rhythm--on placebo or dofetilide--is associated with improved survival.

Quantitative Analysis of T‐wave Morphology Increases Confidence in Drug‐Induced Cardiac Repolarization Abnormalities: Evidence From the Investigational IKr Inhibitor Lu 35–138

This study investigates repolarization changes induced by a new candidate drug to determine whether a composite electrocardiographic (ECG) measure of T‐wave morphology could be used as a reliable marker to support the evidence of abnormal repolarization, which is indicated by QT interval prolongation. Seventy‐nine healthy subjects were included in this parallel study. After a baseline day during which no drug was given, 40 subjects received an IKr‐blocking antipsychotic compound (Lu 35–138) on 7 consecutive days while 39 subjects received placebo. Resting ECGs were recorded and used to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and study power for both measures. Lu 35–138 increased the QTc interval with corresponding changes in T‐wave morphology as determined by MCS. For subjects taking Lu 35–138, T‐wave morphology was a more reliable indicator of IKr inhibition than QTcF (χ2 = 20.3, P = .001). At 80% study power for identifying a 5‐millisecond placebo‐adjusted change from baseline for QTcF, the corresponding study power for MCS was 93%. As a covariate to the assessment of QT interval liability, MCS offered important additive information to the effect of Lu 35–138 on cardiac repolarization.

Acute fatal pulmonary vein occlusion after catheter ablation of atrial fibrillation

AbstractBackground: In treatment of atrial fibrillation (AF) catheter radiofrequency isolation of the pulmonary veins (PVs) has proved to be highly successful. There have been several case reports regarding PV stenosis, however none of these have reported a fatal outcome. Methods and Results: A 31-year-old man was referred to us for treatment of complications related to catheter ablation. According to the documentation from the hospital, the patient underwent segmental ostial PV isolation for treatment of AF. A few hours after the procedure, the patient developed dyspnoea, hemoptysis, and a high fever. The patient was first diagnosed as having pneumonia but five days later transesophageal echocardiography and pulmonal angiography revealed total occlusion of the left superior and inferior PVs. When we received the patient he underwent open-heart surgery, which showed thrombi in the orifices of the left sided PVs protruding into the left atrium. In each of the left sided PVs severe stenosis was seen in the bifurcation area. Thrombus material was removed followed by placement of two stents in each of the left sided pulmonary veins at the first bifurcations. However, the patient died 14 days after the ablation procedure. Selective autopsy of the left lung revealed diffuse alveolar damage, disseminated intravascular coagulation, multiple thrombi formation, and haemorrhagic infarctions. Conclusions: PV stenosis may occur very early after the ablation procedure. Delayed diagnosis can be fatal. The early stenosis may result in thrombus formation in the left atrium and PVs and in this case surgery should be considered.

The Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF) Trial: clinical rationale, study design, and implementation

AIMS No large randomized multicentre trial has evaluated the efficacy of radiofrequency ablation (RFA) vs. anti-arrhythmic drug (AAD) therapy as a first-line treatment of paroxysmal atrial fibrillation (AF). METHODS AND RESULTS The Medical ANtiarrhythmic Treatment or Radiofrequency Ablation (MANTRA-PAF) trial is a randomized, controlled, parallel group, multicentre study designed to test whether catheter-based RFA is superior to optimized AAD therapy in suppressing relapse within 24 months of symptomatic and/or asymptomatic AF in patients with paroxysmal AF without prior AAD therapy. The primary endpoint is cumulative AF burden on repeated 7 days Holter monitoring. Secondary endpoints are: thromboembolic events, hospitalization due to arrhythmia, pro-arrhythmic events, procedure/treatment-related side effects, health economics, quality of life, and change in left ventricular function. Ten centres in Scandinavia and Germany are participating in the study. Enrolment was started in 2005 and as of November 2008, 260 patients have been enrolled into the study. It is expected that enrolment will end by March 2009, when 300 patients have been included. CONCLUSION The MANTRA-PAF trial will determine whether catheter-based RFA is superior to optimized AAD therapy as a first-line treatment in suppressing long-term relapse of symptomatic and/or asymptomatic AF.

Impact of premature atrial contractions in atrial fibrillation.

In spite of the increasing knowledge about paroxysmal atrial fibrillation (PAF), details on mode of initiation in unselected patients are scarce. This paper focuses on trigger mechanisms of spontaneous onset of AF in consecutive patients with PAF. One hundred eight consecutive patients with two or more ECG documented AF episodes within the previous year had a 24‐hours Holter recording performed. All AF episodes (n = 157) were reviewed and, within the last 10 beats prior to AF initiation. PP intervals were measured on 25 mm/s paper printouts and premature atrial contractions (PACs) were counted. Additionally, randomly selected coupling intervals (PP′) for PACs not triggering AF were measured and compared to AF triggering intervals and to PP′ intervals from healthy controls. PACs preceded all AF episodes. AF initiation displayed a wide variety in terms of PP coupling intervals and number of PACs prior to initiation within and between subjects. In episodes with PACs within the last 10 beats prior to initiation, we observed a long‐short PP sequence at the time of initiation. Mean PP′ interval (± SE) for AF triggering PACs was 403 ± 9 ms, significantly shorter, P < 0.0001, than PP′ for nontriggering PACs (584 ± 8 ms) and PACs in healthy controls (589 ± 6 ms). However, a large proportion of nontriggering PACs had short PP′ coupling intervals without triggering AF. These observations highlight the importance of other factors than the trigger per se, such as the arrhythmogenic substrate, and suggest that therapeutic maneuvers aimed at curing PAF should target these as well as the trigger mechanisms. (PACE 2004; 27:447–452)