Safety Of Antiarrhythmic Drugs Research Articles

Written Consent to Use the Drug in Children: The Problem of Off-Label Drugs

Cardiac arrhythmias in pediatric patients have different mechanisms and frequencies compared to adult patients. There are many physiological differences between children and adults that may affect the pharmacodynamic and pharmacokinetic of the antiarrhythmic drugs in pediatric population. Children, and specially breast feeding children, cannot be considered low weighted adults to select antiarrhythmic drug doses. Although radiofrequency ablation has experienced great technological advances, it is performed in selected pediatric patients. Therefore, the main therapeutic strategy is the use of antiarrhythmic drugs in children. The medical management of arrhythmias in pediatric patients is challenging and complex. There are few clinical guidelines. There is scarce and incomplete information about the efficacy and safety of antiarrhythmic drugs in pediatric population. Most of the doses and drug administration intervals are extrapolated from adult population and applied to children. Antiarrhythmic drug doses have been extensively studied in adult population. However, in pediatric population, there are very few clinical trials and the safety of these drugs is not well known. In general, dose regimens are based on small uncontrolled studies, extrapolation of drug doses from studies performed in the adult population or physician experience. As a consequence, there is a need for further studies to assess the most effective antiarrhythmic drug regimens in children reducing the risk of side effects. Evidence suggests that medical research in pediatric population is necessary and morally valuable. But investigators involved must take care of moral and ethical values, including the respect for the child-subject and his parents or legal representatives, and this respect compels them to consider the patient and family in the decision making process. The participation request and the informed consent must be obtained according to the competitions the patient exhibits, trying to anticipate information about benefits and possible damages derived from the investigation in an understandable language for him. In our opinion the pharmacologic clinical investigation of antiarrhythmic treatments in pediatrics is necessary. More clinical studies must be carried out under rigorous scientific rules that contemplate the particular ethical dilemmas this population faces.

Azimilide vs. placebo and sotalol for persistent atrial fibrillation: the A-COMET-II (Azimilide-CardiOversion MaintEnance Trial-II) trial

Treatment of atrial fibrillation remains a major clinical challenge owing to the limited efficacy and safety of anti-arrhythmic drugs, particularly in patients with structural heart disease. To evaluate the efficacy of azimilide, a new class III anti-arrhythmic drug, we studied 658 patients with symptomatic persistent atrial fibrillation, adequate anticoagulant therapy, and planned electrical cardioversion. Patients were randomized to placebo, azimilide (125 mg o.d.), or sotalol (160 mg b.i.d.). Primary efficacy analysis was based on event recurrence, which was defined as atrial fibrillation lasting>24 h, or requiring DC cardioversion. Median time to recurrence was 14 days for azimilide, 12 days for placebo, and 28 days for sotalol (P=0.0320 when comparing azimilide with placebo; P=0.0002 when comparing azimilide with sotalol). The placebo-to-azimilide hazard ratio was 1.291 (95% CI: 1.022-1.629) and the sotalol-to-azimilide hazard ratio was 0.652 (95% CI: 0.523-0.814). Adverse events causing patient withdrawal were more frequent (P<0.01) in patients on azimilide (12.3%) and on sotalol (13.9%) than on placebo (5.4%). Eight patients in the sotalol (3.5%) and 16 in the azimilide (7.6%) group interrupted the study because of QTc prolongation. Torsade de pointes was reported in five patients of the azimilide group. The percentage of patients who completed the 26 week study period without events were 19% for azimilide, 15% for placebo, and 33% for sotalol (P<0.01). Unsuccessful day 4 cardioversion, arrhythmia recurrence, and adverse events were the main causes of withdrawal from the study. This study demonstrates that the anti-arrhythmic efficacy of azimilide is slightly superior to placebo but significantly inferior to sotalol in patients with persistent AF. The modest anti-arrhythmic efficacy and high rate of torsade de pointes and marked QTc prolongation limit azimilide utilization for the treatment of AF.

Pro-arrhythmic effects of amiodarone and concomitant rate-control medication

Amiodarone is one of the most efficient and safe antiarrhythmic drugs in the treatment of atrial fibrillation (AF). Although pro-arrhythmic effects of amiodarone therapy are rare, the aim of the present study was to identify clinical constellations which may lead to amiodarone-associated pro-arrhythmia. Sixty-three consecutive patients (pts) (49 males; 64+/-10.3 years; 35 with coronary heart disease, 17 with lone AF) were retrospectively included in this study. All received an oral (92.1%) or i.v. (7.9%) loading dose of amiodarone for the treatment of AF. Cardiac diseases, concomitant medical treatment, and incidence of pro-arrhythmic effects were analysed. Three pts (4.8% of the total population) developed a clinical relevant, polymorphic ventricular tachyarrhythmia, 3-48 h after initiation of amiodarone loading. Coronary heart disease was present in all of these pts, and in two of them left ventricular ejection fraction was severely reduced. The mean QTc in these pts was only slightly prolonged; mean heart rate was significantly decreased compared with the total study population (61.0+/-7.5 vs. 74.5+/-24.1 bpm; P < or = 0.05). In all pts with pro-arrhythmia, amiodarone (two pts i.v., one patient oral) was initiated during concomitant beta-blocker/digitalis therapy. Twenty-five per cent of the patients receiving this 'triple' therapy developed ventricular arrhythmia. The present study implies that initiation of amiodarone therapy in pts with structural heart disease and AF that are concomitantly treated with beta-blockers and digitalis may have an increased risk of amiodarone-associated pro-arrhythmia.

“Torsade de Pointes” in Patients with Structural Heart Disease and Atrial Fibrillation Treated with Amiodarone, β‐Blockers, and Digitalis

Amiodarone is one of the most efficient and safe antiarrhythmic drugs in the treatment of atrial fibrillation (AF). Yet, though rare, proarrhythmic effects remain a clinical problem. We present three cases of amiodarone-associated "Torsade de pointes" tachycardia (Tdp) in patients treated concomitantly with heart rate controlling medication for AF. Amiodarone loading therapy was started for the treatment of tachyarrhythmic AF in all the three patients. All presented with a history of coronary heart disease, resulting in a severely reduced left ventricular ejection fraction in two patients. One received oral amiodarone loading, in the others, amiodarone was administered intravenously because of hemodynamically relevant AF episodes. Amiodarone therapy was combined with a heart rate controlling medication including a beta-blocking agent and digitalis in all the cases. All the subjects suffered from clinically relevant Tdp in the early run after initiation of amiodarone loading (max. 48 hours). The mean QTc in all patients before induction of Tdp was prolonged. The present case reports imply that amiodarone in combination with beta-blocker/digitalis therapy may be associated with an elevated proarrhythmic risk in selected patients with structural heart disease and AF.

Amodarone loading therapy, beta-blockers and digitalis in patients with atrial fibrillation and structural heart disease: Is there danger of early proarrhythmic effects?

Background: Amiodarone (Amio) is considered the most efficient and safe antiarrhythmic drug in the treatment of atrial fibrillation (AF). Though proarrhythmic effects under Amio are rare, the aim of the present study was to identify clinical constellations which may lead to Amio associated proarrhythmia. Methods: 63 consecutive patients (pts) with persistent or paroxysmal AF [14 female and 49 male, 64 10.3 years; 35 with coronary (CAD) and 11 with congestive (CHD) heart disease] were included in this retrospective analysis. All received an oral (92.1%) or i.v. (7.9%) loading dose of Amio in hospital. Cardiac diseases, concomitant treatment and proarrhythmic effects were analyzed. Results: 11 pts (17.5%) were concomitantly treated with a beta-blocker, 19 pts (30.2%) with digitalis. In 12 pts (19.0%) Amio was used in combination with both beta-blockers and digitalis. 3 pts (4.8%) developed a clinical relevant Torsade de pointes tachycardia (TdP), 3-48h after initiation of Amio loading (2 pts i.v., 1 pt oral). In all pts with proarrhythmia, Amio was initiated with concomitant beta-blocker-/digitalis-therapy. 25% with this ‘triple’ therapy developed TdP. The mean QTc was prolonged (483.7ms 61.8ms), mean heart was decreased (61.0 7.5bpm vs. 74.5 24.1bpm; p 0.05). CAD was present in all of these pts, in 2 pts left ventricular ejection fraction (EF) was severely reduced (30%). EF in pts treated for heart failure with triple therapy (40.8 10.8%) was not signifcantly different as compared to pts with beta-blocker (42.7 11.9%) or digitalis (48.9 11.9%) alone. Conclusion: Out of 63 consecutive pts with initiation of Amio therapy, in 3 pts TdP were observed. These were characterized by CAD and a combination-therapy of Amio with beta-blockers and digitalis. As a result of the changes in the treatment of heart failure, use of beta-blockers with digitalis is more widespread. The present study implicates that additional Amio therapy in such pts with AF may increase the risk of Amio-associated proarrhythmia and predispose to the development of TdP. P6-112 UNUSUAL MANIFESTATIONS OF ENDLESS LOOP TACHYCARDIA IN A CARDIAC RESYNCHRONIZATION DEFIBRILLATOR *Sergio L. Pinski, MD and Marcelo E. Helguera, MD. Cleveland Clinic Florida, Weston, FL.

A new method for evaluation of safety of antiarrhythmic drugs.

A new method for preclinical evaluation of safety of antiarrhythmic drugs is proposed. During chronic stress, class I antiarrhythmic preparations increased mortality of test animals. By contrast, class II-IV antiarrhythmic agents and antioxidants produced no significant effect on mortality of experimental mice. These data agree with published results of multicenter studies.

Adenosine: an effective and safe antiarrhythmic drug in pediatrics.

Adenosine is an effective, safe drug for the diagnosis and treatment of paroxysmal tachycardias in adult and pediatric patients. A starting dose of 0.05-0.10 mg/kg as a rapid bolus injection is recommended for infants and children. An electrophysiologic effect can be expected within 20 seconds after injection. Dosage may be increased up to 0.3 mg/kg in steps of 0.05-0.10 mg/kg or until conversion to sinus rhythm is reached. Due to its basic electrophysiologic properties of slowing conduction in the atrioventricular (AV) node, which may result in transient AV block, adenosine is almost always effective in terminating supraventricular tachycardias in which the AV node forms a critical part of the reentrant circuit (i.e., AV nodal reentrant tachycardia and AV reciprocating tachycardia). Based on its properties, adenosine is also advocated as a useful diagnostic tool for unmasking primary atrial tachycardias by inducing transient high grade AV block. Advantages over other antiarrhythmic agents include the agent's short half-life (<2 seconds) and minimal or no negative influence on blood pressure. Because of its short half-life, however, early recurrence of the tachycardia is observed in up to one-third of patients treated. Based on rare but serious unwanted side effects, patients with known or suspected irritable airways and sinus node dysfunction and those who have undergone orthotopic cardiac transplantation should probably not be given adenosine. Adenosine may be recommended as the drug of choice for treatment of paroxysmal tachycardia in young patients. Primary success rates range between 85% and 100% of all the tachycardia episodes treated. Termination of the tachydysrhythmia, however, does not always mean that the underlying dysrhythmia was of supraventricular origin with the AV node as a critical part of the tachycardia mechanism. Rare but possible life-threatening side effects (prolonged sinus arrest and complete AV block, atrial fibrillation, acceleration of ventricular tachycardia, apnea) necessitate proper monitoring of the patients.

Efficacy and safety of intravenous amiodarone for short-term treatment of paroxysmal supraventricular tachycardia in children.

The use of intravenous amiodarone was assessed during 23 episodes of paroxysmal supraventricular tachycardia in 15 children aged 9 days to 11 years. Five of the fifteen patients had congenital structural heart disease, and three had Wolf-Parkinson-White syndrome. Tachyarrhythmias were returned to sinus rhythm during 20 of the 23 episodes (87%). No major adverse effects occurred. Recurrence of tachycardia was not observed during short-term follow-up. In conclusion, intravenous amiodarone is an effective, safe antiarrhythmic drug for short-term treatment of supraventricular tachycardia in children.

Safety of antiarrhythmic drugs in children.

Safety of antiarrhythmic drugs in children.

Arrhythmias and anaesthesia

Summary Cardiac arrhythmias during anaesthesia are common and almost benign, with the incidence ranging from 60 to 90%. Arrhythmias are one of several significant predictors for severe cardiovascular outcomes. It is essential, therefore, for the anaesthetist to evaluate patients at risk preoperatively with a careful history and to have an appropriate knowledge concerning the aetiology, electrophysiology, diagnosis, drug effects and treatment of arrhythmias. In the normal heart, the sinoatrial node initiates rhythmic cardiac electrical activity by cells with intrinsic pacemaker activity. Sequential atrial and ventricular contractions result in an increased efficiency of the cardiac pumping mechanism, which, in turn, may be affected by arrhythmias. Cardiac arrhythmias are caused by altered automaticity or abnormal impulse propagation, which arise from a variety of factors such as electrolyte disorders, hypoxaemia, hypotension, drugs and other disorders. Patients with underlying heart disease are especially at risk. When there is evidence that a potentially dangerous arrhythmia exists, the patient who presents for elective surgery should be given additional examinations and treated before operation. Although implantable cardioverter defibrillators are now available, there have been reported failures of these devices. In emergency situations, the anaesthetist must know how to treat suspected arrhythmias. Arrhythmias should be treated if they have haemodynamic consequences or if they are potentially dangerous. However, there is growing concern about the safety of antiarrhythmic drugs because these drugs have the potential to fail, increase the severity of arrhythmias or produce other circulatory imbalances. Thus it is important to first eliminate all possible anaesthetic and surgical effects on arrhythmias. Once it is decided to treat an arrhythmic disorder, the available therapeutic approaches are either electrical or pharmacological. Patients with potentially dangerous arrhythmias during anaesthesia must be monitored postoperatively and adequate prophylactic treatment should be initiated under prolonged ECG control.

Safety and efficacy of short- and long-term verapamil therapy in children with tachycardia

Six children aged 3 months to 11 years were treated with verapamil because of resistant symptomatic supraventricular tachycardia or complications of conventional therapy. Two of the three patients with congenital heart disease were in the postoperative state. The other three had no gross cardiac anomalies. Two patients had supraventricular tachycardia with Wolff-Parkinson-White syndrome, three had ectopic supraventricular tachycardia and one had atrial flutter. Intravenous verapamil was given in a dose of 0.15 to 0.25 mg/kg body weight to four patients, three of whom had successful conversion to sinus rhythm. One patient was given oral verapamil only. Treatment failed in the patient with atrial flutter. Five patients were maintained on oral verapamil therapy. Of these, one patient died of postoperative complications while receiving verapamil, and the remaining four have continued oral verapamil therapy for 1 to 3 1 2 years . The dose is 80 mg every 6 or 8 hours depending on response. Two of the latter four patients have ectopic supraventricular tachycardia that recurs when therapy is stopped. Of the two patients with Wolff-Parkinson-White syndrome, one has had no recurrence of supraventricular tachycardia and the other has had a decrease in both the duration of attacks and their number (from one to two per week to one to two per month). There have been no adverse effects with long-term drug administration. None of the five patients who received intravenous verapamil showed any untoward effects during its administration. This experience indicates that verapamil, which has not been used extensively in children, is an effective and safe antiarrhythmic drug capable of controlling both ectopic and reentrant supraventricular tachycardia when conventional methods fail. The presence of underlying congenital heart disease should not be a contraindication to its use.