Clinical efficacy of dofetilide for the treatment of atrial tachyarrhythmias in adults with congenital heart disease.

BACKGROUND: Atrial tachyarrhythmias (AT) including atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia represent a clinical challenge in the adult with congenital heart disease (CHD). Dofetilide (D) is a rapidly activating delayed rectifier potassium channel (IKr) blocker effective in pharmacological conversion and maintenance of normal sinus rhythm in patients with AF and AFL. There is limited knowledge regarding the role of D in adults with CHD. METHODS: Safety and efficacy of D was evaluated in a consecutive group of thirteen adult patients (age 40 ± 11; six women) with CHD and refractory AT. RESULTS: Ten patients had persistent (four AFL, one AF, and five atrial tachycardia) and three paroxysmal (one AF and two atrial tachycardia) AT. All patients were symptomatic during tachycardia, 12 patients had previously failed 2 ± 1 antiarrhythmic drugs. Mean systemic ventricular ejection fraction was 55 ± 9%; baseline QRS complex duration was 129 ± 45 ms (>120 ms in six patients). Patients were followed on D for 33 ± 39 months (median 16). Among 10 patients with persistent AT, seven patients (70%) pharmacologically converted to sinus rhythm on D and three patients (30%) required direct current cardioversion. Two patients (15.4%) experienced complete arrhythmia suppression, and seven (53.8%) experienced significant clinical improvement with sporadic recurrences; average time to recurrence was 5.5 ± 3.5 months. One patient developed torsade de pointes during loading, and the drug was discontinued. D was discontinued in five (38.5%) other patients due to recurrence of AT (n = 4) and renal failure (n = 1). Corrected QT interval (QTc) increased from 452 ± 61 to 480 ± 49 ms (P = .04) and corrected JT interval (JTc) from 323 ± 39 to 341 ± 33 ms (P = .09). CONCLUSIONS: D should be considered a pharmacologic alternative when adult patients with CHD develop AT. D does not depress conduction, sinus node, or ventricular function but needs close monitoring for potential ventricular pro-arrhythmia.

Dofetilide reduces the frequency of ventricular arrhythmias and implantable cardioverter defibrillator therapies.

BACKGROUND: Patients with an implanted cardioverter defibrillator (ICD) and ventricular arrhythmias leading to ICD therapies have poor clinical outcomes and quality of life. Antiarrhythmic agents and catheter ablation are needed to control these arrhythmias. Dofetilide has only been approved for the treatment of atrial fibrillation. The role of dofetilide in the control of ventricular arrhythmias in patients with an ICD has not been established. OBJECTIVE: Evaluate the safety and efficacy of dofetilide in a consecutive group of patients with an ICD and recurrent ventricular tachycardia (VT) and/ or ventricular fibrillation (VF) after other antiarrhythmic drugs have failed to suppress these arrhythmias. METHODS: We studied 30 patients (age 59 ± 11; 5 women) with symptomatic VT or VF and ICDs for secondary prevention of sudden cardiac death. These patients had an average of 1.8 ± 4.5 episodes of VT/VF per month despite antiarrhymic therapy. Twenty-one patients (70%) had recurrent appropriate ICD therapies prior to initiation of dofetilide, and 9 (30%) VTs below the programmed detection rate of the ICD. Twenty-three patients (77%) had coronary artery disease. Mean ejection fraction was 30 ± 14% and 26/30 (87%) had congestive heart failure. All patients had previously failed 2 ± 1 antiarrhythmic drugs including amiodarone (n = 19) and sotalol (n = 10). RESULTS: During the first month of treatment, 25 patients (83%) had complete suppression of VT/VF and of the 21 patients with ICD therapies 16 (76%) had no therapies during the first month of treatment. During a follow-up period of 32 ± 32 months, dofetilide reduced the monthly episodes of VT/VF from 1.8 ± 4.5 to 1.0 ± 3.5 (P = 0.006). Monthly ICD therapies decreased from 0.9 ± 1.4 to 0.4 ± 1.7 (P = 0.037). In 9 patients that presented with slow VTs under the ICD detection zone, dofetilide reduced monthly VT/VF episodes from 0.7 ± 0.6 to 0.1 ± 0.1 (P = 0.01) and 6 (67%) had no further ICD therapies. Dofetilide was discontinued in 13 patients (43%) after 24 ± 30 months due to failure to control VT/VF (n = 7), placement of a left ventricular assist device (n = 3), catheter ablation (n = 1), heart transplantation (n = 1), and left ventricular restoration surgery (n = 1). There were 7 documented deaths (2 patients died suddenly; 3 patients of progressive heart failure; and 2 of non-cardiac causes). CONCLUSIONS: In patients with an ICD and ventricular arrhythmias, dofetilide decreases the frequency of VT/VF and ICD therapies even when other antiarrhythmic agents, including amiodarone, have previously been ineffective. Recurrences still occur in some patients requiring catheter ablation, mechanical support, or heart transplantation.

Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature.

Direct thrombin inhibitors are commonly used anticoagulants in patients with known or suspected heparin-induced thrombocytopenia (HIT). All three direct thrombin inhibitors available in the United States-argatroban, bivalirudin, and lepirudin-are pregnancy category B drugs based on animal studies, but little data are available on the safety of these agents during human pregnancy. Whereas several case reports support the safe use of lepirudin, only one case report has been published with argatroban and none with bivalirudin. We describe a 26-year-old pregnant woman with portal vein thrombosis and thrombocytopenia treated with argatroban for possible HIT during her last trimester. An argatroban infusion was started at 2 microg/kg/minute during her 33rd week of pregnancy, with the dosage titrated based on the activated partial thromboplastin time; infusion rates ranged from 2-8 microg/kg/minute. Treatment continued until her 39th week of pregnancy, when labor was induced. Argatroban therapy was discontinued 7 hours before epidural anesthesia. The patient successfully delivered a healthy male newborn, devoid of any known adverse effects from argatroban. The infant was found to have a small ventricular septal defect and patent foramen ovale at birth, but it is unlikely that these were caused by argatroban since organogenesis occurs in the first trimester. Even though the cause of this patient's thrombocytopenia was later determined to be idiopathic thrombocytopenic purpura, this is an important case that adds to the literature on use of argatroban during pregnancy.

Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter.

BACKGROUND: Dofetilide, an I(Kr) blocker has been demonstrated to be effective in terminating persistent atrial fibrillation and flutter (AF/AFL), and in maintaining sinus rhythm after direct current cardioversion (CV). It is not known, however, whether pharmacological conversion with dofetilide predicts maintenance of sinus rhythm. In addition, there is limited information comparing the efficacy of dofetilide in persistent versus paroxysmal AF/AFL. METHODS AND RESULTS: Eighty consecutive patients with AF/AFL (51 persistent, 29 paroxysmal) admitted for initiation of dofetilide were studied. Termination of persistent AF/AFL occurred in 61% of patients while 39% required CV. After 21 +/- 19 months of follow-up, 37% of patients with persistent AF/AFL were free of recurrence. Acute conversion with dofetilide did not predict long term efficacy. Dofetilide was more effective in maintaining sinus rhythm in patients with AFL (65%) than in those with AF (25%) (p < 0.05). Dofetilide was more likely to maintain sinus rhythm in patients with persistent than paroxysmal AF/AFL (37 vs. 14%; p < 0.05). Torsades de Pointes developed in two patients despite careful dosing and monitoring of QT changes. CONCLUSIONS: Dofetilide is more effective in patients with persistent than in those with paroxysmal AF/AFL. Importantly, short-term response does not necessarily predict long-term efficacy. Significant proarrhythmia can occur even with careful in-hospital monitoring.