CHF and arrhythmias:
Indications for: TIKOSYN
Maintenance of normal sinus rhythm in patients with atrial fibrillation or atrial flutter of >1 week duration who were converted to normal sinus rhythm (use only for highly symptomatic patients). Conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.
Chronic Atrial Fibrillation and/or Atrial Flutter
Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of Tikosyn 1) to convert patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1 week duration to normal sinus rhythm (NSR) and 2) to maintain NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion. A total of 996 patients with a one week to two year history of atrial fibrillation/atrial flutter were enrolled. In both studies, patients were randomized to receive placebo or Tikosyn 125 mcg, 250 mcg, 500 mcg, or in one study a comparator drug, given twice a day (these doses were lowered based on calculated creatinine clearance and, in one of the studies, for QT interval or QTc). All patients were started on therapy in a hospital where their ECG was monitored.
Patients were excluded from participation if they had had syncope within the past 6 months, AV block greater than first degree, MI or unstable angina within 1 month, cardiac surgery within 2 months, history of QT interval prolongation or polymorphic ventricular tachycardia associated with use of antiarrhythmic drugs, QT interval or QTc >440 msec, serum creatinine >2.5 mg/mL, significant diseases of other organ systems; used cimetidine; or used drugs known to prolong the QT interval.
The following results showed the proportion of patients treated with Tikosyn 125 mcg, 250 mcg, and 500 mcg twice daily who achieved acute conversion rates from atrial fibrillation/flutter to normal sinus rhythm (NSR) compared with placebo, respectively:
Study 1 – 6% (n=5/82), 10% (n=8/82), 30% (n=23/77) vs 1% (n=1/84)
Study 2 – 6% (n=8/135), 11% (n=14/133), 29% (n=38/129) vs 1% (n=2/137)
Among patients who converted pharmacologically, approximately 70% converted within 24 to 36 hours.
Electrical cardioversion was administered to patients who did not convert to NSR with randomized therapy within 48 to 72 hours. Patients who remained in NSR after conversion in the hospital were continued on randomized therapy as outpatients for up to 1 year.
Additionally, at 6 and 12 months, the following proportion of patients treated with Tikosyn 125 mcg, 250 mcg, and 500 mcg remained on treatment in NSR and withdrew due to recurrence of atrial fibrillation/flutter or adverse events compared with placebo, respectively:
Study 1 – 6 months
Still on treatment in NSR: 38%, 44%, 52% vs 32%
D/C for recurrence: 55% , 49%, 33% vs 63%
D/C for AEs: 3%, 3%, 8% vs 4%
Study 1 – 12 months
Still on treatment in NSR: 32%, 26%, 46% vs 22%
D/C for recurrence: 58% , 57%, 36% vs 72%
D/C for AEs: 7%, 11%, 8% vs 6%
Study 2 – 6 months
Still on treatment in NSR: 41%, 49%, 57% vs 22%
D/C for recurrence: 48% , 42%, 27% vs 72%
D/C for AEs: 9%, 6%, 10% vs 4%
Study 2 – 12 months
Still on treatment in NSR: 25%, 42%, 49% vs 16%
D/C for recurrence: 59% , 47%, 32% vs 76%
D/C for AEs: 11%, 6%, 12% vs 5%
The effectiveness of Tikosyn 125 mcg, 250 mcg, and 500 mcg twice daily in maintaining NSR using Kaplan Meier analysis showed the following P-values and median time to recurrence of atrial fibrillation/flutter compared with placebo, respectively:
P =.21; P =.10; P <.001
Median time to recurrence (days): 31; 179; >365 vs 27
P =.006; P <.001; P <.001
Median time to recurrence (days): 182; >365; >365 vs 34
The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 62% and 58%, respectively, for Tikosyn 500 mcg BID; 50% and 37%, respectively, for Tikosyn 250 mcg BID; and 37%, and 25%, respectively, for placebo.
The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 71% and 66%, respectively, for Tikosyn 500 mcg BID; 56% and 51%, respectively, for Tikosyn 250 mcg BID; and 26% and 21%, respectively, for placebo.
In both studies, there was a dose-related increase in the number of patients who received Tikosyn and maintained NSR at all time periods and delayed the time of recurrence of sustained AF. Data pooled from both studies show that there is a positive relationship between the probability of staying in NSR, Tikosyn dose, and increase in QTc.
Analysis of pooled data for patients randomized to a Tikosyn dose of 500 mcg twice daily showed that maintenance of NSR was similar in both males and females, in both patients aged <65 years and patients 65 years of age, and in both patients with atrial flutter as a primary diagnosis and those with a primary diagnosis of atrial fibrillation.
During the period of in-hospital initiation of dosing, 23% of patients in Studies 1 and 2 had their dose adjusted downward on the basis of their calculated creatinine clearance, and 3% had their dose down-titrated due to increased QT interval or QTc. Increased QT interval or QTc led to discontinuation of therapy in 3% of patients.
Safety in Patients with Structural Heart Disease: DIAMOND Studies (The Danish Investigations of Arrhythmia and Mortality on Dofetilide)
The two DIAMOND studies were 3-year trials comparing the effects of Tikosyn and placebo on mortality and morbidity in patients with impaired left ventricular function (ejection fraction 35%). Patients were treated for at least one year. One study was in patients with moderate to severe (60% NYHA Class III or IV) congestive heart failure (DIAMOND CHF) and the other was in patients with recent myocardial infarction (DIAMOND MI) (of whom 40% had NYHA Class III or IV heart failure). Both groups were at relatively high risk of sudden death. The DIAMOND trials were intended to determine whether Tikosyn could reduce that risk. In both trials, there was not a reduction in mortality, but they did provide reassurance that, when initiated carefully, in a hospital or equivalent setting, Tikosyn did not increase mortality in patients with structural heart disease, an important finding because other antiarrhythmics [notably the Class IC antiarrhythmics studied in the Cardiac Arrhythmia Suppression Trial (CAST) and a pure Class III antiarrhythmic, d-sotalol (SWORD)] have increased mortality in post-infarction populations. The DIAMOND trials therefore provide evidence of a method of safe use of Tikosyn in a population susceptible to ventricular arrhythmias. In addition, the subset of patients with AF in the DIAMOND trials provide further evidence of safety in a population of patients with structural heart disease accompanying the AF. Note, however, that this AF population was given a lower (250 mcg BID) dose.
In both DIAMOND studies, patients were randomized to 500 mcg BID of Tikosyn, but this was reduced to 250 mcg BID if calculated creatinine clearance was 40–60 mL/min, if patients had AF, or if QT interval prolongation (>550 msec or >20% increase from baseline) occurred after dosing. Dose reductions for reduced calculated creatinine clearance occurred in 47% and 45% of DIAMOND CHF and MI patients, respectively. Dose reductions for increased QT interval or QTc occurred in 5% and 7% of DIAMOND CHF and MI patients, respectively. Increased QT interval or QTc (>550 msec or >20% increase from baseline) resulted in discontinuation of 1.8% of patients in DIAMOND CHF and 2.5% of patients in DIAMOND MI.
In the DIAMOND studies, all patients were hospitalized for at least 3 days after treatment was initiated and monitored by telemetry. Patients with QTc >460 msec, second or third degree AV block (unless with pacemaker), resting heart rate <50 bpm, or prior history of polymorphic ventricular tachycardia were excluded.
DIAMOND CHF included 1518 patients hospitalized with severe CHF who had confirmed impaired left ventricular function (ejection fraction 35%). Patients received a median duration of therapy of greater than one year. There were 311 deaths from all causes in patients randomized to Tikosyn (n=762) and 317 deaths in patients randomized to placebo (n=756). The probability of survival at one year was 73% (95% CI: 70% – 76%) in the Tikosyn group and 72% (95% CI: 69% – 75%) in the placebo group. Similar results were seen for cardiac deaths and arrhythmic deaths. Torsade de Pointes occurred in 25/762 patients (3.3%) receiving Tikosyn. The majority of cases (76%) occurred within the first 3 days of dosing. In all, 437/762 (57%) of patients on Tikosyn and 459/756 (61%) on placebo required hospitalization. Of these, 229/762 (30%) of patients on Tikosyn and 290/756 (38%) on placebo required hospitalization because of worsening heart failure.
DIAMOND MI studied 1510 patients hospitalized with recent myocardial infarction (2–7 days) who had confirmed impaired left ventricular function (ejection fraction 35%). Patients received a median duration of therapy of greater than one year. There were 230 deaths in patients randomized to Tikosyn (n=749) and 243 deaths in patients randomized to placebo (n=761). The probability of survival at one year was 79% (95% CI: 76% – 82%) in the Tikosyn group and 77% (95% CI: 74% – 80%) in the placebo group. Cardiac and arrhythmic mortality showed a similar result. Torsade de Pointes occurred in 7/749 patients (0.9%) receiving Tikosyn. Of these, 4 cases occurred within the first 3 days of dosing and 3 cases occurred between Day 4 and the conclusion of the study. In all, 371/749 (50%) of patients on Tikosyn and 419/761 (55%) on placebo required hospitalization. Of these, 200/749 (27%) of patients on Tikosyn and 205/761 (27%) on placebo required hospitalization because of worsening heart failure.
DIAMOND Patients with Atrial Fibrillation (the DIAMOND AF subpopulation). There were 506 patients in the two DIAMOND studies who had atrial fibrillation (AF) at entry to the studies (249 randomized to Tikosyn and 257 randomized to placebo). DIAMOND AF patients randomized to Tikosyn received 250 mcg BID; 65% of these patients had impaired renal function, so that 250 mcg BID represents the dose they would have received in the AF trials, which would give drug exposure similar to a person with normal renal function given 500 mcg BID. In the DIAMOND AF subpopulation, there were 111 deaths (45%) in the 249 patients in the Tikosyn group and 116 deaths (45%) in the 257 patients in the placebo group. Hospital readmission rates for any reason were 125/249 or 50% on Tikosyn and 156/257 or 61% for placebo. Of these, readmission rates for worsening heart failure were 73/249 or 29% on Tikosyn and 102/257 or 40% for placebo. Of the 506 patients in the DIAMOND studies who had atrial fibrillation or flutter at baseline, 12% of patients in the Tikosyn group and 2% of patients in the placebo group had converted to normal sinus rhythm after one month. In those patients converted to normal sinus rhythm, 79% of the Tikosyn group and 42% of the placebo group remained in normal sinus rhythm for one year. In the DIAMOND studies, although Torsade de Pointes occurred more frequently in the Tikosyn-treated patients, Tikosyn, given with an initial 3-day hospitalization and with dose modified for reduced creatinine clearance and increased QT interval, was not associated with an excess risk of mortality in these populations with structural heart disease in the individual studies or in an analysis of the combined studies. The presence of atrial fibrillation did not affect outcome.
≥18yrs: see full labeling. Initiate only in appropriate clinical setting and continue to be monitored for a minimum of 3 days.
<18yrs: not recommended.
Long QT syndromes. Baseline QT interval or QTc >440msec (500msec in ventricular conduction abnormalities). Severe renal impairment (CrCl <20mL/min). Concomitant hydrochlorothiazide, verapamil, trimethoprim, cimetidine, ketoconazole, or other inhibitors of renal cationic secretion (eg, prochlorperazine, megestrol, dolutegravir).
Must be initiated or re-initiated in a facility that can provide ECG monitoring and management of ventricular arrhythmias.
Monitor QTc, renal function (do baseline CrCl) at least every 3 months, and all concomitant drugs (including OTC drugs, herbs, supplements). Paroxysmal atrial fibrillation. Heart rate <50 beats/min. Sick sinus syndrome. 2nd or 3rd degree heart block, unless paced. Renal or severe hepatic impairment. Maintain normal potassium, magnesium levels. Conditions affecting electrolyte levels. Pregnancy (Cat.C). Nursing mothers: not recommended.
Class III antiarrhythmic.
See Contraindications. Stop dofetilide for at least 2 days before starting an interacting drug. Drugs that prolong QT interval (eg, phenothiazines, cisapride, bepridil, tricyclic antidepressants, some macrolides and fluoroquinolones): not recommended. Caution with drugs that undergo renal cationic secretion (eg, triamterene, metformin, amiloride) and with CYP3A4 inhibitors (eg, macrolides, azole antifungals, protease inhibitors, SSRIs, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazodone, norfloxacin, quinine, zafirlukast); these may increase dofetilide levels. Allow at least 3 half-lives to elapse and monitor when withdrawing Class I or III antiarrhythmics before giving 1st dose of dofetilide (see full labeling); reduce serum amiodarone levels to <0.3mg/L or withdraw at least 3 months before starting dofetilide. Potassium-depleting diuretics, digoxin may increase risk of torsade de pointes.
Headache, chest pain, dizziness, respiratory tract infection, dyspnea, nausea, flu syndrome, insomnia, back pain, diarrhea, rash, abdominal pain, torsade de pointes (esp. in females), serious ventricular arrhythmias, sudden death, conduction disturbances.
This product is being made available only to those hospitals and prescribers who have received appropriate education from the manufacturer.
The terminal half-life of dofetilide is approximately 10 hours. Steady state plasma concentrations are attained within 2–3 days, with an accumulation index of 1.5 to 2.0. Plasma concentrations are dose proportional.
Approximately 80% of a single dose of dofetilide is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol, ketoconazole and dolutegravir).