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. Both studies randomized patients to placebo or to doses of 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 (see DOSAGE AND ADMINISTRATION).
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.
Both studies enrolled mostly Caucasians (over 90%), males (over 70%), and patients ≥65 years of age (over 50%). Most (>90%) were NYHA Functional Class I or II. Approximately one-half had structural heart disease (including ischemic heart disease, cardiomyopathies, and valvular disease) and about one-half were hypertensive. A substantial proportion of patients were on concomitant therapy, including digoxin (over 60%), diuretics (over 20%), and ACE inhibitors (over 30%). About 90% were on anticoagulants.
Acute conversion rates are shown in Table 1 for randomized doses (doses were adjusted for calculated creatinine clearance and, in Study 1, for QT interval or QTc). Of patients who converted pharmacologically, approximately 70% converted within 24–36 hours.
|125 mcg BID||250 mcg BID||500 mcg BID|
Patients who did not convert to NSR with randomized therapy within 48–72 hours had electrical cardioversion. Those patients remaining in NSR after conversion in hospital were continued on randomized therapy as outpatients (maintenance period) for up to one year unless they experienced a recurrence of atrial fibrillation/atrial flutter or withdrew for other reasons.
Table 2 shows, by randomized dose, the percentage of patients at 6 and 12 months in both studies who remained on treatment in NSR and the percentage of patients who withdrew because of recurrence of AF/AFl or adverse events.
|125 mcg BID||250 mcg BID||500 mcg BID||Placebo|
|Note that columns do not add up to 100% due to discontinuations for “other” reasons.|
|Still on treatment in NSR||38%||44%||52%||32%|
|D/C for recurrence||55%||49%||33%||63%|
|D/C for AEs||3%||3%||8%||4%|
|Still on treatment in NSR||32%||26%||46%||22%|
|D/C for recurrence||58%||57%||36%||72%|
|D/C for AEs||7%||11%||8%||6%|
|Still on treatment in NSR||41%||49%||57%||22%|
|D/C for recurrence||48%||42%||27%||72%|
|D/C for AEs||9%||6%||10%||4%|
|Still on treatment in NSR||25%||42%||49%||16%|
|D/C for recurrence||59%||47%||32%||76%|
|D/C for AEs||11%||6%||12%||5%|
Table 3 and Figures 3 and 4 show, by randomized dose, the effectiveness of TIKOSYN in maintaining NSR using Kaplan Meier analysis, which shows patients remaining on treatment.
|125 mcg BID||250 mcg BID||500 mcg BID||Placebo|
|Median time to recurrence of AF/AFl could not be estimated accurately for the 250 mcg BID treatment group in Study 2 and the 500 mcg BID treatment groups in Studies 1 and 2 because TIKOSYN maintained >50% of patients (51%, 58%, and 66%, respectively) in NSR for the 12 months duration of the studies.|
|p-value vs. placebo||P=0.21||P=0.10||P<0.001|
|Median time to recurrence (days)||31||179||>365||27|
|p-value vs. placebo||P=0.006||P<0.001||P<0.001|
|Median time to recurrence (days)||182||>365||>365||34|
Figure 3: Maintenance of Normal Sinus Rhythm, TIKOSYN Regimen vs. Placebo (Study 1)
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.
Figure 4: Maintenance of Normal Sinus Rhythm, TIKOSYN Regimen vs. Placebo (Study 2)
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, TIKOSYN resulted in a dose-related increase in the number of patients maintained in 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 (see Figure 2 in CLINICAL PHARMACOLOGY, Dose-Response and Concentration Response for Increase in QT Interval).
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.
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