CLINICAL STUDIES

14 14.1 ATHENA ATHENA was a multicenter, multinational, double blind, and randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay death from any cause or hospitalization for cardiovascular reasons. Initially patients were to be ≥70 years old, or <70 years old with at least one risk factor (including hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or LVEF<0.40). The inclusion criteria were later changed such that patients were to be ≥75 years old, or ≥70 years old with at least one risk factor. Patients had to have both AF/AFL and sinus rhythm documented within the previous 6 months. Patients could have been in AF/AFL or in sinus rhythm at the time of randomization, but patients not in sinus rhythm were expected to be either electrically or chemically converted to normal sinus rhythm after anticoagulation. Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either MULTAQ 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II receptor blockers (ARBs)(69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%). The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death from any cause. Time to death from any cause, time to first hospitalization for cardiovascular reasons, and time to cardiovascular death and time to all causes of death were also explored. Patients ranged in age from 23 to 97 years; 42% were 75 years old or older. Forty-seven percent (47%) of patients were female and a majority was Caucasian (89%). Approximately seventy percent (71%) of those enrolled had no history of heart failure. The median ejection fraction was 60%. Twenty-nine percent (29%) of patients had heart failure, mostly NYHA class II (17%). The majority had hypertension (86%) and structural heart disease (60%). Results are shown in Table 3. MULTAQ reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2% when compared to placebo. This difference was entirely attributable to its effect on cardiovascular hospitalization, principally hospitalization related to AF. Other endpoints, death from any cause and first hospitalization for cardiovascular reasons, are shown in Table 3. Secondary endpoints count all first events of a particular type, whether or not they were preceded by a different type of event. Table 3: Incidence of Endpoint Events Placebo MULTAQ 400mg BID (N= 2327) (N= 2301) HR 95% CI p-Value Primary endpoint Cardiovascular hospitalization or death from any cause 913 (39.2%) 727 (31.6%) 0.76 [0.68 – 0.83] <0.0001 Components of the endpoint (as first event) Cardiovascular hospitalization 856 (36.8%) 669 (29.1%) Death from any cause 57 (2.4%) 58 (2.5%) Secondary endpoints (any time in study) Death from any cause 135 (5.8%) 115 (5.0%) 0.86 [0.67 – 1.11] 0.24 Cardiovascular hospitalization 856 (36.8%) 669 (29.1%) 0.74 [0.67 – 0.82] <0.0001 Components of the cardiovascular hospitalization endpoint (as first event) AF and other supraventricular rhythm disorders 456 (19.6%) 292 (12.7%) 0.61 [0.53 – 0.71] <0.0001 Other 400 (17.2%) 377 (16.4%) 0.89 [0.77 – 1.03] 0.11 The Kaplan-Meier cumulative incidence curves showing the time to first event are displayed in Figure 1. The event curves separated early and continued to diverge over the 30 month follow-up period. Figure 1: Kaplan-Meier Cumulative Incidence Curves from Randomization to First Cardiovascular Hospitalization or Death from any Cause Reasons for hospitalization included major bleeding (1% in both groups), syncope (1% in both groups), and ventricular arrhythmia (<1% in both groups). The reduction in cardiovascular hospitalization or death from any cause was generally consistent in all subgroups based on baseline characteristics or medications (ACE inhibitors or ARBs; beta-blockers, digoxin, statins, calcium channel blockers, diuretics) (see Figure 2). Figure 2: Relative Risk (MULTAQ versus placebo) Estimates with 95% Confidence Intervals According to Selected Baseline Characteristics: First Cardiovascular Hospitalization or Death from any Cause. a Determined from Cox regression model b P-value of interaction between baseline characteristics and treatment based on Cox regression model c Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil Figure 1 Figure 2 14.2 EURIDIS and ADONIS In EURIDIS and ADONIS, a total of 1237 patients in sinus rhythm with a prior episode of AF or AFL were randomized in an outpatient setting and treated with either MULTAQ 400 mg twice daily (n=828) or placebo (n=409) on top of conventional therapies (including oral anticoagulants, beta-blockers, ACE inhibitors or ARBs, chronic antiplatelet agents, diuretics, statins, digoxin, and calcium channel blockers). Patients had at least one ECG-documented AF/AFL episode during the 3 months prior to study entry but were in sinus rhythm for at least one hour. Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (70%) patients. The most common co-morbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronary heart disease (21.8%). Patients were followed for 12 months. In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%,with an absolute difference in recurrence rate of about 11% at 12 months. 14.3 ANDROMEDA Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index ≤1.2) were randomized to either MULTAQ 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. Patients enrolled in ANDROMEDA were predominantly NYHA Class II (40%) and III (57%), and only 25% had AF at randomization. After enrollment of 627 patients and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group died versus 12 patients in the placebo group (hazard ratio 2.13; 95% CI: 1.07 to 4.25). The main reason for death was worsening heart failure. There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 versus 51 for placebo) [see Boxed Warning and Contraindications (4)]. 14.4 PALLAS Patients with permanent AF (AF documented in 2 weeks prior to randomization and at least 6 months prior to randomization in whom cardioversion had failed or was not planned) and additional risk factors for thromboembolism (coronary artery disease, prior stroke or TIA, symptomatic heart failure, LVEF 75 with hypertension and diabetes) were randomized to dronedarone 400 mg twice daily or placebo. After enrollment of 3236 patients (placebo=1617 and dronedarone=1619) and a median follow up of 3.7 months days for placebo and 3.9 for dronedarone, the study was terminated because of a significant increase in Mortality: 25 dronedarone vs. 13 placebo (HR, 1.94; CI, 0.99 to 3.79). The majority of deaths in the dronedarone group were classified as arrhythmic/sudden deaths (HR, 3.26; CI: 1.06 to 10.0). Baseline digoxin therapy was reported in 11/13 dronedarone patients who died of arrhythmia. None of the arrhythmic deaths on placebo (4) reported use of digoxin. Stroke: 23 dronedarone vs. 10 placebo (HR, 2.32; CI: 1.11 to 4.88). The increased risk of stroke observed with dronedarone was observed in the first two weeks of therapy (10 dronedarone vs. 1 placebo), most of the subjects treated with dronedarone did not have an INR of 2.0 to 3.0.[see Warning and Precaution (5.3) ] Hospitalizations for heart failure in the dronedarone group: 43 dronedarone vs. 24 placebo (HR, 1.81; CI: 1.10 to 2.99).