Multaq® [Dronaderon]

Pharmacological properties

Multaq is an antiarrhythmic drug indicated for use in adult patients in a stable clinical condition who have previously suffered or currently suffer from an unstable form of atrial fibrillation (atrial fibrillation), in order to prevent recurrence of atrial fibrillation or to slow down the ventricular rhythm.

Mechanism of action

In animals, dronedarone prevented atrial fibrillation or restored normal sinus rhythm depending on the experimental model used. He also prevented ventricular tachycardia and ventricular fibrillation in several animal models. Such an action is most likely due to its electrophysiological properties inherent in all four classes according to the Wogan-Williams classification. Dronedarone is a multi-channel blocker that inhibits potassium channels (including IK (_Ach), IK_ur, IK_r, IK_s) and thus lengthens the action potential of the heart muscle and the refractory period (class III). It also inhibits sodium channels (class Ib) and calcium channels (class IV). He is a non-competitive adrenergic receptor antagonist (class II).

Pharmacodynamic properties

In experimental animal models, dronedarone slows heart rate. Extends the duration of the Wenckebach periodical and the intervals AH, PQ, QT; at the same time, it has no noticeable effect or slightly lengthens the QTc, HV, and QRS intervals. It increases effective refractory periods in the atria, atrioventricular node, and ventricle with a minimal degree of reverse dependence on use (reverse-use dependency).

Dronedarone reduces blood pressure and myocardial contractility, without changing the ejection fraction of the left ventricle and reducing myocardial oxygen consumption.

Dronedarone has a vasodilating effect, which is more pronounced relative to the coronary arteries (due to the activation of the signal pathway of nitric oxide), compared with peripheral arteries.

Dronedarone has an indirect antiadrenergic effect; reduces the α-adrenergic response from blood pressure to epinephrine, as well as the response of β₁- and β₂-adrenoreceptors to isoproterenol.

Clinical data

Reduced risk of hospitalization for atrial fibrillation

The effectiveness of dronedarone in reducing the risk of hospitalization due to atrial fibrillation was established in a multicenter, multinational, double-blind, randomized, placebo-controlled study of ATHENA in patients with a history of atrial fibrillation or flutter or with this pathology and who have additional risk factors.

Patients should have at least 1 risk factor (including age, hypertension, diabetes mellitus, previous cerebrovascular accident, left atrial diameter 50 mm or left ventricular ejection fraction 0.40) along with atrial fibrillation / flutter and a sinus rhythm recorded at over the past 6 months. Patients should have atrial fibrillation / flutter or sinus rhythm after spontaneous conversion or after any procedures.

A total of 4628 patients were randomized and received treatment for up to 30 months with a maximum (median duration of follow-up: 22 months) of dronedarone at a dose of 400 mg 2 times a day (2301 patients) or placebo (2327 patients), in addition to traditional therapy, including β-adrenoreceptor blockers (71%), ACE or ARAII inhibitors (69%), cardiac glycosides (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), chronic antiplatelet therapy (5%) and / or diuretics (54%).

The primary endpoint of the study was the period before the first hospitalization due to cardiovascular disease or death for any reason.

The age range of patients is from 23 to 97 years, 42% of which were older than 75 years. Women made up 47% of all patients; white people made up the majority (89%).

Most patients noted hypertension (86%) and structural heart disease (60%) (including coronary artery disease: 30% - congestive heart failure; 30% - left ventricular dysfunction (45-12%).

Atrial fibrillation was detected in 25% of patients.

Compared to placebo, dronedarone reduced the number of hospital admissions due to cardiovascular disease or death for any reason by 24.2% (p0.0001).

The decrease in the number of hospitalizations due to cardiovascular disease or death for any reason was the same in all subgroups, regardless of the initial characteristics or medication (ACE or ARAII inhibitors; β-adrenergic receptor blockers, cardiac glycosides, statins, calcium antagonists and diuretics funds) (table. 1).

The relative risk (dronedarone at a dose of 400 mg 2 times a day compared with placebo) is estimated at a 95% confidence interval according to the selected initial characteristics - the first hospitalization due to cardiovascular diseases or death for any reason.

a - is determined by the Cox regression model; b - p value - the interaction between the initial characteristics and treatment indicators for the Cox regression model; c - calcium antagonists with the effect of reducing heart rate are limited to diltiazem, verapamil and bepridil.

Similar results were obtained regarding the number of hospitalizations due to cardiovascular diseases with a 25.5% reduction in risk (p0.0001).

During the study, the number of deaths for any reason in the group taking dronedarone (116/2301) and in the group taking placebo (139/2 327) was similar.

Sinus rhythm

The EURIDIS and ADONIS studies involved 1237 patients with a history of atrial fibrillation or flutter, which were randomly selected on an outpatient basis; patients received treatment with dronedarone at a dose of 400 mg 2 times a day (n = 828) or placebo (n = 409) in addition to conventional therapy (including the use of oral anticoagulants, β-adrenergic receptor blockers, ACE inhibitors or ARAII, antiplatelet agents in chronic conditions, diuretics, statins, cardiac glycosides and calcium antagonists). Patients reported at least one case of ECG documented atrial fibrillation / flutter during the last 3 months, sinus rhythm for at least 1 hour, and also for 12 months In patients taking amiodarone, the ECG should have been removed 4 hours after taking the first dose in order to check tolerance (tolerance). The administration of other antiarrhythmic drugs was stopped for at least 5 half-lives from blood plasma before taking the first dose.

The age range of patients ranged from 20 to 88 years, with most of them of Caucasian origin (97%), of which the majority were males (69%). The most common concomitant diseases were arterial hypertension (56.8%) and structural heart diseases (41.5%), including coronary heart disease (21.8%).

According to the combined data from the EURIDIS and ADONIS studies, from individual individual studies, dronedarone continually lengthened the time until the first recurrence of atrial fibrillation / flutter (primary endpoint) occurred.Compared with placebo, dronedarone reduced the risk of first recurrence of atrial fibrillation / flutter during the 12-month follow-up period by 25% (p = 0.00007). The average time from randomization to the first recurrence of atrial fibrillation / flutter in the group taking dronedarone was 116 days, that is, it was 2.2 times longer than this indicator in the placebo group (53 days).

The DIONYSOS study compared the efficacy and safety of dronedarone (at a dose of 400 mg 2 times a day) with amiodarone (at a dose of 600 mg / day for 28 days, followed by a dose reduction to 200 mg / day) for 6 months. A total of 504 patients with documented atrial fibrillation were randomly selected, 249 of them received dronedarone, and 255 received amiodarone. The primary efficacy endpoint, which was defined as the first recurrence of atrial fibrillation or early cessation of the study drug due to intolerance or lack of effectiveness, was 12% after 12 months in the dronedarone group and 59% in the amiodarone group (correlation error - 1.59, registered value p0.0001). Cases