Innovative Pharmacological Approaches to Managing Atrial Fibrillation: The Importance of Reducing Cardiovascular Hospitalizations

DOI: 10.19102/icrm.2011.020207

TAMAS BAUERNFEIND, MD DAMIR ERKAPIC, MD and STEFAN H. HOHNLOSER, MD, FACC, FESC, FHRS

J. W. Goethe University, Frankfurt, Germany

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ABSTRACT. Innovative pharmacological therapy of atrial fibrillation (AF) should aim to reduce clinical events, improve prognosis of patients, and relieve AF-associated symptoms. Studies during recent years have convincingly shown that hospitalizations for cardiovascular events in AF patients are of major concern. They occur very frequently, incur significant costs, impair quality of life to a great extent, and appear to be associated with subsequent mortality. A large randomized clinical trial, the ATHENA study, has demonstrated a 25% risk reduction in cardiovascular hospitalizations in patients treated with dronedarone, a novel antiarrhythmic drug. Similarly, cardiovascular mortality was lower in patients on dronedarone than in the control group. Thus, it is conceivable that clinical endpoints such as cardiovascular mortality or hospitalization will play a major role in future antiarrhythmic drug development, and not only electrocardiogram-derived endpoints such as maintenance of sinus rhythm.

KEYWORDS. atrial fibrillation, pharmacological therapy, dronedarone, hospitalization.

Dr. Hohnloser reports being a consultant, investigator, and/or member of the speaker bureau for Sanofi-Aventis, Boehringer Ingelheim, Bristol-Myers Squibb, ARYx, Cardiome, St. Jude Medical, and Merck.
Manuscript received January 4, 2011, final version accepted January 12, 2011.
Address correspondence to: Stefan H. Hohnloser, MD, Department of Cardiology, Division of Clinical Electrophysiology, J. W. Goethe University, Theodor Stern Kai 7, 60590 Frankfurt, Germany. E-mail: Hohnloser@em.uni-frankfurt.de

Atrial fibrillation (AF) is the most commonly encountered clinical arrhythmia, with a prevalence of almost 1% in the unselected adult population. It has been estimated that its prevalence will increase by at least 2.5-fold in the next 50 years as the population ages. In fact, in elderly patients, a prevalence of up to 10% is expected in future years. The clinical presentation of AF is variable, and this variety requires a spectrum of therapeutic responses. Sudden-onset, symptomatic AF usually is treated with pharmacological or electrical cardioversion, recurrent AF demands preventive antiarrhythmic treatment, and permanent AF that is accepted by the patient and the physician is treated with rate control and anticoagulation.

There are two main reasons to treat AF: namely relief of symptoms and improvement in clinical outcomes. AF is associated with increased rates of death, stroke, and other thromboembolic events; heart failure; hospitalizations; impaired quality of life; and reduced exercise capacity and left ventricular function (Table 1).¹ The prevention of these outcomes is the main therapeutic goal in AF patients. The present short review focuses on innovative pharmacological therapy in patients with AF that aims to reduce clinically important outcomes, particularly the need of hospitalization for cardiovascular causes.

Time to first hospitalization for cardiovascular causes has recently been an important component of the primary endpoint of a large outcomes trial in patients with AF.² To better understand the rationale why this endpoint was chosen, the frequency, costs, and potential implications of hospitalizations in AF patients will be reviewed.

Frequency of cardiovascular hospitalization in AF patients

Several reports from large administrative databases and from recent surveys have clearly indicated that hospitalizations for AF have increased dramatically.^3–5 For instance, data from the National Hospital Discharge Survey showed that during the period from 1985 to 1999, hospitalizations for AF had increased twofold to threefold in the US, with rising rates particularly in elderly individuals.³ Similarly, another survey found that over a 12-year period, the population-adjusted emergency department visit rate for treatment of AF increased from 0.6 to 1.2 per 1,000 US population (p for trend =  0.02). Similarly, the absolute number of visits increased by 88% from 300,000 in 1993–4 to 564,000 in 2003–4.⁴ Data from the Euro Heart Survey confirm these observations.⁵ This survey enrolled 5,333 patients with AF and followed them for 1 year. Irrespective of the type of AF (i.e. recent onset, paroxysmal, persistent, or permanent), hospitalization rates for cardiovascular causes were between 30% and 43% in the four patient subsets during the 1-year follow-up period (Figure 1).

Hospitalization-associated costs in AF patients

The economic burden of inpatient care of patients with AF is enormous. Data from a large administrative database found that for primary AF hospitalization, inpatient costs were $11,306 and outpatient costs were $2,826 per patient over a 12-month period.⁶ Another study in a cohort of 973 AF patients who were followed for 2 years similarly showed that the largest driver of AF-associated costs was inpatient care of these patients.⁷ With increasing numbers of AF recurrences, these costs rose almost exponentially. Data from the Euro Heart Survey confirmed these observations, showing that in five participating European countries with detailed cost breakdowns available, inpatient care and interventional procedures were the main drivers of costs, accounting for more than 70% of total annual AF treatment costs in all five countries.⁸

Hospitalization-associated impact on quality of life

In general, AF has a profound negative impact on quality of life.^9,10 Based on assessment of the SF-36 questionnaire, impairment of quality of life in AF patients was similar to that observed, for instance, in patients after myocardial infarction. Recently, Dorian et al¹⁰ developed and validated a new quality-of-life instrument, the so-called Canadian Cardiovascular Society Severity in Atrial Fibrillation (CCS-SAF) scale. During the validation process, the impact of numbers of emergency department visits and hospitalizations on quality of life were examined. Patients reporting emergency room visits and hospitalizations had significantly increased CCS-SAF scores, indicating markedly impaired quality of life. As the number of hospitalizations for treatment of AF increased, quality of life significantly decreased. Thus, hospitalization appears to be one of the most important causes of impaired quality of life perception in patients afflicted with AF.

Hospitalization as a surrogate marker for mortality in AF patients

A retrospective analysis of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial aimed to determine surrogate parameters for mortality in this largest rhythm versus rate control trial in AF.¹¹ Among several parameters explored, only cardiovascular hospitalization occurred more often than death. To take into account the fact that hospitalization to cardiovert AF or to change antiarrhythmic drug therapy was also classified as cardiovascular hospitalization, two patient cohorts were separately analyzed. The inclusive cohort comprised all cardiovascular hospitalizations, whereas in the censored cohort, hospitalizations for cardioversion or drug change were excluded. Cox proportional hazards analysis with cardiovascular hospitalization as a time-dependent covariate demonstrated that this event was significantly associated with death in both the rhythm and rate control arms of AFFIRM (Table 2). There was no evidence of an interaction between cardiovascular hospitalizations and treatment assignment as a predictor of death for both cohorts of patients. Finally, the time to death after cardiovascular hospitalization did not differ between the two treatment groups. Thus, based on this post hoc analysis of the AFFIRM trial, cardiovascular hospitalization appears to constitute an acceptable surrogate endpoint for mortality. This endpoint occurs sooner and more often than death but is highly predictive of the latter outcome irrespective of the treatment modality, i.e. rate or rhythm control.¹²

In summary, therefore, hospitalizations for cardiovascular causes occur very frequently in patients with AF, are the largest drivers of costs associated with the treatment of this arrhythmia, impair quality-of-life perception of patients, and may actually be viewed as a prognostically important event.

Dronedarone for therapy of AF

Dronedarone is a derivative of the amiodarone molecule, which was modified to eliminate the toxicity problems of this effective antiarrhythmic agent.¹³ The most important modifications were the removal of iodine, with the goal of eliminating iodine-related organ toxicity, and the addition of a methane sulphonyl group in order to decrease lipophilicity and thereby prevent tissue accumulation of the drug. Accordingly, the elimination half-life of dronedarone in humans is approximately 24–30 h. Dronedarone functions as a multichannel blocker, exhibits non-competitive antiadrenergic activity, and has calcium antagonist properties. In terms of electrophysiology, it blocks a series of potassium-mediated outward currents as well as inward currents mediated by sodium and calcium, resulting in prolongation of atrial and ventricular refractory periods. Taken together, the electrophysiological and pharmacokinetic features of the molecule suggest beneficial effects on sinus rhythm and ventricular rate, but a low propensity to cause proarrhythmia or organ toxicity.

Dronedarone has been subject to an extensive development program. Two pivotal efficacy studies were conducted, the EURIDIS (EURopean trial In atrial fibrillation of flutter patients receiving Dronedarone for the maintenance of Sinus rhythm) and ADONIS trials (American-Australian-African trial with DronedarONe In atrial fibrillation/flutter patients for the maintenance of Sinus rhythm).¹⁴ These identically designed trials enrolled 612 and 625 outpatients with paroxysmal or persistent AF or atrial flutter, respectively. Patients were randomized 2:1 to receive either dronedarone 400 mg bid (n = 828 pooling data from the two studies) or placebo (n = 409) for 12 months. The primary endpoint was the time to first recurrence of AF. Combining data for the two trials, the median time to the first episode of AF was 53 days in the placebo group, compared with 116 days in the dronedarone group (hazard ratio 0.75, 95% CI 0.65–0.87, p<0.0001). Similar results were obtained when the data for the two trials were analysed separately, with reductions in the risk of AF recurrence over 1 year by 29% (p = 0.0059) and 26% (p = 0.0244) in EURIDIS and ADONIS, respectively. The drug also significantly reduced ventricular rate during the first recurrence of AF/flutter. Mean heart rate was 102.3 bpm and 104.6 bpm in the dronedarone treatment arms compared with 117.5 bpm (p<0.0001) and 116.6 bpm (p<0.0009) in the placebo arms.

Dronedarone for prevention of cardiovascular hospitalization in patients with AF

In a retrospective analysis of the EURIDIS and ADONIS trials, it was found that patients assigned to receive active drug treatment had fewer hospitalizations for cardiovascular reasons than patients on placebo. This observation instigated a large outcome trial, the ATHENA study (A placebo controlled Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of CV Hospitalisations or death from any cause in patiENts with Atrial fibrillation/atrial flutter).² This multinational study recruited 4,628 patients with paroxysmal or persistent AF or flutter who were randomized in a 1:1 ratio to treatment with dronedarone 400 mg bid or placebo. The ATHENA trial is the first to use the novel primary endpoint of a composite of cardiovascular hospitalization and death. Among 2,301 patients randomized to dronedarone, primary outcome events occurred in 734 (31.9%) during a mean follow-up of 21 ± 5 months. Among 2,327 patients randomized to placebo, primary outcome events occurred in 917 (39.4%). The hazard ratio (HR) for the primary endpoint was 0.76 (95% CI 0.69–0.84, p<0.0001). There were 116 deaths (5.0%) in the dronedarone group and 139 (6.0%) in the placebo group (HR 0.84, 95% CI 0.66–1.08, p = 0.18). Among the deaths, there were 63 of cardiovascular origin (2.7%) in the dronedarone group and 90 (3.9%) in the placebo group (HR 0.71, 95% CI 0.51–0.98, p = 0.03), which was largely due to a reduction in arrhythmic death with dronedarone.

Figure 2 shows cumulative Kaplan–Meier event curves for the prespecified secondary outcome of time to first cardiovascular hospitalization. A total of 675 out of 2,301 dronedarone patients (29.3%) were hospitalized for cardiovascular events compared with 859/2,327 placebo patients (36.9%) (HR 0.74, 95% CI 0.67–0.82, p<0.0001). The majority of these hospitalizations were AF-related, but there were also significantly fewer hospital admissions for acute coronary syndromes in patients who were assigned to dronedarone. It is intriguing to see that more than one-third of patients receiving placebo medication had to be hospitalized during a mean follow-up period of 21 months. This number is very similar to those reported from recent administrative databases and surveys (see above). Table 3 depicts details of cardiovascular hospitalizations in ATHENA. Of note, total days in hospital were significantly reduced in the dronedarone group, and this reduction could be observed in terms of days in intensive or coronary care units as well as in days on regular wards. Thus, dronedarone represents the first antiarrhythmic drug for treatment of AF for which a significant and clinically important reduction in hard clinical outcomes, notably in hospitalization for cardiovascular events, was demonstrated.

More recently, however, there have been several post-marketing cases of hepatocellular liver injury and hepatic failure in patients receiving dronedarone, including two cases of acute hepatic failure requiring transplantation. The FDA has issued a “Dear Healthcare Provider” letter addressing the need for careful liver monitoring in patients receiving dronedarone. In contrast to this post-marketing reporting of liver function abnormalities, there has been no signal of liver toxicity in the entire dronedarone trial database. Importantly, liver function will be vigorously monitored in the large outcome trial of dronedarone that is currently being conducted in patients with permanent AF: the PALLAS trial (Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of standard therapy). This trial is a prospective, randomized, double-blind, parallel-group, international, multicenter trial designed to examine the effects of dronedarone compared with placebo in patients with permanent AF and additional risk factors for cardiovascular events. PALLAS will enroll 10,800 patients, and the results will provide additional information on potential liver injuries in patients receiving dronedarone.

Cardiovascular hospitalization rates with other antiarrhythmic drugs

To date, ATHENA is the only prospective trial that has used cardiovascular hospitalization as an important part of its composite primary study endpoint. Hence, there are no similar data for other antiarrhythmic drugs commonly used to treat AF. One of the most widely used drugs for maintenance of sinus rhythm in patients with AF is amiodarone. In this regard, it is superior to dronedarone, as shown in a randomized comparative study.¹⁵ Recently, Doyle and Ho¹⁶ have attempted to evaluate the efficacy of amiodarone, not only for achieving stable sinus rhythm but also for reducing mortality or hospitalizations in patients treated with this compound. They conducted a meta-analysis of 12 randomized controlled trials comprising 5,060 patients with persistent AF. Amiodarone was more effective than placebo or rate control drugs in achieving sinus rhythm. Despite this superiority, however, there was no reduction in mortality or in the need to hospitalize patients for cardiovascular events (Table 4). In addition, amiodarone had to be discontinued due to intolerable adverse effects in many patients, something which has been well known for decades. In summary, therefore, despite its ability to maintain sinus rhythm in many patients, use of amiodarone appears not to be associated with decreased hospitalization rates in contemporary controlled clinical trials.

Clinical implications

Innovative pharmacological therapy of AF is aiming at a reduction in clinically important clinical outcomes, notably in hospitalization for cardiovascular events. This paradigm shift away from electrocardiogram-related clinical endpoints (i.e. maintenance of sinus rhythm, control of ventricular rate) should ultimately result in better care of patients with this frequent arrhythmia. Similarly, future drug development has to take into account these considerations and the results of the ATHENA trial, which might serve as the prototype of AF trials of the future.

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