Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE - 81st Scientific Sessions of the American Heart Association

New Orleans, Louisiana / November 9-12, 2008

Reviewed and edited by:

Paul Dorian, MD

Professor of Medicine, Division of Cardiology, St. Michael’s Hospital, Toronto, Ontario

The morbidity and mortality associated with atrial fibrillation (AF) is both substantial and costly. As discussed by Dr. Kenneth Ellenbogen, Professor of Cardiology and Director, Cardiac Electrophysiology, Virginia Commonwealth University Health System, Richmond, there is a twofold increase in cardiac mortality among patients with AF. Even when adjusted for stroke, AF still reduces survival odds across many patient groups. Furthermore, up to 50% of patients with systolic or diastolic heart failure develop AF. In one study cited by Dr. Ellenbogen, patients with a low ejection fraction (EF) and AF had a striking 40% risk of cardiovascular (CV) death or hospitalization at three years’ follow-up.

EPIDEMIOLOGY AND AF MANAGEMENT

The CHARM (Candesartan in Heart Failure–Assessment of Reduction in Mortality and Morbidity) study also demonstrated that AF at baseline was a marker for worse outcomes whether patients with heart failure had a low or a preserved EF at baseline. But the most worrying and costly of AF-related complications is the risk of thromboembolism. It is common knowledge that AF is a major cause of stroke among the elderly, increasing stroke risk by at least fivefold. Both the severity of the stroke and related mortality are worse if patients have AF than if they do not. Even in patients who do not know they are in AF, stroke risk persists. Indeed, it has been estimated that between 15% and 20% of strokes are related to AF, at an estimated cost of $10 to $13 billion a year in the US (2008 US dollars).

A cornerstone of AF management is to make sure patients are stratified for stroke risk through the use of the CHADS₂ score—i.e. congestive heart failure (1 point), hypertension (1 point), age <u>></u>75 years (1 point), diabetes (1 point), prior stroke/transient ischemic attack (2 points)—and receive anticoagulation when appropriate, as Dr. Ellenbogen emphasized. If rated as a low risk on the CHADS₂ score, ASA should be used to reduce stroke risk; if patients are at high risk, they require anticoagulation with warfarin.

Treatment of AF should be individualized according to current guidelines. Unfortunately, we all know how difficult it is to restore and maintain sinus rhythm in patients with AF, which is why rate control often becomes the default treatment option. When even rate control cannot be achieved pharmacologically, or if patients experience intolerable side effects to recommended anti-arrhythmic agents, guidelines indicate that catheter ablation may be considered, although it should not be considered as first-line therapy except in rare situations. Guidelines also indicate that catheter ablation may be indicated for select symptomatic patients with AF and heart failure or reduced EF.

AF-CHF MAINTENANCE OF SINUS RHYTHM SUBSTUDY

Even though maintenance of sinus rhythm is a desirable treatment goal in AF, results from a substudy presented here by Dr. Mario Talajic, Professor of Medicine, Université de Montréal, and Montreal Heart Institute, Quebec, indicate that achieving this goal does not improve survival odds in heart failure patients with AF. In the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) trial, 1376 patients with heart failure, mean EF of 27% and AF were randomized to either rhythm control strategies or rate control agents. The primary analysis failed to show a difference between death from CV causes—the primary end point of AF-CHF—in either of the two treatment arms: 27% in the rhythm control arm vs. 25% in the rate control arm at a median follow-up of 37 months.

However, as Dr. Talajic pointed out, 15% of the study cohort crossed over from one treatment arm to the alternative arm. AF also recurred in many patients in the rhythm control arm while not all patients remained in AF in the rate control arm. Thus, investigators explored the relationship between sinus rhythm and survival in an on-treatment analysis limited to those patients who did not cross over to the alternative arm.

The primary end point was very similar between the two arms, occurring in 24.9% of patients randomized to rhythm control and 28.4% for those on rate control. The median time spent in sinus rhythm during the trial was 61% and the distribution was bimodal where a large number of patients spent 81% to 100% of the time in sinus rhythm, while considerable numbers also spent very little time in sinus rhythm.

Comparing the incidence of CV death between the high vs. the low percentage of time in the sinus rhythm groups, there was again no significant difference between the arms, the primary end point occurring in 25% of patients in each group. The only positive finding from the AF-CHF study was that the use of warfarin was associated with improved survival.

ATHENA STUDY

The main results of the ATHENA study were reported at the Heart Rhythm Society meeting in May 2008. At the recent annual meeting of the American Heart Association, further analyses of the ATHENA trial, which is the largest study ever involving patients with AF and atrial flutter were presented by Dr. Robert Page, University of Washington, Seattle. ATHENA randomized 2301 patients to dronedarone 400 mg b.i.d. and another 2327 to placebo. All had a history of AF, although only 25% of the cohort were in AF at baseline. They also had to be aged <u>></u>75, or <u>></u>70 years of age and have one or more of the following risk factors: hypertension, diabetes, a prior stroke or TIA, left atrial dimension >50 mm or an EF <40%. Twenty-one per cent of the cohort were also in NYHA II/III heart failure at baseline and 82% of them were already receiving a rate control agent.

Patients were followed for a minimum of 12 months and a mean 21 months. With the primary end point being a composite of CV hospitalization or all-cause death, there was a 24% relative risk reduction in the primary end point in favour of dronedarone (P<0.001). Treatment-emergent side effects were similar in the two arms, with a slight increase in serum creatinine in the dronedarone arm—a tubular secretion issue, Dr. Page noted, rather than a change in glomerular filtration rate.

In a new analysis of the rhythm effects of active therapy vs. placebo presented here, there was a 25% reduction in “AF at any time” during the trial among patients who were in sinus rhythm at baseline. Time to first recurrence in the same group of patients was 498 days in the placebo arm vs. 737 days for the dronedarone arm. All cardioversions were prospectively documented in patients with AF present at each ECG recording, the so-called “permanent AF” group. In this group, there was a clear reduction in patients receiving cardioversion from 33% of placebo controls to 27% of those receiving dronedarone (P=0.01). “Permanent” AF may not be that permanent, Dr. Page indicated, as the incidence of permanent AF throughout the trial was 12.7% in the placebo arm vs. 7.7% in the dronedarone arm, suggesting that fewer patients on treatment remained in permanent AF throughout the study (P<0.001).

Regarding the effect of active therapy on heart rate, investigators also found that the mean heart rate at 87 bpm in the placebo arm was significantly higher than the mean heart rate of 78 bpm in the active treatment arm (P<0.001). While the numbers were small, patients who did not benefit from conversion or maintenance of sinus rhythm in ATHENA still trended towards a reduction in CV hospitalizations and all-cause mortality, despite the fact that they were in AF throughout the study. As Dr. Page observed, this new analysis suggests that outcomes in ATHENA may not be purely related to rhythm status but rather to other effects from the agent.

In a separate analysis of hospitalization rates and reasons for them in ATHENA, other interesting properties of this multi-channel blocker emerged. On behalf of the ATHENA steering committee, Dr. Christian Torp-Pedersen, Professor of Internal Medicine, University of Copenhagen, Denmark, showed that active therapy increased the time to first CV hospitalization for any reason by 25% relative to placebo (P<0.001). As expected, a major proportion of the hospitalizations in ATHENA were related to AF—510 in the placebo group vs. 335 in the dronedarone group for a 27% relative risk reduction (P<0.001) in favour of active therapy. Numerically, hospitalizations for heart failure were lower in the active therapy arm: 132 placebo patients vs. 112 patients in the active treatment arm, as were hospitalizations for acute coronary syndromes at 89 patients vs. 62 patients for placebo vs. active therapy, respectively.

Analysis of the total number of days spent in hospital due to CV causes also showed that patients on active treatment had 35% fewer total hospital days (P<0.001); 47% fewer CCU/ICU days (P=0.015); 45% fewer days in medium care (P<0.001); and 30% fewer days in ward care (P<0.001) compared with placebo. In fact, for every 1000 patients treated with dronedarone for one year, this particular analysis indicated that the healthcare system would save 1020 CV hospital days.

The novel agent had no effect on non-CV hospitalization rates, which is important to note, as side effects from active therapy obviously did not cause an increase in CV hospitalization rates. As Dr. Torp-Pedersen reminded delegates, anti-arrhythmic therapy in the AFFIRM trial, largely amiodarone, did not decrease hospitalization rates relative to rates in the alternative arm. Thus, any hospitalization benefit seen in this particular analysis of ATHENA was in addition to the mortality benefit demonstrated in the study, the first such trial to show that clinical outcomes in AF are improved with anti-arrhythmic therapy.

ION CHANNEL BLOCKADE

If dronedarone is showing promise as a new anti-arrhythmic agent for AF and atrial flutter, it is not the only agent that may make a difference to patient outcome. As discussed by Dr. Peter Kowey, Professor of Medicine and Clinical Pharmacology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, vernakalant, a unique ion channel-blocking agent, has rate-dependant inhibitory action on conduction and atrial-selective prolongation. It has previously been tested in several studies for the acute termination of AF after intravenous administration.

Recent studies indicate that it has no adverse hemodynamic effects and at 500 mg b.i.d., oral vernakalant significantly prolonged time to recurrence of AF while over half of the cohort achieved sinus rhythm. Data is also currently being generated in preclinical models of gap junction modulators, which are hypothesized to restore intercellular conduction in pathologic states, thereby conferring anti-arrhythmic effects.

OTHER AF TREATMENT STRATEGIES

Prevention of either primary AF or its recurrence is clearly ideal. A review of some of the literature by Dr. Carl Pepine, Professor of Medicine, University of Florida College of Medicine, Gainesville, indicated that 50% of the Framingham cohort who developed AF had a history of hypertension, suggesting that optimal control of blood pressure may reduce the risk of developing AF. A series of studies of inhibitors of the renin-angiotensin system all demonstrate that ACE inhibitors and the angiotensin-II receptor blockers prevent the development of AF in a wide variety of patient populations, although a study by Maggioni et al. presented at the 2008 AHA meeting showed that high doses of valsartan did not prevent the recurrence of AF in the GISSI/AF patient population.

Similarly, the statins appeared to prevent either the first episode of AF or its recurrence, according to a series of other studies. Whether omega-3 fatty acids can prevent AF is still uncertain, with some studies showing a benefit while others have not. What does appear to help reduce the incidence of AF is regular, light-to-moderate activity, Dr. Pepine indicated, yet another strong impetus for clinicians to counsel patients on the benefits of regular physical activity to maintain CV health.

SUMMARY

AF is the most common sustained cardiac arrhythmia seen in cardiology today and is associated with significant morbidity, mortality and cost to society. To date, anti-arrhythmic therapy has been less than ideal, often proving inadequate for maintenance of sinus rhythm. Further analyses of a new multi-channel blocker suggest that the clinical course of AF may be altered with timely intervention, the first anti-arrhythmic shown to improve hard clinical end points and as such, would make a welcome addition to the AF armamentarium.

Note: At press time, dronedarone is not available in Canada.