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 - Based on presentations during the 61st Annual Meeting of the Canadian Cardiovascular Congress

Toronto, Ontario / October 25-29, 2008

Reviewed and edited by:

Denis Roy, MD

Montreal Heart Institute, Professor and Chair, Department of Medicine, Université de Montréal, Montreal, Quebec

Atrial fibrillation (AF) may emerge at any point along the cardiovascular (CV) continuum, including in the setting of hypertension, following a myocardial infarction (MI), during the remodelling process after an MI and very often in the setting of congestive heart failure. One of the main consequences with AF is that it causes stroke, observed Dr. Malcolm Arnold, Professor of Medicine, Physiology and Pharmacology, University of Western Ontario, London. Indeed, it is estimated that one-quarter of all strokes in the elderly are caused by AF which translates into over 70,000 strokes each year in the US.

Warfarin reduces stroke risk by about two-thirds vs. no anticoagulation therapy (ASA less so), but like ASA, it is associated with increased bleeding risk, especially in an elderly population, and there is about a 20% discontinuation rate due to adverse events following initiation of warfarin. Thus, the risks associated with AF are due not only to the arrhythmia itself but also to how this patient population is treated, Dr. Arnold noted.

Regardless of where on the spectrum of CV disease AF emerges, it increases morbidity and mortality risk. In the LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) study, which evaluated losartan in a hypertensive population with left ventricular hypertrophy, those who had concomitant AF were at significantly greater risk of all-cause mortality, CV mortality, sudden cardiac death and stroke-related death than those without AF. Patients with hypertrophic cardiomyopathy who develop AF are also significantly less likely to survive over a 10-year follow-up compared with those who do not. Twenty per cent of patients with heart failure are at risk for AF over approximately four years and the presence of AF increases mortality risk in both men and women.

As Dr. Arnold also noted, there is also a specific situation where if AF with a rapid ventricular rate is left untreated or unrecognized, it can directly induce a cardiomyopathy in what was believed to be a previously normal heart. It has also been suggested that a cardiomyopathy like this could be caused by a tachycardia of more than 110 bpm that occurs only 10% to 15% of the time, a fairly significant observation. Moreover, heart failure with preserved left ventricular ejection fraction (LVEF) is as common as systolic heart failure, if not more common in the elderly, and is just as likely to lead to hospitalization as heart failure with reduced EF. Treatment of heart failure with reduced systolic function has led to better outcomes, Dr. Arnold noted, but the same cannot be said for heart failure with preserved systolic function, where outcomes have remained relatively unchanged. Patients with preserved LVEF are also still at considerably higher risk to develop AF than those whose systolic function is reduced.

All of this suggests that the diagnosis of AF carries a substantial burden of morbidity and mortality, as Dr. Arnold concluded, with its attendant cost to the healthcare system as well as to the individual well-being of patients.

AF Burden vs. Patient Well-Being

Outcomes from even the best clinical trials in AF are typically reported in terms of electrocardiographic (ECG) data including time to first recurrence of AF, frequency and duration of AF, and other measures of the “AF burden.” But as Dr. Paul Dorian, Professor of Medicine, University of Toronto, Ontario, postulated, these “evidence-based” end points have relatively little to do with how they affect patients who are experiencing AF. Many episodes of AF are not symptomatic, he pointed out, but even if they are, many of them are minimally symptomatic.

This suggests that measuring “AF burden” does not accurately reflect either the extent of the disability AF imposes on patients or on their quality of life. As importantly, if physicians treat AF with a medication that reduces the ECG diagnosis of AF but which makes patients feel worse, treatment can hardly be considered effective. Thus, Dr. Dorian argued, a “patient-centred” approach that takes into account not only how patients feel but the effect that both the rhythm disturbance and treatment is having on their quality of life are important outcome measures which physicians need to keep in mind when treating AF patients.

As Dr. Dorian reminded delegates, whether causal or correlated, patients with AF tend to experience more heart failure than those without AF; they tend to be hospitalized more because of AF or other CV causes; they have more strokes and transient ischemic attacks than those without AF; and they have higher mortality rates than patients without AF. He also pointed out that patient response to a given anti-arrhythmic agent is also not the same as an ECG response.

In an initiative undertaken by the Canadian Cardiovascular Society, rhythm disturbance experts developed the Severity of Atrial Fibrillation (SAF) Scale, which is a simplified scale that allows practitioners to measure quality of life, well-being and AEs from therapy in patients with AF. Studies validating this scale indicate that there is no relationship between the frequency and the duration of AF episodes and patient perception of the impact of the rhythm disturbance on their well-being and quality of life. Stroke risk is also not determined by the presence or absence of AF nor by the amount of AF that may be present, Dr. Dorian emphasized.

Therefore, particularly from a patient’s perspective but also for the treating practitioner, patient well-being and quality of life as well as objective measures of morbidity and mortality should be the only outcomes considered in the evaluation of anti-arrhythmic medications, Dr. Dorian concluded.

AF-CHF Trial

Given the frequent concurrence of AF and heart failure, investigators sought to determine whether prevention of AF in patients with heart failure improves prognosis of or indeed reduces heart failure. This was addressed in the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) trial, a hard end point multicentre, international trial designed to compare maintenance of sinus rhythm (rhythm control) with control of ventricular rate (rate control) in patients with a LVEF of 35% or less, symptomatic heart failure and a history of recent AF. Most of the 1376 patients enrolled in the trial were in NYHA class III-IV, with a mean LVEF of 27%.

A total of 682 patients were randomized to rhythm control while 694 were assigned to rate control. Sinus rhythm was documented at repeated assessments in 75% to 80% of patients in the rhythm-control arm, while target heart rates were achieved in 82% to 88% of patients in the rate-control arm. Some 82% of patients in the rhythm-control arm were on amiodarone.

At four months, the prevalence of AF decreased from 54% at baseline in the rhythm-control group to 17%. At a mean follow-up of 37 months, death rates from CV causes—the primary end point of the study—were almost identical in the two arms: 27% of patients in the rhythm-control arm died from CV causes vs. 25% in the rate-control arm (P=0.59). Total mortality (at approximately 33% in both groups) and the risk of stroke—as well as worsening heart failure—were also similar between the two groups. The number of patients who required hospitalization at one year of follow-up was higher (46%) in the rhythm-control arm than in the rate-control arm (39%; P=0.057).

Researchers concluded that the findings from this study indicate that rate-control strategies should be considered initially for patients with AF and heart failure and if symptoms persist, rhythm control may be considered. Proponents of catheter ablation should wait until a large randomized study demonstrates its benefit in this group of patients.

ATHENA Trial

Results from ATHENA (The Trial to Assess the Efficacy of Dronedarone 400 mg b.i.d. for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with AF or Atrial Flutter) were discussed by Dr. Stuart J. Connolly, Director, Division of Cardiology and Professor of Medicine, McMaster University, Hamilton, Ontario. ATHENA was not actually the first study to evaluate dronedarone, a multi-channel anti-arrhythmic modelled after amiodarone but minus the iodine molecule. Two earlier trials, EURIDIS and ADONIS, both showed that the time to first recurrence of AF or flutter was significantly longer in patients who received dronedarone 400 mg b.i.d. than for placebo controls. It also reduced symptomatic and asymptomatic recurrences of AF and it had rate-controlling properties similar to those seen with amiodarone as well. However, in another trial (ANDROMEDA), when investigators gave dronedarone to patients with severe heart failure, safety issues emerged.

In an attempt to resolve these issues, ATHENA enrolled 4628 patients with documented AF or atrial flutter in the six months prior to enrolment. ATHENA participants also had to have an additional risk factor, such as hypertension, diabetes, prior stroke/TIA, LVEF <u><</u>40% or enlarged left atrium. Follow-up was a minimum of 12 months and up to 30 months for some participants. Approximately 20% of patients in both arms had a history of heart failure (class II-III) but only 4% of patients in either arm had an LVEF <35%.

Importantly, ATHENA was not designed to study AF recurrence, as both EURIDIS and ADONIS were, but rather hard clinical end points, including CV hospitalization or death from any cause, the primary end point. At follow-up, there was a 24% reduction in the primary end point in patients who received dronedarone 400 mg b.i.d. compared with placebo, which was highly significant (P<0.001). There was also a 29% reduction in CV death (P=0.034) in the dronedarone arm.

There was also a 45% reduction in the risk of arrhythmic death, from a total of 48 deaths in placebo patients vs. 26 deaths in dronedarone patients. Hospitalizations for acute coronary syndrome were reduced by 30% in the dronedarone arm (P=0.03)—indeed, the first time that an anti-arrhythmic has been shown to reduce the incidence of coronary events in patients with AF or atrial flutter. Stroke was not a prespecified outcome in ATHENA but notably, active therapy reduced stroke risk by 34% relative to placebo. Interestingly, it reduced stroke risk for patients both on antithrombotic therapy—the majority of patients in this trial—and those who were not.

Conversely, serious treatment-emergent adverse events were reported in 21% of placebo controls vs. 20% of those in the dronedarone arm. Unlike amiodarone, there was no signal that this particular multi-channel blocker was associated with any respiratory issues, nor did it appear to affect thyroid function or tremor. There was a slight increase in rash and gastrointestinal discomfort in the active therapy group vs. placebo.

Dronedarone does increase serum creatinine in some patients but it does so by means of a reversible effect on the tubular secretion rather than on glomerular filtration.

SUMMARY

Patient well-being and quality of life are important goals in the management of AF but so, too, is a reduction in morbid events. Until now, no anti-arrhythmic agent used for the treatment of AF affected outcomes. Dronedarone may allow the real benefits of AF suppression to be revealed, leading to a reduction in hard clinical end points for the first time in AF anti-arrhythmic drug trials. In the likely event that the new multi-channel blocking agent is approved, practitioners can look forward to influencing important clinical parameters for their patients with AF without negatively affecting well-being, perhaps the most important outcome for our patients.

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