Goodbye to Electrical Cardioversion for Atrial Fibrillation?

David A Fitzmaurice

Br J Cardiol.  2008;15(6):281-2.  ©2008 Medinews (Cardiology) Limited

Posted 01/08/2009

The field of clinical medicine is littered with the bodies of sacred cows. Recent examples include the demise of vagotomy and pyloroplasty as a standard treatment for peptic ulcers and the absolute contraindication of beta blockers in the treatment of heart failure. I would like to suggest that the next sacred cow to be dispensed with is the routine use of electrical cardioversion in the treatment of atrial fibrillation, despite its inclusion as a therapeutic option in the National Institute for Health and Clinical Excellence (NICE) atrial fibrillation guidelines.^[1]

Direct electrical cardioversion has been a mainstay of therapy for the treatment of atrial fibrillation for many years. The theory underpinning its utilisation has some face validity, that by restoring sinus rhythm any problems associated with atrial fbrillation will be ameliorated. This, however, does not take into account the underlying cause of the arrhythmia, with the majority of atrial fbrillation caused by ischaemic heart disease. It is only relatively recently, however, that evidence for the ineffectiveness of cardioversion has begun to emerge. Paradoxically this evidence has derived from trials designed to prove the effectiveness of the procedure.

The Evidence

The utility of cardioversion was originally explored in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study,^[2] which recruited over 4,000 patients aged 65 and over with atrial fbrillation and one additional risk factor for stroke. Patients were randomised to either rhythm control, using electrical cardioversion and medication as necessary, or to rate control using drugs, such as beta blockers or digoxin. To the surprise of the investigators the primary outcome, mortality, was worse in the rhythm control group, as were secondary outcomes such as hospitalisation and serious arrhythmias. Importantly, oral anticoagulation could be stopped at the clinician's discretion following cardioversion.

The AFFIRM investigators conducted a post hoc on-treatment analysis that did show some survival advantage if sinus rhythm was maintained.^[3] The caveat to this was that use of anti-arrhythmic drugs was associated with increased mortality and, in fact, the main predictor of survival was use of warfarin. This left even the AFFIRM investigators to conclude that any advantage from maintaining sinus rhythm through use of anti-arrhythmic agents was offset by their toxicity.

Despite the fact that these findings have been repeated in further studies^[4,5] and the problems associated with ensuring adequate oral anticoagulation prior to undertaking the intervention, cardioversion has remained a common intervention in patients with atrial fibrillation, particularly if there is associated co-morbidity such as heart failure.

A recent paper also seems to lay this issue to rest. Roy and colleagues^[6] in trying to establish the efficacy of cardioversion for patients with atrial fibrillation and heart failure (defined as left ventricular ejection fraction of 35% or less, or symptoms of congestive heart failure) recruited 1,376 patients who were randomised to rhythm control, comprising cardioversion within six weeks of randomisation with additional cardioversions as necessary, or rate control with adjusted doses of beta blockers with digoxin. There was no significant difference in primary outcome of death from cardiovascular causes, nor any significant differences in secondary outcomes including death from any cause, stroke, or worsening heart failure. The authors concluded that "in patients with atrial fibrillation and congestive heart failure, a routine strategy of rhythm control does not reduce the rate of death from cardiovascular causes as compared with a rate-control strategy".

Where Does This Leave Us?

If cardioversion therefore has no place in the routine treatment of atrial fibrillation, nor in the treatment of high-risk patients, for example those with heart failure, where does this leave us? To my mind, cardioversion should no longer be offered routinely to patients with atrial fibrillation. The only clinical scenarios where it may be a useful intervention are for patients presenting acutely, within 24 hours of onset, or for patients who are very symptomatic despite medical therapy. Even in these instances, oral anticoagulation should be considered long term because of the high rate of recurrence

References

Fitzmaurice DA. The NICE guidelines on atrial fibrillation: a personal view. Br J Cardiol 2007;14:29-30. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-33. The AFFIRM investigators. Relationships between sinus rhythm, treatment and survival in the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. Circulation 2004;109:1509-13. Carlsson J, Miketic S, Windeler J et al. Randomized trial of rate-control versus rhythm control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690-6. Opolski G, Torbicki A, Kosior DA et al. Rate control vs rhythm control in patients with nonvalvular atrial fibrillation (HOT CAFE). Chest 2004;126:476-86. Roy D, Talajic M, Nattel S et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667-77.

New guidelines address arrhythmia risk of methadone

23 January 2009

MedWire News: US experts have issued recommendations for arrhythmia screening of patients on methadone treatment, aimed at reducing the incidence of QTc interval prolongation and torsade de pointes.

The guidelines were developed by a multidisciplinary panel of electrophysiologists, epidemiologists, and pain management and substance abuse specialists, headed by Mori Krantz (University of Colorado, Denver, USA). Their goal was to review evidence about adverse effects of methadone on the heart and to develop safety recommendations for doctors prescribing the drug.

They found strong evidence that both oral and intravenous methadone are associated with a dose-dependent increased risk for QTc interval prolongation and torsade de pointes. The incidence of these adverse events and the underlying mechanisms remain unclear.

Accordingly, the panel recommends that clinicians should inform patients of arrhythmia risk when prescribing methadone and ask patients about any history of heart disease, arrhythmia, and syncope.

Krantz et al say that all patients should undergo electrocardiogram (ECG) to measure the QTc interval before treatment, within 30 days of starting treatment, and annually thereafter. If the QTc interval is in the range 450–500 ms, patients should be monitored more frequently, and if it exceeds 500 ms, clinicians should consider discontinuing methadone, reducing the dose, eliminating contributing factors, or using an alternative therapy.

Clinicians should also be aware of interactions between methadone and other drugs that prolong the QT interval or slow methadone elimination.

Writing in the Annals of Internal Medicine, Krantz et al say they believe that increased clinical vigilance will reduce sudden cardiac death among patients receiving methadone in opioid treatment and for chronic pain.

“These recommendations may inform both the product labelling for methadone as well as practice standards for opioid treatment programs,” they add.

Ann Intern Med 2009; Advance online publication 

No Antiarrhythmic Protection With Fish Oil, New Meta-Analysis Shows

From Heartwire — a professional news service of WebMD

January 6, 2009 — Fish-oil supplementation is associated with a significant reduction in death from cardiac causes but has no significant effect on arrhythmias, a new meta-analysis has shown [1].

The analysis, driven primarily by the results of two large clinical trials, showed that fish oil was associated with a 20% reduction in the risk of cardiac death, report investigators. There were trends toward a reduction in the risk of appropriate implantable cardioverter defibrillator (ICD) interventions and a reduction in the risk of sudden cardiac death, but the results failed to achieve statistical significance.

"In light of currently available evidence, the role of fish oil in reducing arrhythmic events in people at risk still remains to be elucidated," write Dr Hernando León (University of Alberta, Edmonton) and colleagues in a report published online December 23, 2008, in BMJ.

In an editorial accompanying the study [2], Drs Eric Brunner (University College London, UK) and Hiroyasu Iso (Osaka University Graduate School of Medicine, Japan) note that the review does not provide answers to questions about the benefit of using fish oil in the secondary prevention of mortality and arrhythmias because little new high-quality evidence is available.

"The review highlights the neglect of an important area of research into nutrient health, and hopefully it will lead to increased investment in research to solve the uncertainty," they write. "Such research is needed not only because of the millions of people with heart disease worldwide, but also because the world's marine fauna is being pushed toward extinction largely for commercial gain, but partly in the name of public health."

Meta-Analysis Includes the JELIS Study

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione study was the first to suggest potential antiarrhythmic properties of fish oil when investigators randomized 11,324 patients to a mixture of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and showed significant reductions in all-cause and cardiovascular mortality, primarily driven by a reduction in sudden cardiac death.

In their meta-analysis, the investigators included 12 studies, including GISSI-Prevenzione and the Japan EPA Lipid Intervention Study (JELIS) studies, which accounted for 92% of the patients, where the primary outcomes of interest were antiarrhythmic end points of appropriate ICD intervention and sudden cardiac death.

In three studies evaluating the benefits of fish oil on ICD firing, there was a nonsignificant 10% reduction in appropriate interventions with treatment. In addition, in six studies with sudden cardiac death as an end point, there was only a trend toward a reduction in risk with fish oil. There was, however, a significant reduction in the risk of death from cardiac causes with fish oil. Again, only a trend toward a reduction in all-cause mortality was observed with the intervention.

Effect of Fish Oil on Arrhythmic Events and Mortality

End point	Patients, n	Odds ratio (95% CI)
Appropriate ICD intervention	1148	0.90 (0.55 - 1.46)
Sudden cardiac death	31,111	0.81 (0.52 - 1.25)
All-cause mortality	32,439	0.92 (0.82 - 1.03)
Death from cardiac causes	32,519	0.80 (0.69 - 0.92)
Sudden cardiac death in subjects with coronary artery disease	15,528	0.74 (0.59 - 0.92)
Death from cardiac causes in subjects with coronary artery disease	16,390	0.80 (0.69 - 0.93)

A subgroup analysis looking at patients with established coronary artery disease showed that fish oil reduced the risk of sudden cardiac death and death from cardiac causes when compared with placebo.

The meta-analysis included a variety of fish-oil products with various formulations, but the researchers did not observe a dose-response relationship between the dose of EPA or DHA and the effect on deaths from cardiac causes. "Therefore, an ideal formulation for fish-oil supplementation cannot be determined with the currently available evidence," according to León and colleagues. They suggest, however, it is reasonable to use a daily formulation similar to that used in the GISSI-Prevenzione trial, which was 465 mg EPA and 386 mg DHA.

In their editorial, Brunner and Iso note that the JELIS study showed a 20% reduction in the risk of nonfatal coronary outcomes, primarily driven by reductions in unstable angina, but fish oil had no effect on fatal outcomes.

"This evidence challenges the proposition, supported by the dramatic reduction in deaths from cardiac disease in a subgroup analysis of GISSI, that the effect of fish oil is mainly the result of electrical stabilization of the myocardium," they write.

The conflicting findings of GISSI and JELIS, however, might be explained by differences in DHA and EPA used in the trials, as well as the low rate of fatal coronary disease in Japan. JELIS, despite enrolling more than 18,000 patients, might have been underpowered to detect the effect of EPA on fatal end points, they note.

Both the editorialists and León and colleagues point out that more data are coming soon with the presentation and publication of the OMEGA trial. That trial includes approximately 4000 acute-myocardial infarction (MI) patients treated with highly purified omega-3 fatty-acid ethyl esters. The primary end point is the rate of sudden cardiac death within one year after acute MI, and secondary end points include total mortality, nonfatal cardiovascular events, and various rhythm abnormalities assessed by Holter monitoring.

Dr. León is a recipient of a research fellowship from the Alberta Heritage Foundation for Medical Research. Coauthor Ross T Tsuyuki is supported by the University of AlbertaMerck Frosst chair in patient health management. The other study authors have disclosed no relevant financial relationships.

Sources

1. León H, Shibata MC, Dorgan M, et al. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ. 2008;DOI:10.1136/bmj.a2931. Available at: http://www.bmj.com/cgi/content/full/337/dec23_2/a2931
2. Brunner E, Iso H. Fish oil and secondary prevention of cardiovascular disease. BMJ. 2008;DOI:10.1136/bmj.a2931. Available at: http://www.bmj.com

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Ablation superior to antiarrhythmic drugs in paroxysmal AF

MedWire News: The A4 trial, which demonstrates the superiority of catheter ablation over antiarrhythmic drug (AAD) therapy for atrial fibrillation (AF), has been hailed as a major step forward in understanding the relative efficacy and risks of these two treatment strategies. 

The Atrial Fibrillation versus Antiarrhythmic Drugs (A4) trial was an international randomized controlled multicenter study that compared catheter ablation with continued AAD therapy in patients with documented paroxysmal AF.

The study’s preliminary results were presented in May 2006 at the Heart Rhythm Society’s Annual Scientific Sessions and the full study report is published this week in the journal Circulation.

The trial enrolled 112 patients with paroxysmal AF who had previously failed at least one AAD. They were randomized to undergo catheter ablation (pulmonary vein isolation with additional extrapulmonary vein lesions where necessary) or to receive “new” AADs alone or in combination.

At 1 year, 89% of patients in the ablation group were free of AF recurrences compared with just 23% of those in the AAD group, a highly significant difference (p<0.0001). Symptom scores, exercise capacity, and quality-of-life scores were also significantly higher in the ablation group.

These differences “constitute an important benefit that may support earlier use of catheter ablation in this context,” Pierre Jaïs (Hôpital Cardiologique du Haut-Lévêque, Bordeaux-Pessac, France) and study co-authors remark.

In an accompanying editorial, David Callans (University of Pennsylvania, Philadelphia, USA) said that the A4 investigators should be congratulated for their “important contribution” to the body of research into AF treatment. He said it is now “unquestionable” that ablation is more effective than AADs, “at least in young mostly healthy patients and when performed by highly skilled practitioners.”

Important questions remain, however. These include the relative merits of ablation and AADs in patients with longstanding persistent AF and/or comorbidities; the impact of ablation on AF-associated thromboembolism and mortality; and the long-term effect of ablation on left atrial remodeling and function.

Callans concluded: “Novel ideas for increased cooperation, not to mention funding, will be required to answer questions of this magnitude, particularly because these questions develop slowly, over the course of a human lifetime.”

Ventricular arrhythmias herald poor outcomes in ACS patients

MedWire News: Ventricular arrhythmias (VA) in patients hospitalized with acute coronary syndromes (ACS) have become less common in recent years but remain a strong predictor of increased mortality, research shows. 

The finding is based on an analysis of 52,380 patients with ACS enrolled in the Global Registry of Acute Coronary Events between 1999 and 2005.

Álvaro Avezum (University of São Paolo, Brazil) and colleagues found that the incidence of in-hospital VA fell steadily over time, from 8.0% in 1999 to 7.0% in 2002 and 5.8% in 2005 (p<0.001). The decrease was driven by a decline in the incidence of ventricular fibrillation/cardiac arrest, whereas the incidence of ventricular tachycardia showed little change over time.

VA was associated with an extremely high risk for death, the authors report. In-hospital case-fatality rates were 52% among patients with VA versus 1.6% in those without (odds ratio [OR] 46.4). The increased mortality risk persisted at 6 months after discharge, although with a reduced OR of 1.32.

In multivariable analysis, ST-segment deviation, Killip class, age, initial cardiac markers, serum creatinine, heart rate, and smoking history were all associated with an increased the risk for VA, whereas prior myocardial infarction and percutaneous coronary intervention were associated with a reduced risk.

Writing in the American Journal of Cardiology, Avezum and fellow investigators note that ACS patients with in-hospital VA had a higher-risk profile than those without, suggesting that such patients might be targeted for preventive measures.

They hypothesize that VA during the first days of hospitalization for ACS may be related to “electrical irritability” associated with ischemic injury, and conclude: “Therapies that prevent the development of this arrhythmogenic substrate by improving left ventricular function should be considered in this clinical setting.”

BRUGADA SYNDROME GENDER INFLUENCE ON ECG AND TESTOSTERONE LEVELS

The clinical Brugada phenotype is 9 times more prevalent in males than in females in patients with Brugada syndrome (BrS). BrS has been reported to be thinner than asymptomatic normal controls. Higher testosterone level associated with lower visceral fat may have a significant role in the Brugada phenotype and male predominance in BrS (1).

Brugada-like ECG confers a higher risk of prostate cancer independent of age, smoking habit, and radiation exposure. Men with a Brugada-like ECG should be regularly examined for prostate cancer and vice versa, especially elderly subjects (2).

In contrast to men, most women with BrS and resuscitated SCD or appropriate ICD shock do not have a spontaneous type-1 ECG pattern. Additionally, the degree of ST elevation is less pronounced in women than men. The predominance of the Brugada ECG phenotype in males is a result of the presence of a more prominent I(to) in males versus females(3). The presence of a more prominent Ito-mediated notch in the Epi of males predisposes males to the development of the Brugada phenotype and that a smaller Epi notch in females relegates them to development of progressive conduction problems under conditions in which inward currents are compromised(4).

While women represent a lower-risk group overall, risk factors established from a predominantly male population may not be helpful in identifying high-risk females (5). Cardiac autonomic neuropathy is an important risk indicator in BrS. Cardiac autonomic neuropathy is more common in men. Male gender, per se, is not an independent risk factor for development of ventricular arrhythmia but also cardiac autonomic neuropathy, which is an important risk factor in BrS, is more common in men; therefore men are susceptible to the development of cardiac events(6).

A history of syncope or SCD, the presence of a spontaneous Type 1Brugada ECG, and male gender predict a more malignant natural history (7).

Men have a higher prevalence of early repolarization variant, AV block, carotid sinus syndrome, atrial fibrillation, supraventricular tachycardia due to accessory pathways, Wolff-Parkinson-White syndrome, reentrant ventricular tachycardia, ventricular fibrillation and sudden death, and the BrS.

The P-wave and P-R intervals are slightly longer in men than in women.  On the other hand, women have a higher mean resting heart rate, a longer QT interval, a shorter QRS duration, and a lower QRS voltage than men. Women have a higher prevalence of sick sinus syndrome, inappropriate sinus tachycardia, atrioventricular nodal reentry tachycardia, idiopathic right ventricular tachycardia, and arrhythmic events in the long-QT syndrome (8). Women have higher resting heart rates than do men, but a longer rate-corrected QT_C interval. Women with the LQT1 and LQT2 variants of congenital long-QT syndrome (LQTS) are at greater risk of adverse cardiac events. Similarly, many drugs associated with acquired LQTS have a greater risk of inducing torsades de pointes (TdP) arrhythmia in women than in men (9). The larger dispersion of I(Na) amplitude within the female cardiac ventricle may contribute to the higher risk of arrhythmias in this gender. By decreasing the transmural dispersion of I(Na), testosterone may exert a protective effect against LQTS-related arrhythmias in males(10).

 

References

 

1)     Shimizu W, Matsuo K, Kokubo Y, et al. Sex hormone and gender difference--role of testosterone on male predominance in Brugada syndrome. J Cardiovasc Electrophysiol. 2007; 18: 415-421.

2)      Haruta D, Matsuo K, Ichimaru S, Soda M, Hida A, Sera N, Imaizumi M, Nakashima E, Seto S, Akahoshi M. Men With Brugada-Like Electrocardiogram Have Higher Risk of Prostate Cancer. Circ J. 2008 Nov 29. [Epub ahead of print]

3)     Di Diego JM, Cordeiro JM, Goodrow RJ, et al. Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation. 2002; 106: 2004-2011.

4)     Fish JM, Antzelevitch C.Cellular and ionic basis for the sex-related difference in the manifestation of the Brugada syndrome and progressive conduction disease phenotypes. J Electrocardiol. 2003; 36 Suppl: 173-179.

5)     Sacher F, Meregalli P, Veltmann C,Are Women with Severely Symptomatic Brugada Syndrome Different from Men? J Cardiovasc Electrophysiol. 2008 Jun 12. [Epub ahead of print]

6)     Bigi MA, Aslani A, Aslani A.Significance of cardiac autonomic neuropathy in risk stratification of Brugada syndrome. Europace. 2008; 10:821-824.

7)     Gehi AK, Duong TD, Metz LD, et al.Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol. 2006; 17: 577-583.

8)     Bernal O, Moro C. Cardiac arrhythmias in women Rev Esp Cardiol. 2006; 59: 609-618.

9)     James AF, Choisy SC, Hancox JC.Recent advances in understanding sex differences in cardiac repolarization. Prog Biophys Mol Biol. 2007; 94: 265-319.

10) Barajas-Martinez H, Haufe V, Chamberland C, et  al.Larger dispersion of INa in female dog ventricle as a mechanism for gender-specific incidence of cardiac arrhythmias. Cardiovasc Res. 2008 Oct 16. [Epub ahead of print]

Linear lesions needed for successful AF ablation

MedWire News: Left atrial (LA) linear lesions are nearly always necessary for successful catheter ablation of atrial fibrillation (AF), French researchers have demonstrated.

Their study found that although persistent AF could be terminated without LA linear lesions, most patients require such lesions to prevent the later development of macro re-entrant atrial tachycardia.

A team led by Sébastien Knecht (Université Victor Segalen Bordeaux II) retrospectively studied 180 patients with persistent AF who had undergone catheter ablation.
AF was successfully terminated in 154 patients, report Knecht et al in the European Heart Journal. Of these, 69 had required both LA linear lesions (ie, the roofline and the mitral isthmus line) to terminate AF whereas 85 had not.

Patients who required linear lesions had a longer duration of AF (9 vs 12 months), but otherwise the two groups were similar with regard to clinical and echocardiographic characteristics.

After 28 months of follow-up, however, the incidence of LA macro re-entrant atrial tachycardia was significantly higher among patients who had not required LA lesions than those who had, at 78% versus 33% (p=0.002).

And the vast majority of patients ultimately required a roof line and/or a mitral line in order to remain in sinus rhythm.

“This study highlights that although pulmonary vein isolation and electrogram-based ablation without linear lesions are effective for terminating persistent AF in a significant number of patients, macro re-entrant AT requiring LA linear ablation is very likely to occur during the overall follow-up period,” Knecht and co-authors conclude.

In a related editorial, Thomas Rostock and Stephan Willems from University Hospital Eppendorf in Germany said it remains unclear whether the atrial tachycardias are a cause or a consequence of AF; nevertheless they added: “It has become clearer that LA linear ablation remains an imperative step on the road to sinus rhythm in patients with chronic AF.”

Eur Heart J 2008; 29: 2359–2366