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.”