7 March 2009

Torsade rare in guideline-treated cases: routine ECG not appropriate.

First Do No Harm ... Reduction? Annals of Internal Medicine 2009 150;6 (Annals on line, pre-publication March 17) Gourevitch MN. http://www.annals.org/cgi/content/full/0000605-200903170-00111v1

Dear Colleagues,

With this stentorian editorial Annals of Internal Medicine finally puts the cardiac health of methadone treatment into its correct perspective. Dr Marc Gourevitch questions the utility of routine ECGs to detect or prevent such side effects, countering Krantz and colleagues (Ref 1) who have an article in this issue recommending routine electrocardiography before and during treatment - claiming some sort of professional consensus. In 2006 Krantz had written: “Although QT prolongation associated with higher doses of methadone is an important safety concern, we do not believe that routine ECG screening is warranted for heroin addicts entering treatment” (Ref 2). As Gourevitch points out, no new evidence is presented in this paper to justify a reversal of this widely held view - in fact four important papers are simply omitted by Krantz et al (Ref 3-6). Each of these is reassuring in that torsade is rare and largely occurs in extraordinary clinical circumstances.

After initial pre-publication on Annals-on-line in December 2008, the article by Krantz et al was withdrawn, only to reappear without CSAT endorsement in its title. After originally declaring: “Potential financial conflicts of interest: None declared” fully three primary authors and one panel member subsequently made specific declarations including funding from Reckitt Benckiser, the manufacturer of buprenorphine. All of this should be of some embarrassment to Krantz et al, the Annals editors (they even wrote a rapid response themselves!) and members of an expert panel convened by CSAT, chaired by veteran Dr Barry Stimmel of Mt Sinai Medical School in Manhattan. Two of the panel members declined to be acknowledged in the final version of the paper. It is gratifying that the controversial recommendations in this paper have been countered by an expert editorial by Dr Gourevitch from NYU.

Some major flaws in Krantz’s paper are pointed out. Regarding routine cardiographs before and during treatment, Gourevitch writes: “Unfortunately, this suggested guideline ventures well beyond the evidence presented.” He examines each aspect of Krantz’s ‘case’ for the dangers of QT prolongation and torsade de pointes and the panel’s ‘consensus’ strategy for prevention. We are even told that mandated cardiographs may cause more harm than good, like many other well-intentioned guidelines (ref 7).

Some of the questions raised by Gourevitch are so fundamental that they should have been asked long before in the peer review process or the ‘expert panel’ deliberations. He seems surprised that the panel members were able to (1) discuss 95 detailed references, (2) confer about torsade risk and (3) develop a 5 point plan to address this purported risk in only 2 days at a ‘consensus’ meeting.

Dr Gourevitch implies that ECG testing should be done on those at high risk since overall the rate of torsade is low and cardiac dangers “typically occur in those who receive exceptionally high doses of methadone or who have other risk factors.” [Krantz writes 'relatively high doses' describing an average of 397mg daily.] He also points out that the time frame of ECGs in the article’s recommendations is arbitrary, and there equally seems no rationale behind the 100mg dose level above which the authors say more frequent supervision is needed.

The author points out that the delays involved in getting pre-treatment testing done in this brittle population will inevitably cause some early drop-outs. Further, since torasde is so rare, this could never be balanced by benefits for those remaining in treatment.

The subject of supposed cardiac toxicity from methadone maintenance treatment has taken on a life of its own well beyond the evidence. The contention by Krantz that cardiac safety in methadone maintenance patients is a ‘national priority’ is an overstatement (Ref 8). Those suggesting this have not even determined an approximate incidence (and it may be zero in addiction clinic patients). Amongst ~70 reported cases of torsade, nearly all in older or complex addiction cases, I could only find one which was fatal (a 47 year old female who reportedly also had a myocardial infarction).

This discussion should not allow clinicians to be distracted from the major problems facing our field, notably the hepatitis C epidemic. The overwhelming statistics on this subject put the above minutiae into stark perspective.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/#news


1. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6: (March 17 issue) http://www.annals.org/cgi/content/full/0000605-200903170-00103v1
2. Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557
3. Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006;101:1333-1338
4. Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1
5. Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5
6. Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552
7. Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet. 2002 359:881-4
8. Krantz MJ. Heterogeneous Impact of Methadone on the QTc Interval: What Are the Practical Implications? Journal of Addictive Diseases 2008 27;4:5-9