No Evidence to Support QTc-Interval Screening in Methadone Maintenance Treatment: Cochrane Review

EKG“Methadone represents today the gold standard of efficacy for the pharmacological treatment of opioid dependence,” states the newly published (June 20) Cochrane Review on QTc interval screening for cardiac risk in methadone treatment. The review goes on to say that “methadone, like many other medications, has been implicated in the prolongation of the [QTc] interval of the electrocardiogram (ECG), which is considered a marker for arrhythmias such as torsade de pointes (TdP).” It further notes that the recommendations and consensus statements regarding QTc screening developed for patients receiving methadone maintenance treatment (MMT) have been questioned

At times, that questioning has been contentious (see issues of the AT Forum newsletter: Spring 2009, Summer 2009, and Winter 2012 ).

Cochrane investigators undertook a review study “to evaluate the efficacy and acceptability of QTc screening” to prevent cardiac-related morbidity and mortality in MMT. The authors performed an extensive search of MEDLINE, EMBASE, other databases, and electronic sources of ongoing trials, and identified 872 pertinent records.

Their finding: “No evidence has been found to support the use of the electrocardiogram (ECG) for preventing cardiac arrhythmias in methadone-treated opioid dependents.”

Gold Standards

Just as methadone is considered the gold standard in treating opioid dependence, Cochrane reviews are internationally recognized as the gold standard in evidence-based medical information. Using predefined criteria, Cochrane researchers conduct meticulous statistical data analyses to determine the efficacy of medical interventions. Cochrane Reviews are published by The Cochrane Collaboration, an independent nonprofit organization with 28,000 volunteers in more than 100 countries.

Existing Screening Recommendations

Screening guidelines recommended several years ago by an Expert Panel (Krantz, 2009) were a pretreatment ECG for all patients being considered for methadone treatment, to measure the QTc interval; a follow-up ECG within 30 days and annually; and additional ECGs if the daily methadone dosage exceeds 100 mg, or if unexplained syncope (loss of consciousness) or seizures occur.

A different Expert Panel (Martin, 2011) recommended instead a baseline ECG at the time of admission and within 30 days only for patients with significant risk factors for QT prolongation, and additional ECGs annually, or whenever the daily dose exceeds 120 mg.

Untoward Consequences of ECG Screening

The Cochrane study points out that the procedures involved in ECG screening may be “too demanding and stressful,” and “may expose patients to health consequences of untreated opioid addiction, including increased mortality risk.”

Untoward health consequences can occur when unnecessary evaluations and false-positive findings result in delays for additional studies and other treatments. In the meantime, some patients’ opioid addiction goes untreated, with potentially fatal outcomes—a factor that “does not seem to have been appropriately ruled out” by those drafting the screening guidelines, according to the authors.

Key Points in the Review

  • QTc prolongation is “not a safety concern per se,” but a “sharply imperfect” surrogate marker for the risk of TdP. A QTc longer than 500 milliseconds—considered the threshold of increased danger—is found in about 2 percent to 16 percent of MMT patients. But the prolongation isn’t necessarily due to methadone; liver disease, low potassium levels, and therapy with a variety of drugs also prolong QTc in MMT patients.
  • Estimated mortality for TdP is about 10 percent to 17 percent. But the “supposed involvement of methadone in TdP-related mortality” is thought to be only 6 deaths per 10,000 patient-years. Studies typically do not rule out other known risk factors, such as heart disease and various medications, so the true figure is probably lower. In contrast, mortality of untreated heroin dependence is estimated to be far higher: 100 to 300 per 10,000 person-years. Methadone maintenance, with an annual mortality rate of 0.1 percent, reduces by 2 to 11 times the mortality risk of people with opioid dependence.
  • The benefits of methadone treatment include increased retention in treatment, and a reduction in opioid use, HIV transmission, and mortality.
  •  Other treatments for opioid dependence with substantially lower risk of cardiac complications, such as buprenorphine, are available, but “their pharmacological profile, efficacy and acceptability by patients do not allow them to be thought of as an easy alternative to methadone.”
  •  ”Undue focus on QTc prolongation,” which may not be an appropriate way to screen for TdP, may decrease patient safety by diverting attention from other risk factors.
  •  Planning and performing ECG screenings isn’t easy; most physicians and many cardiologists cannot correctly calculate a QTc and identify a long QTc.

Unable to find any study that fulfilled methodological criteria for their review, The Cochrane authors said “it is not possible to draw any conclusions about the effectiveness of ECG-based screening strategies for preventing cardiac morbidity/mortality in methadone-treated opioid addicts.” Their recommendation: “Research efforts should focus on strengthening the evidence about the effectiveness of widespread implementation of such strategies and clarifying associated benefits and harms.”

In summing up, the authors note the lack of scientific evidence supporting ECG-based screening, and point out that “many examples of screening tests that were believed to be efficacious and recommended until rigorous evaluation showed their disadvantages are reported in the literature.” So, this appears to be another case of recommendations and guidelines being enacted “without the scientific rigour applied to other areas of medicine.”

The Cochrane study, with a complete description of study methods and results, is available for purchase through the Wiley Online Library at http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008939.pub2/abstract

Resources

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150(6):387-395. doi:10.7326/0003-4819-150-6-200903170-00103. http://www.tandfonline.com/doi/abs/10.1080/10550887.2011.610710#.UdL01zssnj4

Martin JA, Campbell A, Killip T, et al. QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel. J Addict Dis. 2011; Oct;30(4):283-306. doi: 10.1080/10550887.2011.610710. http://www.tandfonline.com/doi/pdf/10.1080/10550887.2011.610710

SAMHSA Panel: No Mandatory ECG Testing for OTP Patients


 A panel convened by the Substance Abuse and Mental Health Services Administration (SAMHSA) has stopped short of recommending mandatory
electrocardiograms (ECGs) on patients treated with methadone in opioid treatment programs (OTPs). In “QT Interval Screening in Methadone Maintenance Treatment: Report of a SAMHSA Expert Panel,” published November 3 in the Journal of Addictive Diseases, the panel described the process that resulted in the inability to recommend ECG screening for all OTP patients.

The panel, convened initially in 2007, was charged with coming up with recommendations for addressing cardiac risk—specifically, an arrhythmia that can lead
to a dangerous condition known as torsade de pointes (TdP).  An erroneous report by this panel on cardiac effects was published—and later retracted—in the prestigious Annals of Internal Medicine (see related links). Finally, the case has been closed: no required baseline ECGs on OTP patients. There was no consensus
—five panel members voted to recommend baseline ECGs, and four voted against.

The story began six years ago when the Food and Drug Administration (FDA) issued an alert relating to methadone and cardiac arrhythmias, followed by a warning label. At higher doses, methadone may prolong the QT interval.

It’s important to note that the presence of QT prolongation does not necessarily lead to TdP, and that TdP can also occur in people who have normal QT intervals. It is also important to know that many medications are related to QT prolongation, alone and in combination with others.

Nobody knows how many OTP patients have suffered methadone-related arrhythmias. “It’s hard to put a finger on it; we really don’t have that much data,” said Anthony Campbell, DO, medical officer with the division of pharmacologic therapies at SAMHSA’s Center for Substance Abuse Treatment (CSAT). “The only way you can capture this is if you have a Holter monitor on the patient at the time of event.”

Panel Recommendations

The recommendations from the panel: Patients with significant risk factors for QT prolongation should have a baseline ECG at admission, and again within 30 days, the panel agreed. These risk factors include a history of cardiac arrhythmia or prolonged QT interval; symptoms suggestive of arrhythmia, such as episodes of syncope, dizzy spells, palpitations, or seizures; medication history; family history of premature death; or any other historical information suggestive of a possible cardiac arrhythmia.

Nothing in the recommendations has the force of law or regulation behind it. These are recommendations only. “Opioid treatment programs and other providers are encouraged to consider these conclusions to the extent that they are practically or financially capable of doing so,” the article concludes. “Nothing in this report is intended to create a legal standard of care for any opioid treatment program or to interfere with clinical judgment in the practice of medicine.”

Not a ‘Major Danger’

OTPs have been divided by this issue. “When we went to the initial meeting the deck was stacked,” said Brian A. McCarroll, DO, of BioMed Behavioral Healthcare in Sterling Heights, Michigan, one of the panel members who voted against requiring ECGs of all patients within 30 days of admission. “It didn’t matter what the clinical evidence was, they wanted something to come out that said this is a major danger with methadone. And it’s not.” Dr. McCarroll is a diplomate of the American Board of Addiction Medicine.

While screening ECGs should not be mandatory for all new OTP patients, complete cardiac histories should be, he said. “If someone has a history of dizzy spells that could be a sign of an arrhythmia, it would be prudent to do an ECG.”

Prevalence of Prolonged QT Interval

The panel concluded that 2 percent of OTP patients have a very prolonged QT interval. If so, of the 250,000 people currently enrolled in OTPs, 5,000 would need “interventions for cardiac risk reduction,” and an additional 40,000 to 60,000 would have a lesser risk but may need an intervention, the article states.

One of the factors the panel considered in coming up with its recommendations was “compelling evidence that the majority of physicians who direct treatment in opioid treatment programs are not fully aware of methadone’s association with adverse cardiac events,” the article stated. In one survey, only 41 percent of 692 physicians in OTPs were aware of methadone’s QT-prolonging properties, and only 24 percent were aware of the possible risk for TdP.

Costs of ECGs

“There were some people who said requiring screening is wrong because OTP patients can’t afford the cost of going to a cardiologist,” said Robert Lubran, MA, MPH, director of CSAT’s Division of Pharmacologic Therapies. “We took the opposing view, which is that it’s
important for patient care and patient safety that the medical staff be aware of this potential problem, and that it’s really incumbent on them to help the patients access needed services.” According to Mr. Lubran, ECGs cost about $100.

If OTPs themselves don’t offer ECGs—and Mr. Lubran acknowledges that many can’t—then it’s “incumbent on the OTP to help the patient find an affordable medical service.” Some OTPs are going to become medical health homes, which means that they will be able to offer affordable ECGs, he said. “And as we’re moving toward health care reform, everybody is supposed to have access to primary medical care. This is another step. We are suggesting that programs understand the consequences of not screening.”

Another argument against requiring ECGs, said Mr. Lubran, was that patients who couldn’t afford them would then be denied treatment. “One side said it was better to get people into treatment, and the other said it was better to get the ECG baseline done at admission.” He has also heard the argument that programs will discharge patients or reduce their dose if they appear to have cardiac risks. “We have never made any recommendation that suggests the answer is discharging patients,” he said. “We don’t want programs to take the easy way out and discharge patients instead of doing a reasonable assessment and treating them as the standard of care provides.”

CSAT was to meet in late January to discuss the issue further. Mr. Lubran admitted that there is still controversy about whether QT prolongation contributes to deaths. But there’s enough data to warrant a cardiac risk assessment on each patient. “Whether that includes an ECG or not is up to the OTP,” he said. “Nobody is being required to do this by the federal government.”

Resources:

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney, MC. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150(6):387-395.
http://www.annals.org/content/150/6/387.full?HITS=10&hits=10&RESULT=&maxtoshow=.
Accessed February 20, 2012.

QTc Interval Screening – AATOD Policy and Guidance Statement. March 30, 2009. American Society for the Treatment of Opioid Dependence, Inc. New York, New York. http://www.aatod.org/qtc.html.  Accessed February 20, 2012.

Mandatory QTc Screening for Methadone Patients – OTPs Respond to Published Guidelines. ATForum. 2009 #2 (Spring); vol 18. http://atforum.com/newsletters/2009spring.php#QTc.
Accessed February 20, 2012.

For a link to the abstract, go to http://www.ncbi.nlm.nih.gov/pubmed/22026519.
Accessed February 20, 2012.

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