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Posted on 04.28.03
What Clinicians Should Know About the QT Interval
By Mike Upchurch
CERTs research is providing one of the most comprehensive looks to date at a dangerous change in the heart's rhythm. This potentially fatal arrhythmia is known as torsades de pointes and is usually associated with QT-interval prolongation.
Lead author Dr. Sana Al-Khatib and her team from the Duke CERTs recently gathered all existing peer-reviewed research on the outcomes of patients with QT prolongation and the effect of how that prolongation was measured. The resulting summary, published in the April 23 issue of the Journal of the American Medical Association gives care providers a thorough look at what they should know about the QT interval and what research questions remain to be answered.
The first challenge in assessing the risk of QT-interval prolongation is determining how to measure it in the first place. So many variables, including time of day, other changes in the heart rhythm, differences between two observers' interpretation of the ECG and others, can cloud the accurate measurement of the QT interval. Mathematical formulas to clarify some of these confounding factors have been developed, but questions remain.
A lack of consensus on the best method has also contributed to the confusion. A panel of long-QT syndrome (LQTS) experts developed guidelines in 2000. But as Al-Khatib and her co-authors point out, some aspects of these guidelines have not been validated by prospective studies comparing various measurement formulas.
The Duke team noted that the cause of QT prolongation most often seems to be "a gene-environment interaction." While previous studies, including pivotal research performed by the Arizona CERTs, have pinpointed several drugs that can lead to QT prolongation, the majority of patients who take these medications never develop the syndrome. Even after adjusting for other risk factors, some patients seem more likely to develop a long QT at specific doses of these drugs. Scientists believe this indicates a genetic predisposition.
But this alone does not guarantee development of QT prolongation or torsades de pointes. The authors point out that most patients with LQTS never develop torsades de pointes and that many who do experience torsades de pointes did not show an abnormal QT interval immediately before it.
Accordingly, the authors suggest that a number of risk factors must be taken into account. These include advanced age, female sex, a low left-ventricular ejection fraction, existing ventricular damage, and a number of abnormalities in the body's electrolyte levels. When added to the drugs known to predispose patients to QT prolongation, the risk of torsades de pointes increases. Thanks to previous CERTs projects, a list of these drugs is now available at http://www.torsades.org.
Armed with this knowledge, a physician must gauge the balance of risk and benefit when prescribing a medication that may lead to LQTS. Most of the medications on the list do not have any known effect on mortality, so their benefit on symptoms and associated morbidity is the most important consideration to weigh against the QT-prolongation risk. Empirical evidence on the known benefits of the medication should always be the care provider's guide.
Because the risk of torsades de pointes with many of these drugs is so low, doctors must also consider the relative benefits of various procedures versus the costs. For many QT-prolonging drugs, the cost of measuring the interval for each and every patient taking the medication would be prohibitive and inappropriate because the rate of torsades de pointes associated with the particular drug is so low.
Al-Khatib and her co-authors suggest some guidelines for employing QT-interval measurement. An ECG should be routinely checked before and after starting any anti-arrhythmic medication that can prolong the QT interval. A patient whose QT interval is already lengthened at baseline should not receive any medication on the list. If the patient is already taking a QT-prolonging drug and another medication needs to be added, knowing if the second drug can also prolong QT is essential. Concurrent prescription of more than one QT-prolonging medication is common, as shown by CERTs research, but the clinical impact is unknown.
If the medication is absolutely necessary and no alternative is available, the authors again recommend ECG before and after therapy is started. If the drug is considered as having a low probability for instigating QT-prolongation, as determined by the LQTS expert panel and reflected on the torsades.org list, the cost of these additional ECG measurements may outweigh the benefit, especially for low-risk patients.
Despite these recommendations, many questions about the clinical impact of QT prolongation remain. The outcomes of patients receiving many of the drugs listed as increasing the risk of LQTS have not been adequately measured. A threshold below which QT-prolongation no longer represents a significant risk for arrhythmia has not been established. Other questions specific to individual drugs also remain, as well as the matter of genetic predisposition.
Consequently, managing the risk of administering QT-prolonging drugs must often be done in murky waters. New FDA regulations requiring cardiac safety testing of new drugs should lead to a much better developed clinical picture. Regulatory bodies are increasingly aware of the dangers of QT-interval prolongation and the medications that increase its risk. More finely honed rules on cardiac safety studies will help winnow the numbers of drugs that can prolong the QT interval to only those that still hold worthwhile potential benefit.
Joining Sana Al-Khatib, MD, MHS; from the Duke Certs were: Nancy Allen LaPointe, PharmD; Judith M. Kramer, MD, MS; and Robert M. Califf, MD