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LETTER TO THE EDITOR |
a Chairman, US Oncology P&T Committee, Pittsburgh, Pennsylvania, USA; b US Oncology, Virginia Beach, Virginia, USA
Correspondence: Nicky Dozier, Pharm.D., Director, Drug Management, US Oncology, Inc., US Oncology, 5501 Greenwich Road, Suite 300, Virginia Beach, Virginia 23462, USA. Telephone: 757-518-2406; Fax: 832-601-6976; e-mail: Nicky.Dozier{at}USONCOLOGY.com
Key Words. Dolasetron • 5-HT3 receptor antagonists • Electrocardiographic changes • QT interval
We read with interest recent articles discussing the relative electrocardiographic (ECG) effects of 5-HT3 receptor antagonists. As representatives of the Pharmacy and Therapeutics Committee for US Oncology, a network of over 800 community oncologists in 28 states, we reviewed the data discussed in recent articles appearing in The Oncologist by Dr. Keefe [1] and Dr. Goodin and Ms. Cunningham [2] in considering therapeutic interchangeability among these products for our office-based practices. Our committee reached different conclusions from those of the above authors regarding ECG effects of this class of drugs. We submit that there are other data that should be highlighted and offer our comments and experience in this regard.
The authors suggest that 5-HT3 receptor antagonists are not equivalent in their myocardial effects and that dolasetron elicits ECG interval changes that are more severe than either ondansetron or granisetron [1, 2]. However, a thorough review of published preclinical and clinical data does not support this conclusion.
Alterations in ECG intervals appear to be a class effect [3–6]. Reversible, clinically asymptomatic changes in ECG parameters have been shown with all 5-HT3 receptor antagonists, but no clinically significant cardiovascular effects have been reported [3, 5, 7–13]. Because ECG interval changes were first observed with earlier agents in this class, dolasetron trials included thorough ECG evaluations. Cardiovascular clinical outcomes were assessed in approximately 70 clinical trials in over 7,000 patients treated with dolasetron and 2,100 patients treated with placebo or comparator. More than 3,000 of those patients had a history of cardiovascular disease, arrhythmia, or concurrent cardiovascular medication. Another 1,000 patients received cardiotoxic chemotherapy, including anthracyclines [14, 15]. These data demonstrate that the frequency of small, transient ECG changes with dolasetron is similar to those of other 5-HT3 receptor antagonists [3, 7, 12, 16–19].
Keefe suggests that dolasetron may block sodium (Na+) channels, thus contributing to cardiac effects [1]. In fact, all three agents have differing degrees of antagonist activity on Na+ and potassium (K+) channels in the cardiac myocyte [20, 21]. In vitro data showed that Na+ channels were blocked in a frequency-dependent manner, with the antagonist potency of granisetron > dolasetron > ondansetron; K+ channel antagonist potencies were ondansetron > granisetron > dolasetron. Thus, dolasetron has less antagonist activity than granisetron on the Na+ channel and exerts the least effect on the K+ channel. Dolasetron causes acute effects on the ECG via Na+ blockade to delay ventricular depolarization, manifested as prolonged PR and QRS duration, without a substantial effect on ventricular repolarization [6]. However, ondansetron largely blocks K+ channels, exerting prolonging effects on QT and JT intervals, and granisetron blocks both Na+ and K+ channels, potentially affecting PR, QRS, QT, and JT intervals [7, 20].
In oncology patients receiving cardiotoxic chemotherapy, small, reversible, and clinically unimportant ECG interval changes have been detected with ondansetron, granisetron, and dolasetron, [3, 10–13, 16–19, 22–25]. The frequency of statistically, but clinically insignificant, increases in PR, QRS, and QTc intervals did not differ among the three agents, and ECG changes, only detectable with computer-assisted ECG methods, returned to baseline values often within 24 hours. Most patients were asymptomatic and no cardiovascular events were reported [3, 9–13, 16, 18, 19, 22–25]. Patients with underlying cardiovascular disease and patients taking concomitant cardiovascular or anthracycline drug therapy were not at a greater risk of cardiovascular adverse events [14].
Taken together, clinical experience supports the remarkable safety of the 5-HT3 receptor antagonists. Despite theoretical concerns, no clinically relevant arrhythmogenic effects have been shown in clinical trials with any of these agents. Although US Oncology has no closed formulary program, our 800 or more oncologists have utilized dolasetron as the "workhorse" agent for the past 5 years in greater than 95% of cases requiring a 5-HT3 antagonist. Neither sentinel event reporting nor changes in physician prescribing behavior suggest that significant adverse events are being detected. These authors assert that the best alternative may be the agent with the most well-defined cardiac effects. Dolasetron is the 5-HT3 receptor antagonist most thoroughly studied for cardiac effects.
ACKNOWLEDGMENT
Nicky Dozier serves on a speakers’ bureau for Aventis Pharmaceuticals.
REFERENCES
This article has been cited by other articles:
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  S. Goodin and R. Cunningham In Reply: Evidence for Equivalent Cardiotoxicity of the 5-HT3 Receptor Antagonists Oncologist, April 1, 2003; 8(2): 219 - 221. [Full Text] [PDF]
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