Adverse outcomes from blood clot therapy may be due to patient characteristics, not dosing errors

04/07/05

Even though incorrect dosing occurs in about 5 percent of patients with heart attack who receive a certain blood clot dissolving therapy, patient-related factors appear to be more responsible for adverse outcomes, not dosing errors, according to a study in the April 13 issue of JAMA.

Several studies have reported higher death, stroke, and major hemorrhagic event rates in patients who received incorrect doses of fibrinolytic (clot-busting) agents, according to background information in the article. However, several patient factors identified as related to risk of incorrect dosing are also markers of higher risk of death, thereby limiting inference about the cause and effect relationship of incorrect dosing and adverse outcomes. It has been assumed that the adverse outcomes are caused by incorrect dosing. However, it is also possible that the adverse outcomes may be due to confounding factors, such that sicker patients with an unstable early clinical course could be more likely to receive incorrect doses.

Rajendra H. Mehta, M.D., M.S., of Duke Clinical Research Institute and Duke University Medical Center, Durham, N.C., and colleagues conducted a study to determine how much of the association between incorrect dosing and adverse outcomes is cause and effect. Because every patient received both an active fibrinolytic and a placebo, the researchers were able to hypothesize that if the incorrect dose was causing adverse outcomes, the association between incorrect dosing of active fibrinolytic and adverse outcome would be much stronger than the association between incorrect dosing of placebo.

The study included 16,949 patients with heart attacks who were enrolled in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) trial. Patients were assigned to one of two clot-dissolving fibrinolytic treatments: either tenecteplase (given as a five second bolus; with alteplase placebo) or alteplase (given as a bolus plus infusion, with tenecteplase placebo).

The researchers found that incorrect dosing occurred in 4.9 percent of patients who received active alteplase and in 4.6 percent of patients who received corresponding placebo. Patients receiving incorrect doses of alteplase or placebo were more likely to be older, female, black, shorter, have lower body weight and systolic blood pressure, and have a higher Killip class (heart failure measurement) at presentation. Thirty-day mortality was higher in patients who received an overdose (9.8 percent) or underdose (19.5 percent) of alteplase compared with those who received a correct dose (5.4 percent). The surprising finding was that the same pattern was observed in patients who received an alteplase placebo (10.0 percent for overdose, 23.5 percent for underdose, and 5.4 percent for correct dose). This strongly suggests that modest errors in dosing this medication, while associated with much worse outcomes, were not the cause of the worse outcomes. This was further supported by the finding that the higher rates of adverse outcomes with incorrect dosing were largely accounted for by adjusting for baseline characteristics.

"Medical errors due to incorrect dosing of fibrinolytic therapy have been shown to be associated with increased risk of adverse events in STEMI [ST-segment elevation heart attack; a certain measurement on an electrocardiogram] patients and with increased risk of litigation against caregivers," the authors write. "When identifying an incorrect dose of a potentially toxic drug associated with an adverse outcome, the reflex and logical conclusion is to assume cause, particularly in malpractice litigation that is principally driven by adverse outcomes. However, this study raises the possibility that much of the adverse outcomes ascribed to dosing errors, at least in some situations, may be due to confounding rather than a direct effect of the error itself."

"Thus, while medication errors need to be minimized, caution should be used in concluding that adverse outcomes associated with errors are primarily caused by the errors. Importantly, more research is needed into dosing errors, with the same rigor as in other clinical research, to better understand factors related to such errors and their impact on patient outcome," the authors conclude.

(JAMA. 2005;293:1746-1750. Available post-embargo at JAMA.com)

Editor's Note: The ASSENT-2 trial was funded by Boehringer Ingelheim and Genentech Inc., but the sponsors did not provide specific funding for this analysis. For financial disclosure information, please see the JAMA article.

Source: Eurekalert & others

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