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Mehta RH, Alexander JH, Van de Werf F, et al. Relationship of Incorrect Dosing of Fibrinolytic Therapy and Clinical Outcomes. JAMA. 2005;293(14):1746–1750. doi:10.1001/jama.293.14.1746
Author Affiliations: Duke Clinical Research
Institute and Duke University Medical Center, Durham, NC (Drs Mehta, Alexander,
Califf, and Granger and Mss Pieper and Garg); Department of Internal Medicine,
Division of Cardiology, University Hospital Leuven, Leuven, Belgium (Dr Van
de Werf); and Department of Internal Medicine, Division of Cardiology, University
of Alberta, Edmonton (Dr Armstrong).
Context Incorrect dosing of alteplase has been associated with worse clinical
outcomes in patients. However, patients at high risk of adverse events are
more prone to dosing errors, thus confounding this relationship.
Objective To determine if the association between incorrect dosing of alteplase
and adverse outcomes is related to cause and effect or to confounding.
Design, Setting, and Patients Observational analysis in May 2004 of a double-blind, double-dummy trial
of 16 949 patients with ST-segment elevation myocardial infarction who
were enrolled in the Assessment of the Safety and Efficacy of a New Thrombolytic
(ASSENT-2) trial and were assigned to either a bolus of tenecteplase (with
alteplase placebo bolus plus infusion) or a bolus of alteplase (with tenecteplase
placebo plus infusion).
Main Outcome Measures Thirty-day mortality, in-hospital stroke, and major bleeding associated
with incorrect dosing of active alteplase compared with placebo alteplase.
Results Incorrect dosing occurred in 4.9% of patients who received active alteplase
and in 4.6% of patients who received alteplase placebo. Patients receiving
incorrect doses of alteplase or alteplase placebo were more likely to be older,
female, black, shorter, have lower body weight and systolic blood pressure,
and have a higher Killip class at presentation. Thirty-day mortality was higher
in patients who received an overdose (9.8%) or underdose (19.5%) of alteplase
compared with those who received a correct dose (5.4%). The same pattern was
present in patients who received an alteplase placebo (10.0% for overdose,
23.5% for underdose, and 5.4% for correct dose). Similar patterns were seen
for in-hospital intracranial hemorrhage and major bleeding. The higher rates
of adverse outcomes with incorrect dosing were largely accounted for by adjusting
for baseline characteristics.
Conclusions The relationship between incorrect dosing and patient outcome in ASSENT-2
is primarily due to confounding factors rather than incorrect dosing itself.
These data highlight the need for caution when ascribing a causal relationship
to associations between incorrect dosing and adverse outcomes.
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