Relationship of Incorrect Dosing of Fibrinolytic Therapy and Clinical Outcomes FREE

Incorrect dosing of fibrinolytic therapy has been reported to occur 5% to 12% of the time.^1- 3 Several studies have reported higher mortality, stroke, and major hemorrhagic event rates in patients who received incorrect doses of fibrinolytic agents.^4- 7 However, several patient factors identified as related to risk of incorrect dosing⁸ are also markers of higher risk of death, thereby limiting inference about the cause and effect relationship of incorrect dosing and adverse outcomes. It is 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.

To determine how much of the association between incorrect dosing and adverse outcomes is cause and effect, we examined the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) trial database.⁹ Our hypothesis was 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 fibrinolytic placebo. Conversely, if incorrect dosing of a fibrinolytic placebo and adverse outcome were equally related to incorrect dosing of an active fibrinolytic drug, the association would be mostly due to confounding.

After providing informed consent, eligible patients in the ASSENT-2 trial (n = 16 949) were randomly assigned in a double-blind, double-dummy fashion to receive (1) a body weight–adjusted bolus of tenecteplase (5- to 10-second bolus; range 30-50 mg) plus a bolus and infusion of placebo (alteplase placebo) or (2) a bolus and infusion of alteplase plus a bolus of placebo (tenecteplase placebo).⁹ Alteplase and alteplase placebo were given as 15-mg boluses and were followed by a 0.75-mg/kg infusion (≤50 mg) over 30 minutes and a 0.50-mg/kg infusion (≤35 mg) over 60 minutes. All patients received 150 to 325 mg of aspirin orally and intravenous heparin adjusted to an activated partial thromboplastin time of 50 to 75 seconds for 48 to 72 hours. Incorrect dosing was defined as any dose more or less than the weight-based dose of fibrinolytic agent.⁹ Each participating center obtained approval from its local ethics board prior to patient enrollment. The race of each patient was noted by a check mark on the case report form selected by the investigator.

Baseline and end point variables are presented as frequencies and percentages for categorical factors and as medians with 25th and 75th percentiles for continuous variables. To evaluate the differences in outcomes between the various comparison treatment groups, previously established multivariable models to predict 30-day mortality,¹⁰ in-hospital stroke,¹¹ and in-hospital major bleeding¹² in patients with ST-segment elevation myocardial infarction (STEMI) were used to adjust for the influence of confounders when calculating adjusted odds ratios (ORs). P<.01 was considered significant because of the large numbers of patients and multiple comparisons. All statistical analyses were performed in May 2004 using SAS software version 8.0 (SAS Institute Inc, Cary, NC).

Incorrect dosing occurred in 4.9% of patients receiving alteplase; 4.6%, alteplase placebo (tenecteplase group); 3.6%, tenecteplase; and 3.6%, tenecteplase placebo (alteplase group). Underdosing occurred in 3.2% of patients receiving alteplase, 3.1% of patients receiving alteplase placebo, and 1.8% of patients receiving tenecteplase and tenecteplase placebo. Overdosing occurred in 1.7% of patients receiving alteplase, 1.5% of patients receiving alteplase placebo, and 1.8% of patients receiving tenecteplase and tenecteplase placebo. The median degree of underdosing was 15% (4%-25%) less than the correct dose and the median degree of overdosing was 5% (2%-10%) more than the correct dose. The incidence of incorrect dosing in the same patient for alteplase and tenecteplase placebo occurred in 0.24%, while the incidence of incorrect dosing in the same patient for alteplase placebo and active tenecteplase occurred in 0.19%.

Characteristics of patients and clinical events among those with and without incorrect dosing of alteplase are shown in Table 1 and Table 2. Compared with patients receiving the correct dose, those receiving either overdoses or underdoses of alteplase were more likely to be older, female, black, shorter, have lower body weight and systolic blood pressure, and have a higher Killip class, which are high-risk characteristics.

Incorrect alteplase dosing was associated with an increased risk for 30-day mortality (Figure 1). However, the risk was increased to a nearly identical extent with incorrect dosing of the alteplase placebo. After adjustment for confounding baseline features, overdosing was no longer significantly associated with higher mortality for either alteplase or alteplase placebo groups compared with correct dosing of alteplase or alteplase placebo (Figure 2). Compared with patients who received the correct doses of alteplase and alteplase placebo, the unadjusted mortality risk was significantly higher for patients who received underdoses of alteplase (OR, 4.27; 95% confidence interval [CI], 3.10-5.89) or alteplase placebo (OR, 5.42; 95% CI, 3.98-7.37). However, the OR decreased substantially with adjustment for both underdosing of alteplase and alteplase placebo. When deaths on the first day were excluded to remove any effect from rapidly fatal complications, which may have caused the study drug to be discontinued early, the impact of underdosing on 30-day mortality was no longer statistically significant in either groups receiving underdoses of alteplase or alteplase placebo compared with the respective correct dosing groups. Furthermore, no difference in death was observed between the underdose alteplase group and underdose alteplase placebo group or between the overdose alteplase group and overdose alteplase placebo group (Figure 1 and Figure 2).

Similar to that observed for 30-day mortality, the same pattern of increased risk with incorrect dosing of alteplase and of alteplase placebo was seen for major bleeding and intracranial hemorrhage (Table 2). The excess risk of stroke and major bleeding with incorrect dosing in the alteplase group and the alteplase placebo group also appeared to be explained by higher baseline risk profile and was attenuated significantly after adjustments for confounders (Table 3). Finally, the relationship between incorrect dosing of tenecteplase placebo and 30-day mortality demonstrated directional consistency similar to that seen with incorrect dosing of alteplase placebo (Figure 1).

Our study shows that even in clinical trials where protocols are specified and a select group of STEMI patients are enrolled, incorrect dosing of alteplase occurred in approximately 5% of patients.^1,3,13 While we observed nearly the same excess risk of death, intracranial hemorrhage, and bleeding with incorrect dosing of alteplase that has been reported in prior studies,^4- 7 this excess risk was nearly identical with both incorrect dosing of alteplase placebo and active alteplase. This suggests that most, if not all, of the association of incorrect dosing of alteplase and adverse outcome was due to confounding rather than directly resulting from incorrect dosing. In fact, when we adjusted for these confounding factors, the risks of these clinical events were significantly attenuated. Importantly, we identified several patient-related factors associated with incorrect dosing of alteplase including advanced age, female sex, black race, shorter stature, lower body weight, lower systolic blood pressure, and a higher Killip class. These factors also have been shown to be associated with increased risk of adverse clinical events in STEMI patients.^10- 12 This may be related to the fact that an unstable acutely ill patient with STEMI, heart failure, or impending shock, and other comorbid conditions may require attention to various aspects of his/her care simultaneously for stabilization, which distracts physicians from reperfusion treatment itself and leads to dosing errors.¹³ The finding of more bleeding with underdosing highlights the limitation of observational analysis. However, this finding may have resulted from early discontinuation of fibrinolytic therapy in patients with early bleeding.

The complexity of dosing and impact of early clinical instability were reduced as potential confounders with dosing of tenecteplase and tenecteplase placebo given as a 10-second bolus. Thus, the proportion of error as well as the relationship of incorrect dosing and adverse outcome with this simple single bolus administration was lower.

Medical errors due to incorrect dosing of fibrinolytic therapy have been shown to be associated with increased risk of adverse events in STEMI patients and with increased risk of litigation against caregivers.^10- 13 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.

While education, appropriate use of technology, expertise, and a systematic approach provide the best potential opportunity for reducing dosing errors, physicians should also be encouraged to pay particular attention to avoid incorrect dosing for patients with the characteristics that are predictive of errors being made.

Inference regarding a lack in the cause and effect relationship between incorrect dosing and adverse outcomes should not be considered definitive because of the observational nature of our analysis. The relationship between underdosing of alteplase and alteplase placebo may be confounded by the fact that drug may be discontinued early because of an adverse event. Nevertheless, our data provide reasonable evidence that adverse events in patients treated with incorrect doses of fibrinolytic agents are not always solely related to incorrect dosing, but they may also be attributable to patient factors that are otherwise associated with poor outcomes. The clinical trial setting differs from general practice and thus our results may not be generalizable to clinical care in which one might expect that error rates would, if anything, be higher. Most of the errors we describe are of modest proportions, and larger errors would likely cause harm. However, these errors would likely also be subject to considerable confounding.

Our data indicate that incorrect dosing of alteplase for patients with STEMI was associated with much worse outcomes. The finding that the same relationship between worse outcome and incorrect dose was seen with placebo, and that it was attenuated when adjusted for baseline risk features, suggests that the adverse outcomes are due to confounding rather than cause and effect. 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.