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Original Contribution |

Relationship of Incorrect Dosing of Fibrinolytic Therapy and Clinical Outcomes FREE

Rajendra H. Mehta, MD, MS; John H. Alexander, MD, MS; Frans Van de Werf, MD; Paul W. Armstrong, MD; Karen S. Pieper, MS; Jyotsna Garg, MS; Robert M. Califf, MD; Christopher B. Granger, MD
[+] Author Affiliations

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).

More Author Information
JAMA. 2005;293(14):1746-1750. doi:10.1001/jama.293.14.1746.
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Published online

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.

Figures in this Article

Incorrect dosing of fibrinolytic therapy has been reported to occur 5% to 12% of the time.13 Several studies have reported higher mortality, stroke, and major hemorrhagic event rates in patients who received incorrect doses of fibrinolytic agents.47 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.

Study Population

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.

Data Analysis

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.

Table Graphic Jump LocationTable 1. Baseline Characteristics (N = 16449)*
Table Graphic Jump LocationTable 2. Complications and Clinical Events*

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).

Figure 1. Acute Fibrinolytic Treatment vs Placebo and 30-Day Mortality
Graphic Jump Location

*Tenecteplase group that received alteplase placebo.
†Alteplase group that received tenecteplase placebo.

Figure 2. Alteplase Dosing and Adjusted 30-Day Mortality
Graphic Jump Location

Adjusted for age, Killip class, age × Killip class, systolic blood pressure, heart rate, anterior myocardial infarction, previous myocardial infarction, height, weight, symptom duration, diabetes, current smoking, prior coronary artery bypass graft surgery, and hypertension.
*Tenecteplase group that received alteplase placebo.

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).

Table Graphic Jump LocationTable 3. Differences in Clinical Events in Incorrect Dosing Groups

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,47 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.1012 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.

Clinical Implications

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.1013 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.

Limitations

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.

Conclusions

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.

Corresponding Author: Christopher B. Granger, MD, Box 3409, Duke University Medical Center, Durham, NC 27710 (grang001@mc.duke.edu).

Author Contributions: Dr Granger had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mehta, Alexander, Granger.

Acquisition of data: Alexander, Armstrong, Califf, Granger.

Analysis and interpretation of data: Mehta, Alexander, Van de Werf, Armstrong, Pieper, Garg, Granger.

Drafting of the manuscript: Mehta, Armstrong, Pieper, Granger.

Critical revision of the manuscript for important intellectual content: Mehta, Alexander, Van de Werf, Armstrong, Pieper, Garg, Califf, Granger.

Statistical expertise: Mehta, Pieper, Garg, Granger.

Obtained funding: Armstrong, Granger.

Administrative, technical, or material support: Alexander, Armstrong, Califf, Granger.

Study supervision: Van de Werf, Armstrong, Granger.

Financial Disclosures: Dr Alexander has received research funding from Boehringer Ingelheim. Dr Van de Werf has served on the speaker’s bureau and has received research grants from Boehringer Ingelheim and Genentech Inc. Drs Armstrong and Granger have received research funding from Boehringer Ingelheim and Genentech Inc. None of the other authors reported financial disclosures.

Funding/Support: The ASSENT-2 trial was funded by Boehringer Ingelheim and Genentech Inc, but the sponsors did not provide specific funding for this analysis.

Role of the Sponsors: Boehringer Ingelheim and Genentech Inc had no role in the design or conduct of the study, in the collection, analysis, interpretation of the data, or in the preparation, review, or approval of the manuscript.

Vorchheimer DA, Baruch L, Thompson TD.  et al.  North American versus non-North American streptokinase use in GUSTO-I: impact of protocol deviation in mortality benefit of tPA.  Circulation. 1997;96:(suppl I)  I535
Link to Article
Granger CB, Moffie I.GUSTO Investigators.  Underuse of thrombolytic therapy in North America is exaggerated: results of the GUSTO-MI registry.  Circulation. 1994;90:(suppl I)  I324
Cannon CP. Thrombolysis medication errors: benefits of bolus thrombolytic agents.  Am J Cardiol. 2000;85:17C-22C
PubMed   |  Link to Article
Phillips DP, Christenfeld N, Glynn LM. Increase in US medication-error deaths between 1983 and 1993.  Lancet. 1998;351:643-644
PubMed   |  Link to Article
Cannon CP. Exploring the issue of appropriate dosing in the treatment of acute myocardial infarction: potential benefits of bolus fibrinolytic agents.  Am Heart J. 2000;140:(6 suppl)  S154-S160
PubMed   |  Link to Article
Gurwitz JH, Gore JM, Goldberg RJ.  et al.  Risk of intracranial hemorrhage after tissue plasminogen treatment for acute myocardial infarction: participants in the National Registry of Myocardial Infarction 2.  Ann Intern Med. 1998;129:597-604
PubMed   |  Link to Article
Coulter SA, McCabe CH, Giugliano RP.  et al.  Dosing errors and outcomes in patients receiving single bolus compared to bolus + infusion thrombolytic regimens: an InTIME-II study.  Circulation. 2000;102:(suppl II)  II590
Smalling RW, Bode C, Kalbfleisch J.  et al. RAPID Investigators.  More rapid, complete and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction.  Circulation. 1995;91:2725-2732
PubMed   |  Link to Article
ASSENT-2 Investigators.  Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial.  Lancet. 1999;354:716-722
PubMed   |  Link to Article
Lee KL, Woodlief LH, Topol EJ.  et al.  Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41,021 patients.  Circulation. 1995;91:1659-1668
PubMed   |  Link to Article
Gore JM, Granger CB, Simoons ML.  et al.  Stroke after thrombolytic therapy: mortality and functional outcomes in the GUSTO-I trial.  Circulation. 1995;92:2811-2818
PubMed   |  Link to Article
Berkowitz SD, Granger CB, Pieper KS.  et al. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) I Investigators.  Incidence and predictors of bleeding following contemporary thrombolytic therapy for myocardial infarction.  Circulation. 1997;95:2508-2516
PubMed   |  Link to Article
Freedman JE, Becker RC, Adams JE.  et al.  Medication errors in acute care: an American Heart Association scientific statement from the Council on Clinical Cardiology subcommittee on acute care, Council on Cardiopulmonary and Critical Care, Council on Cardiovascular Nursing and Council on Stroke.  Circulation. 2002;106:2623-2629
PubMed   |  Link to Article

Figures

Figure 1. Acute Fibrinolytic Treatment vs Placebo and 30-Day Mortality
Graphic Jump Location

*Tenecteplase group that received alteplase placebo.
†Alteplase group that received tenecteplase placebo.

Figure 2. Alteplase Dosing and Adjusted 30-Day Mortality
Graphic Jump Location

Adjusted for age, Killip class, age × Killip class, systolic blood pressure, heart rate, anterior myocardial infarction, previous myocardial infarction, height, weight, symptom duration, diabetes, current smoking, prior coronary artery bypass graft surgery, and hypertension.
*Tenecteplase group that received alteplase placebo.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics (N = 16449)*
Table Graphic Jump LocationTable 2. Complications and Clinical Events*
Table Graphic Jump LocationTable 3. Differences in Clinical Events in Incorrect Dosing Groups

References

Vorchheimer DA, Baruch L, Thompson TD.  et al.  North American versus non-North American streptokinase use in GUSTO-I: impact of protocol deviation in mortality benefit of tPA.  Circulation. 1997;96:(suppl I)  I535
Link to Article
Granger CB, Moffie I.GUSTO Investigators.  Underuse of thrombolytic therapy in North America is exaggerated: results of the GUSTO-MI registry.  Circulation. 1994;90:(suppl I)  I324
Cannon CP. Thrombolysis medication errors: benefits of bolus thrombolytic agents.  Am J Cardiol. 2000;85:17C-22C
PubMed   |  Link to Article
Phillips DP, Christenfeld N, Glynn LM. Increase in US medication-error deaths between 1983 and 1993.  Lancet. 1998;351:643-644
PubMed   |  Link to Article
Cannon CP. Exploring the issue of appropriate dosing in the treatment of acute myocardial infarction: potential benefits of bolus fibrinolytic agents.  Am Heart J. 2000;140:(6 suppl)  S154-S160
PubMed   |  Link to Article
Gurwitz JH, Gore JM, Goldberg RJ.  et al.  Risk of intracranial hemorrhage after tissue plasminogen treatment for acute myocardial infarction: participants in the National Registry of Myocardial Infarction 2.  Ann Intern Med. 1998;129:597-604
PubMed   |  Link to Article
Coulter SA, McCabe CH, Giugliano RP.  et al.  Dosing errors and outcomes in patients receiving single bolus compared to bolus + infusion thrombolytic regimens: an InTIME-II study.  Circulation. 2000;102:(suppl II)  II590
Smalling RW, Bode C, Kalbfleisch J.  et al. RAPID Investigators.  More rapid, complete and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction.  Circulation. 1995;91:2725-2732
PubMed   |  Link to Article
ASSENT-2 Investigators.  Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial.  Lancet. 1999;354:716-722
PubMed   |  Link to Article
Lee KL, Woodlief LH, Topol EJ.  et al.  Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41,021 patients.  Circulation. 1995;91:1659-1668
PubMed   |  Link to Article
Gore JM, Granger CB, Simoons ML.  et al.  Stroke after thrombolytic therapy: mortality and functional outcomes in the GUSTO-I trial.  Circulation. 1995;92:2811-2818
PubMed   |  Link to Article
Berkowitz SD, Granger CB, Pieper KS.  et al. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) I Investigators.  Incidence and predictors of bleeding following contemporary thrombolytic therapy for myocardial infarction.  Circulation. 1997;95:2508-2516
PubMed   |  Link to Article
Freedman JE, Becker RC, Adams JE.  et al.  Medication errors in acute care: an American Heart Association scientific statement from the Council on Clinical Cardiology subcommittee on acute care, Council on Cardiopulmonary and Critical Care, Council on Cardiovascular Nursing and Council on Stroke.  Circulation. 2002;106:2623-2629
PubMed   |  Link to Article

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