Excess Heparin Dosing Among Fibrinolytic-treated Patients with ST-Segment Elevation Myocardial Infarction
Article Outline
Abstract
Background
Although the use of heparin with fibrinolytics is associated with more rapid ST-segment resolution and increased infarct-related artery patency among patients with ST-segment elevation myocardial infarction (STEMI), its associated increase in bleeding risk is well documented and might be augmented by excess heparin dosing.
Methods
We sought to characterize the incidence and associated bleeding risk of excess heparin dosing among patients with STEMI treated with fibrinolysis who were enrolled in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines initiative. Excess dosing was defined as a bolus more than 60 U/kg or an infusion more than 12 U/kg/h per American College of Cardiology/American Heart Association guidelines and was further stratified into major and mild excess (major defined as a bolus
>70 U/kg or infusion >15 U/kg/h).
Results
Among 964 fibrinolytic-treated patients with STEMI, 758 (79%) received adjunctive unfractionated heparin therapy. Of these, 368 patients (49%) received excess dosing of unfractionated heparin and 137 patients (18%) received major excess heparin dosing. Factors significantly associated with excess dosing included low body weight and female sex. Patients who received major excess dosing had higher unadjusted rates of major bleeding (19.2% vs 12.4%, P=.004) and transfusion (13.5% vs 4.7%, P=.0002) than patients without excess dosing. After adjustment, a trend persisted for the association with higher transfusion risk (odds ratio 1.39 [0.61-3.14]).
Conclusion
Approximately half of fibrinolytic-treated patients with STEMI in contemporary practice received an excess dose of unfractionated heparin. Careful attention to dosing is needed to limit the compounded bleeding risk when heparin is added to fibrinolytic therapy.
Keywords: Bleeding, Fibrinolysis, Patient care
Heparin use with fibrinolysis has been associated with a more rapid ST-segment resolution, an increased infarct-related artery patency, and a lower risk of reinfarction among patients with ST-segment elevation myocardial infarction (STEMI).1 However, an associated increase in bleeding risk also has been well documented and directly correlates with the intensity of anticoagulation.2 As such, current practice guidelines recommend a weight-adjusted dosing strategy for unfractionated heparin when used together with fibrin-specific fibrinolytics to minimize bleeding risk while preserving therapeutic benefit.3, 4
Although a weight-based dosing strategy also has been advocated for patients with non–ST-segment acute coronary syndromes, previous studies have shown that up to one third of patients in contemporary practice received excess unfractionated heparin dosing that was associated with increased bleeding and mortality risks.5 The incidence and impact of excess heparin dosing among patients with STEMI have not been well studied. Therefore, using the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) National Quality Improvement Initiative database, we sought to assess the prevalence of excess unfractionated heparin dosing when used with fibrinolytics; examine the factors associated with excess dosing; and delineate the relationship between excess dosing and bleeding and transfusion outcomes.
Materials and Methods
Study Population
CRUSADE is a national registry designed to improve the quality of care for patients with acute coronary syndromes who are treated at hospitals in the United States. Patients with STEMI were included if they had ischemic symptoms within 24 hours of presentation lasting 10 minutes or more and either persistent ST-segment elevation of 1 mm or more in 2 or more contiguous electrocardiographic leads or a documented new left bundle branch block. Participation in CRUSADE required approval of the institutional review board of each hospital. Because patient information was collected anonymously through retrospective chart review without unique patient identifiers, individual informed consent was not required.
The study population for this analysis included 1011 patients with STEMI who were treated with fibrinolytics between April of 2005 and December of 2006. Patients with contraindications to or missing status for acute heparin therapy (n=7) and patients treated with no heparin (n=36), low-molecular-weight heparin (n=170), or both unfractionated heparin and low-molecular-weight heparin within the first 24 hours of hospitalization (n=40) were excluded. This yielded a final population of 758 patients with STEMI who were treated with fibrinolytics and adjunctive unfractionated heparin therapy; dosing analyses were performed on the 685 patients with available bolus and infusion dosing data.
Data Definitions
Recommended antithrombotic dosing was defined in accordance with the American College of Cardiology/American Heart Association/European Society of Cardiology STEMI management guidelines.3, 4 Excess dosing of unfractionated heparin was defined as>60 U/kg bolus or>12 U/kg/h infusion. Excess dosing was further stratified into mild and major excess with major defined as a bolus dose > 70 U/kg or infusion > 15 U/kg/h. Major bleeding was defined as an absolute hematocrit decrease of≥12%, intracranial hemorrhage, retroperitoneal bleeding, red blood cell transfusion with a baseline (admission) hematocrit≥28%, or red blood cell transfusion with a baseline hematocrit<28% and witnessed bleeding. Patients who underwent coronary artery bypass graft surgery during their hospitalization were excluded from the bleeding and transfusion analyses because of confounding with postbypass surgery bleeding and transfusion needs. Patients transferred from a CRUSADE hospital were excluded from the outcomes analyses, because outcomes data could not be ascertained after transfer because of current US privacy laws.
Statistical Methods
Patients were stratified into those with and without excess dosing. Baseline patient and hospital characteristics and in-hospital outcomes were compared between the 2 groups. Continuous variables were presented as medians with 25th and 75th percentiles. Categoric variables were expressed as frequencies with percentages. To test for independence, we used the Mantel-Haenszel chi-square test after controlling for hospital site.
Logistic generalized estimating equations models were used to determine the factors associated with excess unfractionated heparin dosing. This method accounted for within-center correlation of responses, that is, patients at the same hospital were more likely to have similar responses relative to patients in other hospitals.6 Factors entered into the model included patient characteristics (eg, age, sex, body mass index, hypertension, diabetes mellitus, renal insufficiency, previous percutaneous coronary intervention, previous heart failure, and signs of heart failure on admission) and hospital characteristics (eg, the number of inpatient beds, academic versus nonacademic hospitals, and cardiologist versus noncardiologist primary provider). Logistic generalized estimating equations modeling also was performed to evaluate the relationship between excess dosing and bleeding and transfusion outcomes. Variables entered in the model were adapted from baseline characteristics known to increase bleeding risk in the population with STEMI and included age, sex, body mass index, renal insufficiency, and signs of heart failure.7
A P value of less than .05 was considered statistically significant for all tests. All analyses were performed using SAS software version 9.1 (SAS Institute, Cary, NC).
Results
From April of 2005 to December of 2006, 758 patients with STEMI were treated with fibrinolysis and adjunctive unfractionated heparin therapy. Figure 1 shows the patterns of bolus and infusion dosing for unfractionated heparin. Of these patients, 368 (49%) received excess dosing of either the heparin bolus or infusion. Forty-seven patients received excess bolus dosing alone, 128 patients received excess infusion dosing, and 193 patients received excess dosing of both bolus and infusion.
Figure 1.
Dosing patterns of bolus (A) and infusion (B) unfractionated heparin.
Although practice guidelines recommend a 4000-unit maximum bolus dose and 1000 U/h maximum infusion dose,3, 4 336 patients (44%) received a bolus dose>4000 units and 129 patients (17%) received an infusion dose>1000 U/h. Moreover, 212 patients (28%) were given a bolus of exactly 5000 units, and 406 patients (54%) were given an infusion of exactly 1000 U/kg/h when heparin therapy was initiated. Among patients given these doses, 92 of 212 patients (43.4%) receiving the bolus and 148 of 406 patients (36.5%) treated with infusion actually received excess heparin dosing based on body weight. In addition, among patients who received excess dosing, more than one third (137/368 patients) were administered either bolus or infusion heparin doses far above the recommended dosing (major excess).
Patients who received excess dosing were older, with a higher prevalence of female sex, lower body weight, and renal insufficiency (Table 1). After multivariable adjustment, low body weight and female sex remained significantly associated with excess dosing (Table 2).
Table 1. Baseline Patient and Hospital Characteristics Stratified by Excess Dosing
| Variable | No Excess Dosing (n=317) | Excess Dosing (n=368) | P Value |
|---|---|---|---|
| Demographics | |||
| Age (y)⁎ | 58(50-65) | 61(52-71) | .002 |
| Female | 16.4 | 29.9 | <.0001 |
| Clinical characteristics | |||
| Body mass index (kg/m2)⁎ | 30(28-34) | 26(23-29) | <.0001 |
| Hypertension | 54.9 | 51.4 | .27 |
| Diabetes mellitus | 18.6 | 16.8 | .46 |
| Hyperlipidemia | 45.1 | 38.3 | .20 |
| Previous myocardial infarction | 18.0 | 14.1 | .10 |
| Previous PCI | 20.2 | 14.1 | .05 |
| Previous coronary artery bypass graft | 6.3 | 4.9 | .34 |
| Previous heart failure | 2.2 | 5.2 | .007 |
| Previous stroke | 3.2 | 4.6 | .14 |
| Renal insufficiency† | 2.5 | 4.1 | .04 |
| Presentation features | |||
| Systolic blood pressure (mm Hg)⁎ | 135(117-158) | 133(115-154) | .25 |
| Heart rate (beats/min)⁎ | 74(62-87) | 72(62-89) | .40 |
| Signs of heart failure | 11.0 | 8.2 | .42 |
| Hospital characteristics | |||
| Academic hospital | 47.9 | 39.1 | .02 |
| No. of inpatient beds⁎ | 458(323-593) | 372(226-593) | .005 |
| Hospital with PCI/surgical facilities | 88.0 | 79.9 | .03 |
⁎Values are median (25th and 75th percentile). |
†Renal insufficiency defined as serum creatinine |
Table 2. Factors Associated with Excess Unfractionated Heparin Dosing
| Variable | Chi-square | Adjusted OR | 95% CI | P Value |
|---|---|---|---|---|
| BMI (per 5 kg/m2 decrease) | 50.6 | 2.65 | 2.03-3.47 | <.0001 |
| Female | 9.4 | 2.17 | 1.32-3.56 | .002 |
| Previous PCI | 3.5 | 0.67 | 0.44-1.02 | .06 |
| History of heart failure | 2.5 | 2.3 | 0.83-6.4 | .11 |
| No. of hospital beds (per 100 beds) | 2.2 | 0.89 | 0.77-1.04 | .14 |
| Signs of heart failure on admission | 1.6 | 0.64 | 0.32-1.29 | .21 |
| Diabetes mellitus | 1.1 | 1.26 | 0.82-1.93 | .29 |
| Cardiology care | 1.0 | 1.36 | 0.75-2.49 | .31 |
| Age (per 10-y increase) | 0.4 | 1.05 | 0.91-1.20 | .52 |
| Renal insufficiency | 0.4 | 1.33 | 0.53-3.32 | .54 |
Major bleeding occurred in 75 of 477 patients (16%) in the noncoronary artery bypass graft and nontransfer groups. Patients with excess dosing had higher unadjusted rates of major bleeding (18.9% vs 12.4%, P = .007). The incidence of intracranial hemorrhage was low, with only 3 cases occurring in the overall analysis population. Similarly, patients with excess dosing were more likely to receive red blood cell transfusion (10.7% vs 4.7%, P = .003). Higher rates of major bleeding and transfusion were observed with increasing severity of excess dosing (Figure 2).
Figure 2.
Unadjusted bleeding and transfusion outcomes stratified by severity of excess dosing.
After adjustment for baseline clinical characteristics associated with bleeding, patients receiving mild and major excess dosing had no significant increase in major bleeding when compared with patients without excess dosing; however, there was a trend toward increased transfusion among patients who received major excess (Figure 3). There was no significant association between excess heparin dosing and in-hospital mortality (adjusted odds ratio 0.76, 95% confidence interval, 0.32-1.83).
Figure 3.
Adjusted odds ratio of major bleeding and transfusion for patients with STEMI receiving mild and major excess unfractionated heparin dosing referenced to no excess heparin dosing. Odds ratios adjusted for age, sex, body mass index, renal insufficiency, and signs of heart failure. OR
=odds ratio; CI=confidence interval.
Discussion
Our study provides one of the first characterizations of unfractionated heparin dosing among fibrinolytic-treated patients with STEMI in contemporary practice. Most notably, approximately half of the patients treated with unfractionated heparin received either the bolus or infusion dose in excess. Treatment with excess dosing may be associated with an increased risk of transfusion.
Proper dosing of both fibrinolytic and antithrombotic medications is critical for patients with STEMI because the therapeutic window is narrow and small deviations in the intensity of anticoagulation can significantly influence bleeding complications and clinical outcomes.8 Current practice guidelines recommend an initial heparin bolus dose of 60 U/kg and an infusion dose of 12 U/kg/h when used in conjunction with fibrinolytics to target an optimal activated partial thromboplastin time between 50 and 70 seconds.3 The guidelines further recommend not exceeding an upper dose limit of 4000 and 1000 units for the bolus and infusion doses, respectively. Higher activated partial thromboplastin times as a consequence of overdosing have been associated with increased rates of bleeding, mortality, stroke, and reinfarction.9, 10
Several studies have shown that adherence to dosing guidelines in clinical practice is far from ideal.5, 11 The results of this study are of particular concern, because patients with STEMI who are more likely to receive excess heparin dosing are already at higher risk for bleeding (female patients with low body weight).7 Notably, hospital characteristics such as size or academic status do not seem to play a role in dosage administration. One likely contributor to these dosing errors may be the lack of weight-based dosing, as evidenced by the preponderance of patients who were given the 5000-unit bolus/1000-unit infusion/hour heparin dosing combination. It is important to note that more than one third of these patients actually received heparin in excess based on body weight. It is unclear whether this “one-dose-fits-all” approach is related to under-recognition of STEMI dosing guidelines (which recommend a maximum 4000 unit heparin bolus) or is a response to the intense time pressure related to the need for rapid administration of reperfusion therapy to patients with STEMI, a situation that may deter clinicians from taking the time to measure a patient's body weight to guide initial dosing calculations.
The direct relationship between heparin dose and bleeding risk, particularly the risk of intracranial hemorrhage, is well established.12, 13, 14 Our results show a trend toward more transfusion use among patients who received major excess dosing, although the results were not statistically significant. Although the size of our study may be too small to make definitive conclusions regarding the association of excess heparin dosing with the risks of bleeding, intracranial hemorrhage, and transfusion, our findings demonstrate a cause for concern and deserve further validation in larger studies. Recent studies have confirmed the benefit of a multidrug anticoagulation strategy for patients with STEMI treated with fibrinolysis.15, 16 We might expect that, in the setting of concomitant fibrinolytic, aspirin, clopidogrel, and heparin therapies, dosing accuracy is even more critical to minimize the augmented bleeding risk. As studies comparing novel antithrombin strategies with unfractionated heparin evolve,17, 18 dosing accuracy and bleeding risks should be evaluated among patients treated in routine practice, where rigid dosing protocols are not enforced as in a randomized clinical trial. Possible solutions to this problem include pharmacist-assisted dosing verification or computer order entry systems, which could be used to ensure proper dosing of medications when used in conjunction with fibrinolytic agents.
Limitations
Several limitations should be considered in evaluating this analysis. First, the CRUSADE initiative tends to represent hospitals with an inherent interest in quality improvement; reported estimates of excess dosing and bleeding risk are therefore likely to be conservative. Second, wide confidence intervals were demonstrated with adjusted outcomes, reflecting the small size of the analysis population; thus, definitive conclusions could not be drawn about the association of excess dosing with bleeding complications and transfusion use. Third, fibrinolytic dosing and subsequent heparin dose adjustments after the initial dose was given were not collected in the CRUSADE database, and only a small portion of fibrinolytic-treated patients received low-molecular-weight heparin, so we could not evaluate patterns of dosing of this antithrombin agent with fibrinolysis. Fourth, because only in-hospital outcomes were collected in CRUSADE, conclusions about long-term mortality and morbidity cannot be made. Finally, as with any observational study, although we adjusted for a broad range of clinical and hospital factors, the possibility of confounding by unmeasured covariates still exists.
Conclusions
Approximately half of patients with STEMI treated with fibrinolytics and unfractionated heparin received an excess dose of heparin, and our results suggest a signal of increased bleeding complications with excess dosing. Therefore, quality improvement efforts for STEMI should focus not only on increasing the use of reperfusion therapy for all eligible patients but also on ensuring the proper dosing of adjunctive therapies given with fibrinolysis.
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CRUSADE was funded by Schering-Plough Corporation. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership and PDL Pharmaceuticals provided additional funding support. Millennium Pharmaceuticals Inc, also partly funded this work.
PII: S0002-9343(08)00445-2
doi:10.1016/j.amjmed.2008.04.023
© 2008 Elsevier Inc. All rights reserved.
