The quality of antiplatelet and anticoagulant medication administration among ST-segment elevation myocardial infarction patients transferred for primary percutaneous coronary intervention Tracy Y. Wang, MD, MHS, MSc, a David J. Magid, MD, MPH, b Henry H. Ting, MD, MBA, c Shuang Li, MS, a Karen P. Alexander, MD, a Matthew T. Roe, MD, MHS, a and Eric D. Peterson, MD, MPH a Durham, NC; Denver, CO; and Rochester, MN
Background Timely and appropriate use of antiplatelet and anticoagulant therapies has been shown to improve outcomes among ST-segment elevation myocardial infarction (STEMI) patients but has not been well described in patients transferred for primary percutaneous coronary intervention (PCI). Methods We examined 16,801 (26%) transfer and 47,329 direct-arrival STEMI patients treated with primary PCI at 441 Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With The Guidelines hospitals. Medication use was compared between transfer and direct-arrival patients to determine if these therapies were delayed or dosed in excess. Results Although transfer patients were more likely to receive antiplatelet and anticoagulant therapies before catheterization, they had longer delays to initiation of heparin (35 vs 25 minutes), clopidogrel (119 vs 84 minutes), and glycoprotein IIb/IIIa inhibitor (107 vs 60 minutes, P b .0001 for both). Administration of low-molecular-weight heparin and glycoprotein IIb/IIIa inhibitor at the STEMI-referring hospital was associated with longer delays to reperfusion compared with deferred administration at the STEMI-receiving hospital, whereas early use of unfractionated heparin was not. Among treated patients, those transferred were more likely to receive excess heparin dosing (adjusted odds ratio [OR] 1.28 [95% CI 1.041.58] for unfractionated heparin, adjusted OR 1.54 [95% CI 1.09-2.18] for low-molecular-weight heparin) and are associated with higher risks of major bleeding complications (adjusted OR 1.10, 95% CI 1.03-1.17). Conclusions ST-segment elevation myocardial infarction patients transferred for primary PCI in community practice are at risk for delayed and excessively dosed antithrombotic therapy, highlighting the need for continued quality improvement to maximize the appropriate use of these important adjunctive therapies. (Am Heart J 2014;0:1-7.)
Timely and appropriate use of antiplatelet and anticoagulant therapies has been shown to improve outcomes among patients with acute myocardial infarction (MI). 1 For patients with acute ST-segment elevation MI (STEMI), much of the focus of quality improvement initiatives to date has been on improving access to and timeliness of primary percutaneous coronary intervention (PCI). 2,3 The use, timeliness,
From the aDuke Clinical Research Institute, Durham, NC, bUniversity of Colorado, Denver, CO, and cMayo Clinic, Rochester, MN. James L. Januzzi, MD, served as guest editor for this article. Submitted November 22, 2013; accepted March 5, 2014. Reprint requests: Tracy Y. Wang, MD, MHS, MSc, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC 27705. E-mail: [email protected] http://dx.doi.org/10.1016/j.ahj.2014.03.002 0002-8703/ © 2014, Mosby, Inc. All rights reserved.
and dosing of adjunctive antiplatelet and anticoagulant treatments have not been well described in this patient population. With b25% of hospitals in the United States possessing 24/7 capability, many STEMI patients require interhospital transfer to receive primary PCI. 4 This transfer process poses additional challenges given the complexity of care coordination among STEMI referral hospitals, STEMI-receiving hospitals, and emergency medical services to deliver initial triage, transport for reperfusion, and administer early therapies. 5-8 Importantly, the quality of antiplatelet and anticoagulant therapy administration among transfer patients is largely unknown because transfer patients are typically excluded from publicly reported performance measures. 9 Therefore, variations in care patterns likely exist and may even contribute to further delays in reperfusion or increased risk of adverse outcomes such as bleeding.
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We examined a large contemporary STEMI patient population captured by the National Cardiovascular Data Registry Acute Coronary Treatment and Interventions Outcomes Network Registry–Get With The Guidelines (ACTION Registry–GWTG) to compare patterns of use and rates of excess dosing of antiplatelet and anticoagulant therapies between transfer and direct-arrival patients. In addition, we examined the association of transfer status with inhospital major bleeding. The objective of this study was to elucidate potential gaps in antithrombotic therapy use in the context of expediting reperfusion for STEMI patients. These insights will inform and enhance treatment protocols for patients who require interhospital transfer for reperfusion care.
Methods Study population The ACTION Registry–GWTG is a large, quality improvement registry designed to promote evidence-based treatment of patients with acute MI in the United States. Hospital participation requires approval of the institutional review board of each hospital. Because patient information is collected anonymously without unique patient identifiers, individual informed consent is not required. Between January 1, 2007, and December 31, 2010, 66,689 consecutive STEMI patients underwent primary PCI in the ACTION Registry–GWTG. Patients who had missing or invalid hospital arrival time (n = 497) who received primary PCI N12 hours after initial STEMI presentation (n = 716) or who received cardiac catheterization before arrival at the PCI hospital (n = 155) were first excluded. Then, as our goal was to examine medication use within the first 24 hours of hospital arrival, we excluded patients who died (n = 795), were transferred out of the PCI hospital (n = 310), or were discharged (n = 86) within 24 hours of initial hospital arrival, as these patients would not have the opportunity to receive early medications. These exclusions yielded a final study population of 64,130 STEMI patients who underwent primary PCI at 441 primary PCI hospitals in the United States.
Data collection and definitions Participating hospitals collected detailed information on baseline patient characteristics, inhospital treatment, and outcomes using a standardized set of data definitions, as described. 10 Trained data abstractors at each hospital abstracted presenting features, initial treatment, and contraindications into the data collection form from the medical record (including records transferred with the patient). Data were screened upon Webbased entry, and only those meeting predetermined criteria for completeness and accuracy were entered into the database. Ongoing data quality reports, data audits, and annual training sessions for data abstractors serve to ensure overall high-quality data. 11 The overall rate of missing data was b0.5% across all data elements reported in this analysis, except for baseline creatinine clearance (1.3% missing data). We investigated the use and timing of antiplatelet and anticoagulant medications given within the first 24 hours of presentation among all patients regardless of whether the dose
was administered at the STEMI-receiving or referral hospital. Timing of medication was defined as the date and time of initial dose administration (all medications were administered after hospital arrival except aspirin, which was administered prehospital in 17,738 direct-arrival patients [37.5%] and 2,770 transfer patients [16.5%]). We examined dosing only among patients who received the initial dose before cardiac catheterization, as any medications given within the catheterization laboratory may be dosed by measured activated clotting times. We defined excess dosing according to the recommendations made by the American College of Cardiology (ACC)/American Heart Association Guidelines and Acute Myocardial Infarction Performance Measures. 1,9 Timing of aspirin and clopidogrel administration was examined in patients who were not taking these therapies before admission. Door-to-balloon time was defined from time of STEMI patient arrival to the first hospital until device activation. Door-in-door-out time was defined from the time of patient arrival to the first hospital to departure from the first hospital for a STEMI patient transferred for primary PCI. Major bleeding, as defined in previous ACTION Registry–GWTG analyses,12 was defined as an absolute hematocrit drop 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 b28% and witnessed bleeding.
Statistical methods Baseline clinical characteristics, inhospital treatment, and events were compared between transfer and direct-arrival patients. Continuous variables were presented as medians with interquartile range (IQR), whereas categorical variables were expressed as percentages. Univariable comparisons were performed using Wilcoxon rank sum test for continuous variables and Mantel-Haenszel χ 2 test for categorical variables. Multivariable logistic regression with generalized estimating equation modeling was used to examine the association between transfer status and acute medication use, excess dosing, inhospital bleeding, and inhospital mortality. The generalized estimating equations method with exchangeable working correlation matrix was used to account for withinhospital clustering because patients at the same hospital are more likely to have similar responses relative to patients at other hospitals (ie, within-center correlation for responses). 13 In multivariable analyses, covariates used to adjust for mortality, acute medication use, door-in-door-out time, and door-to-balloon time were adapted from the validated mortality risk model previously developed in this registry 14 and included age, peripheral arterial disease, presenting heart rate, presenting systolic blood pressure, signs of heart failure or cardiogenic shock on admission, baseline serum creatinine, and baseline troponin ratio to the institution's upper limit of normal. Covariates for excess dosing were based on a prior model of factors associated with excess dosing and included age, sex, weight, diabetes, prior heart failure, dialysis, and hospital teaching status. 15 Covariates entered into the model to examine adjusted bleeding risk were adapted from the previously developed bleeding risk model and included age, sex, body weight, diabetes, heart rate, systolic blood pressure, heart failure, cardiogenic shock, baseline hemoglobin, creatinine, and home warfarin use. 12 We additionally adjusted for excess dosing
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when examining the association of transfer patients with bleeding outcomes. Patients transferred out from an ACTION Registry–GWTG hospital were excluded from the outcomes analyses, as outcome data could not be ascertained after transfer due to current US privacy laws. P b .05 was considered statistically significant for all tests. All analyses were performed using SAS software version 9.2 (SAS, Cary, NC). This research was supported by the ACC National Cardiovascular Data Registry. The authors are solely responsible for the design and conduct of this study, all analyses, the drafting and editing of the manuscript, and its final contents.
Results Baseline characteristics Among 64,130 STEMI patients reperfused with primary PCI, 16,801 (26%) required interhospital transfer for PCI. Compared with direct-arrival patients, transfer patients were more likely to be of white race and less likely to have prior MI or coronary revascularization (Table I). Transfer patients were modestly more likely to present during “offhours” (ie, nights and weekends). Transfer patients experienced longer delays to primary PCI compared with direct-arrival patients (median door-to-balloon time 125 [IQR 99-172] vs 68 [IQR 52-87] minutes, P b .0001). Early use and timing of anticoagulant therapies Compared with direct-arrival patients, transfer patients were more likely to receive antiplatelet medications and heparin, but not bivalirudin, before receiving cardiac catheterization at the PCI hospital (Table II). Similar associations were seen after multivariable adjustment. Yet with the exception of low-molecular-weight heparin (LMWH), transfer patients had significantly longer delays (P b .05) from hospital arrival to initiation of these therapies than direct-arrival patients, especially for clopidogrel and glycoprotein IIb/IIIa inhibitor (GPI) (Figure). Among transfer patients, aspirin and heparin were more likely to be started before hospital transfer; aspirin was started before arrival at the PCI hospital in 80.4% of transferred patients, and unfractionated heparin was started in 68.0%. In contrast, thienopyridines, bivalirudin, and GPI therapies were more likely to be deferred to the PCI hospital—only 39.2%, 0.3%, and 19.6%, respectively, were started at the first hospital. Unfractionated heparin, if started at the first hospital, was often given as a bolus-only dose with 36.3% of bolused patients transferred to the STEMI-receiving hospital without an infusion. Excess dosing High rates (N60%) of excess unfractionated heparin dosing, particularly with the bolus dose, were observed among STEMI patients who were administered heparin before cardiac catheterization (Table III). Rates of excess heparin dosing were higher among transfer patients than
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Table I. Baseline characteristics Overall Transfer Direct arrival (n = 64130) (n = 16801) (n = 47329) Demographics Age, y⁎ 59 (51, 69) 59 (50, 69) 59 (51, 69) Male sex 72.1% 72.8% 71.8% White race 84.8% 87.7% 83.7% Insurance HMO/private 58.1% 55.4% 59.1% Medicare/ 23.8% 25.0% 23.4% Medicaid VA/military 1.7% 2.4% 1.4% Self/none 15.6% 16.4% 15.4% Other 0.7% 0.8% 0.6% Clinical characteristics Prior MI 18.4% 16.2% 19.1% Prior coronary 23.3% 20.2% 24.3% revascularization Prior heart failure 3.7% 3.5% 3.7% Peripheral arterial 4.8% 4.5% 5.0% disease Prior stroke 4.1% 4.0% 4.2% Hypertension 61.2% 60.6% 61.4% Diabetes mellitus 21.7% 22.1% 21.6% Presenting features Prehospital ECG 33.4% 33.0% 33.5% obtained Off-hour 63.8% 65.2% 63.3% presentation † Time from symptom 92 (55, 188) 90 (50, 206) 92 (57, 183) onset to first hospital arrival, min Systolic blood 140 (119, 160) 142 (121, 162) 139 (119, 159) pressure, mm Hg⁎ Heart rate, 77 (64, 91) 77 (65, 91) 77 (64, 91) beat/min⁎ Symptoms/signs of heart failure Creatinine clearance, mL/min⁎,‡
7.5%
8.0%
7.3%
89 (65, 115)
91 (67, 118)
88 (65, 114)
Abbreviations: HMO, Health maintenance organization; VA, Veterans Affairs; ECG, electrocardiogram. ⁎ Values are presented as median (25th and 75th percentile). † Off-hour presentation denotes admission between 5:00 PM and 8:00 AM on weekdays and on weekends. ‡ Creatinine clearance was calculated by Cockroft-Gault equation among patients not on dialysis.
direct-arrival patients for both unfractionated heparin and LMWH. These results persisted after multivariable adjustment. Adjusted risk of excess GPI dosing was not significantly different between transfer and direct-arrival patients. Among transfer patients whose antithrombotic medications were first started at the STEMI referral hospital, excess dosing was observed in 67.6% of patients treated with unfractionated heparin, 17.1% of those treated with LMWH, and 6.9% of those treated with GPI.
Outcomes Administration of LMWH and GPI at the STEMI referral hospital was associated with longer delays to door-in-
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Table II. Use of antiplatelet and anticoagulant medications overall and before cardiac catheterization comparing transfer and direct-arrival patients Use before catheterization
Aspirin Thienopyridine UFH LMWH Bivalirudin GPI
Transfer
Direct arrival
Unadjusted P
80.6% 40.8% 69.8% 7.4% 1.2% 21.9%
78.7% 32.4% 59.7% 3.1% 2.6% 17.3%
b.001 b.001 b.001 b.001 b.001 b.001
Overall medication use in first 24 h
Adj OR (95% CI) Transfer 1.16 1.39 1.49 2.59 0.56 1.43
(1.06-1.28) (1.24-1.55) (1.32-1.69) (2.13-3.16) (0.33-0.95) (1.22-1.66)
99.1% 95.8% 84.2% 14.6% 23.6% 78.3%
Direct arrival
Unadjusted P
99.1% 95.2% 79.7% 10.9% 23.3% 78.9%
.87 .002 b.001 b.001 .51 .14
Adj OR (95% CI) 0.98 1.17 1.26 1.49 0.92 0.99
(0.78-1.23) (1.03-1.32) (1.12-1.42) (1.37-1.63) (0.85-0.98) (0.93-1.05)
Medications were those given to patients without contraindication or blinded therapies. Missing data were present in b0.5% of patients in each row; patients with missing data were retained in the denominator and considered not to have received therapy. Abbreviations: Adj, Adjusted; UFH, unfractionated heparin.
Figure
Median times to medication administration among transfer and direct-arrival STEMI patients. Timing of medications was provided regardless of where medication (black for antiplatelet therapies, red for anticoagulant therapies) was administered. For aspirin and clopidogrel, denominators excluded patients on these medications at home. P values comparing median times of medication administration between transfer and directarrival patients were all b.0001, except for LMWH (P = .27). Abbreviation: UFH, unfractionated heparin.
door-out time and overall door-to-balloon time compared with deferred administration in the STEMI-receiving hospital (Table IV). In contrast, administration of unfractionated heparin at the referral hospital was not associated with significant delays in door-in-door-out time and was associated with significantly shorter door-toballoon times. After multivariable adjustment, GPI use at the referral hospital remained significantly associated with delays in door-in-door-out time and reperfusion, whereas unfractionated heparin use was not. The use of LMWH at the STEMI referral hospital trended toward delays in reperfusion, but the CI was wide due to lower sample sizes and did not reach statistical significance.
Major bleeding occurred in 11.0% of the STEMI patients treated with primary PCI in our study population. After multivariable adjustment, transfer patients were modestly more likely to have a major bleeding complication (adjusted odds ratio [OR] 1.10, 95% CI 1.03-1.17) compared with direct-arrival patients. This association was unchanged after additionally adjusting for excess dosing: adjusted OR 1.10, 95% CI 1.03 to 1.17.
Discussion To date, tremendous attention has been focused on reducing reperfusion delays for patients with STEMI, yet
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Table III. Rates of excess dosing given before catheterization comparing transfer to direct-arrival patients
Heparin Unfractionated Bolus Infusion LWMH GPI
Transfer
Direct arrival
Unadjusted P
7880/11686 (67.4%) 7481/11467 (65.2%) 2108/7253 (29.1%) 194/1137 (17.1%) 222/3118 (7.1%)
17429/27080 (64.4%) 16771/26872 (62.4%) 3831/14063 (27.2%) 132/1119 (11.8%) 484/5257 (8.4%)
b.0001 b.001 .005 .0004 .03
Adj OR (95% CI)
1.28 1.25 1.15 1.54 0.85
(1.03-1.58) (1.00-1.56) (0.95-1.39) (1.09-2.18) (0.68-1.07)
Medications were those given to patients without contraindication or blinded therapies. Dosing was considered only for doses given before catheterization laboratory arrival.
little is known about the quality of adjunctive anticoagulant and antiplatelet treatment for these patients. This study raises the question: Are these important adjunctive therapies for transferred STEMI patients omitted, delayed, or dosed incorrectly? Several insights emerge from this study. First, although transfer patients were more likely to receive antiplatelet and anticoagulant therapies before catheterization, we observed significant delays to therapy initiation compared with direct-arrival patients. Second, administration of LMWH and GPI at the STEMI referral hospital was associated with longer delays in reperfusion compared with administration at the STEMI-receiving hospital. Third, transfer patients were at higher risk for receiving excess anticoagulant dosing than direct-arrival patients. Finally, transfer patients were associated with a higher adjusted risk of major bleeding compared with direct-arrival STEMI patients. The ACC/American Heart Association Guidelines provide a Class I recommendation for antiplatelet and anticoagulant therapy among STEMI patients treated with primary PCI. 1 Prior studies have demonstrated early clopidogrel pretreatment to be associated with improved infarct artery patency and clinical outcomes after primary PCI. 16,17 However, we observed significant delays (N30 minutes) in the initiation of clopidogrel, bivalirudin, and GPIs among transferred patients. A recent study showed an association between the log time delay to treatment and bleeding risk (adjusted OR 1.44), even within the first few hours of presentation, suggesting that the delays seen in our study are clinically relevant. We observed low rates of clopidogrel administration before catheterization, suggesting room for improvement as earlier administration permits prodrug activation to exert its effect during primary PCI. Although GPIs may be deferred to interventionalist preference at the STEMI-receiving hospital, delays in administration of aspirin and heparin are less acceptable because these therapies are recommended for both revascularized and medically managed MI patients, readily available in nonPCI settings, and, in some cases, can even be provided by emergency medical services before hospital arrival. Prolonged door-in-door-out times at the STEMI referral hospital have been associated with greater reperfusion delays and mortality 18; therefore, shortening door-in-
door-out time is a priority for STEMI patients transferred for primary PCI. Our study showed that early administration of LMWH and GPIs at the STEMI referral hospital was associated with longer delays in door-in-door-out time and, ultimately, longer delays to reperfusion, compared with deferred administration. We cannot distinguish if early administration of these medications at the STEMI referral hospital delayed transportation to reperfusion or if longer transportation lags at the STEMI referral hospital afforded greater opportunity for the patient to receive these therapies. Greater patient complexity may also lead to delays in both medication use and transfer. The FINESSE trial reported no benefit from pretransfer versus intraprocedural abciximab treatment among STEMI patients transferred for primary PCI. 19 As a result, the 2009 STEMI guidelines modified the recommendation for GPI timing from “as early as possible before primary PCI” to “at the time of primary PCI” (Class IIa recommendation). Weighing the potential for delaying door-in-doorout time and higher bleeding risk against possible benefits, our results support the deferral of GPI until arrival at the STEMI-receiving hospital. Why subcutaneous LMWH administration is associated with longer doorin-door-out time, whereas intravenous unfractionated heparin is not, is less clear. Less familiarity with dosing, discomfort with early use in the absence of creatinine data, and lack of ready access in the emergency STEMI triage area may contribute to its association with delayed care. Another important observation in this study is the high rate of excess dosing among STEMI patients who received heparin before catheterization. Current guidelines recommend weight-based heparin dosing among STEMI patients when given before catheterization laboratory arrival. 20 Although rates of excess heparin dosing have been previously reported for non-STEMI patients and fibrinolytic-treated STEMI patients, 15,21 this is the first report of excess heparin dosing among STEMI patients treated with primary PCI. This high rate of dosing error in community practice likely reflects a heuristic approach to dosing in the bustle of expedited transfer for reperfusion. These errors may also be reflective of early medication dosing using estimates rather than measurements of body weight and before the
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Table IV. Door-in-door-out time among transfer patients comparing medication administration at the STEMI referral (first) versus the STEMIreceiving (second) hospital Given at STEMI referral hospital Median door-in-door-out time UFH 56 (38, 83) LMWH 78 (48, 130) GPI 63 (45, 91) Median door-to-balloon time UFH 122 (98, 161) LMWH 160 (115, 244) GPI 131 (106, 174)
Given at STEMIreceiving hospital
P
58 (36, 92) 65 (44, 105) 55 (36, 85)
.07 .002 b.0001
130 (99, 191) 142 (111, 209) 122 (97, 168)
b.0001 .005 b.0001
Given at STEMI referral hospital Door-in-door-out N30 min 9186/11394 (80.6%) 1050/1243 (84.5%) 2702/3242 (83.3%) Door-to-balloon N120 min 5881/11394 (51.6%) 884/1243 (71.1%) 1951/3242 (60.2%)
Given at STEMIreceiving hospital
Adj OR (95% CI)
1665/2168 (76.8%) 212/263 (80.6%) 7464/9628 (77.5%)
1.16 (0.98-1.60) 1.40 (0.81-2.41) 2.42 (2.03-2.89)
1234/2168 (56.9%) 175/263 (66.5%) 4904/9628 (50.9%)
0.91 (0.80-1.03) 1.43 (0.96-2.11) 1.52 (1.31-1.77)
All continuous values expressed as median (25th and 75th percentiles) in minutes. Medications were those given to patients without contraindication or blinded therapies. Bivalirudin was not included in this table as only 30 patients were treated with bivalirudin at the STEMI referral hospital.
availability of laboratory information (eg, renal function). Excess dosing has been associated with increased bleeding risk among patients with non–ST-elevation acute coronary syndrome. 15 The higher risk of excess dosing observed in our study along with the longer durations of antiplatelet and anticoagulant therapy use due to longer delays to PCI potentially contributes to the higher risk of major bleeding among transferred patients compared with direct-arrival STEMI patients. As N60% of patients, regardless of transfer status, received excess heparin dosing, this is certainly a target of quality improvement interventions in both direct-arrival and transferred patients. Several elements of ongoing STEMI quality improvement programs provide potential solutions to the challenges observed in our study. Glickman et al 22 found that a STEMI system with a single designated hospital-specific reperfusion protocol was a key factor to reducing door-in-door-out delays at STEMI referral hospitals in North Carolina. Use of standardized order sets with dosing guides and multidisciplinary (eg, nurse, pharmacist) checklists may eliminate human error during a demanding time when simultaneous arrangements need to be made for triage, treatment, and transportation. 23 In the North Carolina initiative, unfractionated heparin was preferred for STEMI patients transferred for primary PCI, and the protocol recommended bolus dosing without maintenance infusion during transfer, resulting in 67% of STEMI referral hospitals eliminating intravenous infusions during transfer. A similar initiative in Pennsylvania also developed a transfer protocol that eliminated intravenous infusion dosing of heparin and GPIs. 7 An “MI kit” used in the Minnesota MI program contained pertinent order sets and adjunctive medications, which were helpful to promote availability, appropriate dosing, and expedited dosing of adjunctive therapies. 24 Improvement in primary PCI timeliness lies in coherent and effective STEMI networks; 1 strategy suggests the potential for prehospital administration of antiplatelet and anticoagulant medications 25 after early STEMI diagnosis.
Study limitations These data need to be considered in the light of some limitations. First, the ACTION Registry–GWTG does not capture STEMI patients who were eligible for primary PCI but were not transferred (ie, those who received fibrinolytic therapy or no reperfusion therapy and those who died before arrival). Second, the ACTION Registry– GWTG captures transfer patients from the perspective of the participating STEMI-receiving hospitals; data from the referral hospital were indirectly abstracted via transferred medical records. Although data “completeness” was similar between transfer and direct-arrival patients, we have no insight into the hospital characteristics and process descriptors of the initial STEMI referral hospital (such as triage process, decision making, and communication to facilitate transfer), which are likely to influence initial antiplatelet and anticoagulant use. Third, the exclusion of patients who died within the first 24 hours of admission was necessary as these patients may not have had the opportunity to receive medication therapies but may introduce a selection bias because the greatest STEMI mortality lies within this time window. Fourth, participation in the ACTION Registry–GWTG is voluntary and likely reflects an inherent hospital interest in quality improvement; therefore, there is potential for selection bias when comparing initial quality of care between direct-arrival (participating hospital) patients and transfer (nonparticipating hospital) patients. Finally, although the observational nature of this study permits real-world assessment of care patterns, the association between excess dosing and bleeding does not necessarily prove causality. Future studies will need to examine the association with longitudinal outcomes as only inhospital mortality is collected in this database.
Conclusions In summary, although transferred patients are more likely to receive antiplatelet and anticoagulant therapies before catheterization laboratory arrival, these therapies
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are often delayed and dosed in excess among transfer patients compared with direct-arrival STEMI patients treated with primary PCI. This may, in part, contribute to the association of transfer status with greater bleeding risk. These results highlight an important target for quality improvement in the care of transferred STEMI patients.
Acknowledgements We thank Erin Hanley, MS, for her editorial assistance with this manuscript. Ms Hanley did not receive compensation for her assistance, apart from her employment at the Duke Clinical Research Institution where this study was conducted.
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11. Messenger JC, Ho KK, Young CH, et al. The National Cardiovascular Data Registry (NCDR) Data Quality Brief: the NCDR Data Quality Program in 2012. J Am Coll Cardiol 2012;60:1484-8. 12. Mathews R, Peterson ED, Chen AY, et al. In-hospital major bleeding during ST-elevation and non–ST-elevation myocardial infarction care: derivation and validation of a model from the ACTION Registry–GWTG. Am J Cardiol 2011;107:1136-43. 13. Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986;42:121-30. 14. Chin CT, Chen AY, Wang TY, et al. Risk adjustment for in-hospital mortality of contemporary patients with acute myocardial infarction: the ACTION Registry–Get With The Guidelines acute myocardial infarction mortality model and risk score. Am Heart J 2011;161:113. e2-22. e2. 15. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non–ST-segment elevation acute coronary syndromes. JAMA 2005;294:3108-16. 16. Vlaar PJ, Svilaas T, Damman K, et al. Impact of pretreatment with clopidogrel on initial patency and outcome in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a systematic review. Circulation 2008;118: 1828-36. 17. Larson DM, Duval S, Sharkey SS, et al. Clopidogrel pretreatment in STelevation myocardial infarction patients transferred for percutaneous coronary intervention. Am Heart J 2010;160:202-7. 18. Wang TY, Nallamothu BK, Krumholz HM, et al. Association of doorin to door-out time with reperfusion delays and outcomes among patients transferred for primary percutaneous coronary intervention. JAMA 2011;305:2540-7. 19. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008;358: 2205-17. 20. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the ACC/AHA Task Force on Practice Guidelines. Circulation 2008;117:296-329. 21. Wang TY, Chen AY, Alexander KP, et al. Excess heparin dosing among fibrinolytic-treated patients with ST-segment elevation myocardial infarction. Am J Med 2008;121:805-10. 22. Glickman SW, Lytle BL, Ou FS, et al. Care processes associated with quicker door-in-door-out times for patients with ST-elevationmyocardial infarction requiring transfer: results from a statewide regionalization program. Circ Cardiovasc Qual Outcomes 2011;4: 382-8. 23. Freedman JE, Becker RC, Adams JE, et al. Medication errors in acute cardiac care: an AHA scientific statement from the Council on Clinical Cardiology Subcommittee on Acute Cardiac Care, Council on Cardiopulmonary and Critical Care, Council on Cardiovascular Nursing, and Council on Stroke. Circulation 2002;106:2623-9. 24. Henry TD, Unger BT, Sharkey SW, et al. Design of a standardized system for transfer of patients with ST-elevation myocardial infarction for percutaneous coronary intervention. Am Heart J 2005;150: 373-84. 25. Concannon TW, Kent DM, Normand SL, et al. Comparative effectiveness of ST-segment-elevation myocardial infarction regionalization strategies. Circ Cardiovasc Qual Outcomes 2010;3: 506-13.
Background Timely and appropriate use of antiplatelet and anticoagulant therapies has been shown to improve outcomes among ST-segment elevation myocardial infarction (STEMI) patients but has not been well described in patients transferred for primary percutaneous coronary intervention (PCI). Methods We examined 16,801 (26%) transfer and 47,329 direct-arrival STEMI patients treated with primary PCI at 441 Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With The Guidelines hospitals. Medication use was compared between transfer and direct-arrival patients to determine if these therapies were delayed or dosed in excess. Results Although transfer patients were more likely to receive antiplatelet and anticoagulant therapies before catheterization, they had longer delays to initiation of heparin (35 vs 25 minutes), clopidogrel (119 vs 84 minutes), and glycoprotein IIb/IIIa inhibitor (107 vs 60 minutes, P b .0001 for both). Administration of low-molecular-weight heparin and glycoprotein IIb/IIIa inhibitor at the STEMI-referring hospital was associated with longer delays to reperfusion compared with deferred administration at the STEMI-receiving hospital, whereas early use of unfractionated heparin was not. Among treated patients, those transferred were more likely to receive excess heparin dosing (adjusted odds ratio [OR] 1.28 [95% CI 1.041.58] for unfractionated heparin, adjusted OR 1.54 [95% CI 1.09-2.18] for low-molecular-weight heparin) and are associated with higher risks of major bleeding complications (adjusted OR 1.10, 95% CI 1.03-1.17). Conclusions ST-segment elevation myocardial infarction patients transferred for primary PCI in community practice are at risk for delayed and excessively dosed antithrombotic therapy, highlighting the need for continued quality improvement to maximize the appropriate use of these important adjunctive therapies. (Am Heart J 2014;0:1-7.)
Timely and appropriate use of antiplatelet and anticoagulant therapies has been shown to improve outcomes among patients with acute myocardial infarction (MI). 1 For patients with acute ST-segment elevation MI (STEMI), much of the focus of quality improvement initiatives to date has been on improving access to and timeliness of primary percutaneous coronary intervention (PCI). 2,3 The use, timeliness,
From the aDuke Clinical Research Institute, Durham, NC, bUniversity of Colorado, Denver, CO, and cMayo Clinic, Rochester, MN. James L. Januzzi, MD, served as guest editor for this article. Submitted November 22, 2013; accepted March 5, 2014. Reprint requests: Tracy Y. Wang, MD, MHS, MSc, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC 27705. E-mail: [email protected] http://dx.doi.org/10.1016/j.ahj.2014.03.002 0002-8703/ © 2014, Mosby, Inc. All rights reserved.
and dosing of adjunctive antiplatelet and anticoagulant treatments have not been well described in this patient population. With b25% of hospitals in the United States possessing 24/7 capability, many STEMI patients require interhospital transfer to receive primary PCI. 4 This transfer process poses additional challenges given the complexity of care coordination among STEMI referral hospitals, STEMI-receiving hospitals, and emergency medical services to deliver initial triage, transport for reperfusion, and administer early therapies. 5-8 Importantly, the quality of antiplatelet and anticoagulant therapy administration among transfer patients is largely unknown because transfer patients are typically excluded from publicly reported performance measures. 9 Therefore, variations in care patterns likely exist and may even contribute to further delays in reperfusion or increased risk of adverse outcomes such as bleeding.
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We examined a large contemporary STEMI patient population captured by the National Cardiovascular Data Registry Acute Coronary Treatment and Interventions Outcomes Network Registry–Get With The Guidelines (ACTION Registry–GWTG) to compare patterns of use and rates of excess dosing of antiplatelet and anticoagulant therapies between transfer and direct-arrival patients. In addition, we examined the association of transfer status with inhospital major bleeding. The objective of this study was to elucidate potential gaps in antithrombotic therapy use in the context of expediting reperfusion for STEMI patients. These insights will inform and enhance treatment protocols for patients who require interhospital transfer for reperfusion care.
Methods Study population The ACTION Registry–GWTG is a large, quality improvement registry designed to promote evidence-based treatment of patients with acute MI in the United States. Hospital participation requires approval of the institutional review board of each hospital. Because patient information is collected anonymously without unique patient identifiers, individual informed consent is not required. Between January 1, 2007, and December 31, 2010, 66,689 consecutive STEMI patients underwent primary PCI in the ACTION Registry–GWTG. Patients who had missing or invalid hospital arrival time (n = 497) who received primary PCI N12 hours after initial STEMI presentation (n = 716) or who received cardiac catheterization before arrival at the PCI hospital (n = 155) were first excluded. Then, as our goal was to examine medication use within the first 24 hours of hospital arrival, we excluded patients who died (n = 795), were transferred out of the PCI hospital (n = 310), or were discharged (n = 86) within 24 hours of initial hospital arrival, as these patients would not have the opportunity to receive early medications. These exclusions yielded a final study population of 64,130 STEMI patients who underwent primary PCI at 441 primary PCI hospitals in the United States.
Data collection and definitions Participating hospitals collected detailed information on baseline patient characteristics, inhospital treatment, and outcomes using a standardized set of data definitions, as described. 10 Trained data abstractors at each hospital abstracted presenting features, initial treatment, and contraindications into the data collection form from the medical record (including records transferred with the patient). Data were screened upon Webbased entry, and only those meeting predetermined criteria for completeness and accuracy were entered into the database. Ongoing data quality reports, data audits, and annual training sessions for data abstractors serve to ensure overall high-quality data. 11 The overall rate of missing data was b0.5% across all data elements reported in this analysis, except for baseline creatinine clearance (1.3% missing data). We investigated the use and timing of antiplatelet and anticoagulant medications given within the first 24 hours of presentation among all patients regardless of whether the dose
was administered at the STEMI-receiving or referral hospital. Timing of medication was defined as the date and time of initial dose administration (all medications were administered after hospital arrival except aspirin, which was administered prehospital in 17,738 direct-arrival patients [37.5%] and 2,770 transfer patients [16.5%]). We examined dosing only among patients who received the initial dose before cardiac catheterization, as any medications given within the catheterization laboratory may be dosed by measured activated clotting times. We defined excess dosing according to the recommendations made by the American College of Cardiology (ACC)/American Heart Association Guidelines and Acute Myocardial Infarction Performance Measures. 1,9 Timing of aspirin and clopidogrel administration was examined in patients who were not taking these therapies before admission. Door-to-balloon time was defined from time of STEMI patient arrival to the first hospital until device activation. Door-in-door-out time was defined from the time of patient arrival to the first hospital to departure from the first hospital for a STEMI patient transferred for primary PCI. Major bleeding, as defined in previous ACTION Registry–GWTG analyses,12 was defined as an absolute hematocrit drop 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 b28% and witnessed bleeding.
Statistical methods Baseline clinical characteristics, inhospital treatment, and events were compared between transfer and direct-arrival patients. Continuous variables were presented as medians with interquartile range (IQR), whereas categorical variables were expressed as percentages. Univariable comparisons were performed using Wilcoxon rank sum test for continuous variables and Mantel-Haenszel χ 2 test for categorical variables. Multivariable logistic regression with generalized estimating equation modeling was used to examine the association between transfer status and acute medication use, excess dosing, inhospital bleeding, and inhospital mortality. The generalized estimating equations method with exchangeable working correlation matrix was used to account for withinhospital clustering because patients at the same hospital are more likely to have similar responses relative to patients at other hospitals (ie, within-center correlation for responses). 13 In multivariable analyses, covariates used to adjust for mortality, acute medication use, door-in-door-out time, and door-to-balloon time were adapted from the validated mortality risk model previously developed in this registry 14 and included age, peripheral arterial disease, presenting heart rate, presenting systolic blood pressure, signs of heart failure or cardiogenic shock on admission, baseline serum creatinine, and baseline troponin ratio to the institution's upper limit of normal. Covariates for excess dosing were based on a prior model of factors associated with excess dosing and included age, sex, weight, diabetes, prior heart failure, dialysis, and hospital teaching status. 15 Covariates entered into the model to examine adjusted bleeding risk were adapted from the previously developed bleeding risk model and included age, sex, body weight, diabetes, heart rate, systolic blood pressure, heart failure, cardiogenic shock, baseline hemoglobin, creatinine, and home warfarin use. 12 We additionally adjusted for excess dosing
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when examining the association of transfer patients with bleeding outcomes. Patients transferred out from an ACTION Registry–GWTG hospital were excluded from the outcomes analyses, as outcome data could not be ascertained after transfer due to current US privacy laws. P b .05 was considered statistically significant for all tests. All analyses were performed using SAS software version 9.2 (SAS, Cary, NC). This research was supported by the ACC National Cardiovascular Data Registry. The authors are solely responsible for the design and conduct of this study, all analyses, the drafting and editing of the manuscript, and its final contents.
Results Baseline characteristics Among 64,130 STEMI patients reperfused with primary PCI, 16,801 (26%) required interhospital transfer for PCI. Compared with direct-arrival patients, transfer patients were more likely to be of white race and less likely to have prior MI or coronary revascularization (Table I). Transfer patients were modestly more likely to present during “offhours” (ie, nights and weekends). Transfer patients experienced longer delays to primary PCI compared with direct-arrival patients (median door-to-balloon time 125 [IQR 99-172] vs 68 [IQR 52-87] minutes, P b .0001). Early use and timing of anticoagulant therapies Compared with direct-arrival patients, transfer patients were more likely to receive antiplatelet medications and heparin, but not bivalirudin, before receiving cardiac catheterization at the PCI hospital (Table II). Similar associations were seen after multivariable adjustment. Yet with the exception of low-molecular-weight heparin (LMWH), transfer patients had significantly longer delays (P b .05) from hospital arrival to initiation of these therapies than direct-arrival patients, especially for clopidogrel and glycoprotein IIb/IIIa inhibitor (GPI) (Figure). Among transfer patients, aspirin and heparin were more likely to be started before hospital transfer; aspirin was started before arrival at the PCI hospital in 80.4% of transferred patients, and unfractionated heparin was started in 68.0%. In contrast, thienopyridines, bivalirudin, and GPI therapies were more likely to be deferred to the PCI hospital—only 39.2%, 0.3%, and 19.6%, respectively, were started at the first hospital. Unfractionated heparin, if started at the first hospital, was often given as a bolus-only dose with 36.3% of bolused patients transferred to the STEMI-receiving hospital without an infusion. Excess dosing High rates (N60%) of excess unfractionated heparin dosing, particularly with the bolus dose, were observed among STEMI patients who were administered heparin before cardiac catheterization (Table III). Rates of excess heparin dosing were higher among transfer patients than
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Table I. Baseline characteristics Overall Transfer Direct arrival (n = 64130) (n = 16801) (n = 47329) Demographics Age, y⁎ 59 (51, 69) 59 (50, 69) 59 (51, 69) Male sex 72.1% 72.8% 71.8% White race 84.8% 87.7% 83.7% Insurance HMO/private 58.1% 55.4% 59.1% Medicare/ 23.8% 25.0% 23.4% Medicaid VA/military 1.7% 2.4% 1.4% Self/none 15.6% 16.4% 15.4% Other 0.7% 0.8% 0.6% Clinical characteristics Prior MI 18.4% 16.2% 19.1% Prior coronary 23.3% 20.2% 24.3% revascularization Prior heart failure 3.7% 3.5% 3.7% Peripheral arterial 4.8% 4.5% 5.0% disease Prior stroke 4.1% 4.0% 4.2% Hypertension 61.2% 60.6% 61.4% Diabetes mellitus 21.7% 22.1% 21.6% Presenting features Prehospital ECG 33.4% 33.0% 33.5% obtained Off-hour 63.8% 65.2% 63.3% presentation † Time from symptom 92 (55, 188) 90 (50, 206) 92 (57, 183) onset to first hospital arrival, min Systolic blood 140 (119, 160) 142 (121, 162) 139 (119, 159) pressure, mm Hg⁎ Heart rate, 77 (64, 91) 77 (65, 91) 77 (64, 91) beat/min⁎ Symptoms/signs of heart failure Creatinine clearance, mL/min⁎,‡
7.5%
8.0%
7.3%
89 (65, 115)
91 (67, 118)
88 (65, 114)
Abbreviations: HMO, Health maintenance organization; VA, Veterans Affairs; ECG, electrocardiogram. ⁎ Values are presented as median (25th and 75th percentile). † Off-hour presentation denotes admission between 5:00 PM and 8:00 AM on weekdays and on weekends. ‡ Creatinine clearance was calculated by Cockroft-Gault equation among patients not on dialysis.
direct-arrival patients for both unfractionated heparin and LMWH. These results persisted after multivariable adjustment. Adjusted risk of excess GPI dosing was not significantly different between transfer and direct-arrival patients. Among transfer patients whose antithrombotic medications were first started at the STEMI referral hospital, excess dosing was observed in 67.6% of patients treated with unfractionated heparin, 17.1% of those treated with LMWH, and 6.9% of those treated with GPI.
Outcomes Administration of LMWH and GPI at the STEMI referral hospital was associated with longer delays to door-in-
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Table II. Use of antiplatelet and anticoagulant medications overall and before cardiac catheterization comparing transfer and direct-arrival patients Use before catheterization
Aspirin Thienopyridine UFH LMWH Bivalirudin GPI
Transfer
Direct arrival
Unadjusted P
80.6% 40.8% 69.8% 7.4% 1.2% 21.9%
78.7% 32.4% 59.7% 3.1% 2.6% 17.3%
b.001 b.001 b.001 b.001 b.001 b.001
Overall medication use in first 24 h
Adj OR (95% CI) Transfer 1.16 1.39 1.49 2.59 0.56 1.43
(1.06-1.28) (1.24-1.55) (1.32-1.69) (2.13-3.16) (0.33-0.95) (1.22-1.66)
99.1% 95.8% 84.2% 14.6% 23.6% 78.3%
Direct arrival
Unadjusted P
99.1% 95.2% 79.7% 10.9% 23.3% 78.9%
.87 .002 b.001 b.001 .51 .14
Adj OR (95% CI) 0.98 1.17 1.26 1.49 0.92 0.99
(0.78-1.23) (1.03-1.32) (1.12-1.42) (1.37-1.63) (0.85-0.98) (0.93-1.05)
Medications were those given to patients without contraindication or blinded therapies. Missing data were present in b0.5% of patients in each row; patients with missing data were retained in the denominator and considered not to have received therapy. Abbreviations: Adj, Adjusted; UFH, unfractionated heparin.
Figure
Median times to medication administration among transfer and direct-arrival STEMI patients. Timing of medications was provided regardless of where medication (black for antiplatelet therapies, red for anticoagulant therapies) was administered. For aspirin and clopidogrel, denominators excluded patients on these medications at home. P values comparing median times of medication administration between transfer and directarrival patients were all b.0001, except for LMWH (P = .27). Abbreviation: UFH, unfractionated heparin.
door-out time and overall door-to-balloon time compared with deferred administration in the STEMI-receiving hospital (Table IV). In contrast, administration of unfractionated heparin at the referral hospital was not associated with significant delays in door-in-door-out time and was associated with significantly shorter door-toballoon times. After multivariable adjustment, GPI use at the referral hospital remained significantly associated with delays in door-in-door-out time and reperfusion, whereas unfractionated heparin use was not. The use of LMWH at the STEMI referral hospital trended toward delays in reperfusion, but the CI was wide due to lower sample sizes and did not reach statistical significance.
Major bleeding occurred in 11.0% of the STEMI patients treated with primary PCI in our study population. After multivariable adjustment, transfer patients were modestly more likely to have a major bleeding complication (adjusted odds ratio [OR] 1.10, 95% CI 1.03-1.17) compared with direct-arrival patients. This association was unchanged after additionally adjusting for excess dosing: adjusted OR 1.10, 95% CI 1.03 to 1.17.
Discussion To date, tremendous attention has been focused on reducing reperfusion delays for patients with STEMI, yet
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Table III. Rates of excess dosing given before catheterization comparing transfer to direct-arrival patients
Heparin Unfractionated Bolus Infusion LWMH GPI
Transfer
Direct arrival
Unadjusted P
7880/11686 (67.4%) 7481/11467 (65.2%) 2108/7253 (29.1%) 194/1137 (17.1%) 222/3118 (7.1%)
17429/27080 (64.4%) 16771/26872 (62.4%) 3831/14063 (27.2%) 132/1119 (11.8%) 484/5257 (8.4%)
b.0001 b.001 .005 .0004 .03
Adj OR (95% CI)
1.28 1.25 1.15 1.54 0.85
(1.03-1.58) (1.00-1.56) (0.95-1.39) (1.09-2.18) (0.68-1.07)
Medications were those given to patients without contraindication or blinded therapies. Dosing was considered only for doses given before catheterization laboratory arrival.
little is known about the quality of adjunctive anticoagulant and antiplatelet treatment for these patients. This study raises the question: Are these important adjunctive therapies for transferred STEMI patients omitted, delayed, or dosed incorrectly? Several insights emerge from this study. First, although transfer patients were more likely to receive antiplatelet and anticoagulant therapies before catheterization, we observed significant delays to therapy initiation compared with direct-arrival patients. Second, administration of LMWH and GPI at the STEMI referral hospital was associated with longer delays in reperfusion compared with administration at the STEMI-receiving hospital. Third, transfer patients were at higher risk for receiving excess anticoagulant dosing than direct-arrival patients. Finally, transfer patients were associated with a higher adjusted risk of major bleeding compared with direct-arrival STEMI patients. The ACC/American Heart Association Guidelines provide a Class I recommendation for antiplatelet and anticoagulant therapy among STEMI patients treated with primary PCI. 1 Prior studies have demonstrated early clopidogrel pretreatment to be associated with improved infarct artery patency and clinical outcomes after primary PCI. 16,17 However, we observed significant delays (N30 minutes) in the initiation of clopidogrel, bivalirudin, and GPIs among transferred patients. A recent study showed an association between the log time delay to treatment and bleeding risk (adjusted OR 1.44), even within the first few hours of presentation, suggesting that the delays seen in our study are clinically relevant. We observed low rates of clopidogrel administration before catheterization, suggesting room for improvement as earlier administration permits prodrug activation to exert its effect during primary PCI. Although GPIs may be deferred to interventionalist preference at the STEMI-receiving hospital, delays in administration of aspirin and heparin are less acceptable because these therapies are recommended for both revascularized and medically managed MI patients, readily available in nonPCI settings, and, in some cases, can even be provided by emergency medical services before hospital arrival. Prolonged door-in-door-out times at the STEMI referral hospital have been associated with greater reperfusion delays and mortality 18; therefore, shortening door-in-
door-out time is a priority for STEMI patients transferred for primary PCI. Our study showed that early administration of LMWH and GPIs at the STEMI referral hospital was associated with longer delays in door-in-door-out time and, ultimately, longer delays to reperfusion, compared with deferred administration. We cannot distinguish if early administration of these medications at the STEMI referral hospital delayed transportation to reperfusion or if longer transportation lags at the STEMI referral hospital afforded greater opportunity for the patient to receive these therapies. Greater patient complexity may also lead to delays in both medication use and transfer. The FINESSE trial reported no benefit from pretransfer versus intraprocedural abciximab treatment among STEMI patients transferred for primary PCI. 19 As a result, the 2009 STEMI guidelines modified the recommendation for GPI timing from “as early as possible before primary PCI” to “at the time of primary PCI” (Class IIa recommendation). Weighing the potential for delaying door-in-doorout time and higher bleeding risk against possible benefits, our results support the deferral of GPI until arrival at the STEMI-receiving hospital. Why subcutaneous LMWH administration is associated with longer doorin-door-out time, whereas intravenous unfractionated heparin is not, is less clear. Less familiarity with dosing, discomfort with early use in the absence of creatinine data, and lack of ready access in the emergency STEMI triage area may contribute to its association with delayed care. Another important observation in this study is the high rate of excess dosing among STEMI patients who received heparin before catheterization. Current guidelines recommend weight-based heparin dosing among STEMI patients when given before catheterization laboratory arrival. 20 Although rates of excess heparin dosing have been previously reported for non-STEMI patients and fibrinolytic-treated STEMI patients, 15,21 this is the first report of excess heparin dosing among STEMI patients treated with primary PCI. This high rate of dosing error in community practice likely reflects a heuristic approach to dosing in the bustle of expedited transfer for reperfusion. These errors may also be reflective of early medication dosing using estimates rather than measurements of body weight and before the
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Table IV. Door-in-door-out time among transfer patients comparing medication administration at the STEMI referral (first) versus the STEMIreceiving (second) hospital Given at STEMI referral hospital Median door-in-door-out time UFH 56 (38, 83) LMWH 78 (48, 130) GPI 63 (45, 91) Median door-to-balloon time UFH 122 (98, 161) LMWH 160 (115, 244) GPI 131 (106, 174)
Given at STEMIreceiving hospital
P
58 (36, 92) 65 (44, 105) 55 (36, 85)
.07 .002 b.0001
130 (99, 191) 142 (111, 209) 122 (97, 168)
b.0001 .005 b.0001
Given at STEMI referral hospital Door-in-door-out N30 min 9186/11394 (80.6%) 1050/1243 (84.5%) 2702/3242 (83.3%) Door-to-balloon N120 min 5881/11394 (51.6%) 884/1243 (71.1%) 1951/3242 (60.2%)
Given at STEMIreceiving hospital
Adj OR (95% CI)
1665/2168 (76.8%) 212/263 (80.6%) 7464/9628 (77.5%)
1.16 (0.98-1.60) 1.40 (0.81-2.41) 2.42 (2.03-2.89)
1234/2168 (56.9%) 175/263 (66.5%) 4904/9628 (50.9%)
0.91 (0.80-1.03) 1.43 (0.96-2.11) 1.52 (1.31-1.77)
All continuous values expressed as median (25th and 75th percentiles) in minutes. Medications were those given to patients without contraindication or blinded therapies. Bivalirudin was not included in this table as only 30 patients were treated with bivalirudin at the STEMI referral hospital.
availability of laboratory information (eg, renal function). Excess dosing has been associated with increased bleeding risk among patients with non–ST-elevation acute coronary syndrome. 15 The higher risk of excess dosing observed in our study along with the longer durations of antiplatelet and anticoagulant therapy use due to longer delays to PCI potentially contributes to the higher risk of major bleeding among transferred patients compared with direct-arrival STEMI patients. As N60% of patients, regardless of transfer status, received excess heparin dosing, this is certainly a target of quality improvement interventions in both direct-arrival and transferred patients. Several elements of ongoing STEMI quality improvement programs provide potential solutions to the challenges observed in our study. Glickman et al 22 found that a STEMI system with a single designated hospital-specific reperfusion protocol was a key factor to reducing door-in-door-out delays at STEMI referral hospitals in North Carolina. Use of standardized order sets with dosing guides and multidisciplinary (eg, nurse, pharmacist) checklists may eliminate human error during a demanding time when simultaneous arrangements need to be made for triage, treatment, and transportation. 23 In the North Carolina initiative, unfractionated heparin was preferred for STEMI patients transferred for primary PCI, and the protocol recommended bolus dosing without maintenance infusion during transfer, resulting in 67% of STEMI referral hospitals eliminating intravenous infusions during transfer. A similar initiative in Pennsylvania also developed a transfer protocol that eliminated intravenous infusion dosing of heparin and GPIs. 7 An “MI kit” used in the Minnesota MI program contained pertinent order sets and adjunctive medications, which were helpful to promote availability, appropriate dosing, and expedited dosing of adjunctive therapies. 24 Improvement in primary PCI timeliness lies in coherent and effective STEMI networks; 1 strategy suggests the potential for prehospital administration of antiplatelet and anticoagulant medications 25 after early STEMI diagnosis.
Study limitations These data need to be considered in the light of some limitations. First, the ACTION Registry–GWTG does not capture STEMI patients who were eligible for primary PCI but were not transferred (ie, those who received fibrinolytic therapy or no reperfusion therapy and those who died before arrival). Second, the ACTION Registry– GWTG captures transfer patients from the perspective of the participating STEMI-receiving hospitals; data from the referral hospital were indirectly abstracted via transferred medical records. Although data “completeness” was similar between transfer and direct-arrival patients, we have no insight into the hospital characteristics and process descriptors of the initial STEMI referral hospital (such as triage process, decision making, and communication to facilitate transfer), which are likely to influence initial antiplatelet and anticoagulant use. Third, the exclusion of patients who died within the first 24 hours of admission was necessary as these patients may not have had the opportunity to receive medication therapies but may introduce a selection bias because the greatest STEMI mortality lies within this time window. Fourth, participation in the ACTION Registry–GWTG is voluntary and likely reflects an inherent hospital interest in quality improvement; therefore, there is potential for selection bias when comparing initial quality of care between direct-arrival (participating hospital) patients and transfer (nonparticipating hospital) patients. Finally, although the observational nature of this study permits real-world assessment of care patterns, the association between excess dosing and bleeding does not necessarily prove causality. Future studies will need to examine the association with longitudinal outcomes as only inhospital mortality is collected in this database.
Conclusions In summary, although transferred patients are more likely to receive antiplatelet and anticoagulant therapies before catheterization laboratory arrival, these therapies
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are often delayed and dosed in excess among transfer patients compared with direct-arrival STEMI patients treated with primary PCI. This may, in part, contribute to the association of transfer status with greater bleeding risk. These results highlight an important target for quality improvement in the care of transferred STEMI patients.
Acknowledgements We thank Erin Hanley, MS, for her editorial assistance with this manuscript. Ms Hanley did not receive compensation for her assistance, apart from her employment at the Duke Clinical Research Institution where this study was conducted.
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