European Heart Journal Advance Access published online on March 18, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn126
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Impact of home warfarin use on treatment patterns and bleeding complications for patients with non-ST-segment elevation acute coronary syndromes: observations from the CRUSADE quality improvement initiative
1 Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Room 0311, Terrace Level, Durham, NC 27705, USA
2 University of Cincinnati College of Medicine, Cincinnati, OH, USA
Received 12 June 2007; revised 25 February 2008; accepted 29 February 2008.
* Corresponding author. Tel: +1 919 668 8907, Fax: +1 919 668 7057, Email: wang0085{at}mc.duke.edu
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Abstract |
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Aims: To examine treatment patterns and outcomes of patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) receiving long-term warfarin anticoagulation.
Methods and results: We examined acute medication and invasive cardiac procedure use and in-hospital outcomes among 101 078 patients with NSTE ACS included in the CRUSADE registry. On admission, 7201 patients (7%) were on home warfarin therapy. Compared with non-anticoagulated patients, these patients were older and had more comorbidities, but were less likely to receive acute antiplatelet and antithrombin medications. Patients on warfarin were also less likely to undergo coronary angiography (adjusted OR 0.77, 95% CI 0.70–0.86) and percutaneous coronary intervention (adjusted OR 0.80, 95% CI 0.75–0.86), and had longer waiting times for these procedures when performed. Although patients on warfarin had higher rates of death and major bleeding compared with non-anticoagulated patients, these differences were no longer significant after multivariable adjustment [ORs 0.90 (95% CI 0.80–1.02) and 1.02 (95% CI 0.93–1.11)]. Among patients on warfarin, however, early use of antiplatelet medications was associated with increased transfusion risk.
Conclusion: Despite higher-risk characteristics, warfarin-anticoagulated patients are often more conservatively managed, as early use of antithrombotic therapies may be associated with increased bleeding. Further investigation is needed to determine the optimal choice of therapies for this population.
Key Words: NSTE ACS • Warfarin • Anticoagulation • Bleeding
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Introduction |
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An estimated 2.5 million patients in the United States are treated with warfarin anticoagulant therapy, and many of these patients have concurrent risk factors for coronary artery disease.1 However, patients on warfarin who present with acute coronary syndrome (ACS) represent a clinical conundrum, as management guidelines for ACS are based on clinical trials that have largely excluded patients who receive long-term anticoagulation therapy.2 Although antithrombotic medications and revascularization procedures effectively reduce cardiovascular morbidity and mortality,3 the risk of bleeding associated with these treatment strategies may be particularly heightened in the setting of therapeutic anticoagulant levels.4 In the absence of evidence-based guidelines, the optimal treatment strategy for patients on long-term warfarin remains unclear and likely results in significant variations in physician practice and clinical outcomes.
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) Quality Improvement Initiative database offers a unique opportunity to examine current patterns of early antithrombotic medication and invasive cardiac procedure use among patients chronically anticoagulated with warfarin, and to correlate the use of these therapies with bleeding complications in this population.
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Methods |
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Study population
CRUSADE is a national registry designed to improve the quality of care for patients hospitalized with non-ST-segment elevation (NSTE) ACS. Consecutive patients with ischaemic symptoms within 24 h of presentation lasting
10 min and high-risk features such as ischaemic ST-segment electrocardiographic changes (ST depression 0.5 mm, transient ST elevation 0.5–1.0 mm lasting <10 min) and/or cardiac biomarkers (troponin I or T and/or creatine kinase-MB) greater than normal upper limit within 24 h of hospital admission were included. Hospital participation in CRUSADE was voluntary and open to all hospitals in the United States. Participation required the approval of the institutional review board of each hospital. As patient information was collected anonymously without unique patient identifiers, individual informed consent was not required. The CRUSADE data collection form captured baseline demographic and clinical characteristics, use and dosing of acute evidence-based medical therapies (i.e. within 24 h of presentation), and use of in-hospital coronary angiography and revascularization procedures using standardized data elements and data definitions.5 Patient data were captured retrospectively via chart review and entered by sites into a web-based data collection form. Data were screened upon entry, and only those meeting predetermined criteria for completeness and accuracy could be entered into the database. In 2002, de-identified records from one quarter of the CRUSADE hospitals (randomly selected) were audited, revealing an overall data accuracy of 95%. The overall degree of missing data averaged 5% across all data elements, with variables such as age and gender missing in <0.5% of all cases. Each quarter, sites received a report summarizing any observed data quality issues, thus iteratively improving the overall quality of the database.
The study population for this analysis included 101 078 patients enrolled in CRUSADE between February 2003 and June 2006 across 475 US hospitals of varying size, teaching status, and interventional or cardiac surgical capabilities. Use of home warfarin was not collected in CRUSADE until version 2 of the data collection form was implemented in February, 2003. Patients transferred out from a CRUSADE hospital were excluded from the outcomes analyses, as clinical outcomes could not be ascertained after transfer because of current U.S. privacy laws.
Data definitions
Patients on home warfarin anticoagulation were defined as those for whom warfarin was documented as a home medication at hospital admission. Recommended antithrombotic dosing was defined in accordance with guidelines and package inserts.2,6 Under-dosing was defined as enoxaparin administered at <0.95 mg/kg or unfractionated heparin (UFH) administered at <50 units/kg bolus or <10 units/kg/h infusion. In-hospital clinical outcomes were collected using standardized definitions:5 post-admission myocardial infarction was defined as clinical signs and symptoms of a repeat infarction distinct from the presenting event, associated either with new significant Q waves in at least two contiguous ECG leads or new biomarker elevation. Among patients without revascularization, biomarker elevation was defined by a creatine kinase-MB (CK-MB) or troponin increase above the upper limit of normal (ULN) if the most recent markers prior to the event were normal or an increase of 50% above the most recent value in patients whose most recent values were above the ULN. Among patients within 24 h of a revascularization procedure, biomarker elevation was defined by a CK-MB increase of 50% of preprocedure level (if preprocedure markers were above the ULN) or increased to 3x the ULN in patients (if preprocedure markers were normal) within 24 h of percutaneous coronary intervention (PCI), or increase to 5x the ULN in patients within 24 h of coronary artery bypass grafting (CABG). Stroke was defined as a focal neurological deficit lasting 24 h. Major bleeding was defined as an absolute haematocrit drop of 12%, intracranial haemorrhage, retroperitoneal bleeding, a baseline (admission) haematocrit 28% with a red blood cell transfusion, or a baseline haematocrit <28% with witnessed bleeding that was accompanied by a red blood cell transfusion. Transfusion was defined as any non-autologous transfusion of either whole blood or packed red blood cells. Patients who had in-hospital CABG were excluded from the bleeding and transfusion analyses because of confounding with post-CABG bleeding and transfusion needs.
Statistical methods
Patients were stratified into those who were receiving home warfarin at time of hospital admission and those who were not. Baseline patient and hospital characteristics, use of acute medical therapies and revascularization procedures, and in-hospital outcomes were compared between the two groups. Continuous variables were presented as medians with 25th and 75th percentiles. Categorical variables were expressed as frequencies with percentages. Continuous and ordinal categorical variables were compared using stratum adjusted Wilcoxon rank-sum tests, whereas nominal categorical variables were compared using stratum-adjusted 
2 tests where stratification is by hospital.
Logistic generalized estimating equations models were used to compare treatment patterns and outcomes between chronically anticoagulated and non-chronically anticoagulated patients.7 This method accounted for within-centre correlation of responses; i.e. patients at the same hospital were more likely to have similar responses relative to patients in other hospitals. The type of covariance matrix used to model the within-centre correlations is the exchangeable correlation structure. Variables entered in the models were adapted from a validated mortality risk model for patients with NSTE ACS (c-index = 0.81)8 and included age, sex, race, body mass index, insurance status (Medicare, Medicaid, self-insured, or health maintenance organization/private insurance), family history of coronary artery disease, hypertension, diabetes mellitus, current/recent smoker, hyperlipidaemia (defined as known total cholesterol >200 mg/dL or chronic treatment with a lipid-lowering agent), previous myocardial infarction, previous PCI, previous CABG, previous heart failure (HF), previous stroke, renal insufficiency, presenting systolic blood pressure, heart rate, ST-segment (depression, elevation, neither), signs of HF at presentation, positive cardiac biomarkers, physician specialty (cardiologist vs. non-cardiologist), hospital region (West, Northeast, Midwest, or South), facility type (no services, surgery, catheterization laboratory only, or percutaneous but no surgical revascularization capability), teaching hospital status (academic vs. non-academic), and total number of beds.
The relationship between acute use of antiplatelet medications such as aspirin, clopidogrel, and GP IIb/IIIa inhibitor within the first 24 h of admission and subsequent bleeding and transfusion outcomes were explored among the patients on home warfarin. Because admission INR was not a variable collected in this database, we repeated this analysis within the group of patients on warfarin who were also treated with acute heparin.
A P value of <0.05 was considered statistically significant for all tests and all tests of statistical significance were two-tailed. All analyses were performed using SAS software version 9.1 (SAS Institute, Cary, NC).
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Results |
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Patient characteristics
Among 101 078 ACS patients included in CRUSADE during the period of analysis, 7201 (7.1%) were on home warfarin therapy at the time of ACS admission. Patients on warfarin were older and had a higher prevalence of comorbid risk factors, such as hypertension, diabetes mellitus, and renal insufficiency, as well as evidence of existing cardiovascular disease, including prior stroke, myocardial infarction, revascularization, and HF (Table 1).
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Comparison of treatment patterns between patients with and without home warfarin use
After adjustment for baseline patient and hospital characteristics, patients on home warfarin were significantly less likely to be treated with acute antithrombotic medications (aspirin, clopidogrel, heparin, and glycoprotein IIb/IIIa inhibitors) than patients who were not on warfarin (Table 2), in contrast to other guidelines-recommended medications such beta-blockers, angiotensin-converting enzyme inhibitors, and statins. Notably, 74.9% of patients on warfarin received heparin anticoagulation, 37.7% received clopidogrel, and 25.5% received glycoprotein IIb/IIIa inhibitors within the first 24 h of hospitalization.
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Patients on home warfarin therapy were less likely to receive recommended dosages of these acute medications (Table 3). A full loading dose (
325 mg) of aspirin was given in only 57.9% of warfarin-anticoagulated patients compared with 67.7% of patients not on warfarin (adjusted OR 0.76, 95% CI 0.71–0.81). Among patients on warfarin who were treated with UFH, 30.4% were started on an intravenous infusion alone without a bolus dose and 33.0% were given a lower than recommended bolus dose (defined as <50 units/kg bolus). There were no significant differences in the dosing of the UFH infusion or low-molecular-weight heparin between patients with and without home warfarin use.
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Patients on home warfarin were less likely to undergo diagnostic cardiac catheterization, PCI, or CABG compared with those who were not on warfarin (Table 4). Patients on warfarin undergoing PCI trended towards slightly lower rates of drug-eluting stent use (69.1 vs. 72.8%; adjusted OR 0.93, 95% CI 0.85–1.01). Median waiting times for procedures were also longer for patients on home warfarin (Figure 1). Patients on warfarin undergoing PCI were less likely to receive upstream glycoprotein IIb/IIIa inhibitors (adjusted OR 0.79, 95% CI 0.68–0.93) compared with patients who were not on warfarin.
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Comparison of outcomes between patients with and without home warfarin use
Patients on home warfarin had higher rates of adverse clinical outcomes than patients who were not on warfarin; however, after adjusting for baseline clinical characteristics, there were no longer any significant differences in the adjusted risks of in-hospital death, post-admission myocardial infarction, major bleeding, and stroke (Table 5). Non-CABG-related transfusion rates were slightly higher in the group of patients on warfarin (13.2 vs. 9.0%, adjusted OR 1.09, 95% CI 1.00–1.19).
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Correlation of acute medication use with bleeding outcomes among patients on home warfarin
Among patients who were on home warfarin, those treated with early clopidogrel or glycoprotein IIb/IIIa inhibitors tended to be younger, male, and less likely to have had a history of prior HF compared with patients who did not receive early antiplatelet therapy. However, even after adjusting for these differences, early use of clopidogrel use among these patients was associated with increased risk of transfusion, and early glycoprotein IIb/IIIa inhibitor use was associated with both increased bleeding and transfusion risks (Figure 2). In a secondary analysis restricted to warfarin patients treated with acute heparin, a similar increase in major bleeding and transfusion was seen with the acute use glycoprotein IIb/IIIa inhibitors [adjusted ORs 1.74 (95% CI 1.35–2.25) and 1.41 (95% CI 1.05–1.89), respectively].
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Discussion |
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Our study provides one of the first characterizations of acute treatment patterns among patients who were receiving home warfarin anticoagulation at time of hospitalization for NSTE ACS. A sizable proportion of NSTE ACS patients (7%) were on home warfarin anticoagulation. These patients had a higher risk profile compared with patients who were not on chronic anticoagulation, yet were less likely to receive acute antithrombotic and invasive therapies. Although overall bleeding rates were similar, chronically anticoagulated patients were slightly more likely to receive a transfusion than non-anticoagulated patients. Among patients receiving home warfarin, early use of antiplatelet agents was associated with higher bleeding and transfusion risks.
Use of antithrombotic medications in the warfarin-anticoagulated patient
The haemorrhagic risk of warfarin therapy remains significant and appears to be compounded by the multi-tiered antithrombotic strategy recommended for ACS.4 Practice guidelines for the use of antithrombotic and invasive therapies in ACS patients are largely based on clinical trials with highly selected populations.2 As a result, there is very little evidence to guide management of chronically anticoagulated patients. To complicate matters further, patients requiring long-term anticoagulation, as our study shows, are in a higher category of risk by any measurable ACS risk score. Thus, clinicians are faced with the dilemma of increased thrombotic risk as a result of insufficient antithrombotic therapy use, or increased bleeding risk as a result of potential interactions with acute ACS therapies.
Current practice patterns reflect conservative use of antithrombotic strategies among warfarin-treated patients in the absence of adequate safety data, yet notably 75% of patients on home warfarin received heparin therapy within the first 24 h of hospitalization. While international normalized ratios (INRs) on admission were not collected in the CRUSADE database, subtherapeutic INR levels have been reported in 28–43% of patients on long-term warfarin therapy,9,10 suggesting that at least one in four patients were treated with heparin despite therapeutic warfarin levels. No randomized clinical trial to date has examined the safety of using glycoprotein IIb/IIIa inhibitors in patients who are on warfarin. Our study shows that early use of glycoprotein IIb/IIIa inhibitors occurred in 26% of ACS patients who were on warfarin at time of admission. Although treated patients were less likely to have bleeding risk factors,4 glycoprotein IIb/IIIa inhibitor use was still associated with significant bleeding and transfusion risks. In contrast to an earlier study that showed no significant effect of concomitant clopidogrel and warfarin therapy on bleeding risk,11 our results suggest an association of early clopidogrel treatment with increased transfusion risk. However, patients treated with either glycoprotein IIb/IIIa inhibitors or clopidogrel are usually simultaneously treated with aspirin and antithrombin therapy; thus, a synergistic effect from concomitant anticoagulating therapies may further contribute to the increase in bleeding risk.
Newer antithrombotic agents have been promoted as alternative therapies in both ACS and PCI on the basis of reduced bleeding risk when compared with traditional heparin-based strategies.12,13 These medications may be particularly valuable in reducing the bleeding risk of ACS patients receiving long-term anticoagulation and further investigation is warranted.
Use of invasive procedures in the warfarin-anticoagulated patient
Although an early invasive strategy is recommended for patients who present with NSTE ACS,2 patients on warfarin are less likely to undergo in-hospital catheterization and revascularization. The common clinical practice of deferring cardiac catheterization until a lower INR is reached is associated with increased hospital stay and cost, and may be associated with increased cardiovascular risk, particularly among patients with left ventricular dysfunction or left main or multivessel disease. Likewise, the risk and inconvenience of bridging heparin administration, the potential risk of thromboembolic complications resulting from warfarin interruption, and the transient prothrombotic state associated with warfarin re-initiation can further contribute to adverse outcomes.14
The concern for bleeding is a major determinant of the timing of an invasive procedure. Patients with ST-segment elevation myocardial infarction frequently proceed to urgent PCI despite therapeutic INR levels; however, periprocedural anticoagulation and outcomes in this population are not well characterized. With the advent of haemostasis devices, arterial sheaths can now be safely removed in the setting of full short-term anticoagulation with a low incidence of haemorrhagic or vascular complications.15 In a recent study, Jessup and colleagues showed no in-hospital bleeding or vascular complications in a small cohort of patients undergoing elective coronary angiography with INRs between 1.8 and 3.5.16 Of note in this non-controlled study, additional heparin was given to a target-activated clotting time (ACT) of 300 s; clopidogrel was given post-stent implantation, and no glycoprotein IIb/IIIa inhibitors were used. Although warfarin is known to increase the activated coagulation time (ACT) monitored during interventional procedures,17 the interaction between warfarin and adjunctive medications (such as clopidogrel and glycoprotein IIb/IIIa inhibitors) commonly used in the catheterization laboratory is largely unknown.
Study limitations
This study adds to our knowledge of ACS patients receiving long-term anticoagulation; however, several issues should be borne in mind when interpreting these results. First, CRUSADE did not specifically collect indications for warfarin administration or the intensity of anticoagulation (i.e. admission INR) prior to hospitalization. Despite this limitation, the CRUSADE database was selected for its national scope and large size, thereby ensuring an adequately large population of warfarin-treated patients in whom current clinical practice can be assessed. Additional data on INR levels may help elucidate clinical decision-making, particularly among the 50–70% of patients on long-term warfarin who present for emergent care with therapeutic levels of anticoagulation.10 Second, the database only reports in-hospital outcomes, so conclusions about long-term mortality and morbidity (and, in particular, potential downstream benefits from intensive early ACS treatment) cannot be made. Finally, as in any nonrandomized trial, our study is inherently subject to potential confounders. Although we attempted to address this by adjusting for a broad range of clinical and hospital factors, the possibility of confounding by unmeasured covariates remains. Of note, warfarin-treated patients who received clopidogrel and glycoprotein IIb/IIIa inhibitor therapies had fewer bleeding risk factors, yet were still more likely to bleed or require transfusion. These findings suggest that, independent of baseline risk factors, warfarin-treated patients may still be more vulnerable to bleeding when treated with antiplatelet agents.
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Conclusion |
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In this observational study, we note that a sizable proportion of patients with NSTE ACS are on long-term warfarin anticoagulation at the time of hospital presentation. Although these patients constitute a higher-risk population, they are less likely to receive antithrombotic and invasive therapies. Early use of antiplatelet agents in these patients is associated with increased bleeding and transfusion risks. The long-term impact of this strategy, however, deserves further study to better inform decision making for NSTE ACS management in this complex patient population.
Conflict of interest: E.D.P. received research grants from Bristol-Myers Squibb, BMS/Sanofi pharmaceuticals partnership, BMS/Merck partnership, E.M.O., W.B.G., and M.T.R. received research grants from Millenium pharmaceuticals, Bristol-Myers Squibb/Sanofi pharmaceuticals partnership, Schering Corporation.
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Funding |
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CRUSADE is funded by Schering-Plough Corporation. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership provides additional funding support. Millennium Pharmaceuticals, Inc. also partly funded this work.
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