Thrombosis Research 135 (2015) 249–254

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Thrombosis Research

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Regular Article Safety of venous thromboembolism prophylaxis with fondaparinux in ischemic stroke☆

C.T. Hackett a,d,1, R.S. Ramanathan a,1, K. Malhotra a,M.R.Quigleyb,c,K.M.Kellya,c,M.Tiana,J.Protetcha, C. Wong a,c,D.G.Wrighta,c,A.H.Tayala,c,⁎ a Department of Neurology and Allegheny General Hospital Comprehensive Stroke Center, University of South Carolina b Department of Neurosurgery and Allegheny General Hospital, University of South Carolina c Drexel University College of Medicine, University of South Carolina d Department of Psychology, University of South Carolina article info abstract

Article history: Introduction: Unfractionated (UFH), low molecular weight heparin or fondaparinux are recommended Received 19 June 2014 for venous thromboembolism (VTE) prophylaxis in acutely ill medical patients. There are limited data on the Received in revised form 11 September 2014 safety of fondaparinux for VTE prophylaxis in ischemic stroke. We examined adverse event frequency in Accepted 4 November 2014 hospitalized patients with ischemic stroke who received VTE prophylaxis with fondaparinux versus UFH. Available online 13 December 2014 Materials and Methods: We performed a propensity score matched analysis on a retrospective cohort of 644 consecutive patients with acute ischemic stroke receiving fondaparinux (n = 322) or UFH (n = 322) for VTE prophylaxis. Patients who received intravenous tPA and continuous intravenous infusions of UFH were excluded. The primary outcome was major hemorrhage (intracranial or extracranial) and the secondary outcome was total hemorrhage (major and minor hemorrhage) during hospitalization. We also examined the rate of symptomatic VTE. Results: Mean age of the matched cohort was 71.3 ± 14.1 years, median NIHSS score was 4 (IQR 1–11), median duration of exposure was 5 (IQR 3–8) days, and 98.1% received antiplatelet medications. In the matched cohort, there were less observed major hemorrhages in the fondaparinux group 1.2% (4/322) compared to UFH 3.7% (12/322), but this difference was not significant (OR = 0.33, 95% CI 0.08–1.10, p = 0.08). There were also no significant differences in total hemorrhage (p = 0.15), intracranial hemorrhage (p = 0.48), major extracranial hemorrhage (p = 0.18) and symptomatic VTE (p = 1.00) between the groups. Conclusions: Fondaparinux is not associated with increased hemorrhagic complications compared with UFH in patients with ischemic stroke. There were low rates of symptomatic VTE in both groups. © 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Introduction stroke have demonstrated a high prevalence of total VTE (20–40%) in the absence of VTE prophylaxis [3,4],however,theincidenceofsymp- Recent worldwide estimates of incident stroke are 16.9 million tomatic VTE is significantly lower (b1%) [5]. Expert consensus group cases, 5.9 million stroke deaths, 33 million stroke survivors, and 102 guidelines recommend low dose unfractionated heparin (LDUH), low million disability-adjusted life-years (DALYs) lost reflecting an overall molecular weight heparin (LMWH) or intermittent pneumatic com- increasing global burden of stroke (1990-2010) [1]. Ischemic stroke ac- pression (IPC) for VTE prophylaxis in patients with acute ischemic counts for 87% of all strokes, leading to high rates of disability and death; stroke and restricted mobility [6]. Unfractionated and LMWH 50% of survivors have hemiparesis and 30% require assistance to walk reduce the incidence of prospectively identified asymptomatic deep [2]. Prospective studies of hospitalized patients with acute ischemic (DVT) and symptomatic (PE), but are associated with increased major extracranial hemorrhage and nonsignificant trends toward increased symptomatic intracranial hemorrhage [7–9]. Fondaparinux was associated with decreased ☆ Statistical Analysis: conducted by authors M. R. Quigley and C. T. Hackett asymptomatic and symptomatic VTE without increased major hemor- ⁎ Corresponding author at: Allegheny General Hospital, Comprehensive Stroke Center, rhage in a prospective randomized placebo controlled trial of VTE Allegheny Health Network 490 East North Avenue, Suite 500, Pittsburgh, PA 15212. prophylaxis in non-ambulatory patients age N 60 years with acute Tel.: +1 412 358 8841; fax: +1 412 442 2232. E-mail address: [email protected] (A.H. Tayal). medical conditions [10]. This study excluded patients with ischemic 1 Co-first authors each contributed equally to the manuscript. stroke considered to be at increased risk of hemorrhage [10]. There is

http://dx.doi.org/10.1016/j.thromres.2014.11.041 0049-3848/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). 250 C.T. Hackett et al. / Thrombosis Research 135 (2015) 249–254 insufficient published data regarding hemorrhagic complications relat- M.T., and K.M.). Patient demographics, stroke risk factors, admission ed to fondaparinux for VTE prophylaxis in patients with ischemic stroke. National Institute of Health Stroke Scale (NIHSS) score, CrCl, weight, Fondaparinux sodium (Arixtra; Aspen) mediates its duration of fondaparinux and UFH exposure, use of IPC applied to the effect through highly selective factor Xa inhibition and has several calf (Covidien, MA, USA), concomitant use of antithrombotic and favorable antithrombotic properties for VTE prophylaxis in stroke antiplatelet agents, hemorrhagic complications, and VTE events were patients: 1) 100% bioavailability; 2) rapid onset of action (1.7 hours); collected and reviewed. Hemorrhagic risk factors (age, admission 3) 24-hour antithrombotic activity (half-life 14–18 hours); 4) no NIHSS, diabetes, atrial fibrillation, weight and CrCl) were collected at effect on measures of prothrombin time, APTT or platelet function; baseline. Exposure to antiplatelet medications and were and 5) linear (low interindividual variability) [11]. collected during the course of hospitalization up to an outcome event Additionally, fondaparinux does not bind complex, or discharge from the hospital. Similarly, the duration of fondaparinux which suggests a lower theoretical risk of heparin-induced thrombocy- or UFH was defined as the number of days of exposure during hospital- topenia (HIT) compared with LDUH or LMWH [12,13]. ization up to an outcome event or discharge from the hospital without We sought to provide data about the safety of fondaparinux by an outcome event. examining adverse hemorrhagic events among ischemic stroke patients treated with fondaparinux or UFH for VTE prophylaxis. The null hypoth- Outcome Measures esis was that there would be no significant difference in adverse hemor- rhagic event rates between the fondaparinux and UFH groups during The primary outcome was major hemorrhage during hospitalization, acute hospitalization for ischemic stroke. which included both symptomatic intracranial hemorrhage and major extracranial hemorrhage. We used the International Society on Throm- Materials and Methods bosis and Haemostasis (ISTH) definition of major hemorrhage, defined as symptomatic bleeding in a critical area or organ, or a bleed that Standard Protocol Approvals, Registrations, and Patient Consents resulted in a decrease in baseline hemoglobin ≥ 20 g/L or transfusion requiring ≥ 2 units of blood, or when a hemorrhagic event was fatal This retrospective cohort study was approved by an ethical stan- [15]. Intracranial hemorrhage was diagnosed by CT head or MRI brain dards committee; the Institutional Review Board of Allegheny General interpreted by neuroradiologists. All radiographic images of intracranial Hospital, in order to examine health records of patients at our institu- hemorrhages were also reviewed by a vascular neurologist (A.T.) tion. Fondaparinux was approved by the anticoagulation management blinded to anticoagulant exposure. An adverse hemorrhagic event was subcommittee of Allegheny General Hospital for off-label use in patients defined by the presence of a new symptomatic parenchymal hematoma with ischemic stroke for VTE prophylaxis. or extra-axial hemorrhage. Asymptomatic hemorrhagic infarction characterized by petechial hemorrhage only within the area of ischemic Study Design and Population infarction (hemorrhagic infarction types 1 or 2) without clinical deteri- oration, was not designated as an adverse hemorrhagic event [16]. From March 2009 to November 2012, a total of 1275 consecutive pa- The secondary outcome was total hemorrhage (major and minor). tients was admitted with ischemic stroke and received VTE prophylaxis Minor extracranial hemorrhage included epistaxis lasting more than with fondaparinux 2.5 mg subcutaneously once daily or UFH 5000 units 5 minutes or requiring intervention, gastrointestinal bleeds not meeting subcutaneously every 8 hours. VTE anticoagulant was not randomly the definition for major hemorrhage, ecchymosis or hematoma larger assigned and there were no predetermined criteria for use of than 5 cm at its widest point and hematuria not associated with urinary fondaparinux or UFH for VTE prophylaxis in patients with ischemic catheter trauma [17]. stroke. There were no other significant systematic changes to patient We also examined new venous thrombotic events during hospitali- management instituted during this time period. zation, specifically, symptomatic deep venous thrombosis (DVT) and Inclusion criteria were: 1) age N 18 years; 2) final diagnosis of fatal/nonfatal pulmonary embolism (PE). All adverse events occurred ischemic stroke; and 3) fondaparinux or UFH exposure ≥ 48 hours. while patients were receiving treatment with UFH or fondaparinux. We surmised that brief exposures to VTE anticoagulant would be Diagnostic studies to detect DVT or PE were performed when insufficient to assess the risk of hemorrhagic complications. clinically suspected by the treating physician. Patients did not undergo Exclusion criteria were: 1) a final diagnosis other than ischemic diagnostic screening studies for DVT. All DVT and PE events were there- stroke; 2) creatinine clearance (CrCl) b 30 milliliters per minute because fore designated symptomatic in this study. DVT events were categorized fondaparinux would be contraindicated; 3) intravenous tissue plasmin- into proximal and distal sites of venous thrombosis and thrombotic ogen activator or intravenous heparin administration during hospitali- events related to indwelling venous catheters were not considered as zation; and 4) no measured weight in the medical record. The criteria DVT events. DVT was diagnosed using standardized protocols for com- for a final diagnosis of ischemic stroke were based upon accepted pression duplex ultrasound (CDU) of the upper or lower extremity standard clinical and radiographic definitions [14]. Patients receiving and all studies were completed in a dedicated vascular laboratory both warfarin and concomitant VTE prophylaxis (fondaparinux or accredited by the Intersocietal Commission for Accreditation of Vascular UFH) during periods of subtherapeutic anticoagulation (INR b 2.0) Laboratories (ICAVL). All cases of PE were diagnosed by pulmonary CT were included in the study. angiography interpreted by chest radiologists.

Data Collection and Management Statistical Analysis

Consecutive patients who received fondaparinux or UFH during the Descriptive and frequency statistical analyses were performed and study period were identified by a health records analyst (M.P.) at Alle- comparisons were made with SPSS (version 20.0, SPSS Inc.). Summary gheny General Hospital using Sunrise Acute Care software (Allscripts statistics were computed for demographics, antithrombotic and antico- Healthcare Solutions Inc., Chicago, IL). The health records analyst was agulant agents, and primary and secondary outcomes. Univariate analy- unaware of the study design and was not directly involved in the ses (Student t-test, Mann Whitney, Chi square or Fisher’s exact where study. Once patients were identified, data were collected by means of appropriate) of variables associated with major hemorrhagic complica- a review of paper and electronic health records, discharge summaries, tions were performed. A p value b 0.05 was considered significant. diagnostic imaging studies and laboratory reports. Data were abstracted Because fondaparinux or UFH was not randomly assigned in the onto standardized case report forms by four investigators (S.R., C.H., study population and there were a low number of outcome events C.T. Hackett et al. / Thrombosis Research 135 (2015) 249–254 251 relative to the number of covariates, we performed a propensity score antiplatelet medication, atrial fibrillation, warfarin, duration of VTE matched analysis to reduce the risk of bias owing to confounding anticoagulant exposure and IPC use [22]. The method of standardized [18–20]. Propensity score matching is a method of statistical analysis differences was used to assess balance of the covariates before and that reduces systematic imbalance of chosen covariates between treat- after matching with an absolute standardized difference b10% consid- ment groups in an observational study, allowing for a more precise ered desirable [20]. In the final propensity score matched sample, we estimation of the effect of a treatment on the outcome of interest. The compared the main outcome (major hemorrhages), total hemorrhages, fondaparinux and UFH groups were matched by pair matching (1:1), intracranial hemorrhage, major extracranial hemorrhage and symp- without replacement, using a caliper width of 0.2 of the standard devi- tomatic VTE events between those receiving fondaparinux and UFH ation of the logits of the propensity scores [19,21]. The propensity score using McNemar’s test for the binary variables. was estimated using a logistic regression model in which receipt of VTE anticoagulant (fondaparinux versus UFH) was regressed on eleven Results baseline covariates derived from factors reported or thought to be asso- ciated with the primary outcome of interest (major hemorrhage): age, Of the 1275 patients reviewed, a total of 866 (70%) patients was gender, admission NIHSS (stroke severity), weight, CrCl, diabetes, included in the unmatched analysis. The unmatched cohort included

Fig. 1. Study Profile. CrCl indicates creatinine clearance; NIHSS, National Institute of Health Stroke Scale; tPA, tissue . 252 C.T. Hackett et al. / Thrombosis Research 135 (2015) 249–254

492 patients in the fondaparinux group and 374 patients in the UFH conditions” excluding ischemic stroke was 0.2% (1/425) [10].In group. The propensity score matched cohort was comprised of 322 contrast, enoxaparin for VTE prophylaxis has been studied in patients patients in the fondaparinux group and 322 patients in the UFH group. with ischemic stroke with a reported rate of major hemorrhage of Fig. 1 presents the details of the 409 patients who were excluded from 1.3% (11/877), comprised of intracranial hemorrhages 0.5% (4/877) the study. and extracranial hemorrhages 0.8% (7/877) [17]. We applied the same Baseline clinical variables before and after propensity score matched strict definitions of safety outcomes reported in prospective VTE pro- analysis are presented in Table 1. After propensity score matching, the phylaxis trials of fondaparinux and enoxaparin and found comparable absolute standardized differences in all eleven baseline covariates low rates of total and major hemorrhages in patients with ischemic were b10% suggesting appropriate balance between the fondaparinux stroke treated with fondaparinux [10,17]. A retrospective study of and UFH groups. A visual representation of the reduction of imbalance fondaparinux, UFH and LMWH for VTE prophylaxis in patients with of covariates after propensity matching is presented in Fig. 2. Nearly ischemic stroke reported major hemorrhages in the UFH group of 6.2% all patients received antiplatelet medication during hospitalization (22/353) versus the fondaparinux group of 0.7% (2/285) [22]. This (Table 1). In the matched cohort, there were no significant differences study included patients receiving intravenous thrombolytic therapy, in the exposure to (fondaparinux group 96.3% vs UFH group which may have increased the risk of major hemorrhages in the UFH 95%, p = 0.56) or (fondaparinux group 18.3% vs. UFH group. We excluded patients receiving intravenous thrombolytic from group 19.6%, p = 0.76). No patients received target specificoral our study. A pooled analysis of eight large randomized controlled trials . (n = 13,085) of fondaparinux versus placebo (LMWH or LDUH) in med- Primary and secondary adverse outcomes in the unmatched and ical and surgical patients reported that age, fondaparinux, lower body propensity score matched cohorts are presented in Table 2.Inthe weight and lower CrCl were predictors of major hemorrhage [23].We matched analysis, we found a nonsignificant trend toward less major reduced bias in our study by matching patients based on age, body hemorrhages in the fondaparinux group, 1.2% (4/322) compared to weight and CrCl, in addition to a number of other covariates (gender, the UFH group, 3.7% (12/322), (OR 0.33, 95% CI 0.08–1.10, p = 0.08). NIHSS, atrial fibrillation, diabetes, antiplatelet use, warfarin use, the Similarly, there was a nonsignificant trend toward less total hemor- duration of VTE anticoagulant and IPC use) in order to examine the rhages in the fondaparinux group, 1.6% (5/322) compared with the relationship between VTE anticoagulant (fondaparinux versus UFH) UFH group, 3.7% (12/322), (OR 0.42, 95% CI 0.12–1.27, p = 0.15). and hemorrhagic events. Though our study differs in design and Symptomatic VTE were detected in 0.6% (2/322) of patients receiving methodology from prospective trials, we found no evidence that fondaparinux and 0.9% (3/322) of patients administered with UFH fondaparinux increased the risk of hemorrhagic complications relative (OR 0.67, 95%CI 0.06–5.82, p = 1.00). to UFH in patients with ischemic stroke of wide ranging severity [10,17]. The observed symptomatic VTE rates were no different in the two Discussion groups; 0.6% (2/322) in the fondaparinux group, and 0.9% (3/322) in the UFH group, (OR 0.67, 95% CI 0.06–5.82, p = 1.00), in the matched The main finding of this study was that patients hospitalized for analysis. Patients did not undergo screening CDU and cases of symp- ischemic stroke receiving VTE prophylaxis with fondaparinux had a tomatic DVT or PE were identified when treating physicians suspected similar, low rate of major hemorrhage 1.2% (4/322) compared with VTE and requested diagnostic studies reflecting “real life” practice. UFH 3.7% (12/322), p = 0.08, based upon the propensity score matched Medical records were examined for VTE events during hospitalization analysis. The fondaparinux group also had a similar incidence of and did not extend into the post-hospitalization phase. We cannot, total hemorrhage 1.6% (5/322) compared with the UFH group 3.7% therefore, provide data regarding the rate of asymptomatic DVT during (12/322), p = 0.15. Major hemorrhages were comprised mainly of hospitalization or the rate of VTE detected after hospitalization as extracranial hemorrhages and there were no intracranial hemorrhages demonstrated in prospective trials of extended prophylaxis [10,17]. in the fondaparinux group. IPC was applied in 59.9% (193/322) of the fondaparinux group and A previous study found that the rate of major hemorrhage in 59.9% (193/322) of the UFH group, which may have also reduced the patients receiving fondaparinux in patients with “acute medical risk of symptomatic VTE independent of the VTE anticoagulants [24].

Table 1 Cohort demographic characteristics, medical history and clinical data before and after propensity score matched analysis.

Unmatched Cohort Propensity Score Matched Cohort

Variable Fondaparinux Unfractionated Heparin da Fondaparinux Unfractionated Heparin da (n = 492) (n = 374) (n = 322) (n = 322)

Risk factors for stroke or VTE Age (years) 68.72 ± 13.98 71.45 ± 14.73 -19.5 71.77 ± 13.14 70.77 ± 14.97 7.1 Sex (female) 234 (47.6) 196 (52.4) -9.6 171 (53.1) 167 (51.9) 2.4 NIHSS 4 (IQR 2–10) 3 (IQR 0–11) -3.0 4 (IQR 2–11) 3 (IQR 0–12) 5.1 Weight (kg) 83.50 ± 20.22 81.01 ± 21.44 11.9 80.11 ± 18.38 80.93 ± 21.57 -4.1 Creatinine clearance (mL/min) 93.82 ± 46.55 75.02 ± 38.36 44.1 77.02 ± 30.58 78.64 ± 39.53 -4.6 Atrial fibrillation 123 (25.0) 118 (31.6) -14.7 98 (30.4) 93 (28.9) 3.3 Diabetes 165 (33.5) 146 (39.0) -11.5 113 (35.1) 120 (37.3) -4.6 Hypertension 388 (78.9) 312 (83.4) -11.5 267 (82.9) 263 (81.7) 3.1 VTE anticoagulant administration (days) 4 (IQR 3–6) 5 (IQR 3–6) -27.5 5 (IQR 3–7) 5 (IQR 3–7) 2.0 Previous stroke/TIA 94 (19.1) 77 (20.6) -3.8 59 (18.3) 67 (20.8) -6.3 Previous VTE 10 (2.0) 9 (2.4) -2.7 5 (1.6) 9 (2.8) -8.2 Intermittent pneumatic compression 264 (53.7) 235 (62.8) -18.5 193 (59.9) 193 (59.9) 0.0

Concomitant medications Antiplatelet medications 487 (99.0) 357 (95.5) 21.5 317 (98.4) 315 (97.8) 4.4 Warfarin 61 (12.4) 36 (9.6) 9.0 38 (11.8) 32 (9.9) 6.1

All values are mean ± standard deviation or n (%) NIHSS, National Institute of Health stroke scale; TIA, transient ischemic attack; VTE, venous thromboembolism. a Standardized difference. C.T. Hackett et al. / Thrombosis Research 135 (2015) 249–254 253

Fig. 2. Standardized difference bias across covariates. CrCl indicates creatinine clearance; NIHSS, National Institute of Health Stroke Scale.

There are several limitations to our study. VTE anticoagulant was not events post-hospitalization. Patient outcomes were adjudicated in an randomly assigned and data were obtained retrospectively, which may unblinded fashion, which may have resulted in ascertainment bias. have introduced bias. Patient groups were generally well balanced in We minimized the risk of this bias by using strict a priori definitions of terms of baseline characteristics and significant differences in baseline outcome events. We are limited in our conclusions regarding the effica- covariates were reduced through propensity score matching. There is cy of fondaparinux for VTE prophylaxis in ischemic stroke as compared the potential for residual confounding from unknown factors. Data to UFH because we were not able to examine asymptomatic VTE. We collected for baseline characteristics and outcomes were reliably found a low rate of observed symptomatic VTE during hospitalization available within the medical records and there were no missing data. in a large cohort and recognize that a rigorous evaluation of the efficacy In addition, we limited our investigation to acute hospitalization and of fondaparinux in ischemic stroke would require a prospective study of we did not examine hemorrhagic complications and symptomatic VTE extended VTE prophylaxis [10,17]. Finally, based upon our sample size,

Table 2 Adverse events: hemorrhagic and symptomatic venous thromboembolic complications in the unmatched and propensity score matched cohorts.

Variable Unmatched Cohort Propensity Score Matched Cohort

Fondaparinux Unfractionated OR (95% CI) p valuea Fondaparinux Unfractionated OR (95% CI) p valueb (n = 492) Heparin (n = 322) Heparin (n = 374) (n = 322)

Hemorrhagic Complications Hemorrhagic complications (total)c 6 (1.2) 14 (3.7) 0.32 (0.12–0.83) 0.01 5 (1.6) 12 (3.7) 0.42 (0.12–1.27) 0.15 Major hemorrhagic complicationsd 4 (0.8) 14 (3.7) 0.21 (0.07–0.65) 0.003 4 (1.2) 12 (3.7) 0.33 (0.08–1.10) 0.08 Intracranial hemorrhage 0 (0.0) 2 (0.5) - 0.19 0 (0.0) 2 (0.6) - 0.48 Major extracranial hemorrhagee 4 (0.8) 12 (3.2) 0.25 (0.08–0.77) 0.01 4 (1.2) 10 (3.1) 0.40 (0.09–1.39) 0.18 Minor extracranial hemorrhagef 2 (0.4) 0 (0.0) - 0.51 2 (0.6) 0 (0.0) - 0.48

VTE Complications Symptomatic venous thrombotic events (total) 2 (0.4) 5 (1.3) 0.30 (0.06–1.56) 0.25 2 (0.6) 3 (0.9) 0.67 (0.06–5.82) 1.00 Pulmonary embolism 2 (0.4) 1 (0.3) 1.52 (0.14–16.85) 1.00 2 (0.6) 1 (0.3) 2.00 (0.10–117.99) 1.00 Symptomatic DVT (total)g 0 (0.0) 4 (1.1) - 0.03 0 (0.0) 3 (0.9) - 0.25 Proximal DVT 0 (0.0) 1 (0.3) - 0.43 0 (0.0) 1 (0.3) - 1.00 Distal DVT 0 (0.0) 2 (0.5) - 0.19 0 (0.0) 1 (0.3) - 1.00 Proximal and distal DVT 0 (0.0) 1 (0.3) - 0.43 0 (0.0) 1 (0.3) - 1.00

All values are n (%). OR indicates odds ratio; DVT, deep venous thrombosis; VTE, venous thromboembolism. a All p values are two-sided Fisher’s exact or chi square, as appropriate, for the unmatched analysis. b All p values are McNemar’s for the matched analysis. c Hemorrhagic complications (total) included all intracranial hemorrhages, major extracranial hemorrhages and minor extracranial hemorrhages. d Major hemorrhagic complications were defined as all intracranial hemorrhages and major extracranial hemorrhages. e Major extracranial hemorrhagic complications were defined as a hemorrhage that resulted in: death, drop of hemoglobin ≥ 20 g/L, transfusion of ≥ 2 units of blood or a symptomatic bleed in a critical area or organ [15]. f Minor extracranial hemorrhage included epistaxis lasting more than 5 minutes or needing intervention, gastrointestinal bleeds not meeting the definition for major bleed, ecchymosis or hematoma larger than 5 cm at its widest point and hematuria not associated with urinary catheter trauma [17]. g All DVTs were unrelated to indwelling venous catheter placement and considered symptomatic. 254 C.T. 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