The Clinical Respiratory Journal

ORIGINAL ARTICLE

Inverse relationship of bleeding risk with clot burden during pulmonary embolism treatment with LMW heparin Chen Wang1,2*, Zhenguo Zhai1*, Yuanhua Yang1*, Zhaozhong Cheng3, Kejing Ying4, Lirong Liang1, Huaping Dai1, Kewu Huang1, Weixuan Lu5, Zhonghe Zhang6, Xiansheng Cheng7, Ying Hu Shen8 and Bruce L. Davidson9, for China National Venous Thromboembolism (VTE) Study Group 1 Beijing Key Laboratory of Respiratory and Pulmonary Circulation, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China 2 Beijing Hospital, Ministry of Health, Beijing, China 3 The Affiliated Hospital of Medical College of Qingdao, Shandong, China 4 Sir Run Run Shaw Hospital, Affiliated with Zhejiang University, Zhejiang, China 5 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China 6 The Affiliated Hospital of Dalian Medical University, Liaoning, China 7 Beijing Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China 8 Baylor College of Medicine, Houston, TX, USA 9 University of Washington School of Medicine, Seattle, WA, USA

Abstract Introduction: Clinically relevant bleeding occurs three times as frequently as recurrent venous thromboembolism in the modern early treatment of pulmonary embolism (PE) with fixed-dose, unmonitored anticoagulants. Unfractionated heparin (UFH) is monitored and adjusted to assure efficacy and minimize bleeding risk, but low molecular weight heparin (LMWH) is not. PE requires more anticoagulant than isolated deep venous thrombosis. Speculating that PE with low clot burden could lead to excess bleeding with unadjusted LMWH treatment but not with UFH, we compared PE patients receiving either UFH or LMWH with high and low clot burden for clinically significant bleeding in an observational study. Materials and Methods: Patients with acute PE at multiple Chinese teaching hospitals had been randomized to UFH or LMWH for initial treatment. These treatment cohorts had baseline measurement of pulmonary artery obstruction (PAO) score, which was prospectively separated into quartiles, lowest to highest PAO. All patients were followed for bleeding episodes, which were subsequently analyzed by quartile of PAO. Results: Two hundred seventy-four patients divided between the two groups had similar efficacy and safety outcomes (12 clinically significant bleeds in the UFH group vs 15 in the LMWH group). LMWH recipients with the smallest clot burdens (lowest PAO quartiles) had highest bleeding rates (Cochran–Armitage trend test, P trend = 0.048), but there was no such trend for UFH recipients. Conclusions: For UFH, excess anticoagulant pro-hemorrhagic potential is downadjusted via activated partial thromboplastin time monitoring, but for LMWH it is not. For PE patients at high bleeding risk, UFH may be safer if the clot burden is small. Please cite this paper as: Wang C, Zhai Z, Yang Y, et al., for China National Venous Thromboembolism (VTE) Study Group. Inverse relationship of bleeding risk with clot burden during pulmonary embolism treatment with LMW heparin. Clin Respir J 2015; ••: ••–••. DOI:10.1111/crj.12262.

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd

Key words bleeding – heparin – low molecular weight heparin – pulmonary artery – pulmonary embolism Correspondence Chen Wang, MD, PhD, Department of Respiratory Medicine, Capital Medical University; National Clinical Research Center for Respiratory Diseases; China-Japan Friendship Hospital. Yinghua Dongjie, Hepingli Beijing 100029, China Tel: +86 (10) 84206166 Fax: +86 (10) 64289840 email: [email protected] Received: 25 June 2014 Revision requested: 17 July 2014 Accepted: 21 January 2015 DOI:10.1111/crj.12262 Authorship and contributorship Chen Wang takes full responsibility for the integrity of the submission and publication, and was responsible for the data verification, analysis and draft of the manuscript. Zhenguo Zhai and Yuanhua Yang takes responsibility for the integrity of the data and the accuracy of the data analysis. Kejing Ying, Zhaozhong Cheng, Huaping Dai, and Kewu Huang were responsible for the patient enrolment and the data collection. Lirong Liang takes responsibility for the integrity of the data and the accuracy of the data analysis. Xiansheng Cheng, Wexuan Lu, and Zhonghe Zhang were involved in study design as part of the Steering committee. Ying H Shen and Bruce L Davidson, was responsible for the data verification, analysis and draft of the manuscript.

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Bleeding and clot burden in acute PE

Ethics The study was approved by the ethics committee at the Beijing Chao Yang Hospital and fulfilled the Declaration of Helsinki. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. *These authors contributed equally.

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Clinical trial registered with www.ClincalTrial .gov (Identifier: NCT00796692) Abbreviations: aPTT activated partial thromboplastin time CI confidence interval CTPA computed tomographic pulmonary angiography DVT deep vein thrombosis HIT heparin-induced thrombocytopenia INR international normalized ratio LMWH low molecular weight heparin

Introduction Clinically significant bleeding occurs three times as frequently as recurrent thromboembolism in the modern early treatment of acute pulmonary embolism (PE) with fixed-dose unmonitored anticoagulants (1). In the past, PE was treated acutely with unfractionated heparin (UFH) adjusted by its ex vivo anticoagulant effect in a laboratory assay, the activated partial thromboplastin time, aPTT. The interpretation of accumulated evidence was that ‘both recurrent thromboembolism (VTE) and bleeding can best be prevented if the heparin dose is adjusted in each patient to maintain the results of an in vitro test of blood coagulation within a defined range’ (2). With the use of low molecular weight heparin (LMWH), most, and certainly routine, anticoagulant monitoring and adjustment for PE patients stopped. This is now also true for the new oral unmonitored, unadjusted clotting factor inhibitors being developed, such as the thrombin inhibitor dabigatran, and the factor Xa inhibitors rivaroxaban, apixaban and edoxaban (3). Current LMWH dosing for PE adjusts the dose by patient weight, and for the newer oral anticoagulants there are no adjustments unless there is severe renal insufficiency. Averaged outcomes from meta-analyses of clinical trials of UFH and LMWHs, from which higher bleeding risk patients were routinely excluded, show similar (not superior) efficacy and safety for LMWH and UFH for acute PE treatment (4). For PE patients at high, intermediate or low bleeding risk treated with LMWH and the new oral agents, individualizing dosage with monitoring and adjustment is not recommended. However, LMWHs and the newer anticoagulants have not been studied in PE patients with higher bleeding risk caused by recent visceral interventions, trauma, renal insufficiency, fragile vessels in critical organs like the brain, and combinations of these and other risks. For real-world PE patients at increased bleeding risk receiving unmonitored, unad-

2

PAO PE SD UFH VTE

pulmonary artery obstruction pulmonary embolism standard deviation unfractionated heparin venous thromboembolism

justed anticoagulants, how robustly does the decision not to monitor and adjust protect against possibly preventable bleeding? Study results over several decades have shown that acute PE requires higher anticoagulant levels than acute deep venous thrombosis (DVT) (2, 5, 6). Lower heparin levels and aPTT values for PE patients compared with DVT patients receiving UFH (because of more rapid UFH clearance in PE), and worse efficacy outcomes for PE patients receiving idraparinux compared with conventional therapy, were obtained when similar investigational dosing regimen were applied to PE and DVT patients – dosing high enough to prevent recurrence in DVT, but not PE. An explanation could be that, on average, PE patients require more anticoagulant than DVT patients in part due to larger clot burdens. PE patients might not only have a higher burden of acute phase reactant proteins binding (‘consuming’) more UFH and LMWH than average DVT patients, but the PE themselves, more exposed to the circulation, may bind more anticoagulant than DVT sequestered behind sluggish flow in an extremity’s partially or totally obstructed deep vein. For PE patients receiving infused UFH with monitoring and adjustment, this situation would be alleviated because doses can be up-adjusted to prevent the circulating aPTT from remaining subtherapeutic. With smaller PE clot burdens, UFH consumption would be lower, and with more of an administered dose circulating in plasma up-adjustment would be required less frequently. Instead, down-adjustment might occur, reducing pro-hemorrhagic risk. In contrast, LMWHs and the newer anticoagulants have been developed to assure efficacy success with weight-based or fixed dosing without monitoring and adjustment for the DVT and PE patients included in their clinical trials, even for the most severely ill PE patients, so long as they are not so ill as to be excluded due to presentation with shock. We speculate that when these doses are found noninferior to comparator treatment, they, like currently recommend UFH

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd

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treatment doses, likely are more than the minimum effective dose for DVT and small PE. Further, we speculate that for patients at increased bleeding risk, those with a small clot burden may be more likely to bleed than similar patients with the largest clot burdens. Hence, a small amount of clot burden, similar to significant renal insufficiency, might increase bleeding risk in vulnerable patients receiving an unmonitored fixed-dose anticoagulant for PE. This hypothesis predicts that while PE patients receiving unmonitored, unadjusted anticoagulant drugs, such as LMWH, would be at higher bleeding risk if their clot burdens were small compared with those with larger clot burdens, similar PE patients receiving UFH would not show this difference irrespective of clot burden size. Our group has been interested in reducing bleeding while providing effective PE treatment (7, 8). Therefore, in order to test our hypothesis, we took advantage of data from an unpublished clinical trial we performed some years ago comparing UFH with an LMWH in PE patients. We assessed the degree of pulmonary artery obstruction (PAO) at presentation and used it as a surrogate for amount of clot burden. We analyzed the frequencies of bleeding in the two treatment cohorts, comparing patients with higher clot burdens with those with lower clot burdens within each treatment group, to see if the result differed depending upon whether the patient received monitored and adjusted UFH or unmonitored, unadjusted LMWH.

Materials and methods Research design and patients We conducted this cohort study in patients randomized, in a prospective, open-label, multicenter trial in China between 2002 and 2006. A central steering committee took charge of that trial’s design, protocol development and standardization, quality control, and data verification and analysis. The study protocols were reviewed and approved by ethics committees of all participating centers, and the study was registered at www.clinicaltrials.gov (NCT00796692). Patients with clinically suspected PE with or without symptomatic DVT underwent CT pulmonary angiography (CTPA) to confirm the diagnosis. If leg symptoms were present, compression ultrasonography examinations to the level of the calf vein trifurcation (or below if imaging was possible) confirmed or refuted the diagnosis of DVT. Exclusion criteria were hemodynamic instability, acute normotensive PE with right ventricular dysfunction by echocardiography

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd

Bleeding and clot burden in acute PE

(unless contraindicated, this should receive intravenous thrombolysis in China), chronic thromboembolic pulmonary hypertension without evidence of an acute episode, contrast allergy, severe hepatic or renal failure, pregnancy, a predicted life expectancy of less than 3 months, suspected poor compliance, and inaccessibility for follow-up. All patients enrolled in the study signed the informed consent form.

Anticoagulant treatment regimens Enrolled patients were randomly centrally assigned to receive either UFH or LMWH. The UFH group received an initial intravenous bolus dose of 80 U/kg UFH, followed by a continuous infusion at an initial rate of 18 U/kg/h. aPTT was measured every 4 h after the start of treatment and subsequently until the target range was reached and if a dose adjustment were made, and once daily when stable in the target range. The heparin dose was adjusted to maintain the aPTT at 1.5–2.5 times the control value. Patients in the LMWH group received subcutaneous injections of nadroparin dosed at 86 anti-factor Xa IU/kg every 12 h. Treatment was unblinded. In both groups, overlapping oral warfarin (initial dose of 3–5 mg per day) was started on days 1–3 of heparin treatment. Warfarin dosing was adjusted daily to maintain a stable international normalized ratio (INR) of between 2.0 and 3.0. UFH or LMWH was discontinued five or more days after initial treatment, when the INR was stabilized and >2.0 for at least 2 days. Warfarin was continuously used for at least 3–6 months, and the dose was adjusted to maintain the INR within a target range of 2.0–3.0. The use of antiplatelet and anti-inflammatory drugs was avoided when possible during the study period.

Assessment of clinical outcome after anticoagulation All patients were clinically examined daily during injected treatment for recurrent or refractory PE, for DVT and for bleeding. CTPA, echocardiography and compression ultrasonography, or rarely CT venography, of the lower extremities were done in all patients at baseline and day 14, or earlier if signs of recurrent PE or new or extending DVT occurred. Deaths were classified by the investigator as being due to PE (when there was strong clinical evidence or evidence at autopsy), bleeding or other causes (including myocardial infarction and unknown causes). A blood sample was drawn daily for hemoglobin and platelet count during parenteral anticoagulant treatment. 3

Bleeding and clot burden in acute PE

Heparin-induced thrombocytopenia (HIT) was defined as a platelet count of below 100 000 per cubic millimeter or fall by at least 30% from the baseline value together with a positive HIT ELISA result. Clinical follow-up assessments were also made 3 months after treatment. The patients were instructed to come to the hospital immediately if signs or symptoms of recurrent PE or DVT were noticed. A central committee whose members were blinded to treatment assignment adjudicated all outcome events.

Assessment of PAO Baseline and subsequent CTPA images were reviewed on workstations by two independent readers who were unaware of treatment allocation and the sequence in which the tests were done. The location and severity of thrombus obstruction of the pulmonary vascular bed were evaluated using the PAO scoring system. A PAO score was calculated for each CTPA available (9, 10). Each segmental artery was scored according to the degree of obstruction, where partial obstruction is defined as 1 and total obstruction is 2. The arterial tree of each lung is regarded as having 10 segmental pulmonary arteries (three to the upper lobes, two to the middle lobe or lingula, and five to the lower lobes). The maximum total score (20 segments × 2) is 40 according to the formula.

Bleeding complications after initial treatment with UFH and LMWH At the time the trial protocol was designed, major bleeding was defined as the following: (i) fatal bleeding that occurs in a critical area or organ, e.g. intracranial bleeding or bleeding contributing to death; and (ii) overt bleeding with a fall in hemoglobin concentration by at least 2 g/dL or more, or requiring transfusion of more than 2 or more units red blood cells or whole blood. Clinically relevant nonmajor bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with a medical intervention, an unscheduled contact with a physician, cessation of study treatment, or associated with discomfort for the patient such as pain, or impairment of activities of daily life. All bleeding episodes were recorded from the initiation of UFH or LMWH therapy until 2 days after their discontinuation. Bleeding assessment was also made at day 14 and 3 months after treatment.

Statistical analysis Data were analyzed according to the intention-totreat principle. Baseline characteristics were compared

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Wang et al.

between the two groups by unpaired t-test or nonparametric tests as appropriate for continuous data and the χ2 test for categorical data. Continuous data were expressed as mean +/− standard deviation or median for skewed distributions. Categorical data were expressed as percentages. For each treatment cohort, we tested the relationship of bleeding and baseline clot burden, i.e. PE clot burden defined by baseline PAO score. We prospectively decided to divide the patient cohorts in quartiles by baseline PAO score. When several patients had the same PAO score, uneven numbers of patients in the quartiles could occur rather than creating an artifactual cut-point in patients with the same score. Cochran–Armitage trend testing with exact methods (because of small event rates) was used to analyze the linear relationships between baseline clot burden and bleeding for the quartiles for each treatment group; event rates were too small for multivariate analysis. P < 0.05, two-sided, was considered significant. All analyses were done using SAS software version 9.1.3 (SAS Institute 2006, Cary, NC, USA).

Results Characteristics of the patients Clinically suspected PE in 295 patients was confirmed by CTPA. Of these, 21 (7%) were excluded before randomization because they met one or more predefined exclusion criteria. Of the 274 patients enrolled in the study, 131 were randomized to receive intravenous UFH and 143 to receive nadroparin (Fig. 1). There were no significant differences between the two groups in baseline demographics and clinical characteristics (Table 1).

Clinical outcome after anticoagulation During the 3 months of follow-up, recurrent VTE was confirmed in six (4.6%) patients in the UFH group and three (2.1%) in the nadroparin group, a difference of 2.5 % [95% confidence interval (CI), −1.8 to 6.8%]. Symptomatic DVT was seen in four (3.1%) patients in the UFH group and one (0.7%) in the nadroparin group, a difference of 2.4% (95% CI, −0.9 to 5.6%). Two patients (1.5%) in the UFH group and two (1.4%) in the nadroparin group developed symptomatic PE. One patient in the UFH group died due to recurrent PE; there were no deaths in the nadroparin group. HIT developed in three UFH recipients.

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Bleeding and clot burden in acute PE

Assessed for eligibility (n = 295) Excluded (n = 21) Lack of consent (n = 5) Work overload (n = 7) Decision of aendant clinician (n = 7) Undisclosed reason (n = 2) Enrolled (n = 274)

Randomized to UFH group (n = 131) Received UFH (n = 131)

Randomized to nadroparin group (n = 143) Received nadroparin (n = 143)

Follow-up through the end of study (n = 131)

Follow-up through the end of study (n = 143)

Included in the efficacy analysis (n = 131) Included in the safety analysis (n = 131)

Included in the efficacy analysis (n = 143) Included in the safety analysis (n = 143)

Paent enrollment, randomizaon and follow-up Figure 1. Study flow diagram. UFH, unfractionated heparin.

Inverse relationship between bleeding complications and baseline clot burden for nadroparin, but not for UFH treatment There were 12 patients suffering clinically relevant bleeds in the UFH group and 15 in the nadroparin group. All occurred within 10 days after initial heparin treatment (Table 2). Major bleeding occurred in one patient in the UFH group and two in the nadroparin group; clinically relevant nonmajor bleeds occurred in 11 and 13 patients in those groups, respectively. An inverse relationship between bleeding incidence and baseline clot burden amount was found for the nadroparin but not the UFH group. Table 3 and Fig. 2 show that when divided into quartiles based on PAO score, nadroparin patients with lower PAO scores had a higher bleeding incidence (Cochran–Armitage exact trend testing, P trend = 0.048).

Discussion In this cohort study of patients accumulated during an unpublished controlled trial of UFH vs LMWH for treatment of acute PE, we show that increased bleeding

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risk is significantly associated with decreased baseline clot burden for LMWH but not for UFH treatment. This provocative finding, confirming our prospective hypothesis, suggests that with currently approved and recommended dosing of LMWHs, clot burden size at the start of treatment may be worth considering, along with assessment of renal function impairment and similar factors, as a risk factor for bleeding in vulnerable patients. That larger clot burdens at the start of PE treatment could reduce the amount of circulating anticoagulant, and pro-hemorrhagic potential is scientifically plausible. When thrombin cleaves fibrinogen in vitro, UFH binds to fibrin via specific saccharide sequences rather than solely related to charge. Binding of UFH is tighter still to thrombin-fibrin complexes, 5.5-fold tighter than to fibrinogen, likely due to doubling the number of binding sites, which are of considerably higher affinity than what exists on circulating or bound fibrinogen alone (11). As hemostasis segues into tissue repair at the clot and endothelial site of injury, heparin-binding domains have been identified not only on the fibrin that becomes plentiful, but also on von Willebrand factor, fibronectin and vitronectin. Moreover, binding 5

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Table 1. Baseline clinical characteristics Characteristics

UFH (n = 131)

Nadroparin (n = 143)

Gender (male/female) Age mean ± SD (year) Weight mean ± SD (kg) BMI means (kg/m2) Systolic BP mean ± SD (mmHg) Diastolic BP mean ± SD (mmHg) Respiratory rate mean ± SD (rpm) Heart rate mean ± SD (bpm) Prior DVT or PE, n (%) Cardiac disease, n (%) Hypertension, n (%) Diabetes mellitus, n (%) COPD, n (%) Malignancy, n (%) Hb mean ± SD (g/L) Platelet count (per cu mm) Isolated PE PE and DVT

86/45 56.6 ± 13.3 68.8 ± 13.0 24.3 ± 3.5 127 ± 17 79 ± 11 20 ± 3 86 ± 16 6 (4.6) 18 (13.7) 35 (26.7) 8 (6.1) 6 (4.6) 17 (13.0) 129.6 ± 19.4 237 ± 93 68 (51.9) 63 (48.1)

89/54 56.6 ± 14.6 68.2 ± 11.5 24.4 ± 3.8 126 ± 19 78 ± 11 21 ± 3 87 ± 13 12 (8.4) 13 (9.1) 36 (25.2) 11 (7.7) 9 (6.3) 7 (4.9) 127.5 ± 19.9 217 ± 85 62 (43.4) 81 (56.6)

Data presented as means or number of cases (proportion %). P > 0.05 for all comparisons between the groups. BP, blood pressure; DVT, deep venous thrombosis; PE, pulmonary embolism; COPD, chronic obstructive pulmonary disease; BMI, body mass index; SD, standard deviation; UFH, unfractionated heparin.

of the fibrin clot to endothelial cells nearby is heparindependent (12). Although similar investigations regarding LMWH binding to nascent clots are not reported, the same considerations likely pertain. LMWHs have the same saccharide sequences as UFH, just fewer per molecule. LMWHs do not entirely escape heparin’s nonspecific binding to acute phase reactants (13) during illnesses such as acute thromboembolism. Available data are few but supportive: When added to plasma from rats pretreated with endotoxin, protein binding of UFH was 100%, but binding of LMWH was still 68%; in control saline-pretreated rats, protein binding of added UFH was 80%, but binding of added LMWH was still 43% (14). Nonspecific binding is certainly less for LMWH than for UFH but still present. It would be surprising if identical doses of LMWHs did not exhibit less circulating anticoagulant activity in a patient subset with large clot burdens and high acute phase reactant amounts, even if they were otherwise similar to the rest of a cohort with smaller clot burdens. How our findings might relate to the new fixed-dose oral specific inhibitors of factors IIa and Xa is uncertain. Dabigatran, rivaroxaban, apixaban and edoxaban are each reversible, noncovalently bound and specific inhibitors of their target molecules. Hence, their plasma levels may be unaffected by baseline clot

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burden and not increase pro-hemorrhagic risk when used in vulnerable patients with minimal clot burdens and acute phase reactants – but it is too early to be certain. In vitro and ex vivo experiments to see if these new drugs are clot-bound in proportion to clot size or surface area, and/or to acute phase reactant protein amounts, would be welcome. Earlier work has shown that significant interindividual variation exists in anticoagulant response to LMWH (15). Some patients are at particular risk of major bleeding, such as after recent major surgery, or blunt trauma, or with fragile intracerebral vessels, or with any of these accompanied by important renal insufficiency. Our report has several limitations. While our hypothesis was prospectively tested and randomization seemed to create similar patient groups, this is not a controlled trial adjusting dosage by clot burden. PAO is a semi-quantitative marker of clot burden and may have been a surrogate for a different causative factor preferentially associated with increased bleeding in the nadroparin group with low PAOs. The number of bleeding patients in our trial was relatively small, leading to a P value for the trend test that was just significant. Our results are hypothesis-generating. Other clinical trial data addressing our hypothesis are not readily

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Bleeding and clot burden in acute PE

Table 2. Major and clinically relevant nonmajor bleeding complications within 2 days after stopping heparin Code and type UFH group Major bleedings 50003 PE Clinically significant nonmajor bleedings 35001 PE and DVT 32001 PE and DVT 47001 PE 26004 PE and DVT 22018 PE and DVT 27003 PE 05002 PE and DVT 27002 PE and DVT 08001 PE and DVT 49022 PE 18001 PE Nadroparin group Major bleedings 46001 PE 40001 PE Clinically significant nonmajor bleedings 22005 PE 33003 PE 22015 PE 22016 PE and DVT 34001 PE 05012 PE and DVT 22006 PE and DVT 28007 PE and DVT 47019 PE 41002 PE 01059 PE and DVT 01003 PE and DVT 18002 PE and DVT

Sex

Age (years)

PAO score

Time

Type and site of bleedings

Outcome

M

74

11.0

Day 5

Epistaxis*

Resolved

M M M M M F M F M M F

70 45 73 72 60 74 71 75 34 38 67

1.0 1.0 2.0 3.0 5.0 5.0 6.0 7.0 10.0 13.0 20.0

Day Day Day Day Day Day Day Day Day Day Day

Skin ecchymosis, hemoptysis Genitourinary Epistaxis, skin hematoma Genitourinary, skin purpura Epistaxis ,skin ecchymosis Gastrointestinal, skin ecchymosis Gastrointestinal Genitourinary, skin ecchymosis Epistaxis, skin ecchymosis Gastrointestinal Epistaxis, genitourinary

Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved

M M

45 53

9.0 10.0

Day 4 Day 7

Pre-retinal, gastrointestinal† Gastrointestinal‡

Resolved Improved

F M F M F F M M F F F F F

28 51 50 68 36 60 67 28 68 48 73 41 75

1.0 1.0 2.0 4.0 4.0 5.0 5.0 5.0 5.0 6.0 7.0 11.0 20.0

Day Day Day Day Day Day Day Day Day Day Day Day Day

Skin hematoma Gastrointestinal Gastrointestinal Epistaxis Epistaxis Epistaxis Epistaxis Gastrointestinal, skin ecchymosis Genitourinary, gastrointestinal Genitourinary, epistaxis Epistaxis Genitourinary Genitourinary

Improved Resolved Resolved Improved Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved

7 1 1 2 0 6 1 6 3 4 6

6 5 4 3 2 7 6 3 4 1 4 6 2

*Hb dropped 21 g/L, improved 2 days later. †Hb dropped 43 g/L, pre-retinal hemorrhage with gastrointestinal bleedings, recovered 4 days later. ‡Hb dropped 59 g/L, improved with transfusion 4 u RBC. UFH, unfractionated heparin; PAO, pulmonary artery obstruction; PE, pulmonary embolism; DVT, deep venous thrombosis; RBC, red blood cells.

available because patients at increased bleeding risk are uncommonly enrolled into sponsored trials of new anticoagulants – although they are more commonly encountered in clinical practice – and PAO in studies is rarely reported. Reported rates of major and clinically relevant bleeding from clinical trials of PE patients are likely to reflect the wisdom behind dose selection for the newer unmonitored anticoagulant, exclusion criteria, and the diligence with which UFH is monitored and adjusted, rather than the effect of the very few high bleeding risk patients who found their way into the studies.

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However, our concern and hypothesis are clinically relevant. A recently published report of a large PE clinical trial showed a clinically significant bleeding rate of 11%, a major bleeding rate of 2.2% and a PE recurrence rate of only 2.1%. During the first 90 days of treatment, both treatment groups had nearly identical rates for clinically significant bleeding and thromboembolism recurrence, at a ratio of approximately 3:1 (1). Anticoagulated patients are living longer and developing additional comorbidities. Monitoring and adjusting anticoagulant treatment in patients at exceptional bleeding risk after an assessment of clot burden 7

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Table 3. Comparison of bleeding events in patients with different baseline PAO score quartiles sorted by treatment groups Group UFH Quartile 1st (n = 33) Quartile 2nd (n = 32) Quartile 3rd (n = 30) Quartile 4th (n = 36) P trend (two-sided) Nadroparin Quartile 1st (n = 33) Quartile 2nd (n = 37) Quartile 3rd (n = 37) Quartile 4th (n = 36) P trend (two-sided)

PAO range

Number of bleeding

1–4 5–8 9–12 13–25

4 4 2 2

12.1 12.5 6.7 5.6 0.252

1–4 5–7 8–11 12–29

5 6 3 1

15.2 16.2 8.1 2.8 0.048

%

UFH, unfractionated heparin; PAO, pulmonary artery obstruction.

seem a rational approach to study. Recent magnetic resonance technology shows the feasibility of imaging clot burden (in coronary arteries at least) without additional radiation exposure (16). A recent American College of Chest Physicians document recommended (17) using intravenous UFH in patients for acute PE when there is concern about subcutaneous absorption. We conclude that monitored and adjusted intravenous UFH may reduce bleeding risk during acute PE treatment when patients at increased bleeding risk have a modest clot burden, and this hypothesis is worthy of further study.

Acknowledgments This study was supported by the China Key Research Projects of the 10th National Five-Year Development Plan (2004BA703B07), Fund of China 973 Program (2009CB522107), and the Major International Joint Research Project of Natural Science Foundation of China (30810103904), Fund of Science and Technology of China (2006BAI01A06); Beijing Natural Science Foundation(7152062); Beijing Youth Star of Science and Technology Program (No. 2007B037). Funding sources reviewed and approved the protocols and received reports of how the funds were used but otherwise played no role in the research or this report. The authors thank the patients who participated in the study. The contribution of the whole team in China was crucial to the success of this study. We thank all investigators in the China National Venous Thromboembolism (VTE) Study Group for their great contributions to this study. The authors thank Dr. Wanmu

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Figure 2. Pulmonary artery obstruction (PAO) scores by PAO quartile of patients with hemorrhage receiving (A) unfractionated heparin and (B) low molecular weight heparin (LMWH). The unfractionated heparin (UFH) group bleeds are relatively evenly distributed between quartiles, but the bleeds for the LMWH group are concentrated in the quartiles with lowest PAO scores.

Xie and Dr. Tuguang Kuang, who participated in the collection of clinical data, and Dr. Jingfeng Ji for assistance in statistical analysis. They also thank Dr. Jianguo Zhu and Dr. Zhu Zhang for technical support.

References 1. Einstein PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366: 1287–97. 2. Hirsh J, van Aken WG, Gallus AS, Dollery CT, Cade JF, Yung WL. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation. 1976;53: 691–5.

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Appendix The members of the study group were as follows: Steering Committee – Chen Wang, Xiansheng Cheng, Xinzhi Weng, Weixuan Lu, Quanying He, Yiming Zhao, Binrong Ma, Nanshan Zhong; Independent Central Adjudication Committee – Xiansheng Cheng, Ruping Dai, Youmin Guo, Tie Wang, Weixuan Lu, Quanying He, Yiming Zhao, Chen Wang; Data and Coordinating Center – Yuanhua Yang, Zhenguo Zhai, Lirong Liang. The following investigators participated in this study: Beijing Chao-Yang Hospital, Capital Medical University – Chen Wang, Yuanhua Yang, Zhenguo Zhai, Baosen Pang, Yafeng Wu, Xiaojuan Wang, Tie Wang, Lei Zhang, Xin Deng, Kewu Huang, Huaping Dai, Zhaohui Tong; The Affiliated Hospital of Medical College Qingdao – Zhaozhong Cheng; Handong Jiang; Sir Run Run Shaw Hospital, Affiliated with Zhejiang University – Kejing Ying, Liying Chen; Peking Union Medical College Hospital, Chinese Academy of Medical Sciences – Weixuan Lu, Chunping Liu, Yongjian Liu; Guangzhou Institute of Respiratory Disease, Guangzhou Medical University – Nanshan Zhong, Rongchang Chen, Hua Wu; The General Hospital of Shenyang Military Command – Zhuang Ma, Ping Chen, Lei Liu; Peking University People’s Hospital – Quanying He, Xingyu Tan; The Affiliated Hospital of Ningxia Medical University – Jin Zhang, Xiwei Zheng; Tianjin Medical University General Hospital – Qi Wu, Yanling Yin, Wei Zhou; The Second Affiliated Hospital of Hebei Medical University – Yadong Yuan, Baofa Wang; Shandong Yantaishan Hospital – Yan Tang, Dongmei Zhou; Shanghai Pulmonary Hospital – Jinming Liu, PeilanGao; The First Affiliated Hospital Sun Yat-Sen University – Canmao Xie, Mian Zeng; The First Affiliated Hospital of Guangxi Medical University – Yiqiang Chen, Shenglan Guo, Tangwei Liu; The First Affiliated Hospital of Zhengzhou University – Peizong Sun, Jie Chen; Shenzhen People’s Hospital – Shengwen Chen, Chen Qiu; Beijing General Hospital of the Air-force PLA – Bo Zhang, He Gao; Peking University Third Hospital – Yongchang Sun Wanzhen Yao; The Affiliated Hospital of Medical College Jining – Luning Jiang; Qilu

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Bleeding and clot burden in acute PE

Hospital Affiliated to Shandong University – Dawei Wu, Yuwen Xue; Shanxi Datong 5th Hospital – AijunLin,You Wang; Beijing No 6 Hospital – Xiaoping Xiang, Chun Zhang; Liaoning AngangTiedong Hospital – Xiuhuan Qi; Shanghai Changhai Hospital – QiangLi; The First Affiliated Hospital of Shanxi Medical University – Yongcheng Du, Jianying Xu, Xiaoyun Hu; The Second Affiliated Hospital of Shanxi Medical University – Zhuola Liu, Xu Wang; The First Affiliated Hospital of Wenzhou Medical College – Shaoxian Chen, Yupeng Xie; Peking University First Hospital – Guangfa Wang, Chunhua Chi; Wuhan Union Hospital – Ming Bai; Xinjiang People’s Hospital

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– Xiaohong Yang; The First Hospital of China Medical University – Jian Kang, Lili Tian; Beijing Naval General Hospital – Yunyou Duan, Zhoushan Nie; The Affiliated Hospital of Shenyang Medical University – Shi Wang, Shuyue Xia; Tangshan Worker’s Hospital, Hebei Medical University – Huilin Liu, Yingqi Zhang; Beijing Friendship Hospital, Capital Medical University – Zheng-yi He; Beijing Hospital – Baomin Fang, Tieying Sun; Tianjin Thoracic Hospital – Shuhua Li; Shanghai Ruijin Hospital – Shaoguang Huang, Chaoguo Shi; The Third Affiliated Hospital, Sun Yat-Sen University – Tiantuo Zhang; The Affiliated Hospital of Hubei Coal University – Xinrong Liu, Hongyang Wang.

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd

Inverse relationship of bleeding risk with clot burden during pulmonary embolism treatment with LMW heparin.

Clinically relevant bleeding occurs three times as frequently as recurrent venous thromboembolism in the modern early treatment of pulmonary embolism ...
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