Journal of Thrombosis and Haemostasis, 12: 1746–1749

DOI: 10.1111/jth.12683


Prevention of venous thromboembolism in hospitalized medical cancer patients: guidance from the SSC of the ISTH M. DI NISIO,*† M. CARRIER,‡ G. H. LYMAN§ and A. A. KHORANA,¶ FOR THE SUBCOMMITTEE ON HAEMOSTASIS AND MALIGNANCY *Department of Medical, Oral and Biotechnological Sciences, University ‘G. D’Annunzio’ of Chieti-Pescara, Chieti, Italy; †Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; ‡Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; §Department of Medicine, University of Washington School of Medicine and the Divisions of Public Health Sciences and Clinical Research, Fred Hutchinson Cancer Research Center; and ¶Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

To cite this article: Di Nisio M, Carrier M, Lyman GH, Khorana AA, for the Subcommittee on Haemostasis and Malignancy. Prevention of venous thromboembolism in hospitalized medical cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1746–9. See also Douketis JD, Weitz JI. Guidelines, guidance, and communications. This issue, pp 1744–5.

Scope and methodology Cancer patients hospitalized for an acute medical illness are at increased risk of venous thromboembolism (VTE). Pharmacologic thromboprophylaxis is considered to be standard practice for these patients, and current guidelines recommend prophylactic doses of low molecular weight heparins (LMWHs), unfractionated heparin (UFH) or fondaparinux in the absence of bleeding or other contraindications [1–4]. These recommendations are extrapolated from large placebo-controlled randomized clinical trials (RCTs) of VTE thromboprophylaxis in broad, mixed populations of medical inpatients, none involving exclusively cancer patients or presenting efficacy and safety data for this subgroup [5–8]. Because cancer inpatients represent a unique population with an increased risk of VTE and major hemorrhage, validation of the efficacy and safety of thromboprophylaxis in this group is critical. This statement will provide clinicians with guidance on how best to prevent VTE in patients with active cancer, defined as having evidence of disease or ongoing systemic or locoregional therapy, hospitalized for acute medical illnesses (e.g. acutely decompensated heart failure, acute respiratory insufficiency, or acute infections), and offer an Correspondence: Marcello Di Nisio, Department of Medical, Oral and Biotechnological Sciences, University ‘G. D’Annunzio’ of Chieti-Pescara, Chieti, Italy. Tel.: +39 871 358255; fax: +39 871 357361. E-mail: [email protected] Received 13 June 2014 Manuscript handled by: M. Levi Final decision: F. R. Rosendaal, 29 July 2014

expert consensus to help decision-making in challenging situations. As previously defined, the wording ‘recommend’ indicates a strong guidance statement with strong consensus among the panel members, meaning that the clinician should consider adopting the practice in most cases [9]. The wording ‘suggest’ reflects a weak guidance statement with moderate consensus among the panel members, meaning that the clinician may adopt the guidance statement or use an alternative approach to manage patients. Evidence on thromboprophylaxis in medical hospitalized cancer patients Prophylaxis with LMWH, UFH or fondaparinux significantly reduces the risk of VTE in patients hospitalized for acute medical illnesses [5–8]. A recent review summarized the rates of VTE and major bleeding in 307 cancer patients, using data from three placebo-controlled RCTs of prophylaxis in hospitalized patients with acute medical illnesses [10]. Thromboprophylaxis with daily enoxaparin 40 mg, dalteparin 5000 IU or fondaparinux 2.5 mg did not reduce the overall rate of VTE as compared with placebo. These findings need to be interpreted cautiously, because of the relatively small number of cancer patients included, the large confidence intervals around the pooled estimates, and the significant between-study heterogeneity. Furthermore, none of the trials reported on symptomatic VTE or major bleeding according to cancer status. Fondaparinux seemed to have lower efficacy than LMWH, although the comparison was indirect and underpowered. Finally, the standard doses of pharmacologic prophylaxis evaluated in these studies may be suboptimal for cancer patients, as suggested by preliminary observations in the ambulatory setting [11]. The absolute risk of VTE in cancer patients varied widely from 1% to 8% across studies, which could be © 2014 International Society on Thrombosis and Haemostasis

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attributable to coexisting patient-related risk factors [12,13]. Risk assessment models have been developed for ambulatory cancer patients [1]. Although most cancer inpatients are probably at risk of VTE and have additional risk factors such as immobility or medical comorbidities, risk assessment models have not been validated in cancer inpatients [14–18]. Despite these apparent knowledge gaps, thromboprophylaxis seems to be justified for most acutely ill medical inpatients with cancer, given their high risk of VTE. The low complication rates of prophylaxis observed in the major medical trials further support this assumption, although bleeding risk was not specifically evaluated in the cancer subgroup, and close monitoring of these patients is advisable. In the absence of dedicated studies, we assumed that patients admitted for minor procedures or short-term chemotherapy infusion have a lower VTE risk because of shorter hospital stay and no concomitant acute illnesses. Guidance statement

1 In patients with active cancer hospitalized for an acute medical illness, we recommend the use of pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications. 2 In patients admitted for minor procedures or shortterm chemotherapy infusion, we suggest not using pharmacologic thromboprophylaxis. Selection of agent and duration of thromboprophylaxis The current options for pharmacologic prophylaxis in medical hospitalized patients are UFH, LMWH, and fondaparinux. Because of the potentially lower risk of major bleeding episodes, LMWH may be preferable over UFH, although patients’ preference and compliance should be taken into account [4]. In medical hospitalized patients with cancer, fondaparinux has uncertain benefits [10], and could be considered in patients with current or previous heparin-induced thrombocytopenia in whom heparin is contraindicated. The direct oral anticoagulants are not licensed for primary thromboprophylaxis in medical patients with or without cancer [19,20]. VTE prophylaxis is currently provided for 6–14 days, as in most trials of thromboprophylaxis [5–8]. LMWH prophylaxis extended to 28 days after 10 days of open-label LMWH significantly reduced VTE by 38% (4.0% vs. 2.5%) as compared with placebo, but increased the risk of major bleeding three-fold (0.8% vs. 0.3%) [21]. In the subgroup with active cancer (n = 96), the rate of VTE was reduced by 63%, although the difference was not statistically significant. Bleeding according to cancer status was not reported. Although current guidelines recommend VTE © 2014 International Society on Thrombosis and Haemostasis

prophylaxis throughout hospitalization, cancer patients may remain at risk of VTE after hospital discharge [1,2]. Dedicated studies are needed to ensure that the benefits of prolonging anticoagulation are not offset by an increased risk of bleeding complications. Guidance statement

1 In patients with active cancer hospitalized for an acute medical illness, we recommend the use of heparins throughout hospitalization, and suggest the use of LMWH rather than UFH. 2 In medical hospitalized cancer patients, we recommend not using the new oral anticoagulants for VTE thromboprophylaxis. Patients with active bleeding Hospitalized cancer patients have a high bleeding risk because of cancer-specific features, such as the extent and location of the disease, thrombocytopenia resulting from chemotherapy, and/or other cancer-related comorbidities [22]. In cases of active bleeding or a risk of bleeding, most guidelines recommend not using anticoagulation, and often advise the use of mechanical methods of prophylaxis, including pneumatic compression devices or graduated compression stockings [1–4]. Although mechanical prophylaxis seems to be effective in reducing postoperative VTE, evidence in the medical setting is limited to ischemic stroke, with disappointing results, at least for graduated compression stockings [23]. In a meta-analysis of 16 164 hospitalized patients from 70 RCTs, pneumatic compression devices were more effective in reducing VTE than no prophylaxis, and appeared to be as effective as pharmacologic thromboprophylaxis, but with a reduced bleeding risk [24]. As none of these studies included only patients with cancer, it remains unclear how these findings can be translated to this group. Guidance statement

1 In patients with active cancer hospitalized for an acute medical illness, we suggest mechanical prophylaxis with pneumatic compression devices in patients with concomitant bleeding or a high risk of bleeding. 2 We recommend initiating or resuming pharmacologic thromboprophylaxis once bleeding resolves. Patients with thrombocytopenia Studies with retrospective cohorts, mostly of patients undergoing hematopoietic stem cell transplantation, have suggested that LMWH prophylaxis may be relatively safe for patients with platelet counts as low as 10–20 9 109 L–1

1748 M. Di Nisio et al

[25–29]. In contrast, a low platelet count (< 50 9 109 L–1) was one of the strongest independent predictors for inhospital bleeding in a large registry of medical inpatients [22], and was recently shown to be the most frequently advocated reason for not giving thromboprophylaxis [17]. Possibly, the group of patients undergoing hematopoietic stem cell transplantation is different from the group of patients with solid tumors and thrombocytopenia regarding bleeding risk. Overall, there is no high-quality evidence on the safety of thromboprophylaxis in patients with thrombocytopenia, and the platelet threshold that should trigger the decision not to use prophylaxis remains difficult to define, as other comorbidities often need to be factored in. These uncertainties are reflected in clinical guidelines; some advise against anticoagulation in cases of severe thrombocytopenia or severe platelet dysfunction, whereas others do not refer specifically to thrombocytopenia or platelet count cut-offs [1–4]. Guidance statement

1 In patients with active cancer hospitalized for an acute medical illness, we recommend pharmacologic thromboprophylaxis if the platelet count is ≥ 50 9 109 L–1 in the absence of other contraindications. 2 If the platelet count is between 25 9 109 L–1 and 50 9 109 L–1, we suggest an individualized ‘case-bycase’ approach. 3 We suggest not using pharmacologic prophylaxis in patients with a platelet count of < 25 9 109 L–1.

Guidance statement

1 In hospitalized medical cancer patients with a creatinine clearance rate (Cockcroft–Gault) of ≥ 30 mL min 1, we recommend standard prophylactic doses of LMWH in the absence of other contraindications. 2 In cancer patients with a creatinine clearance below 30 mL min-1, we suggest LMWH with a low degree of bioaccumulation or UFH. Addendum M. Di Nisio and A. Khorana concept and design. M. Di Nisio, M. Carrier, G. H. Lyman, and A. Khorana interpretation of data, critical writing and revision the intellectual content, and final approval of the version to be published. Acknowledgements A. Khorana would like to acknowledge research support from the Sondra and Stephen Hardis Chair in Oncology Research and the Scott Hamilton CARES Initiative. Disclosure of Conflict of Interests M. Carrier reports receiving grants from LEO Pharma and Bristol Meyers Squibb, outside the submitted work. A. Khorana reports receiving personal fees from Leo Pharma, Boehringer Ingelheim, and Daiichi Sankyo, outside the submitted work. H. Lyman was Chairperson on the ASCO Guidelines on VTE Treatment and Prevention.

Patients with renal insufficiency Renal insufficiency results in a two-fold higher risk of in-hospital bleeding [22]. Owing to predominantly renal clearance, LMWH and fondaparinux may accumulate with significant renal insufficiency (creatinine clearance of < 30 mL min 1), resulting in excessive anticoagulation, which predisposes to bleeding. The degree of accumulation of the various LMWHs with moderate-to-severe renal impairment differs, with tinzaparin appearing to have the lowest tendency and enoxaparin showing significant accumulation [30]. In a multicenter, single-arm clinical trial of deep vein thrombosis prophylaxis with dalteparin among critically ill patients with a creatinine clearance of < 30 mL min 1, there was no evidence for an excessive anticoagulant effect resulting from drug bioaccumulation [31]. Thus, standard prophylactic doses of LMWH can be used without adjustments in most patients, whereas LMWHs with little or no bioaccumulation, such as dalteparin and tinzaparin, should be preferred in patients with severe renal impairment. UFH could be an alternative, especially for patients with extremely low rates of creatinine clearance (< 15 mL min 1).

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Prevention of venous thromboembolism in hospitalized medical cancer patients: guidance from the SSC of the ISTH.

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