Journal of Thrombosis and Haemostasis, 12: 1746–1749
DOI: 10.1111/jth.12683
RECOMMENDATIONS AND GUIDELINES
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
VTE prevention among cancer medical inpatients 1747
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).
References 1 Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, Kakkar AK, Key NS, Levine MN, Liebman HA, Tempero MA, Wong SL, Prestrud AA, Falanga A. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2013; 31: 2189–204. 2 National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease 2013. http://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Accessed 14 August 2014. 3 Mandala M, Falanga A, Roila F. Management of venous thromboembolism in cancer patients: ESMO clinical recommendations. Ann Oncol 2008; 19(Suppl. 2): ii126–7. 4 Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, Le H, Schulman S, Murad MH. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e195S–226S. 5 Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Jambon C, Leizorovicz A, Nguyen H, Olsson C-G, Turpie AG, Weisslinger N, for the Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism © 2014 International Society on Thrombosis and Haemostasis
VTE prevention among cancer medical inpatients 1749
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in acutely ill medical patients. N Engl J Med 1999; 341: 793–800. Leizorovicz A, Cohen AT, Turpie AGG, Olsson CG, Vaitkus PT, Goldhaber SZ. Randomized, placebo-controlled trial of Dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110: 874–9. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, Turpie AGG, Egberts JFM, Lensing AW, for the ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332: 325–9. Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146: 278–88. Carrier M, Khorana AA, Zwicker JI, Noble S, Lee AYY. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost 2013; 11: 1760–5. Carrier M, Khorana AA, Moretto P, La Gal G, Karp R, Zwicker JI. Lack of evidence to support thromboprophylaxis in hospitalized medical patients with cancer. Am J Med 2014; 127: 82–6. Di Nisio M, Porreca E, Otten H-M, Rutjes AWS. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev 2012, Issue 2. Art. No.: CD008500. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122: 1712–23. Pabinger I, Thaler J, Ay C. Biomarkers for prediction of venous thromboembolism in cancer. Blood 2013; 122: 2011–18. Samama MM, Combe S, Conard J, Horellou M-H. Risk assessment models for thromboprophylaxis of medical patients. Thromb Res 2012; 129: 127–32. Zakai NA, Wright J, Cushman M. Risk factors for venous thrombosis in medical inpatients: validation of a thrombosis risk score. J Thromb Haemost 2004; 2: 2156–61. Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, De Bon E, Tormene D, Pagnan A, Prandoni P. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8: 2450–7. Zwicker JI, Rojan A, Campigotto F, Rehman N, Funches R, Connolly G, Webster J, Aggarwal A, Mobarek D, Faselis C, Neuberg D, Rickles FR, Wun T, Streiff MB, Khorana AA. Pattern of frequent but nontargeted pharmacologic thromboprophylaxis for hospitalized patients with cancer at academic medical centers: a prospective, cross-sectional, multicenter study. J Clin Oncol 2014; 32: 1792–6. Dobromirski M, Cohen M. How I manage venous thromboembolism risk in hospitalized medical patients. Blood 2012; 120: 1562–9. Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI, for the ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365: 2167–77. Cohen AT, Spiro TE, B€ uller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V, for the MAGELLAN Investigators. Rivaroxaban for
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thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368: 513–23. Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AGG, Yusen RD, for the EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010;153:8–18. Decousous H, Tapson VF, Bergmann JF, Chong BH, Froehlich JB, Kakkar AK, Merli GJ, Monreal M, Nakamura M, Pavanello R, Pini M, Piovella F, Spencer FA, Spyropoulos AC, Turpie AG, Zotz RB, Fitzgerald G, Anderson FA, IMPROVE Investigators. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011; 139: 69–79. The CLOTS Trials Collaboration. The effect of graduated compression stockings on long-term outcomes after stroke: the CLOTS Trials 1 and 2. Stroke 2013; 44: 1075–9. Ho KM, Tan JA. Stratified meta-analysis of intermittent pneumatic compression of the lower limbs to prevent venous thromboembolism in hospitalized patients. Circulation 2013; 128: 1003–20. Herishanu Y, Misgav M, Kirgner I, Ben-Tal O, Eldor A, Naparstek E. Enoxaparin can be used safely in patients with severe thrombocytopenia due to intensive chemotherapy regimens. Leuk Lymphoma 2004; 45: 1407–11. Cortelezzi A, Fracchiolla NS, Maisonneuve P, Moia M, Luchesini C, Ranzi ML, Monni P, Pasquini MC, Lambertenghi-Deliliers G. Central venous catheter-related complications in patients with hematological malignancies: a retrospective analysis of risk factors and prophylactic measures. Leuk Lymphoma 2003; 44: 1495–501. Or R, Nagler A, Shpilberg O, Elad S, Naparstek E, Kapelushnik J, Cass Y, Gillis S, Chetrit A, Slavin S, Eldor A. Low molecular weight heparin for the prevention of veno-occlusive disease of the liver in bone marrow transplantation patients. Transplantation 1996; 61: 1067–71. Simon M, Hahn T, Ford LA, Anderson B, Swinnich D, Baer MR, Bambach B, Bernstein SH, Bernstein ZP, Czuczman MS, Slack JL, Wetzler M, Herzig G, Schriber J, McCarthy PL Jr. Retrospective multivariate analysis of hepatic veno-occlusive disease after blood or marrow transplantation: possible beneficial use of low molecular weight heparin. Bone Marrow Transplant 2001; 27: 627–33. Forrest DL, Thompson K, Dorcas VG, Couban SH, Pierce R. Low molecular weight heparin for the prevention of hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplantation: a prospective phase II study. Bone Marrow Transplant 2003; 31: 1143–9. Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother 2009; 43: 1064–83. Douketis J, Cook D, Meade M, Guyatt G, Geerts W, Skrobik Y, Albert M, Granton J, Hebert P, Pagliarello G, Marshall J, Fowler R, Freitag A, Rabbat C, Anderson D, Zytaruk N, HeelsAnsdell D, Crowther M, for the Canadian Critical Care Trials Group. Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low-molecularweight heparin dalteparin an assessment of safety and pharmacodynamics: the DIRECT Study. Arch Intern Med 2008; 168: 1805–12.
DOI: 10.1111/jth.12683
RECOMMENDATIONS AND GUIDELINES
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
VTE prevention among cancer medical inpatients 1747
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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