TR-05506; No of Pages 3 Thrombosis Research xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis Ryma Ihaddadene a, Grégoire Le Gal a,b, Aurélien Delluc b, Marc Carrier a,c,⁎ a b c
Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ontario Canada Département de Médecine Interne, EA3878, University of Brest, Brest, France Institut de Recherche de l’Hôpital Montfort, University of Ottawa, Ottawa, Ontario, Canada
a r t i c l e
i n f o
Article history: Received 13 February 2014 Received in revised form 25 March 2014 Accepted 25 April 2014 Available online xxxx Keywords: Venous thrombosis Venous thromboembolism Neoplasm Hemorrhage Heparin, Low molecular weight
a b s t r a c t Introduction: Patients with cancer-associated thrombosis are at a high risk of developing recurrent events despite anticoagulant therapy. Escalation of the dose of low molecular weight heparin (LMWH) has been suggested as a potential treatment option to manage these patients. We sought to confirm the benefit and risk of this management strategy in patients with recurrent cancer-associated thrombosis. Material and Methods: A retrospective cohort study of consecutive cancer outpatients seen for management of a symptomatic recurrent cancer-associated thrombosis while on anticoagulation was undertaken. Objectively confirmed episodes of recurrent thrombosis were treated with either dose escalation of LMWH or initiation of therapeutic dose of LMWH in patients already anticoagulated with LMWH or vitamin K antagonist (VKA) respectively. Included patients were followed for a minimum of 3 months after the index recurrent event. Results: Fifty-five cancer patients with a recurrent venous thromboembolism (VTE) despite anticoagulation were included. At the time of the recurrence, 89% of patients were on LMWH. The median time between the initial cancer-associated thrombosis to the index recurrent event was 2.3 months (range 0.1 to 30.4 months). Four patients (7.3%; 95% CI: 2.0 to 17.6%) had a second recurrent VTE during the 3-month follow-up period. Three patients (5.5%; 95% CI 1.1 to 15.1%) had major bleeding complications after dose escalation of LMWH. There were no recurrent fatal VTE or major bleeding episodes. Conclusion: Escalating the dose of LMWH seems effective and safe for managing patients with recurrent cancerassociated thrombosis despite anticoagulant therapy. © 2014 Elsevier Ltd. All rights reserved.
Introduction Cancer patients are at increased risk of developing a venous thrombosis compared to the general population [1,2]. Although low molecular weight heparins (LMWH) have improved patient outcomes, patients with cancer-associated thrombosis remain at an increase risk of developing recurrent thrombosis despite anticoagulant therapy [3–5]. Approximately 10 to 17% of patients with cancer-associated thrombosis managed with a vitamin K antagonist (VKA) and 6 to 10% of patients treated with therapeutic doses of LMWH will have recurrent VTE during the initial 3 to 6 month of therapy [6–8]. Previous retrospective cohort
Abbreviations: CI, confidence intervals; CNS, central nervous system; DVT, deep vein thrombosis; GI, gastro-intestinal; GU, genito-urinary; ISTH, International Society of Thrombosis and Haemostasis; LMWH, low molecular weight heparin; PE, pulmonary embolism; VKA, vitamin K antagonist (VKA); VTE, venous thromboembolism. ⁎ Corresponding author at: Ottawa Hospital Research Institute, University of Ottawa, The Ottawa Hospital – General Campus, 501 Smyth Road, Box 201A, Ottawa, ON, Canada. Tel.: +1 613 737 8899x73034; fax: +1 613 739 6266. E-mail address: [email protected] (M. Carrier).
studies have suggested that switching cancer patients with recurrent cancer-associated thrombosis while on VKA to therapeutic doses of LMWH seemed safe and effective [9,10]. Similarly, an observation cohort study has also shown that escalating the dose of LMWH (by approximately 25% or increased to therapeutic doses if receiving lower doses) might be a potential treatment option to manage patients with recurrent cancer-associated thrombosis despite LMWH [9]. Although only one retrospective cohort study (n = 47) has shown potential benefit of dose escalation of LMWH, it has been proposed as a management strategy to treat patients with recurrent cancer-associated thrombosis despite anticoagulation [11–13]. We sought to confirm the benefits and risks associated with this empiric approach. Material & methods A retrospective cohort study of consecutive cancer outpatients seen for management of a symptomatic recurrent cancer-associated thrombosis while on anticoagulation was undertaken from July 2008 to December 2012. Patients were included if they had: 1) documented active malignancy (receiving therapy (chemotherapy or radiotherapy)
http://dx.doi.org/10.1016/j.thromres.2014.04.028 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article as: Ihaddadene R, et al, Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.028
2
R. Ihaddadene et al. / Thrombosis Research xxx (2014) xxx–xxx
or with metastatic disease); 2) objectively proven first episode of symptomatic cancer-related thrombosis (Proximal lower/upper extremity deep vein thrombosis (DVT) or pulmonary embolism (PE); and 3) objectively documented symptomatic recurrent venous thromboembolism (VTE) while on anticoagulant therapy (LMWH or a VKA). All objectively confirmed episodes of recurrent cancer-associated thrombosis while patients were receiving full therapeutic weightadjusted doses of LMWH were assessed to confirm drug compliance and ensure that heparin-induced thrombocytopenia has been excluded. All recurrent cancer-associated thrombosis despite anticoagulation with LMWH were treated by increasing of the dose of LMWH by 20 to 25% for a minimum of 4 weeks. Therapeutic dose of LMWH was defined as dalteparin 200 units/kg daily, tinzaparin 175 units/kg daily, or enoxaparin 1 mg/kg twice daily. Patients receiving intermediate (75 to 80% of the full therapeutic weight adjusted doses) or prophylactic doses of LMWH at the time of the recurrent cancer-associated thrombosis were managed by increasing the LMWH to the full weight-adjusted therapeutic doses. Switching the patient to another brand of LMWH was not routinely done. Patients with recurrent cancer-associated thrombosis despite anticoagulation with VKA (therapeutic or subtherapeutic INR) were treated by switching anticoagulation to full weight-adjusted doses of LMWH. All patients were followed for a minimum of 3 months after the index recurrent cancer-associated thrombosis and dose escalation of LMWH. The primary efficacy outcome measure was the incidence of additional recurrent VTE diagnosed over a 3-month follow-up period. Venous thromboembolism were defined and reported as recommended by the International Society of Thrombosis and Haemostasis (ISTH) SSC Haemostasis & Malignancy [14]. Recurrent DVT was defined as a new non-compressible site or proximal extension from a previously noncompressible site. Recurrent PE was defined as a new mismatched or greater perfusion defect on V/Q scan or a new intraluminal filling defect in a segmental or larger pulmonary artery on computed tomographic pulmonary angiography. The primary safety outcome measure was major bleeding during the three month follow-up period as per the ISTH definition [15]. Secondary outcome measures included overall mortality, fatal bleeding episodes and fatal recurrent pulmonary embolism. Outcomes were extracted independently by two investigators. Disagreements on information were resolved by consensus. We reported the proportions, with 95% confidence intervals (CI), of patients with additional episodes of recurrent cancer-associated thrombosis and major bleeding during the 3-month follow-up period. A Kaplan-Meier survival curve was constructed to estimate the time to the index recurrent cancer-associated thrombosis from the initial diagnosis. Patients were censored after the last known date of follow-up or death. The median time between the initial and index recurrent VTE, and the median time between the index and death were determined. Analyses were performed using SPSS.
Table 1 Baseline Characteristics. Study Population (N = 55) (n, %; 95% CI) Female Age (Median; range) Metastatic Disease Anticoagulation at time of recurrent event LMWH VKA Cancer location Lung Colon Breast CNS GU Gynaecological Haematological Other Initial VTE Lower extremity DVT Upper extremity DVT Catheter related PE DVT and PE
28 (50.9%; 37.1-67.6) 63 (22 to 83) 30 (54.5%; 40.5-68.0) 49 (89.1%; 77.8-95.9) 6 (10.9%; 4.1-22.2) 19 (34.5%; 22.2-48.6) 15 (27.3%; 16.1-41.0) 2 (3.6%; 0.4-12.5) 3 (5.5%; 1.1-15.1) 6 (10.9%; 4.1-22.2 3 (5.5%; 1.1-15.1) 5 (9.1%; 3.0-20.0) 2 (3.6%; 0.4-12.5) 19 (34.5%; 22.2-48.6) 13 (23.7%; 13.2-37.0) 6 (10.9%; 4.1-22.2) 19 (34.5%; 22.2-48.6) 4 (7.3%; 2.0-17.6)
CNS: central nervous system; DVT: deep vein thrombosis; GI: gastro-intestinal; GU: genito-urinary; PE: pulmonary embolism; VTE: venous thromboembolism.
recurrence, 89% of patients were on LMWH and 11% were on VKA. Out of the 49 patients on LMWH, 18 (33%), 27 (49%) and 4 (7%) were on therapeutic, intermediate and prophylactic-doses respectively. One of the six patients on VKA had a sub-therapeutic INR at the time of the recurrent event. The median time between the initial cancer-associated thrombosis to the index recurrent event was 2.3 months (range 0.1 to 30.4 months; 95% CI: 1.2 to 3.3) (Fig. 1). All patients were treated with LMWH, 37 patients were treated with therapeutic doses and 18 patients received 120% of a weight-adjusted therapeutic dose of LMWH for the index recurrent cancer-associated thrombosis. All patient received dose escalation for a minimum of 4 weeks (median: 6 weeks (range: 412 weeks)). Three patients also had an inferior vena cava filter inserted. The inferior vena cava filters were inserted as an adjunct to dose escalation of LMWH. Four patients (7.3%; 95% CI 2.0 to 17.6%) had a second recurrent cancer-associated thrombosis during the 3-month follow-up period. Three patients (5.5%; 95% CI 1.1 to 15.1%) had major bleeding
Results Fifty-five cancer patients with a recurrent cancer-associated thrombosis despite ongoing anticoagulation were included. Baseline characteristic are depicted in Table 1. The median age was 63 years old (range 22-83). Twenty-eight (50.9%) were female and thirty (54.5%) had metastatic disease at the time of the initial cancer-associated thrombosis. Twenty eight (50.9%) were undergoing chemotherapy at the time of the recurrent event and three (5.5%) underwent a surgical procedure within the previous month. The most common type of cancer was lung carcinoma (34.5%). The most common histology was adenocarcinoma (32.7%). The initial cancer associated thrombosis was a proximal lower extremity DVT or PE in 38 (69.1%) patients. Four patients (7.3%) had both DVT and PE. Of the 55 patients with recurrent cancer-associated thrombosis, 21 (38.2%), 13 (23.6%) and 21 (38.2%) had recurrent lower extremity DVT, upper extremity DVT, or PE, respectively. At the time of the
Fig. 1. Time to index recurrent VTE after initial diagnosis of cancer-associated thrombosis.
Please cite this article as: Ihaddadene R, et al, Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.028
R. Ihaddadene et al. / Thrombosis Research xxx (2014) xxx–xxx
complications after the switch or dose escalation of LMWH. There were no recurrent fatal VTE or major bleeding episodes. Out of 24 deaths, 14 (58.3%) occurred during the initial 3 months follow-up period. The median time between the index recurrence to death was 13.0 months (range 0 to 43.0 months; 95% CI 4.0 to 22.1). All four patients with a second recurrent cancer-associated thrombosis despite dose escalation were diagnosed within two weeks and were receiving weight-adjusted therapeutic doses of LMWH at the time of the recurrent event. All were treated by increasing the weightadjusted dose by an additional 20 to 25% (120% of weight-adjusted therapeutic doses) for at least 4 weeks. None of these patients had any further recurrent thrombotic or major bleeding events during the 3-month follow-up period. Discussion Our cohort study confirms that recurrent cancer-associated thrombosis can be effectively and safely managed by switching from VKA to LMWH or escalating the dose of LMWH. Dose escalation of LMWH has been suggested as a treatment option to manage patients with recurrent cancer-associated thrombosis despite anticoagulation following confirmation of drug compliance and exclusion of heparin-induced thrombocytopenia (HIT) [11–13]. However, this approach was only described and reported in a limited number of cancer patients (n = 70) [9,10]. Our cohort study adds to the literature by expanding the number of patients managed using dose escalation of LMWH and providing reassurance about the efficacy of safety of such an approach. Our rates of additional recurrent cancer-associated thrombosis (7.3%; 95% CI: 2.0 to 17.6%) or major bleeding episodes (5.5%; 95% CI: 1.1 to 15.1%) following dose escalation with LMWH is similar to those previously published [9,10]. Two previous cohort studies have reported a risk of recurrent cancer-associated thrombosis of 8.6% (95% CI: 4.0 to 17.5%) and 9% (95% CI: 2 to 25%) [9,10]. Similarly, a previous cohort study of cancer patients reported a rate of major bleeding of 4.3% (95% CI: 1.5 to 11.9%). Including the data from our analysis, a total of 145 patients with recurrent cancer-associated thrombosis despite anticoagulation receiving dose escalation of LMWH have now been reported [9,10]. All patients had symptomatic improvement with small risk of additional recurrent thrombosis or major bleeding emphasizing that dose escalation of LMWH is well tolerated with few bleeding complications. An ISTH Registry on the management of recurrent cancer-associated thrombosis is on-going and will more insight on the different management options for these patients (http://www.isth.org/? RecurrentVenousThrom). Expert consensus has suggested that patients without symptomatic improvement or with additional recurrent cancer-associated thrombosis despite dose escalation with LMWH should be considered for another dose escalation [12,13]. All four patients with additional recurrent cancer-associated thrombosis despite dose escalation received another incremental increase of their dose of LMWH by 20 to 25% for a minimum of 4 weeks without any further recurrent event or major bleeding complications. Although anti-Xa levels can be used to estimate the next dose escalation [12,13], the levels were not used within our analysis. There are limitations of our study. This is a retrospective cohort study and the results might be subjected to selection bias or misdiagnosis. We tried to minimize selection bias by including all consecutive patients and by extracting the data by two reviewers independently. Furthermore, only symptomatic objectively confirmed recurrent event were included. Another limitation is the relatively small sample size potentially leading to imprecision in the estimates of the risk of recurrent cancer-associated thrombosis, major bleeding episodes or overall survival after dose escalation with LMWH. Larger prospective trials are required to provide more reliable estimates. Finally, we did not assess the use of other anticoagulants including direct oral Xa inhibitors
3
(rivaroxaban, apixaban, endoxaban) or thrombin inhibitor (dabigatran). However, there are no published data on the efficacy and safety of the direct oral anticoagulants in the management of recurrent cancerassociated thrombosis despite anticoagulation. Furthermore, the use of these direct oral anticoagulants for the management of cancerassociated thrombosis is currently not recommended [12,16]. Our study confirms that escalating the dose of LMWH can be effective and safe to manage patients with recurrent cancer-associated thrombosis despite anticoagulation. Future trials are desperately needed to prospectively assess the effectiveness and safety of this management approach. Conflict of interest statement All authors have fulfilled the conditions required for authorship and the authors report no potential conflicts of interest. Acknowlegements MC is a recipient of a New Investigator Award from the Heart and Stroke Foundation of Canada and of a Tier 2 Research Chair in Thrombosis and Cancer References [1] Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715–22. [2] Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160:809–15. [3] Hutten BA, Prins MH, Gent M, Ginsberg JS, Buller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078–83. [4] Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484–8. [5] Elting LS, Escalante CP, Cooksley C, Avritscher EB, Kurtin D, Hamblin L, et al. Outcomes and cost of deep venous thrombosis among patients with cancer. Arch Intern Med 2004;164:1653–61. [6] Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, et al. Long-term lowmolecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006;119:1062–72. [7] Lee AYY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecularweight Heparin versus a coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146–53. [8] Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002;162:1729–35. [9] Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost 2009;7:760–5. [10] Luk C, Wells PS, Anderson D, Kovacs MJ. Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy. Am J Med 2001;111:270–3. [11] Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013;11:56–70. [12] Carrier M, Khorana AA, Zwicker J, Noble S, Lee AY. Management of challenging cases of patients with cancerassociated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost 2013;11:1760–5. [13] Lee AY. Thrombosis in cancer: an update on prevention, treatment, and survival benefits of anticoagulants. Hematology Am Soc Hematol Educ Program 2010:144–9. [14] Carrier M, Khorana AA, Zwicker JI, Lyman GH, Le Gal G, Lee AYY. Venous thromboembolism in cancer clinical trials: recommendation for standardized reporting and analysis. J Thromb Haemost 2012;10:2599–601. [15] Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–4. [16] Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, et al. 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.
Please cite this article as: Ihaddadene R, et al, Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.028
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis Ryma Ihaddadene a, Grégoire Le Gal a,b, Aurélien Delluc b, Marc Carrier a,c,⁎ a b c
Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ontario Canada Département de Médecine Interne, EA3878, University of Brest, Brest, France Institut de Recherche de l’Hôpital Montfort, University of Ottawa, Ottawa, Ontario, Canada
a r t i c l e
i n f o
Article history: Received 13 February 2014 Received in revised form 25 March 2014 Accepted 25 April 2014 Available online xxxx Keywords: Venous thrombosis Venous thromboembolism Neoplasm Hemorrhage Heparin, Low molecular weight
a b s t r a c t Introduction: Patients with cancer-associated thrombosis are at a high risk of developing recurrent events despite anticoagulant therapy. Escalation of the dose of low molecular weight heparin (LMWH) has been suggested as a potential treatment option to manage these patients. We sought to confirm the benefit and risk of this management strategy in patients with recurrent cancer-associated thrombosis. Material and Methods: A retrospective cohort study of consecutive cancer outpatients seen for management of a symptomatic recurrent cancer-associated thrombosis while on anticoagulation was undertaken. Objectively confirmed episodes of recurrent thrombosis were treated with either dose escalation of LMWH or initiation of therapeutic dose of LMWH in patients already anticoagulated with LMWH or vitamin K antagonist (VKA) respectively. Included patients were followed for a minimum of 3 months after the index recurrent event. Results: Fifty-five cancer patients with a recurrent venous thromboembolism (VTE) despite anticoagulation were included. At the time of the recurrence, 89% of patients were on LMWH. The median time between the initial cancer-associated thrombosis to the index recurrent event was 2.3 months (range 0.1 to 30.4 months). Four patients (7.3%; 95% CI: 2.0 to 17.6%) had a second recurrent VTE during the 3-month follow-up period. Three patients (5.5%; 95% CI 1.1 to 15.1%) had major bleeding complications after dose escalation of LMWH. There were no recurrent fatal VTE or major bleeding episodes. Conclusion: Escalating the dose of LMWH seems effective and safe for managing patients with recurrent cancerassociated thrombosis despite anticoagulant therapy. © 2014 Elsevier Ltd. All rights reserved.
Introduction Cancer patients are at increased risk of developing a venous thrombosis compared to the general population [1,2]. Although low molecular weight heparins (LMWH) have improved patient outcomes, patients with cancer-associated thrombosis remain at an increase risk of developing recurrent thrombosis despite anticoagulant therapy [3–5]. Approximately 10 to 17% of patients with cancer-associated thrombosis managed with a vitamin K antagonist (VKA) and 6 to 10% of patients treated with therapeutic doses of LMWH will have recurrent VTE during the initial 3 to 6 month of therapy [6–8]. Previous retrospective cohort
Abbreviations: CI, confidence intervals; CNS, central nervous system; DVT, deep vein thrombosis; GI, gastro-intestinal; GU, genito-urinary; ISTH, International Society of Thrombosis and Haemostasis; LMWH, low molecular weight heparin; PE, pulmonary embolism; VKA, vitamin K antagonist (VKA); VTE, venous thromboembolism. ⁎ Corresponding author at: Ottawa Hospital Research Institute, University of Ottawa, The Ottawa Hospital – General Campus, 501 Smyth Road, Box 201A, Ottawa, ON, Canada. Tel.: +1 613 737 8899x73034; fax: +1 613 739 6266. E-mail address: [email protected] (M. Carrier).
studies have suggested that switching cancer patients with recurrent cancer-associated thrombosis while on VKA to therapeutic doses of LMWH seemed safe and effective [9,10]. Similarly, an observation cohort study has also shown that escalating the dose of LMWH (by approximately 25% or increased to therapeutic doses if receiving lower doses) might be a potential treatment option to manage patients with recurrent cancer-associated thrombosis despite LMWH [9]. Although only one retrospective cohort study (n = 47) has shown potential benefit of dose escalation of LMWH, it has been proposed as a management strategy to treat patients with recurrent cancer-associated thrombosis despite anticoagulation [11–13]. We sought to confirm the benefits and risks associated with this empiric approach. Material & methods A retrospective cohort study of consecutive cancer outpatients seen for management of a symptomatic recurrent cancer-associated thrombosis while on anticoagulation was undertaken from July 2008 to December 2012. Patients were included if they had: 1) documented active malignancy (receiving therapy (chemotherapy or radiotherapy)
http://dx.doi.org/10.1016/j.thromres.2014.04.028 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article as: Ihaddadene R, et al, Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.028
2
R. Ihaddadene et al. / Thrombosis Research xxx (2014) xxx–xxx
or with metastatic disease); 2) objectively proven first episode of symptomatic cancer-related thrombosis (Proximal lower/upper extremity deep vein thrombosis (DVT) or pulmonary embolism (PE); and 3) objectively documented symptomatic recurrent venous thromboembolism (VTE) while on anticoagulant therapy (LMWH or a VKA). All objectively confirmed episodes of recurrent cancer-associated thrombosis while patients were receiving full therapeutic weightadjusted doses of LMWH were assessed to confirm drug compliance and ensure that heparin-induced thrombocytopenia has been excluded. All recurrent cancer-associated thrombosis despite anticoagulation with LMWH were treated by increasing of the dose of LMWH by 20 to 25% for a minimum of 4 weeks. Therapeutic dose of LMWH was defined as dalteparin 200 units/kg daily, tinzaparin 175 units/kg daily, or enoxaparin 1 mg/kg twice daily. Patients receiving intermediate (75 to 80% of the full therapeutic weight adjusted doses) or prophylactic doses of LMWH at the time of the recurrent cancer-associated thrombosis were managed by increasing the LMWH to the full weight-adjusted therapeutic doses. Switching the patient to another brand of LMWH was not routinely done. Patients with recurrent cancer-associated thrombosis despite anticoagulation with VKA (therapeutic or subtherapeutic INR) were treated by switching anticoagulation to full weight-adjusted doses of LMWH. All patients were followed for a minimum of 3 months after the index recurrent cancer-associated thrombosis and dose escalation of LMWH. The primary efficacy outcome measure was the incidence of additional recurrent VTE diagnosed over a 3-month follow-up period. Venous thromboembolism were defined and reported as recommended by the International Society of Thrombosis and Haemostasis (ISTH) SSC Haemostasis & Malignancy [14]. Recurrent DVT was defined as a new non-compressible site or proximal extension from a previously noncompressible site. Recurrent PE was defined as a new mismatched or greater perfusion defect on V/Q scan or a new intraluminal filling defect in a segmental or larger pulmonary artery on computed tomographic pulmonary angiography. The primary safety outcome measure was major bleeding during the three month follow-up period as per the ISTH definition [15]. Secondary outcome measures included overall mortality, fatal bleeding episodes and fatal recurrent pulmonary embolism. Outcomes were extracted independently by two investigators. Disagreements on information were resolved by consensus. We reported the proportions, with 95% confidence intervals (CI), of patients with additional episodes of recurrent cancer-associated thrombosis and major bleeding during the 3-month follow-up period. A Kaplan-Meier survival curve was constructed to estimate the time to the index recurrent cancer-associated thrombosis from the initial diagnosis. Patients were censored after the last known date of follow-up or death. The median time between the initial and index recurrent VTE, and the median time between the index and death were determined. Analyses were performed using SPSS.
Table 1 Baseline Characteristics. Study Population (N = 55) (n, %; 95% CI) Female Age (Median; range) Metastatic Disease Anticoagulation at time of recurrent event LMWH VKA Cancer location Lung Colon Breast CNS GU Gynaecological Haematological Other Initial VTE Lower extremity DVT Upper extremity DVT Catheter related PE DVT and PE
28 (50.9%; 37.1-67.6) 63 (22 to 83) 30 (54.5%; 40.5-68.0) 49 (89.1%; 77.8-95.9) 6 (10.9%; 4.1-22.2) 19 (34.5%; 22.2-48.6) 15 (27.3%; 16.1-41.0) 2 (3.6%; 0.4-12.5) 3 (5.5%; 1.1-15.1) 6 (10.9%; 4.1-22.2 3 (5.5%; 1.1-15.1) 5 (9.1%; 3.0-20.0) 2 (3.6%; 0.4-12.5) 19 (34.5%; 22.2-48.6) 13 (23.7%; 13.2-37.0) 6 (10.9%; 4.1-22.2) 19 (34.5%; 22.2-48.6) 4 (7.3%; 2.0-17.6)
CNS: central nervous system; DVT: deep vein thrombosis; GI: gastro-intestinal; GU: genito-urinary; PE: pulmonary embolism; VTE: venous thromboembolism.
recurrence, 89% of patients were on LMWH and 11% were on VKA. Out of the 49 patients on LMWH, 18 (33%), 27 (49%) and 4 (7%) were on therapeutic, intermediate and prophylactic-doses respectively. One of the six patients on VKA had a sub-therapeutic INR at the time of the recurrent event. The median time between the initial cancer-associated thrombosis to the index recurrent event was 2.3 months (range 0.1 to 30.4 months; 95% CI: 1.2 to 3.3) (Fig. 1). All patients were treated with LMWH, 37 patients were treated with therapeutic doses and 18 patients received 120% of a weight-adjusted therapeutic dose of LMWH for the index recurrent cancer-associated thrombosis. All patient received dose escalation for a minimum of 4 weeks (median: 6 weeks (range: 412 weeks)). Three patients also had an inferior vena cava filter inserted. The inferior vena cava filters were inserted as an adjunct to dose escalation of LMWH. Four patients (7.3%; 95% CI 2.0 to 17.6%) had a second recurrent cancer-associated thrombosis during the 3-month follow-up period. Three patients (5.5%; 95% CI 1.1 to 15.1%) had major bleeding
Results Fifty-five cancer patients with a recurrent cancer-associated thrombosis despite ongoing anticoagulation were included. Baseline characteristic are depicted in Table 1. The median age was 63 years old (range 22-83). Twenty-eight (50.9%) were female and thirty (54.5%) had metastatic disease at the time of the initial cancer-associated thrombosis. Twenty eight (50.9%) were undergoing chemotherapy at the time of the recurrent event and three (5.5%) underwent a surgical procedure within the previous month. The most common type of cancer was lung carcinoma (34.5%). The most common histology was adenocarcinoma (32.7%). The initial cancer associated thrombosis was a proximal lower extremity DVT or PE in 38 (69.1%) patients. Four patients (7.3%) had both DVT and PE. Of the 55 patients with recurrent cancer-associated thrombosis, 21 (38.2%), 13 (23.6%) and 21 (38.2%) had recurrent lower extremity DVT, upper extremity DVT, or PE, respectively. At the time of the
Fig. 1. Time to index recurrent VTE after initial diagnosis of cancer-associated thrombosis.
Please cite this article as: Ihaddadene R, et al, Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.028
R. Ihaddadene et al. / Thrombosis Research xxx (2014) xxx–xxx
complications after the switch or dose escalation of LMWH. There were no recurrent fatal VTE or major bleeding episodes. Out of 24 deaths, 14 (58.3%) occurred during the initial 3 months follow-up period. The median time between the index recurrence to death was 13.0 months (range 0 to 43.0 months; 95% CI 4.0 to 22.1). All four patients with a second recurrent cancer-associated thrombosis despite dose escalation were diagnosed within two weeks and were receiving weight-adjusted therapeutic doses of LMWH at the time of the recurrent event. All were treated by increasing the weightadjusted dose by an additional 20 to 25% (120% of weight-adjusted therapeutic doses) for at least 4 weeks. None of these patients had any further recurrent thrombotic or major bleeding events during the 3-month follow-up period. Discussion Our cohort study confirms that recurrent cancer-associated thrombosis can be effectively and safely managed by switching from VKA to LMWH or escalating the dose of LMWH. Dose escalation of LMWH has been suggested as a treatment option to manage patients with recurrent cancer-associated thrombosis despite anticoagulation following confirmation of drug compliance and exclusion of heparin-induced thrombocytopenia (HIT) [11–13]. However, this approach was only described and reported in a limited number of cancer patients (n = 70) [9,10]. Our cohort study adds to the literature by expanding the number of patients managed using dose escalation of LMWH and providing reassurance about the efficacy of safety of such an approach. Our rates of additional recurrent cancer-associated thrombosis (7.3%; 95% CI: 2.0 to 17.6%) or major bleeding episodes (5.5%; 95% CI: 1.1 to 15.1%) following dose escalation with LMWH is similar to those previously published [9,10]. Two previous cohort studies have reported a risk of recurrent cancer-associated thrombosis of 8.6% (95% CI: 4.0 to 17.5%) and 9% (95% CI: 2 to 25%) [9,10]. Similarly, a previous cohort study of cancer patients reported a rate of major bleeding of 4.3% (95% CI: 1.5 to 11.9%). Including the data from our analysis, a total of 145 patients with recurrent cancer-associated thrombosis despite anticoagulation receiving dose escalation of LMWH have now been reported [9,10]. All patients had symptomatic improvement with small risk of additional recurrent thrombosis or major bleeding emphasizing that dose escalation of LMWH is well tolerated with few bleeding complications. An ISTH Registry on the management of recurrent cancer-associated thrombosis is on-going and will more insight on the different management options for these patients (http://www.isth.org/? RecurrentVenousThrom). Expert consensus has suggested that patients without symptomatic improvement or with additional recurrent cancer-associated thrombosis despite dose escalation with LMWH should be considered for another dose escalation [12,13]. All four patients with additional recurrent cancer-associated thrombosis despite dose escalation received another incremental increase of their dose of LMWH by 20 to 25% for a minimum of 4 weeks without any further recurrent event or major bleeding complications. Although anti-Xa levels can be used to estimate the next dose escalation [12,13], the levels were not used within our analysis. There are limitations of our study. This is a retrospective cohort study and the results might be subjected to selection bias or misdiagnosis. We tried to minimize selection bias by including all consecutive patients and by extracting the data by two reviewers independently. Furthermore, only symptomatic objectively confirmed recurrent event were included. Another limitation is the relatively small sample size potentially leading to imprecision in the estimates of the risk of recurrent cancer-associated thrombosis, major bleeding episodes or overall survival after dose escalation with LMWH. Larger prospective trials are required to provide more reliable estimates. Finally, we did not assess the use of other anticoagulants including direct oral Xa inhibitors
3
(rivaroxaban, apixaban, endoxaban) or thrombin inhibitor (dabigatran). However, there are no published data on the efficacy and safety of the direct oral anticoagulants in the management of recurrent cancerassociated thrombosis despite anticoagulation. Furthermore, the use of these direct oral anticoagulants for the management of cancerassociated thrombosis is currently not recommended [12,16]. Our study confirms that escalating the dose of LMWH can be effective and safe to manage patients with recurrent cancer-associated thrombosis despite anticoagulation. Future trials are desperately needed to prospectively assess the effectiveness and safety of this management approach. Conflict of interest statement All authors have fulfilled the conditions required for authorship and the authors report no potential conflicts of interest. Acknowlegements MC is a recipient of a New Investigator Award from the Heart and Stroke Foundation of Canada and of a Tier 2 Research Chair in Thrombosis and Cancer References [1] Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715–22. [2] Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160:809–15. [3] Hutten BA, Prins MH, Gent M, Ginsberg JS, Buller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078–83. [4] Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484–8. [5] Elting LS, Escalante CP, Cooksley C, Avritscher EB, Kurtin D, Hamblin L, et al. Outcomes and cost of deep venous thrombosis among patients with cancer. Arch Intern Med 2004;164:1653–61. [6] Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, et al. Long-term lowmolecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006;119:1062–72. [7] Lee AYY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecularweight Heparin versus a coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146–53. [8] Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002;162:1729–35. [9] Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost 2009;7:760–5. [10] Luk C, Wells PS, Anderson D, Kovacs MJ. Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy. Am J Med 2001;111:270–3. [11] Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013;11:56–70. [12] Carrier M, Khorana AA, Zwicker J, Noble S, Lee AY. Management of challenging cases of patients with cancerassociated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost 2013;11:1760–5. [13] Lee AY. Thrombosis in cancer: an update on prevention, treatment, and survival benefits of anticoagulants. Hematology Am Soc Hematol Educ Program 2010:144–9. [14] Carrier M, Khorana AA, Zwicker JI, Lyman GH, Le Gal G, Lee AYY. Venous thromboembolism in cancer clinical trials: recommendation for standardized reporting and analysis. J Thromb Haemost 2012;10:2599–601. [15] Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–4. [16] Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, et al. 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.
Please cite this article as: Ihaddadene R, et al, Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.028
