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Monday 22 October 2018
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Thromboprophylaxis during treatment with lenalidomide

PRACTICAL THERAPEUTICS
Inés Yeste Gómez PharmD
Department of Pharmacy,
Hospital General Universitario Gregorio
Marañón, Madrid, Spain
Patients with multiple myeloma (MM) have an increased risk of venous thromboembolism (VTE) as a consequence of an impairment of both anticoagulant and fibrinolytic pathways. The incidence of VTE in MM is estimated to be between 3% and 10%1 and it may be increased by the presence of underlying risk factors, such as advanced age, previous history of thrombosis, immobility, hormone therapy, concomitant infections, chemotherapy, high levels of endothelial growth factor and cancer procoagulants and paraproteinemia. The pathogenesis of VTE in MM includes multiple factors, such as increased blood viscosity, infections, high levels of immunoglobulin, autoantibody directed against natural anticoagulants and the procoagulant activity of inflammatory mediators(2).
However, despite this procoagulantion activity, thromboembolism was not recognised as a major complication of multiple myeloma until the advent of inmmunomodulatory drugs (IMiDs): thalidomide and its analogue, lenalidomide. 
Immunomodulatory drugs in MM: lenalidomide
In the past two decades, the introduction of IMiDs has improved the clinical outcome of patients diagnosed with MM. The first IMiD used in the treatment of MM was thalidomide, which had the advantages of oral administration and, apparently, a better toxicity profile compared with other effective chemotherapy agents. However, it was only after its clinical practice use that thalidomide demonstrated significant and dose-limiting side-effects, including sedation, fatigue, constipation, thrombotic complications and peripheral neuropathy. The dose-limiting toxicities of thalidomide prompted the search for more potent but less toxic derivatives.
Lenalidomide is a more potent immunomodulatory derivate of thalidomide. It acts by stimulating T-cell proliferation, as well as interleukin-2 and interferon-gamma production, leading to induced host anti-MM immune response. Lenalidomide has a more favourable side-effect profile than does thalidomide and shows significant activity in relapsed and refractory MM patients.(3) Lenalidomide presents a better side-effect profile than does thalidomide, but both agents are associated with a high risk of VTE, resulting in a considerable morbidity and mortality. The mechanism of action that explains these events is not clear; however, it is suggested that lenalidomide and thalidomide induce a transient elevation of factor VIII and von Willebrand factor, decrease soluble thrombomodulin and restore PAR-1 expression on endothelial cells.(1) 
Several studies have evaluated the incidence of VTE in patients receiving lenalidomide. As a single agent, lenalidomide does not significantly increase the risk of VTE.(4) In the absent of thromboprophylaxis and in combination with high doses of dexamethasone, the VTE incidence is estimated to be between 26% and 75% in newly diagnosed patients and between 11% and 15% in relapsed/refractory patients. In addition, the combination of lenalidomide with ciclophosphamide has shown to increase the VTE risk, but not in combination with bortezomib.(5)
Therapeutic options for VTE prophylaxis
The goal of an effective VTE prophylaxis is to identify all patients at risk, determine each level of risk, select and implement prophylactic regimens that provide sufficient VTE protection, all the while minimising the complications derived from their use. The most extensively studied agents for VTE prophylaxis in patients treated with thalidomide or lenalidomide are aspirin, low molecular weight heparins (LMWHs) and warfarin.
Aspirin
Acetylsalicylic acid (ASA, or aspirin) is a well-known antiplatelet agent which is often used for the prevention of arterial thrombosis. As platelets play a role in the initiation and propagation of VTE, antiplatelet agents may therefore be considered promising agents for the treatment and prevention of VTE. ASA is a relatively safe, inexpensive and easy to administer drug; however, it is much less effective than either LMWH or warfarin in reducing the VTE incidence. A number of investigators have reported that the incidence of VTE in thalidomide- and lenalidomide-treated myeloma patients is substantially reduced with aspirin.(6) Unfortunately, many of the studies reporting on the efficacy of aspirin have serious limitations in their design. Until further evidence becomes available, aspirin should only be recommended for low-risk patients.
LMWH
LMWHs are well-established drugs that have been used successfully for many years for the prevention and treatment of VTE. They are derived by chemical or enzymatic depolymerisation of unfractionated heparins. LMWHs act by binding to the natural inhibitor antithrombin, and inhibit activated coagulation factors, mainly thrombin and activated factor X. These agents are injected subcutaneously once or twice daily and do not typically require routine monitoring. The most widely used schema of LMWH prophylaxis employs enoxaparin 40mg or dalteparin 5 IU, both as a once-daily regimen. Renal failure may limit the use of LMWH because renal clearance is the primary route of elimination for this drug. In patients with reduced creatinine clearance (< 30 ml/ min), LMWH is not a significant option because it may accumulate and consequently increase the risk of bleeding. In addition, special considerations for monitoring should be taken in obese patients and, due to the risk of heparin-induced thrombocytopaenia, platelet counts need to be routinely verified. In patients receiving IMiDs in combination with chemotherapy or dexamethasone, there is evidence to support the fact that LMWHs play an important role in reducing the incidence of VTE.(5,7) For this reason, in addition to the lower risk of secondary bleeding and shorter half-life, LMWHs are a more suitable option than either warfarin or aspirin. 
Vitamin K antagonists (VKAs)
The coumarins, or VKAs, have been the mainstay of oral anticoagulant therapy for more than 60 years. Their effectiveness has been established by well-designed clinical trials for the primary and secondary prevention of thrombotic episodes. They produce their anticoagulant effect by interfering with the carboxylation of coagulation factors II, VII, IX and X. When used to prevent VTE, coumarins should be given to maintain an international normalised ratio (INR) between 2.0 and 3.0. Oral administration and low cost give VKAs some advantages over the LMWHs. However, VKAs are challenging to use in clinical practice for several reasons: they present a narrow therapeutic window, exhibit considerable variability in dose response among individuals, are subject to interactions with other drugs or diet, need laboratory control sometimes difficult to standardise, and they carry a substantial risk of major bleeding. They should be recommended only when a well-coordinated monitoring system is available.(8) In Europe, there are three coumarins commercially available (warfarin, acenocumarol and phenprocumon), but most of the studies are made with warfarin. The data regarding the use of warfarin as a thromboprophylactic agent in MM patients treated with IMiDs are controversial. Some studies conclude that the use of fixed-dose warfarin does not decrease the risk of VTE associated with thalidomide. In studies using fixed, low-dose warfarin and even others using a full-dose of warfarin, the incidence of VTE has been shown to vary from 8% to 31%.(7) One study demonstrated similar efficacy of both dosing regimens in reducing VTE incidences; however, the risk of bleeding was significantly higher in patients who received the full-dose warfarin regimen.(9) Coumarins should be avoided in patients for whom severe thrombocytopaenia is likely to develop, such as those treated with IMiDs combined with chemotherapy. 
Alternative thromboprophylaxis
Mechanical methods of prophylaxis, including graduated compression stockings, the use of intermittent pneumatic compression devices and the venous foot pump, reduce stasis within the leg veins and reduce the frequency of VTE. Those methods have the advantage of not being associated with a risk of bleeding. Unfortunately, no efficacy data from large studies are available. The use of mechanical prophylaxis is a reasonable alternative for patients in whom anticoagulant prophylaxis may carry an excessive bleeding risk owing to the presence of coexisting conditions, such as active gastrointestinal or intracranial bleeding. 
The new oral direct thrombin inhibitor, dabigatran, has not yet been studied in MM patients. This agent has been recently introduced into clinical practice and there is not enough evidence to support its use in this clinical setting. Dabigatran does not require coagulation monitoring; nevertheless, there is no antidote available in case of overdosage. In addition, because of its renal elimination, dabigatran is contraindicated in patients with a creatinine clearance of < 30ml/min, and recent meta-analysis have found that it is associated with a high risk of acute coronary events.(10) Because there is no evidence of efficacy and security in the prevention of VTE in patients with MM during the treatment with IMiDs, this agent should not be recommended in these patients until further evidence becomes available.
Choosing an optimal thromboprophylactic agent
Considering that already there is a lack of strong evidence from well-designed prospective studies that compare different anticoagulation regimens in these patients, and in order to get the best efficacy/security profile, thromboprophylaxis should be selected according to the risk level. The International Myeloma Working Group (IMWG) has proposed guidelines for primary VTE prevention based on a risk-adapted model.(5) The stated goal of their recommendations is to reduce the risk of MM treatment-related VTE to < 10%. 
Risk factors
  • Individual risk factors include obesity (BMI > 30kg/m2); previous VTE; central venous catheter or pacemaker; co-morbidities (cardiac disease, chronic renal disease, diabetes, acute infection, immobilisation); recent surgery; use of erythropoietin and blood clotting disorders
  • Myeloma-related risk factors (the diagnosis itself as well as hyperviscosity)
  • Therapy-related risk factors: high-dose dexamethasone; doxorubicin and multi-agent chemotherapy
  • The IMWG elaborated the following recommendations, based on the presence of risk factors:5
  • Lenalidomide alone does not induce a high risk of VTE; for this reason, thromboprophylaxis is not recommended when lenalidomide is used as a single agent
  • For patients receiving lenalidomide and low-dose dexamethasone without any other risk factor, a daily low dose aspirin (81mg) is recommended
  • For patients with only one individual or myeloma-related risk factor, it is recommended to give a daily dose of aspirin between 81–325mg
  • For patients with the presence of at least two individual or myeloma-related risk factors, it is recommended to give LMWH (equivalent to enoxaparin 40mg once daily) or a full-dose warfarin (target INR 2-3)
  • Patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy, regardless of the presence of additional risk factors, should receive LMWH (equivalent to enoxaparin 40mg once daily) or a full-dose warfarin (target INR 2-3)
  • Because most VTE events in clinical studies have occurred during the first six months and all episodes occurred within the first 12 months, anticoagulant prophylaxis may be given for four to six months, whereas longer periods may be considered in the presence of additional patient- or treatment-specific risk factors
Limitations of thrombopropylaxis in MM
Patients with MM are at higher risk of developing thrombocytopenia due to the extensive disease burden in the bone narrow. This puts these patients at an increased risk of bleeding complications from thromboprophylaxis. The highest risk of haemorrhagic complications is demonstrated in patients treated with full-dose warfarin. Conversely, low-dose aspirin has been shown to be safe in this setting. Similarly, prophylactic doses of LMWHs have been used without major bleeding risks in patients with thrombocytopenia after stem cell transplantation. However, the possibility of developing heparin-induced thrombocytopaenia should be considered.
Renal impairment is another factor that can determine the choice of a thromboprophylaxis regimen. Unfortunately, there is no data available in MM patients with renal dysfunction. Patients with a creatinine clearance below 30ml/min should require LMWH dose adjustment. In addition, anti-Xa should be monitored closely to minimise risk of excessive anticoagulation.
The role of hospital pharmacists 
As members of a multidisciplinary team, hospital pharmacists should know the different anticoagulant regimens as well as constantly be updating their knowledge in this subject. Pharmacists should be able to verify that the therapy for each patient is adequate, based on thrombosis risk factors, as well as to participate with other professionals in the development of protocols. Pharmacists should review the drug prescription profile of MM patients to check for potential interactions between antithrombotic and/or IMiDs agents. 
Patients with MM treated with lenalidomide who receive thromboprophylaxis should be monitored closely in order to assess efficacy, to evaluate the risk of thrombocytopaenia and bleeding and to consider a modification of thromboprophylaxis regimen in the event that new risk factors appear.
References
  1. Carrier M et al. Rates of thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J. Throm Haemost 2011;9(4):653–63.
  2. Zamagni E et al. Multiple myeloma, venous thromboembolism, and treatment-related risk of thrombosis. Semin Throm Hemost 2011;37(3):209–19.
  3. Tariman JD. Lenalidomide: a new agent for patients with relapsed or refractory multiple myeloma. Clin J Oncol Nurs 2007;11(4):569–74.
  4. Richardson PG et al. A randomized phase 2 study of lenalidomide therapy for patient with relapsed or relapsed and refractory multiple myeloma. Blood 2006;108(10):3458–64.
  5. Palumbo A et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414–23.
  6. Hirsh J. Risk of thrombosis with lenalidomide and its prevention with aspirin. Chest 2007;131:275–22.
  7. Musallam K. Incidence and prophylaxis of venous thromboembolic events in multiple myeloma patients receiving immunomodulatory therapy. Throm Res 2009;123:679-86.
  8. Ansell J et al. The pharmacology and management of the vitamin K antagonists: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126:204S–33S.
  9. Ikhlaque N. Efficacy of prophylactic warfarin for prevention of thalidomide-related deep  venous thrombosis. Am J Hematol 2006;81:420–2.
  10. Uchino K, Hernández A. Dabigatran association with higher risk of acute coronary events. Arch Intern Med 2012. http://archinte.ama-assn.org/cgi/content/full/archinternmed.2011.1666 

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