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Management of challenging cases of patients with cancerassociated thrombosis including recurrent thrombosis and bleeding: guidance from the ssc of the isth

Received Date : 06-Feb-2013
Accepted Date : 23-Jun-2013
Article type : SSC Communication
Management of challenging cases of patients with cancer-associated thrombosis
including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH.
CARRIER M1, KHORANA AA2, ZWICKER JI3, NOBLE S4, LEE AYY5 on behalf of the
subcommittee on Haemostasis and Malignancy for the SSC of the ISTH
1 Article Thrombosis Program, Division of Hematology, Department of Medicine, University of
Ottawa, Ottawa, Ontario, Canada. 2 James P. Wilmot Cancer Center and Department of Medicine, University of Rochester, Rochester, USA. 3 Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 4 Royal Gwent Hospital, Cardiff Road, Newport NP202UB, UK. 5 Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Correspondence: Dr Agnes Y Y Lee Director of Thrombosis Division of Hematology University of British Columbia 2775 Laurel Street 10th floor Vancouver, BC, V5Z 1M9 Phone: 604-875-4952; fax: 604-875-4696 Email: alee14@bccancer.bc.ca Scope and methodology
This manuscript gives guidance on common clinical problems complicating the Acceptedmanagement of anticoagulation in patients with cancer-associated thrombosis (CAT).
Although low molecular weight heparins (LMWH) have improved patient outcomes and This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/jth.12338 This article is protected by copyright. All rights reserved. simplified therapy, high-quality evidence on the optimal management of CAT is lacking. This guidance statement will specifically address: 1) treatment of recurrent VTE using dose escalation of LMWH; 2) management in patients with thrombocytopenia; 3) management in patients with active bleeding; and 4) the role of inferior vena caval (IVC) filters. It will also discuss the use of novel oral anticoagulants (NOACs) for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Some of these topics are covered in published consensus guidelines [1-5] but the aim of this Articleguidance statement is to outline expert experience and biological rationale that may
influence decision-making and offer concrete approaches on the management of anticoagulation in individual cancer patients with these therapeutic challenges. Recognizing the lack of high-quality evidence in many of these areas, it is important that patients are informed of the uncertainties, risks and benefits of the management plan, and that proper documentation of the discussion is included in the medical chart. The guidance statements included in this document are similar to other guidance manuscripts and are predicated on the following premises [6]: 1) For each of the clinical situations, our guidance statements are applicable to an average patient with cancer-associated DVT and/or PE. We anticipate that there will be clinical circumstances for which our guidance statements do not apply. As for all cases, our statements may provide guidance but do not replace clinical judgement for the management of individual patients. 2) The wording “we recommend” reflects a strong guidance statement with strong Accepted consensus among the panel members, whereby the clinician should consider
adopting the practice in a majority of cases. This article is protected by copyright. All rights reserved. 3) The wording “we suggest” reflects a weak guidance statement with moderate consensus among the panel members, whereby the clinician may adopt the guidance statement or use an alternative approach to manage patients. Definition of terms:
The definitions of terms used in this guidance manuscript are: 1) Cancer-associated thrombosis: Symptomatic proximal lower limb DVT (involving Article the popliteal vein or more proximal vessels) or PE (involving a segmental or more
proximal pulmonary artery). The guidance statement does not apply to treatment of VTE in unusual sites, including splanchnic, cerebral or upper extremity veins thrombosis, or to arterial thrombotic events. 2) Acute CAT: diagnosis of the index DVT or PE was made within the past one 3) Sub-acute CAT: diagnosis of the index DVT or PE was made between one and 4) Chronic CAT: diagnosis of the index DVT or PE was made more than three Management of recurrent cancer-associated thrombosis despite anticoagulation.
Recurrent VTE despite appropriate anticoagulation is common among cancer patients. Gender, tumor type, TNM staging and prior history of VTE seem to be important Acceptedpredictors of recurrent VTE in cancer patients [7]. Approximately 10-17% of patients
with CAT treated with a vitamin K antagonist (VKA) and 6-9% of patients treated with This article is protected by copyright. All rights reserved. LMWH will have recurrent VTE during follow-up [8-10]. The causes for VKA failure are multi-factorial and cancer patients can develop recurrent VTE despite maintaining therapeutic INR values [11]. LMWHs for at least the first 3 months are known to be more effective than VKA in the treatment of CAT [8-10] and observational studies have also shown that switching cancer patients with recurrent VTE on VKA to therapeutic doses of LMWH is safe and effective [12;13]. Raising the anticoagulation target of the VKA (e.g. INR 2.5-3.5) is not recommended given the lack of cancer-specific data and Articlethe heightened risk of bleeding with a higher target INR [11;14]. Mechanisms for LMWH
failure have not been studied. One retrospective cohort study has shown that dose escalation of LMWH (approximately 25% or increased to weight-adjusted therapeutic doses if receiving lower doses) in cancer patients with recurrent VTE is effective and safe [12]. It is not known if dividing the escalated dose of LMWH to a twice-daily An empiric approach to managing cancer patients with symptomatic recurrent VTE despite anticoagulation has been proposed [15;16]. It is important to confirm drug compliance and ensure that heparin-induced thrombocytopenia (HIT) has been excluded. Patients with CAT who were treated with VKA should be switched to LMWH, while those managed with LMWH should have their dose increased by 25% (or increased to therapeutic, weight-adjusted doses if receiving lower doses). All patients should be reassessed in 5 to 7 days to ensure symptomatic improvement. Patients Acceptedwithout symptomatic improvement should be considered for another dose escalation
and anti-Xa level can be used to estimate the next dose escalation. For once daily This article is protected by copyright. All rights reserved. regimen, clinicians should aim for a peak anti-Xa level of 1.6-2.0 U/mL whereas for a twice daily regimen, a level of 0.8-1.0 U/mL is suggested [15;16]. These values are empiric and have not been assessed in clinical trials. Checking anti-Xa levels is not routinely recommended for dose adjustment because there is weak correlation with Other therapeutic options including the insertion of an IVC filter or switching to a Articledifferent anticoagulant (e.g. fondaparinux or VKA) have been proposed. However, there
are no published data on their efficacy in treating cancer patients with symptomatic recurrent VTE despite LMWH. The insertion of an IVC filter in addition to anticoagulation provides no net benefit to patients in preventing recurrent thrombosis and has no impact on patient survival (see Section on Role of IVC Filter) [17-21]. The use of fondaparinux and VKA are associated with higher risk of recurrent thrombosis compared with LMWH in patients with CAT [9;22]. Therefore, these therapeutic options 1) We recommend that cancer patients with symptomatic recurrent VTE despite therapeutic anticoagulation with VKA be switched to therapeutic weight-adjusted 2) We suggest that cancer patients with symptomatic recurrent VTE despite Accepted anticoagulation with LMWH continue with LMWH at a higher dose, starting at an
This article is protected by copyright. All rights reserved. increase of approximately 25% of the current dose or increasing it back up to the therapeutic weight-adjusted dose if receiving non-therapeutic dosing. 3) We recommend that all cancer patients with recurrent VTE despite anticoagulation be reassessed 5 to 7 days after a dose escalation of their anticoagulant therapy. Patients with symptomatic improvement should continue the same dose of LMWH and resume their usual follow-up. In patients without symptomatic improvement, we suggest using the peak anti-Xa level to estimate Article the dose of the next escalation.
Management of cancer-associated thrombosis in patients with thrombocytopenia.
Thrombosis is commonly diagnosed in patients with malignancy and thrombocytopenia [23] but the literature on management is scarce [9;24]. In order to tailor the therapeutic strategy, clinicians need to assess: 1) the possible etiology of the thrombocytopenia (e.g. HIT, thrombotic thrombocytopenic purpura, immune thrombocytopenia, chemotherapy effect, etc); 2) the severity; 3) the expected duration and course (e.g. is the thrombocytopenia transient or permanent; is the current platelet count the nadir or will drop further); 4) if there are potentially reversible causes that can be corrected; and 5) if there are other risk factors for bleeding, such as advanced age or renal insufficiency. Anticoagulation in patients with thrombocytopenia should be made on an individual patient basis after assessing the risks and benefits, direction of care and in AcceptedFor situations when the use of anticoagulant therapy is considered, it is important to
weigh the relative risks of recurrent thrombosis and serious bleeding. In the initial This article is protected by copyright. All rights reserved. month (acute period) following the diagnosis of VTE, the risk of recurrent thrombosis is highest [8;9]. Consequently, giving maximal or therapeutic anticoagulant therapy is important. In patients with acute CAT and platelet count ≥50 X 109/L, full therapeutic anticoagulation without platelet transfusion is appropriate. But, in patients with a platelet count <50 X 109/L, platelet transfusion support to maintain a platelet count ≥50 X 109/L to allow full, therapeutic anticoagulation should be considered [23]. Hospitalization is required unless there is adequate and timely support for outpatient Articletransfusion and close monitoring. If platelet transfusions are not possible or
contraindicated, we suggest insertion of a retrievable IVC filter, which should be removed when platelet recovery (>50 x 109/L) is achieved and anticoagulation can resume. The cut-off of 50 X 109/L is empiric but there is general consensus that the risk of spontaneous bleeding is very low above this level. In the subacute or chronic treatment periods when the risk of VTE recurrence is not as high, published data provide weak support for LMWH dose reduction in patients with thrombocytopenia (<50 X 109/L) [24;25]. Platelet transfusion is probably not warranted. Consequently, in patients with a platelet count between 25 and 50 X 109/L, clinicians can consider reducing the dose of LMWH by half or using a prophylactic dose of LMWH, depending on individual patients’ characteristics (e.g. tumor burden, clot burden, risk factors for bleeding, etc) [9;24;26]. In patients with a platelet count <25 X 109/L, withholding anticoagulant therapy might be prudent. However, prophylactic Accepteddoses of LMWH have been used safely in patients with platelet count <25 X 109/L and
This article is protected by copyright. All rights reserved. 1) We recommend giving full therapeutic doses of anticoagulation without platelet transfusion in patients with CAT and platelet count ≥50 X 109/L. 2) For acute CAT and thrombocytopenia (<50 X 109/L): a. We recommend full therapeutic doses of anticoagulation with platelet transfusion to maintain a platelet count ≥50 X 109/L. b. If platelet transfusion is not possible or contraindicated, we suggest Article insertion of a retrievable filter and removal of the filter when platelet count
recovers and anticoagulation can resume. 3) For sub-acute or chronic CAT and thrombocytopenia (<50 X 109/L): a. We suggest reducing the dose of LMWH to 50% of the therapeutic dose or to use prophylactic dose LMWH in patients with platelet count of 25 to 50 b. We suggest discontinuing anticoagulation in patients with platelet count Management of cancer-associated thrombosis in patients who are bleeding.
Major or serious bleeding episodes occurs in approximately 7% of patients with CAT on anticoagulation [8-10]. A number of cancer-specific factors (e.g. tumor type, location, metastatic disease), treatment-specific factors (e.g. chemotherapy-induced Acceptedthrombocytopenia), poor nutritional status (hypoalbuminemia) , impaired renal function,
and the need for more frequent invasive procedures, all contribute to increase the risk of This article is protected by copyright. All rights reserved. bleeding in cancer patients [16]. Recent major bleeding, renal dysfunction (creatinine clearance <30 mL/min), immobility (≥4 days), metastatic disease and low body weight (<60 kg), have been identified as important predictors of major bleeding complications and of fatal bleeding in cancer patients [29;30]. As in any patient with active bleeding, clinicians need to assess, identify and control the source of bleeding whenever possible. Supportive treatments (e.g. red blood cell Articletransfusion) should be given when required. Patients with CAT who have active major
bleeding (e.g. not amendable to intervention, in a critical site or life-threatening) should have their anticoagulation withheld. In those who are also at a high risk of recurrent VTE (e.g. acute or sub-acute CAT), insertion of an IVC filter could be considered. In patients who are not at high risk of recurrent VTE (e.g. chronic CAT) filter insertion is not recommended. Once the bleeding has resolved, anticoagulation can be initiated or resumed and the IVC filter, if inserted, should be removed. Decision of initiating or resuming anticoagulation following an episode of intra-cranial bleeding should be done in collaboration with the neurologist or neurosurgeon. Minor bleeding (e.g. minor epistaxis) during anticoagulation will usually occur without any significant physiological or symptomatic consequences. From our experience, most patients with minor bleeding will tolerate anticoagulation but it is recognized that such experience is subjective and will vary between patients. Accepted
This article is protected by copyright. All rights reserved.
1) We recommend careful and thorough assessment of each bleeding episode, including identification of the source, its severity or impact, and reversibility. 2) We recommend usual supportive care with transfusion and surgical intervention to correct the bleeding source, whenever indicated and possible. 3) We recommend withholding anticoagulation in patients having a major or life- Article threatening bleeding episode.
4) We suggest IVC filter insertion in patients with acute CAT or sub-acute CAT who are having a major or life-threatening bleeding episode . 5) We recommend against IVC filter insertion in patients with chronic CAT. 6) We recommend initiating or resuming anticoagulation and removing retrievable IVC filter (if inserted) once the bleeding resolves. Role of IVC Filter
The rationale for IVC filter insertion is to prevent or reduce the risk of fatal or clinically significant PE from a large embolus arising from thrombus in the veins of the pelvis or lower limbs. Consequently, filter insertion is commonly done in the setting of recurrent PE or DVT extension despite anticoagulation and in patients with an acute PE or DVT who also have a contraindication for anticoagulation. However, evidence for the Acceptedefficacy of filters in reducing fatal PE is lacking from large observational studies [19;21]
This article is protected by copyright. All rights reserved. and randomized controlled trials [17;18;20]. Furthermore, reduction in non-fatal PE occurs at the cost of an increase in recurrent DVT [17;20]. The use of IVC filter in cancer patients is controversial and a frequently encountered clinical problem because of the high risk of recurrent VTE and bleeding in these patients. Data in cancer patients are limited to a small clinical trial that showed no benefit with IVC insertion in addition to anticoagulation with fondaparinux [18] and Articleretrospective studies showing high rates of lower limb DVT following filter insertion [21].
This high rate of DVT in the setting of IVC insertion is reflective of the persistently heightened prothrombotic state in cancer patients, which is not suppressed by IVC filters. Indeed, filter thrombus and fatal PE are not uncommon in cancer patients with filter placement [21;31]. More recently, serious safety concerns over embolization, fracturing, and migration of retrievable filters have been raised [32;33], prompting clinicians to rethink the indications for filter insertion and to remove retrievable filters as In summary, considering that filter insertion: 1) does not reduce morbidity or mortality; 2) does not suppress hypercoagulability in patients with cancer; and 3) is associated with serious complications and cost, the panel’s consensus is that IVC filters should not be systematically inserted in cancer patients with recurrent VTE and their use should be limited to situations where strong contraindication(s) to anticoagulation exists and the r Acceptedisk of potentially fatal PE is high. If a filter is inserted, it is prudent to re-introduce
This article is protected by copyright. All rights reserved. anticoagulation when it is safe to do so, in order to suppress the underlying hypercoagulable state and reduce the risk of further DVT or PE. 1) We recommend against IVC filter insertion in the absence of contraindications to Article 2) We suggest IVC filter insertion in cancer patients with contraindications to
anticoagulation and a high risk of potentially fatal PE. 3) We recommend resuming anticoagulation with LMWH and removing the retrievable filter in cancer patients when the contraindication has resolved. Role of the new oral anticoagulants in the management of cancer-associated
thrombosis
Recently, new oral direct Xa inhibitors (rivaroxaban, apixaban, endoxaban) and a direct thrombin inhibitor (dabigatran) have been developed and some are approved for the acute and long-term treatment of VTE [34-38]. The NOACs are an attractive option for the treatment of CAT because they are taken orally at fixed doses without the need for laboratory monitoring. Unfortunately, there are no published data on the efficacy and safety of the NOACs in the management of CAT. In the clinical trials evaluating NOACs i Acceptedn DVT and PE treatment, only 0.1% to 6.8% of patients randomized to receive a NOAC
had a diagnosis of cancer (approx 300 patients) [34-38]. The acute VTE trials This article is protected by copyright. All rights reserved. compared a NOAC to initial LMWH with transition to VKA (rather than LMWH monotherapy), while the extended therapy trials compared a NOAC to placebo. Given the higher risk of recurrent thrombosis despite anticoagulation and the higher risk of anticoagulant-related bleeding in cancer patients, we cannot assume that the efficacy and safety outcomes observed in these trials of largely non-cancer patients also apply to cancer patients. Furthermore, indirect, post-hoc data from trials comparing fondaparinux or rivaroxaban with enoxaparin suggest that specific factor Xa inhibition Articlemight be less efficacious than LMWH inhibition in cancer patients. [22;39] Although
more comfortable than injections, the oral route of administration may not be ideal in patients with nausea, vomiting and diarrhea, which are common side effects of chemotherapy. Also, gastrointestinal absorption and bioavailability may be altered in patients with mucositis or diarrhea, and gastrointestinal bleeding may be more frequent with NOACs [40]. None of these agents have an antidote to rapidly reverse the anticoagulant effect and there is a lack of experience in managing these agents in the peri-operative/procedural period and in patients with thrombocytopenia. Although NOACs have fewer drug interactions than warfarin, their dependence on the P- glycoprotein transport and CYP3A4 metabolic pathways for their uptake and clearance must be considered in cancer patients. Different chemotherapy agents may induce (e.g. dexamethasone, doxorubicin, vinblastine) or inhibit (e.g. tamoxifen, cyclosporine, sunitinib, and other tyrosine kinase inhibitors) these pathways, leading to potentially clinically-important changes in drug levels which may predispose patients to higher risks Acceptedof recurrent thrombosis or bleeding [16]. Finally, the lack of assays for measuring the
anticoagulant effect of the NOACs poses challenges in the management of cancer This article is protected by copyright. All rights reserved. patients presenting with recurrent VTE or with serious bleeding. Given these important limitations and lack of cancer-patient specific data, we discourage the use of NOACs in 1) We recommend against the use of NOACs for the initial and/or long-term Article 2) We recommend investigating the efficacy and safety of NOACs in randomized,
controlled clinical trials specifically in cancer patients with VTE, with particular emphasis on drug-drug interactions with anti-neoplastic agents. Addendum
designed, collected literature, analyzed and interpreted data; wrote designed, collected literature, analyzed and interpreted data; wrote designed, collected literature, analyzed and interpreted data; critical revising of the intellectual content. S Noble designed, collected literature, analyzed and interpreted data; critical revising of the intellectual content. A Lee designed, collected literature, analyzed and interpreted data; wrote Reference List
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pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry. J Thromb Haemost 2006; 4:1950-1956. This article is protected by copyright. All rights reserved. (31) Getzen TM, Rectenwald JE. Inferior vena cava filters in the cancer patient: current use and indications. J Natl Compr Canc Netw 2006; 4:881-888. (32) Nicholson W, Nicholson WJ, Tolerico P, Taylor B, Solomon S, Schryver T, McCullum K, Goldberg H, Mills J, Schuler B, Shears L, Siddoway L, Agarwal N, Tuohy C. Prevalence of fracture and fragment embolization of Bard retrievable vena cava filters and clinical implications including cardiac perforation and tamponade. Arch Intern Med 2010; 170:1827-1831. (33) U.S.Food and Drug Administration. Inferior vena cava [IVC] filters: Risk of adverse events with long term use. Safety Alert report issued August 9, 2010. 2010. (34) Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Article Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells
PS, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499-2510. (35) Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells PS, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366:1287-1297. (36) Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342-2352. (37) Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368:699-708. (38) Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ. Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism. N Engl J Med 2013; 368:709-718. (39) Cohen AT, Spiro TE, Buller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, Tapson V. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368:513-523. Accepted(40) Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old
anticoagulants, and when and how to switch. Blood 2012; 119:3016-3023. This article is protected by copyright. All rights reserved.

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