La terapia del TEV nel paziente oncologico nell'era dei DOAC

XXVI CONGRESSO NAZIONALE FCSA Bologna, 5-7 Novembre 2015 Tromboembolismo venoso La terapia del TEV nel paziente oncologico nell'era dei DOAC ANNA FALANGA Immunoematologia e Medicina Trasfusionale e Centro Emostasi e Trombosi Ospedale Papa Giovanni XXIII, Bergamo

Cancer and VTE Patients with cancer have a 4 7 fold increased risk for VTE as compared to non-cancer patients; 15 20% of all VTE cases occur in patients with cancer. VTE in cancer patients is associated with important complications, including an 8 10% annual risk of bleeding with anticoagulant therapy and an annual 21 27% risk of VTE recurrence. Falanga et al. Curr Opin Hematol 2014; Agnelli et al. JTH 2011; Lee A., 2013

Important Consequences of VTE in Cancer Increased morbidity Hospitalization Anticoagulation Postphlebitic syndrome Increased mortality (worse overall survival outcome) Increased risk of recurrent VTE (21% vs 7% in non cancer patients) Bleeding complications (2 times higher during anticoagulation) Cancer treatment delays Increased healthcare costs

Optimising treatment of VTE in the cancer patients Treatment Recurrent VTE Bleeding Quality of life

ASCO 2013 & Update 2014: Clinical Practice Guideline Treatment 1. LMWH is preferred over UFH for the initial 5 to 10 days of anticoagulation for the cancer patient with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance < 30 ml/min). 2. For long term anticoagulation, LMWH for at least 6 months is preferred due to improved efficacy over Vitamin K antagonists. Vitamin K antagonists are an acceptable alternative for long-term therapy if LMWH is not available. 3. Anticoagulation with LMWH or Vitamin K antagonist beyond the initial 6 months may be considered for select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. Lyman GH et al, JCO 2013

LMWH versus Vitamin K Antagonist: Long-term Treatment in Cancer Patients Study Pt, N Long-term Treatment Recurr. VTE, % Major Bleed, % Death, % P value Meyer 2002 Lee 2003 71 Warfarin 21.1 22.7.09 67 Enoxaparin 1.5 mg/kg 10.5 11.3 336 Warfarin 17 4 41.002 336 Dalteparin 200/150 IU/kg 9 6 39 30 Warfarin 10 2.9 8.8 NS Deitcher 2006 Hull 2006 29 Enoxaparin 1.0 mg/kg 6.9 6.5 6.5 32 Enoxaparin 1.5 mg/kg 6.3 11.1 19.4 100 Warfarin 10 7 19 NS 100 Tinzaparin 175 IU/kg 6 7 20 Meyer G, et al. Arch Intern Med. 2002:162:1729-1735; Lee AY, et al. N Engl J Med. 2003;349:146-153; Deitcher SR, et al. Clin Appl Thromb Hemost. 2006:12:389-396; Hull RD, et al. Am J Med. 2006;119:1062-1072.

Pooled analysis of the bleeding risk of LMWH and VKA in patients with cancer Minor bleeding Major bleeding Akl et al, Cochrane rev 2011

Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer: a Randomized Clinical Trial The CATCH Study: randomized, open label, multicenter, phase III trial aimed to assess the efficacy of tinzaparin in preventing recurrent VTE compared with warfarin. Experimental design: 1. 449 patients were randomized to receive tinzaparin 175 IU/kg once daily for 6 months 2. 451 patients were randomized to receive initial tinzaparin 175 IU/kg once daily for 5 10 days overlapped and followed by dose-adjusted warfarin (target INR 2.0 3.0) for 6 months Primary efficacy: recurrent VTE verified by objective, standard imaging Primary safety: major bleeding A.Y.Y. Lee et al. JAMA 2015

Recurrent venous thromboembolism Results 10,5% A.Y.Y. Lee et al. JAMA 2015 Major bleeding 7.2% HR: 0.89 [95% CI 0.40-1.99; P=0.77] HR: 0.65 [95% CI 0,41-1,03; P=0.07] All-Cause Mortality 34.7% 32.2% HR: 1.08 [95% CI 0.85-1.36; P=0.54] In patients with active cancer and acute symptomatic VTE, full-dose tinzaparin (175 IU/kg daily) versus warfarin for 6 months: - did not significantly reduce the composite measure of recurrent VTE - and was not associated with reductions in overall mortality or major bleeding, - but was associated with a lower rate of clinically relevant non major bleeding.

LMWH is recommended for the initial 5 to 10 days of treatment of established VTE as well as for long-term secondary prophylaxis for at least 6 months.

Limitations of LMWH Therapy One randomized trial published showing superiority over warfarin in efficacy recurrent thrombosis and major bleeding still significant lack of long-term data beyond 12 months once-daily subcutaneous injections are uncomfortable and difficult to maintain long-term expensive compared with warfarin LMWH may cause toxicity in patients with renal failure.

Direct Oral Anticoagulants (DOACs) FONDAPARINUX RIVAROXABAN APIXABAN EDOXABAN Prothrombinase Xa, Va lipid DESIRUDIN ARGATROBAN BIVALIRUDIN Factor IIa Inhibitors (XIMELAGATRAN) Factor Xa Inhibitors Prothrombin Thrombin DABIGATRAN Platelet activation Fibrin formation Fibrinolysis inhibition Cellular effects

DOAC in Patients with Cancer The new oral anticoagulants offer an attractive option because of their oral administration, fixed-dose, and lack of routine laboratory monitoring. The results of phase III trials support the efficacy and safety of the new oral anticoagulants in the management of VTE. However, generalizing these findings to cancer patients with VTE is difficult since very few cancer patients were included.

The DOAC and the Treatment of VTE Cancer subgroup analysis from phase III randomized controlled trials comparing DOACs vs conventional treatment after VTE 1. Schulman et al. New Engl J Med 2009. Schulman ASH 2013. 2. Buller et al. New Engl J Med 2010. 3. Buller et al. New Engl J Med 2012. 4. Agnelli et al N Engl J Med 2013. 5. Hokusai N Engl J Med 2013; Raskob ASH 2013. Trials included very few patients with malignant disease. The strict inclusion criteria limited patients with end-organ dysfunction (e.g., renal and liver dysfunction) and elevated risk of bleeding from enrolling, resulting in an overall study population likely not-representative of patients with advanced cancer. Wharin C. and Tagalakis V. Blood Reviews 2014

DOACs and Treatment of VTE There are insufficient data to show that DOACs are non-inferior to warfarin in patients with cancer. The small number of highly selected cancer patients in these studies precludes the extrapolation of the available results to the general oncology population. A head-to-head comparison of LMWH with DOACs is necessary to determine if DOACs is an acceptable alternative for the treatment of cancer-associated thrombosis. A. Lee and M. Carrier. Thromb Res 2014

Efficacy and safety of DOACs in patients with active cancer Use of DOAC and major bleeding Use of DOAC and clinically relevant bleeding The efficacy and safety profile of DOAC for VTE treatment in patients with cancer is similar to that observed in patients without cancer. A favorable trend toward reduction of recurrent VTE was observed without concern in terms of clinically relevant bleedings. Vedovati et al. CHEST 2015

The risk of recurrent VTE (A) and major bleeding (B) in cancer patients The most important results of this study are the RRs of 0.66 (95% CI 0.38 1.2) for recurrent VTE and 0.94 (95% CI 0.70 1.3) for major bleeding and clinically relevant non-major bleeding, indicating that both the efficacy and safety of NOACs in cancer patients were at least comparable to those of VKAs. Van der Hulle et al. JTH 2015

Oral apixaban for the treatment of VTE in cancer patients: results from the AMPLIFY trial The AMPLIFY trial compared apixaban with enoxaparin followed by warfarin for the treatment of acute VTE. Patients with symptomatic VTE were randomized to a 6-month course of apixaban or enoxaparin followed by warfarin. The primary efficacy outcome and principal safety outcome were recurrent VTE or VTE-related death and major bleeding, respectively. G. Agnelli et al. JTH 2015

Results The results of this subgroup analysis suggest that apixaban is a convenient option for cancer patients with VTE. However, additional studies are needed to confirm this concept and to compare apixaban with LMWH in these patients. G. Agnelli et al. JTH 2015

Long-term treatment of VTE with NOACs: patients with active cancer In six randomized controlled on treatment of VTE a total of 1227 patients with active cancer were enrolled. M. Verso, G. Agnelli, P. Prandoni. Intern Emerg Med 2015

Discussion The preliminary results of trials on long-term VTE treatment suggest that DOAC could be an attractive alternative to conventional anticoagulation in patients with active cancer. However, further clinical trials in patients with active cancer should be performed to confirm these results. In particular, studies should be performed with LMWH as comparator, and should probably investigate different doses of DOAC to determine the best clinical benefit in the treatment of VTE in patients with cancer. M. Verso, G. Agnelli, P. Prandoni. Intern Emerg Med 2015

Efficacy and Safety of Anticoagulant Therapy for the Treatment of Acute Cancer-Associated Thrombosis: A Systematic Review and Meta-Analysis Baseline characteristics M. Carrier et al. TR 2014

Recurrent VTE Major bleeding DOAC vs. VKA DOAC vs. VKA LMWH alone vs. VKA LMWH alone vs. VKA M. Carrier et al. TR 2014

Results Compared with VKA, LMWH was associated with a significant reduction in the risk of recurrent VTE (HR: 0.52; 95% CI: 0.36 to 0.74) without a significant increase in major bleeding episodes (RR: 1.06; 95% CI: 0.5 to 2.23). In contrast, treatment using DOACs was associated with a non-significant lower risk of recurrent VTE (RR: 0.66; 95% CI: 0.39-1.11) and major bleeding episodes (RR: 0.78; 95% CI: 0.42 to 1.44) In summary, LMWH monotherapy should be used for the treatment of acute cancer-associated thrombosis. This review is in-line with current clinical practice guidelines and further recommendations regarding the use of DOACs cannot be supported until trials comparing them to LMWH are conducted. M. Carrier et al. TR 2014

Patients with cancer have multiple factors to consider: They are at high risk for hemorrhage for reasons including chemotherapy-induced thrombocytopenia or receipt of antiangiogenic therapy. Limited trial level data are available to clearly define the role of DOAC in patients with cancer. DOAC may cause drug interactions with chemotherapeutic agents, which may result in less efficacy and higher bleeding than that observed in patients without cancer Sardar et al. Am J Therap, 2014

Drug Interactions inhibitors and inducers of P-glycoprotein and CYP3A4: antifungals* ritonavir* amiodarone dronederone* quinidine tamoxifen anastrozole lomustine cyclophosphamide bicalutamide* abiraterone* imatinib* & TKIs cyclosporine* tacrolimus Inhibitors Inducers rifampicin phenytoin carbamazepine phenobarbital dexamethasone* prednisone* vemurafenib* paclitaxel* doxorubicin etoposide vinblastine St. John s wort Short & Connors 2014; Lee. Blood 2013.

Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE.

Discussion: DOACs for treatment of CAT The novel anticoagulant drugs seem to be more convenient, as they are orally administered at a fixed dose without routine laboratory monitoring and seem to have fewer drug interactions, in particular with chemotherapeutic agents. However, these drugs may have a potential limitation in cancer patients who suffer abnormal liver function and severe renal impairment or have poor attitude to oral intake.

Conclusions: VTE treatment in Cancer Patients Treatment of CAT could be improved with oral agents over LMWH use Current evidence does not yet support the use of DOACs in patients with active cancer Properly designed cancer-specific trials are needed

DOAC Clinical Trials for treatment of Cancer-associated VTE RIVAROXABAN: Select-d http://controlled-trials.com/isrctn86712308 phase 3, 2-phase randomized, multicentre study in treatment open label dalteparin vs rivaroxaban x 6 mos placebo vs rivaroxaban in patients with residual vein DVT at 6 12 mos Rivaroxaban trial http://clinicaltrials.gov/ct2/show/nct01989845?term=nct01989845&rank=1 phase 4 multicentre, open-label, study in treatment single arm prospective cohort treated with rivaroxaban x 6 mos EDOXABAN: Edoxaban trial http://clinicaltrials.gov/ct2/show/nct02073682?term=nct02073682&rank=1 phase 3 multicentre trial in treatment of CAT edoxaban vs dalteparin x 6 mos Hokusai VTE-Cancer Study

Hokusai VTE-cancer study The Hokusai VTE cancer study is a randomised, open-label, clinical trial to evaluate whether edoxaban, an oral factor Xa inhibitor, is non-inferior to LMWH for treatment of VTE in patients with cancer. Outcomes: the composite primary outcome of recurrent VTE and major bleeding during a 12-month study period. van Es et al., Thromb Hem 2015