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Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
I nuovi anticoagulanti nel paziente oncologico Anna Falanga, Bergamo
Cancro e Trombo-Embolismo Venoso (TEV)
Il cancro è un fattore di rischio indipendente per TEV
I pazienti oncologici hanno un rischio di TEV (trombosi venosa profonda, embolia polmonare) di 4–7 volte maggiore rispetto alla popolazione non oncologica.
L’incidenza di TEV nei pazienti oncologici è compresa tra l’1 e il 20%.
Negli studi autoptici l’incidenza sale fino al 50%.
Il 15–20% di tutti i casi di TEV si verifica in pazienti con neoplasie.
Falanga A et al. Thromb Res 2012 Timp JF et al. Blood 2013
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Fattori di rischio generali
• Età
• Etnia (rischio più alto negli afro-americani, più basso nelle etnie asiatiche)
• Comorbilità (infezioni, malattie renali, malattie polmonari, tromboembolismo arterioso)
• Obesità
• Anamnesi positiva per TEV
• Basso performance status
• Trombofilia ereditaria
Fattori di rischio specifici della malattia neoplastica e del suo trattamento
• Tipo di tumore
• Caratteristiche istologiche (rischio più alto negli adenocarcinomi che nei carcinomi squamocellulari)
• Periodo intercorso dalla diagnosi (rischio più alto nei primi 3-6 mesi)
• Chemioterapia
• Farmaci antiangiogenici (talidomide, lenalidomide)
• Fattori di crescita eritrocitari, trasfusioni di sangue
• Catetere venoso centrale
• Radioterapia
• Chirurgia oncologica maggiore
Marcatori biologici di trombosi (in corso di studio)
• Piastrinosi (conta piastrinica >350,000/µl)
• Leucocitosi (conta leucocitaria > 11,000/µl)
• Anemia (Hb < 10 g/dL)
• D-dimero, Fattore Tissutale, P selectina solubile, Proteina C reattiva
Falanga A, Russo L. Hamostaseologie. 2012
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Aumentata morbilità
Ospedalizzazione
Terapia anticoagulante
Sindrome postflebitica
Aumentata mortalità
Aumentato rischio di recidive di TEV (21% vs 7% nei pazienti senza cancro) in corso di TAO
Aumentato rischio emorragico (2 volte più alto) in corso di TAO
Ritardo nelle terapie antineoplastiche
Aumentati costi per la gestione globale del paziente
Importanti conseguenze del TEV nel paziente oncologico
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Treatment of VTE in cancer patients
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Optimising treatment of VTE in the cancer patients
Treatment
Recurrent VTE
Bleeding
Quality of life
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
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.
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Prothrombinase
Xa, Va lipid
Thrombin Prothrombin
FONDAPARINUX
(XIMELAGATRAN)
BIVALIRUDIN
ARGATROBAN
DESIRUDIN
Fibrin formation
Platelet activation
Fibrinolysis inhibition
Cellular effects
Direct oral anticoagulants (DOAC)
APIXABAN
RIVAROXABAN
DABIGATRAN
EDOXABAN
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Principali caratteristiche farmacologiche dei nuovi anticoagulanti orali diretti (NAOD)
Dabigatran Rivaroxaban Apixaban Edoxaban
Target IIa Xa Xa Xa
Hours to Cmax 2 2-4 1-3 1-2
Prodrug Yes No No No
CYP metabolism No Yes (CYP3A4/A5, CYP2J2)
Yes (CYP3A4, CYP1A2, CYP2J2)
Yes (CYP3A4)
Efflux transporter P-gp Yes Yes Yes Yes
Bioavilability 7% 80% 66% >45%
Protein binding 35% >90% 87% 55%
Half-life (Hours) 12-14 9-13 8-15 8-10
Renal elimination 80% 66% 25% 35%
Dosing Twice a day Once a day Twice a day Once a day
Bid= twice daily; od= once daily; Tmax= time to peak plasma concentration
Pengo V et al. JTH 2012.
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Metabolismo e Eliminazione dei DOAC
DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN
Metabolismo • Convertito da pro-farmaco in farmaco attivo dall’esterasi nel plasma o nel fegato;
• Eliminato dai meccanismi di trasporto della P-gp nei reni e nell’intestino
• Metabolizzato da: • CYP3A4, • CYP2J2,
• meccanismi
indipendenti dal CYP450
• Eliminato dai meccanismi di trasporto della P-gp nei reni e nell’intestino
• Metabolizzato da: • CYP3A4, •CYP3A5, • meccanismi indipendenti dal CYP450
• Eliminato dai meccanismi di trasporto della P-gp nei reni e nell’intestino
•Metabolizzato da: • CYP3A4, •CYP3A5, • meccanismi indipendenti dal
CYP450,
• Eliminato dai meccanismi di trasporto della P-gp nei reni e nell’intestino
Eliminazione 85% Renale 6% Fecale*
66% Renale 33% Fecale
25% renale 75% fecale
35% renale 62% fecale
*= Eliminazione del profarmaco non-assorbito
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Metabolism of novel oral anticoagulants
Lippi G. et al. Semin Thromb Hemost 2014
Efflux transporter P-gp
Cytochrome P metabolism
Renal elimination
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
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 in the general population.
However, generalizing these findings to cancer patients with VTE is difficult since very few cancer patients were enrolled in those trials.
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE.
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
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.
The DOAC vs VKA for the Treatment of VTE
Cancer subgroup analysis from phase III randomized controlled trials comparing DOACs vs
conventional treatment with Warfarin after VTE
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
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
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
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Efficacy and safety of DOACs in patients with active cancer
Use of
DOAC
and
major
bleeding
Use of
DOAC
and
clinically
relevant
bleeding
Vedovati et al. CHEST 2015
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.
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Forest plot of relative risks across clinical trials comparing DOAC vs VKA and LMWH alone vs VKA for recurrent cancer-associated VTE.
This meta-analysis evaluated 9 randomized trials involving 2310 patients with cancer-associated thrombosis treated with DOACs.
In comparison to VKA, LMWH showed a significant reduction in recurrent VTE events (RR: 0.52; 95 % CI 0.36–0.74) whereas DOACs did not (RR: 0.66; 95 % CI 0.39–1.11).
LMWH was associated with a non-significant increase in the risk of major bleeding (RR: 1.06; 95 % CI 0.5–2.23) whereas DOACs showed a non-significant reduction (RR: 0.78; 95 % CI 0.42–1.44) compared to VKA.
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.
Carrier M. et al. Thromb Res 2014
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Recurrent VTE Major bleeding
LMWH alone vs. VKA
DOAC vs. VKA
LMWH alone vs. VKA
DOAC vs. VKA
M. Carrier et al. Thr.Res. 2014
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
• Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute VTE.
• The role of DOACs for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear.
• In this network meta-analysis, the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE are compared.
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Treatment of venous thromboembolism in patients with cancer: a network meta-analysis comparing efficacy and safety of anticoagulants
Relative risks (RR) for recurrent VTE
Posch F. et al. Thromb Res 2015
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Relative risks (RR) for major bleeding
Posch F. et al. Thromb Res 2015
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
DISCUSSION
In this network meta-analysis estimates are provided of the relative efficacy and safety of DOACs, LMWH and VKA for the treatment of VTE in patients with cancer.
LMWH and DOAC appeared to be comparable with respect to prevention of recurrent VTE and the risk of major bleeding.
This finding prevailed after adjusting for potential heterogeneity between DOAC and LMWH trials.
A future head-to-head comparison between LMWH and DOAC for the treatment of cancer-associated VTE is warranted, and may be best performed using a non inferiority design.
Posch F. et al. Thromb Res 2015
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Guidance for the prevention and treatment of cancer-associated VTE
The efficacy and safety of DOACs in patients with cancer-associated VTE remains uncertain.
Guidance Statements:
We suggest that patients with active cancer (i.e. known disease or receiving some form of anti-cancer therapy) and VTE be treated with LMWH for at least 6 months.
Ongoing and planned studies aim to determine the relative safety and efficacy of DOACs in cancer-associated VTE compared with LMWH.
Khorana A.A. et al. J Thromb Thrombolysis 2016
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
DOAC Clinical Trials for treatment of Cancer-associated VTE
SELECT-D TRIAL Prospective, randomized, open-label, multicentre pilot phase III
study dalteparin vs rivaroxaban x 6 mos placebo vs rivaroxaban in patients with residual vein DVT at 6-12
mos To assess the efficacy and safety of rivaroxaban versus dalteparin for
the treatment of VTE in patients with cancer not currently receiving chemotherapy
RIVAROXABAN TRIAL phase 4 multicentre, open-label, study in treatment single arm prospective cohort treated with rivaroxaban x 6 mos
EDOXABAN TRIAL (Hokusai VTE-Cancer Study)
phase 3 multicentre trial in treatment of CAT edoxaban vs dalteparin x 6 mos
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
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
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
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
rifampicin phenytoin
carbamazepine phenobarbital
dexamethasone* prednisone*
vemurafenib* paclitaxel* doxorubicin etoposide vinblastine
St. John’s wort
Inducers
Short & Connors 2014; Lee. Blood 2013.
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Conclusions: VTE treatment in Cancer Patients
Treatment of CAT could be improved with oral agents over LMWH use
Current evidence does not support the use of DOACs in patients with active cancer
underpowered, subgroup analyses
poorly and inconsistently defined cancer populations
methodological heterogeneity (dose, duration, FUP)
lack of comparison with LMWH
The results of properly designed cancer-specific trials are needed
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Prevention of VTE in cancer patients
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
The role of primary prophylaxis of VTE in Cancer Patients
This role has been established for:
High risk Cancer Surgery (peri- and post-operative prophylaxis)
Acutely ill hospitalized cancer patients
This role is not yet established for:
Ambulatory cancer patients receiving anti-tumor therapies
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Thromboprophylaxis
In spite the evidence that VTE occurs in the outpatients setting, however, the guidelines agree on:
not recommending routine thromboprophylaxis in ambulatory cancer patients
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Prevention in Patients with Cancer: focus on Drug Therapy
Surgical Cancer Patients: An ongoing trial is evaluating the efficacy and safety of apixaban versus enoxaparin in women undergoing surgery for suspected pelvic malignancy https://clinicaltrials.gov/ct2/show/NCT02366871.
Hospitalized Cancer Patients: Trials on VTE prophylaxis with DOACs in hospitalized medical patients have led to disappointing results, and data are not available for the subgroups with cancer. Therefore, the use of DOACs in these patients cannot be recommended at this moment.
Ambulatory Cancer Patients Receiving Chemotherapy: The use of DOACs as thromboprophylaxis in ambulatory cancer patients was evaluated in a dose-finding study (ABLE trial) and in the ongoing AVERT trial. https://clinicaltrials.gov/ct2/show/NCT02048865
Nick van Es. Drugs 2016
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer
In this phase II trial, 12 weeks of APIXABAN appeared to be well tolerated and acceptable for the prevention of VTE in ambulatory subjects undergoing first-line or second-line chemotherapy for advanced or metastatic cancer. Symptomatic VTE was diagnosed in 3 of 29 patients (10%) in the placebo group and in 9 of those on apixaban.
Levine M.N. JTH 2012
In this phase II trial, 12 weeks of apixaban appeared to be well tolerated and acceptable for the prevention of VTE in ambulatory subjects undergoing first-line or second-line chemotherapy for advanced or metastatic cancer.
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Apixaban for the Prevention of Venous Thromboembolism in Cancer Patients (AVERT)
A Randomized Placebo-Controlled, Double-Blind Clinical Trial, which randomly allocates cancer patients with a high VTE risk to either apixaban 2.5 mg twice daily or placebo.
The primary outcome is symptomatic or asymptomatic VTE during 7 months of follow-up.
The targeted sample size is 574 patients, and enrolment is expected to be complete in 2017.
ClinicalTrials.gov Identifier: NCT02048865 https:// clinicaltrials.gov/ct2/show/NCT02048865
Carrier. Ottawa Hospital Research Institute
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
• Safety and efficacy study of apixaban to prevent clots in children with leukemia who have a CVC and are treated with PEG asparaginase (NCT02369653)
• Evaluation of apixaban in the prevention of thromboembolic disease in patients with myeloma treated with iMiDs (Myelaxat) (NCT 02066454)
Prophylaxis of VTE in ambulatory cancer patients (cont’ed)
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016
Conclusions
DOACs could have a role for VTE prevention in ambulatory patients with cancer who are receiving chemotherapy and for the prevention of central vein catheter thrombosis.
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.
It is imperative that the potential efficacy and safety of these agents is evaluated in prospective trials in the cancer setting.
Anna Falanga - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 9 maggio 2016