Top 10 Thrombosis and Anticoagulation Highlights from ASH 2014

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1 Top 10 Thrombosis and Anticoagulation Highlights from ASH 2014 Stephan Moll, MD UNC School of Medicine, Chapel Hill, NC 1. New Anticoagulant Factor XI lowering drug NEJM publication Dec 7 th (late- breaking abstract 1, Bueller H et al): A phase 2 study presented at ASH and published at the same time in the NEJM as a full paper showed that lowering of coagulation factor XI (with an anti- sense oligonucleotide drug) was effective in preventing post- operative DVT without increasing the risk of perioperative bleeding. The findings challenge the long- held belief that an anticoagulant automatically increases the risk for bleeding. May be it is possible that a drug works as an anticoagulant and prevents thrombosis, yet does not increase the risk for bleeding. Conclusion #1: Interesting early data. Of no clinical consequence at this point. 2. NOAC Antidotes Three main antidotes for the NOACs are in development and have recently been reviewed on Clot Connect ( ): Andexanet for the anti- Xa drugs (Xarelto, Eliquis ), Idarucizumab for Pradaxa, and Aripazine (PER977) as a more global reversal agent for all NOACs. No striking new data on these reversal agents were presented at ASH. a. Andexanet Abstract 4269 (Crowther M et al.): A Phase 2 Randomized, Double- Blind, Placebo- Controlled Trial Demonstrating Reversal of Edoxaban- Induced Anticoagulation in Healthy Subjects By Andexanet Alfa (PRT064445), a Universal Antidote for Factor Xa (fxa) Inhibitors. A phase 2 randomized, placebo- controlled trial that investigated reversal of the anti- Xa anticoagulant edoxaban in healthy subjects was presented at ASH. Andexanet rapidly reversed edoxaban s anticoagulant effect, as measured by coagulation tests. This study provides background efficacy and safety data on the use of Andexanet and is the prelude for the phase 3 clinical trial that is in the planning stages (not yet listed on clinicaltrials.gov) to use the drug in patients who present with major bleeding. b. Idarucizumab Abstract 344 (Glund S et al.): Idarucizumab, a Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Elderly and Renally Impaired Subjects. A phase 2 randomized, double- blind, placebo controlled study in healthy volunteers presented at ASH investigated the reversal of coagulation tests by intravenous idarucizumab and showed effective reversal. A phase 3 clinical trial in patients with major bleeding or who

2 need urgent reversal of dabigatran is ongoing (ClinicalTrials.gov Identifier: NCT ). c. PCC and apcc Abstract 345 (Perlstein I et al.): Reversal of Apixaban Anticoagulation By 4- Factor Prothrombin Complex Concentrates in Healthy Subjects. 15 healthy volunteers who took apixaban 10 mg bid received a 4 factor prothrombin complex concentrate (PCC). PCC reversed apixaban s anticoagulant effect as measured by several coagulation parameters (endogenous thrombin potential), suggesting that 4- factor PCCs (in the U.S.: Kcentra ) may be useful in the management of major bleeding in patients on apixaban. Abstract 4259 (Shaw J et al.): FEIBA for Patients on Direct Oral Anticoagulants Requiring Urgent Surgery. In a retrospective one- center chart review 5 patients on NOACs who required urgent reversal of anticoagulation for surgery were identified. All received FEIBA before surgery. The conclusion was that FEIBA was effective and not associated with adverse thrombotic complications. Conclusion #2: The development of several antidotes is promising. Non- activated and activated PCCs MAY be effective reversal agents for NOAC- associated major bleeding. A practical, clinical reversal strategy for the various anticoagulants and anti- platelet agents is presented on Clot Connect (link here: 3. Cancer and VTE a. VTE Treatment CATCH trial (Lee A et al.) Late- breaking abstract 2: A Randomized Trial of Long- Term Tinzaparin, a Low Molecular Weight Heparin (LMWH), Versus Warfarin for Treatment of Acute Venous Thromboembolism (VTE) in Cancer Patients - the CATCH Study ). In this open- label multicenter international study 900 patients with cancer and acute VTE were randomized into receiving either the low molecular weight heparin tinzaparin (Innohep ) for 6 months or LMWH for 5-10 days overlapping with warfarin to a target INR of 2-3. Symptomatic DVT was significantly less in the tinzaparin group compared to the warfarin group (2.7% vs 5.3%; HR 0.48;95% CI ). Major bleeding was the same in both groups, but non- major clinically relevant bleeding was less in the tinzaparin group (11% vs 16%). This study confirms what the CLOT study (dalteparin vs warfarin in patient with cancer and VTE) showed > 10 years ago: that LMWH is superior to warfarin in this patient population. However, it is noteworthy that (a) the warfarin failure rate in this current CATCH trial was much less than in the previous CLOT trial and (b) that the benefit of LMWH over warfarin was also much less pronounced in the current trial.

3 It needs to be seen how well the NOACs perform in cancer patients with VTE in comparison to warfarin and LMWH. A recent publication ( Direct Oral Anticoagulants in Patients with VTE and Cancer: A Systematic Review and Meta- Analysis ; Vedovati CM et al. Chest; epub Sept 11, 2014) of all the NOACs- in- VTE trials found that NOACs were at least as effective as warfarin in the patients enrolled into the trials who had cancer. However, it is important to point out that none of those trials were dedicated VTE- in- cancer trials. Two such cancer trials are noteworthy: (1) Young A et al. Anticoagulation therapy in selected cancer patients at risk of recurrence of VTE (Select- d trial): rivaroxaban vs. dalteparin; ongoing and enrolling. (2) Edoxaban vs. dalteparin (NCT NCT ) in the planning stages. Conclusion #3: LMWH is still the standard of care in cancer patients with acute VTE. However, if a patient cannot afford LMWH or objects to the s.c. injections, then either a NOAC or warfarin are both good and appropriate treatment choices. Education session Prevention and treatment of VTE in patients with cancer by Lee A [Hematology 2014; Education Program, ]. The talk and published article present existing guidelines on state- of the art prevention and treatment of VTE in patients with cancer; one of the author s conclusions is that the use of NOACs in patients with cancer is strongly discouraged due to (a) the lack of existing efficacy and safety data and (b) possible drug interactions of the NOACs with various chemotherapeutic agents. b. Unsuspected/incidental PE - Treatment Abstract 1546 (Bleker S et al.): Unsuspected PE in cancer patients: a multicenter, international, prospective, observational study. Clinically unsuspected PE is frequently diagnosed in cancer patients undergoing routine CTs for staging purposes or treatment response evaluation. Current guidelines suggest that such patients should receive similar initial and long- term anticoagulant treatment as for symptomatic PE. However, direct evidence is scarce. This ongoing trial will eventually give insight into the current treatment strategies in cancer patients with unsuspected PE and provide outcome data in respect to VTE recurrence, bleeding and mortality. Conclusion #4: Useful ongoing study. Of no clinical consequence at this point. Abstract 590 (van der Hulle T et al.): Risk of Recurrent Venous Thromboembolism and Major Bleeding in Cancer- Associated Incidental Pulmonary Embolism Amongst Treated and Untreated

4 Patients: A Pooled Analysis of 926 Patients. In this literature review, 926 cancer patients with incidental PE from 11 observational studies and ongoing registries were included. The key finding was that there was a 12% 6- month risk of symptomatic recurrent VTE in patients with cancer- associated incidental PE who did not receive anticoagulant treatment, which is more than double the risk of patients who were anticoagulated. These numbers support the judicious initiation of anticoagulant treatment in cancer- associated incidental PE. Conclusion #5: Patients with incidentally discovered PE may benefit from anticoagulation. c. IVC Filter Abstract 4247 (Cull EH et al.) Temporary vena cava filters in oncology patients. This is a prospective, single- institution registry of IVC filters in patients with active malignancy or receiving adjuvant therapy for a recent active malignancy. 179 filers were placed. The study showed that (a) 31 % of filters were placed without the patient having a contra- indication for anticoagulant therapy (which is the only clear- cut indication for filter placement), (b) 20 % or these filters were not removed, (c) the overall cost of filter placements and filter removals was over $2 million, i.e. an average of > $ 11,500 per IVC filter. Conclusion #6: IVC filters are commonly placed in patients with cancer and malignancy, at a significant $ cost. Clear indications for IVC filters placements are only: acute DVT and inability to anticoagulated. Other indications, such as (a) recurrent DVT in spite of therapeutic anticoagulation, (b) large DVT burden, and (c) limited cardio- pulmonary reserve are softer indications with a lack of evidence whether IVC filters are beneficial in this situation. As a side note: An interesting new IVC filter design is presently being studied (clincaltrials.gov, NCT ) in 135 patients, a bioconvertible IVC filter (Sentry filter images here: Following implantation a small bioabsorbable filament which holds the filter arms together at the apex of the filter cone begins to slowly degrade over a minimum of 60 days. Once the filament is dissolved, the filter arms are released, separating and retracting towards the IVC wall where they become endothelialized and incorporated into the IVC wall, leaving a patent lumen and unobstructed blood flow. d. Central venous catheter- associated DVT: Abstract 4260 (Delluc A et al.): Outcomes of central venous catheter associated upper extremity DVT in cancer patients.

5 In this retrospective one- center study 99 patients with upper extremity DVT associated with central venous catheter were treated with full- dose LMWH at first, then either intermediate dose, low- dose, or no LMWH. On full- dose LMWH no recurrent VTE occurred, but 2 major bleeding episodes. Conclusion #7: Given the heterogeneity of the population studied, no solid conclusions are possible, but the full manuscript will be interesting to see. Education session Central Venous Catheters by Geerts W [Hematology 2014; Education Program, ]. The talk and published article summarize that (a) symptomatic catheter- related DVT is treated with anticoagulation, typically without removing the catheter, and (b) the intensity and duration of anticoagulation depends on the extent of thrombosis, risk of bleeding, and need for continued use of the catheter; (c) the author presents two practical tables entitled My personal approach to the detection and management of catheter- related thrombosis and another one on the prevention. 4. TTP Treatment with a New Drug Abstract 229 (Peyvandi F et al.): Caplacizumab, anti- vwf nanobody potentially changing the treatment paradigm in TTP: results of the TITAN trial. An anti- von Willebrand factor (vwf) drug (nanobody; caplacizumab)) was used in patients with TTP in a clinical trial called TITAN. As the thrombotic complications of TTP are mediated by enhanced platelet binding to sub- endothelial collagen via overly active (high molecular weight) vwf, it makes sense to develop a drug for the treatment of TTP and the prevention of thrombosis, platelet activation and platelet destruction (i.e. thrombocytopenia) that inhibits vwf. 75 patients with acute TTP were treated either with caplacizumab or placebo added to daily plasma exchange (PLEX) in this randomized, placebo controlled, single- blind study. Patients treated with caplacizumab had more rapid achievement of platelet normalization and lower number of TTP exacerbations. Conclusion #8: Interesting. Of no clinical consequence at this point. 5. Unusual Clots a. Splanchnic vein thrombosis Abstract 592 (Ageno W et al.): Antithrombotic treatment and outcomes of splanchnic vein thrombosis in an international prospective registry: results of 2- year follow- up. In a multicenter international registry 604 consecutive patients with splanchnic vein thrombosis were enrolled and assessed for recurrent thrombosis, major bleeding and mortality over a 2 year follow- up period. 77 % of patients were on anticoagulants, 23 % not. The study found that (a) the risk for bleeding and recurrent

6 thrombosis depended on the etiology of the first thrombotic event (patients with liver cirrhosis had the highest bleeding and recurrent VTE rate), (b) major bleeding occurred in 3.8 %/year, recurrent thrombosis in 7.3%/year, i.e. not an unsubstantial risk for both. Conclusion #9: Limited data exist on best management of patients with splanchnic vein thrombosis. Individualized decisions need to be made based on (a) cause of the thrombotic event, (b) risk factors for recurrence, and (c) risk factors for bleeding. Abstract 4276 (Nicoletta R et al.): Safety of vitamin K antagonist treatment for splanchnic vein thrombosis: a multicenter retrospective cohort study. In this retrospective study 375 patients with splanchnic vein thrombosis were included. In 63 % of patients there was an explanation for the thrombosis (hematologic disease, liver cirrhosis, cancer, abdominal surgery, intra- abdominal inflammation or infection), 37 % were unexplained. 94 % of patients were treated with warfarin with a target INR of 2-3. Major bleeding occurred in 1.24 per 100 patient- years, recurrent thrombosis on treatment occurred in 1.37 per 100 patient- years. Presence of esophageal varices was a predictor of major bleeding. Conclusion #10: Oral anticoagulation is safe in many patients with splanchnic vein thrombosis; presence of esophageal varices leads to a higher risk for major bleeding. b. Ovarian vein thrombosis Abstract 587 (Assal A et al): Ovarian vein thrombosis: clinical features, risk factors, and outcomes. This is the largest ovarian vein thrombosis study to date: 223 cases of confirmed ovarian vein thrombosis over 10 years were retrospectively identified. (a) The majority occurred after abdominal surgery, particularly hysterectomy; (b) Right and left side were equally affected, 14 % were bilateral; (c) Anticoagulation was started in only 9.4 % of patients; (d) 11.7 % had a recurrent VTE, of which 20 were DVTs, 6 PEs; (e) 4/21 patients (19 %) who were on anticoagulation had a recurrent VTE. Conclusion #11: No clinical implications at this point. Many patients with ovarian vein thrombosis do not seem to need anticoagulation; others develop recurrent VTE in spite of anticoagulation. 6. DVT and PE Other Issues a. Abstract 591 (van der Hulle T et al): Recurrence Risk after Limited Duration of Anticoagulant Treatment for Late Second Venous Thromboembolism.

7 The fact that a patient has had 2 episodes of VTE does notnecessarily mean that the patient has be on long- term anticoagulation. The risk for a 3 rd VTE depends on whether the 2 nd thrombotic event was provoked or unprovoked: the former group of patients has a risk of recurrent VTE of 5.6 per 100 patient- years, the latter group on of 12 per 100 patient- years. Conclusion #12: Patients with a 2 nd episode of VTE do not necessarily need long- term anticoagulation, if the 2 nd clot was triggered by a transient risk factor. b. Educational talk by Moll S [Hematology 2014; Education Program, ]. The talk and article discuss in a clinical- practical manner VTE management issues from acute treatment to management of long- term complications, addressing new data gained in the last 2 years and putting them into a clinical context. Conclusion #13: This article addresses many of the treatment issues relevant for the acute and chronic management of VTE. 7. Thrombophilia Abstract 1544 (Schulman S et al): Influence of Thrombophilia on the Efficacy of Dabigatran Versus Warfarin for the Extended Treatment of Acute Venous Thromboembolism in RE- MEDY. A post- hoc subgroup analysis of the phase 3 dabigatran VTE trial (warfarin vs dabigatran for acute VTE) was done. The trial had not required thrombophilia testing, but in routine practice about 48% of patients had thrombophilia testing done. As expected the majority of thrombophilias detected were factor V Leiden and the prothrombin mutation, Protein C, S and AT deficiency and APLA antibodies were less common. The analysis found that patients with or without thrombophilia did equally well and treatment efficacy was not affected by the presence of thrombophilia. Conclusion #14: This analysis appropriately argues that the finding of a thrombophilia does not need to be a reason to deny a patient treatment with a NOAC. This is of clinical relevance. 8. Hematology and Reproduction Three detailed reviews on thrombophilia and thrombosis and women s health were presented and published. a. In vitro fertilization (Bates, SM; Hematology 2014, Education Program, : Anticoagulation and in vitro fertilization and ovarian stimulation). b. Pregnancy and VTE (Rodger M; Hematology 2014, Education Program, : Pregnancy and venous thromboembolism: TIPPS for risk stratification). c. Pregnancy complications (Middeldorp S; Hematology 2014, Education Program, : Anticoagulation in pregnancy complications).

8 Conclusion #15: These articles contain clinically helpful, evidence- based conclusions on best management of women at risk for or with established thrombosis and/or pregnancy complications. 9. Warfarin Management a. Bleeding Abstract 2867 (Morton CT et al): Initial Experience with 4- Factor PCC for the Reversal of Warfarin: Patterns of Use and Safety Outcomes. In this real world patient management situation, 33 patients at one institution were treated with 4- factor PCC (Kcentra for warfarin associated coagulopathy and the authors found Kcentra to (a) be effective in the rapid reversal of INR and (b) have a low complication rate, with only one patient developing a thrombotic phenomenon (acute coronary event) within 72 hours of administration of Kcentra. b. Low dose vit K Abstract 2872 (Crowther M et al): Low Dose Oral Vitamin K Does Not Increase Time in Therapeutic Range: Results of a Multicentre Clinical Trial. In this randomized 4- center trial 253 patients on warfarin were enrolled, to receive either 150 mcg of daily vitamin or placebo. 235 patients appropriate for analysis after a maximum of 9 months in the trial. The time- in- therapeutic INR range (TTR) increased in both the placebo and vitamin K group over the trial (from ca. 53.2%) to 65.6%, but the vitamin K patient group did not better than the placebo group. The authors appropriately conclude that in unselected patients on warfarin the addition of vitamin K does not lead to a better TTR. Conclusion #16: Vitamin K supplementation for all patients on warfarin is not indicated and not beneficial. However, previous studies have shown that it is beneficial in selected patients who have unstable INRs. 10. Choosing Wisely Campaign ASH continues its Choosing Wisely publications and this year again chose five Don't do topics in hematology; two of these deal with thrombosis and anticoagulation issues: a. Do not treat with an anticoagulant for > 3 months in a patient with a first VTE occurring in the setting of a major transient risk factor b. Do not test or treat for suspected HIT in patients with a low pre- test probability of HIT. Conclusion #17: Useful recommendation: In a patient with DVT or PE associated with a major transient risk factor, anticoagulation is only needed for 3 months.