Updates in Anticoagulation for Atrial Fibrillation and Venous Thromboembolism

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1 Disclosures Updates in Anticoagulation for Atrial Fibrillation and Venous Thromboembolism No financial conflicts of interest Member of the ABIM Focused- Practice in Hospital Medicine Self Examination Process committee No exam questions will be disclosed in the presentation MARGARET C. FANG, MD, MPH DIRECTOR, UCSF ANTICOAGULATION CLINIC Learning Objectives Stroke risk in AF Anticoagulant options for AF and VTE Anticoagulant options for cancerassociated VTE Reversing anticoagulant effect Atrial Fibrillation and Stroke Atrial fibrillation causes strokes How do we know who should be anticoagulants? Stroke risk scores Combinations of risk factors to estimate annual risk of stroke Guidelines recommend risk-based scoring systems such as the CHA 2 DS 2 -VASc Score to estimate stroke risk

2 CHA 2 DS 2 -VASc Risk Score Stroke Risk by CHA 2 DS 2 -VASc Score Risk Factor Points C ongestive heart failure 1 H ypertension 1 A ge 75 2 D iabetes mellitus 1 S troke/tia 2 V ascular disease 1 A ge S ex category=female % 18.0% 16.0% 14.0% 12.0% 10.0% 8.0% 6.0% 4.0% 2.0% 0.0% Antithrombotic Therapy Based on CHA 2 DS 2 -VASc Score CHA 2 DS 2 -VASc Score 2014 AHA/ACC/HRS Guidelines 2018 CHEST Guidelines Examples 60 year old man 0 points No antithrombotic treatment 0 No antithrombotic therapy Nothing vs. No antithrombotic therapy 60 year old woman 1 point for being female No antithrombotic treatment 1 Aspirin vs. Oral anticoagulant 2 Oral anticoagulant Oral anticoagulant if 1 clinical risk factor (i.e., not gender) 60 year old man with HTN 1 point for HTN 60 year old woman with HTN 2 points (female + HTN) Oral anticoagulant

3 Changing Recommendations Newest guidelines now disregard female sex as a risk factor Risk is based on clinical risk factors Lowered threshold for anticoagulation If 1+ clinical risk factor, then anticoagulate Do not recommend antiplatelet treatment for stroke prevention in AF Anticoagulant Options for AF Oral Anticoagulants for AF Vitamin K Antagonists (e.g., warfarin) Direct oral anticoagulants Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) How Anticoagulants Work Trauma VKAs FXa Inhibitors VKAs Xa Direct Thrombin thrombin inhibitors Fibrin clot

4 Oral Anticoagulants: Overview Oral Anticoagulants: Overview Category Agents Monitoring Drug interactions Vitamin K antagonists (e.g., warfarin) Works indirectly on vitamin K dependent clotting proteins Direct oral anticoagulants (DOACs) Works by inhibiting targeted areas in the clotting cascade Vitamin K Antagonists Direct Thrombin Inhibitors Warfarin Coumadin Dabigatran Pradaxa INR None routinely (thrombin time) Many P-gp inducers (rifampin), inhibitors (ketoconazole, amiodarone) INR reflects anticoagulant intensity Requires frequent monitoring and doseadjustment INR does not reflect therapeutic intensity Fixed-dose and does not need routine monitoring Factor Xa Inhibitors Rivaroxaban Xarelto Apixaban Eliquis Edoxaban Savaysa None routinely (Anti-Xa level) CYP3A4/P-gp inducers (carbamazepine, phenytoin, rifampin) Strong CYP3A4/P-gp inhibitors (protease inhibitors, ketoconazole, clarithromycin) Anticoagulants for AF: Dosing Warfarin Coumadin Dabigatran Pradaxa Dosing Adjusted to INR mg po BID DOACs vs. Warfarin in AF Comparable efficacy in preventing stroke RR=0.92 [ ] Rivaroxaban Xarelto 20 mg daily Apixaban Eliquis Edoxaban Savaysa 5 mg BID (2.5 mg BID if 2 of following: age>80, weight <60kg, creatinine > 1.5 mg/dl) 60 mg po daily (30 mg daily if CrCl<50) Half the risk of ICH RR=0.48 [ ] DOACS better Warfarin better Somewhat higher risk of GI bleed RR=1.25 [ ] Ruff CT et al. Lancet 2014

5 2018 CHEST Guidelines: Updated recommendations Recommend DOACs over warfarin for AF If on warfarin, goal INR is and TTR should be consistently 65% If TTR <65%, consider interventions to improve anticoagulation quality DOACs and Chronic Kidney Disease Patients with end stage kidney disease have higher bleeding risk with anticoagulants Potentially bigger concern with DOACs: renally-cleared to varying degrees Generally not recommended for patients with severe CKD stage IV (CrCl <30 ml/min) Dabigatran and rivaroxaban use in CKD associated with worse outcomes Apixaban ~ 25% renally-cleared Medicare Patients on Dialysis Take home points 25,523 patients with end stage kidney disease on dialysis ( ) By 2015, 27% of new anticoagulant prescriptions were for apixaban Apixaban had similar efficacy to warfarin RR=0.88 [ ] The net benefits of anticoagulation for people with end stage kidney disease are still unclear It may be reasonable to consider apixaban for people with AF on dialysis and lower bleeding risk RR=0.72 [ ] Siontis et al, Circulation 2018

6 Summary: Atrial Fibrillation Use risk-based approach (e.g., CHA 2 DS 2 - VASc) to identify LOW RISK patients who should not get antithrombotic meds Anticoagulants recommended if 1 clinical CHA 2 DS 2 -VASc risk factors DOACs generally recommended over warfarin, except in severe CKD Apixaban may be acceptable alternative in dialysis patients Venous Thromboembolism Oral Anticoagulants for VTE Vitamin K Antagonists (e.g., warfarin) Direct oral anticoagulants Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Anticoagulants for VTE: Dosing Warfarin Coumadin Dabigatran Pradaxa Rivaroxaban Xarelto Apixaban Eliquis Dosing Adjusted to INR mg po BID *After an initial 5-10 days of treatment with a parenteral anticoagulant (e.g., enoxaparin, heparin) 15mg po BID for 3 weeks, followed by 20mg daily 10mg po BID for 1 week, followed by 5mg BID Edoxaban Savaysa 60mg po daily *After an initial 5-10 days of treatment with a parenteral anticoagulant (e.g., enoxaparin, heparin)

7 DOACs vs. Warfarin for VTE DOACs vs. Warfarin for VTE Recurrent VTE RR=0.88 [ ] Major Bleed RR=0.6 [ ] Fatal PE RR=1.0 [ ] All-cause mortality RR=0.97 [ ] Non-fatal critical site bleed RR=0.4 [ ] Clinically relevant non-major bleed RR=0.8 [ ] Favors DOACs Favors Warfarin Van Der Hulle et al. J Thromb Haemost, 2014 Favors DOACs Favors Warfarin Van Der Hulle et al. J Thromb Haemost, 2014 How Long to Treat VTE? Provoked events with a reversible risk factor (e.g., surgery) 3 months VTE in people with active cancer Life-long anticoagulation Unprovoked VTE At least 3 months and then consider extended therapy Why Extend Anticoagulation? Risk of recurrent VTE rises back to baseline once off anticoagulation Some people have high baseline risks for VTE Cancer Heredity Men with unprovoked VTE Decision to continue treatment depends on baseline VTE risk, bleeding risk, preference

8 Aspirin for Extended Prevention Options for Extended Antithrombotic Treatment Aspirin (100mg) reduces recurrent VTE risk by ~40% without increasing bleeding risk Becattini C et al. N Engl J Med 2012;366: Apixaban for Extended Prevention Rivaroxaban for Extended Prevention Apixaban at full and low doses reduced recurrent VTE risk [1.7% vs 1.7% vs 8.8%, p<0.001] Rivaroxaban at full and low doses was better than aspirin for preventing recurrent VTE (1.5% vs 1.2% vs 4.4%, p<0.001)..without significantly increasing bleeding rates [4.2% vs 3.0% vs 2.3%] without significantly increasing bleeding (0.5% vs 0.4% vs 0.3%) Agnelli G et al. N Engl J Med 2013;368: Weitz JI et al. N Engl J Med 2017;376:

9 Options for Extended VTE Treatment Options for Extended VTE Treatment: Dosing Unprovoked VTE Treated for 3 months Warfarin Coumadin Low dose Full dose Adjusted to INR 2-3 Stop anticoagulation Extend anticoagulation Rivaroxaban Xarelto 10mg po daily 20 mg po daily No treatment Start aspirin (100mg daily) Low dose anticoagulation Full dose anticoagulation Apixaban Eliquis 2.5mg po BID 5mg po BID Aspirin 100 mg po daily Summary Multiple options for acute and extended VTE prevention Provoked VTE treat for 3 months and then stop Unprovoked VTE treat for 3 months and then weigh risks vs. benefits of extending Low or full dose rivaroxaban or apixaban are reasonable options for extended VTE prevention If anticoagulants are not possible, give aspirin Treatment of Cancer- Associated VTE

10 Cancer and VTE Cancer significantly increases VTE risk Guidelines recommend life-long anticoagulation for cancer-associated VTE Previous guidelines recommended LMWH as the preferred anticoagulants in cancer But adherence to LMWH may be challenging DOACs for Cancer-Associated VTE Two recent randomized trials: HOKUSAI-Cancer Trial: edoxaban versus dalteparin SELECT-D Trial: rivaroxaban versus dalteparin Edoxaban comparable to dalteparin in preventing recurrent VTE HR=0.71 [ ] Rivaroxaban better than dalteparin in preventing recurrent VTE HR=0.43 [ ] but more bleeding but had more bleeding, especially upper GI bleeding in people with gastrointestinal cancers HR=1.77 [ ] Major bleed: HR=1.83 [ ] Clinically-relevant nonmajor bleeds: HR=3.8 [ ] GE Raskob et al. N Engl J Med 2018;378: Young et al. J Clin Oncology 2018

11 2018 ISTH Guidance Statement Suggest using DOACs in cancer-associated VTE who have low bleeding risk (LMWH are acceptable alternatives) Suggest using LMWH in high bleeding risk Luminal gastrointestinal cancers Active gastrointestinal mucosal abnormalities (e.g., ulcers, colitis) Genitourinary cancers with high bleeding risk Reversing Warfarin Vitamin K IV or oral Prothrombin complex concentrate (PCC) Purified clotting factors from plasma 4 factor-pcc is first-line treatment for lifethreatening bleeding on warfarin Fresh frozen plasma (FFP) Requires much more volume than PCC How Dabigatran Works Trauma Reversing Dabigatran: Idarucizumab (Praxbind ) Xa Thrombin Dabigatran Fibrin clot

12 Idarucizumab Binds Dabigatran, Preventing Thrombin Inhibition REVERSE-AD Study 350x stronger 90 patients who had urgent need for dabigatran reversal 51 patients with acute bleeding (18 with ICH, 20 GI bleed, 9 with trauma, 11 other) 39 patients with urgent procedural need (fractures, abdominal infections, etc.) Effect of Idarucizumab on dilute thrombin time Reversing Rivaroxaban and Apixaban: Andexanet alfa (Andexxa ) Pollack CV Jr et al. N Engl J Med 2015;373:

13 How Factor Xa Inhibitors Work Trauma Xa Inhibitors bind Andexanet instead of Factor Xa FXa Inhibitors Xa Factor Xa Inhibitor Catalytically inactive protease domain Thrombin Fibrin clot Removal of γ- carboxyglutamic acid membrane binding domain ANNEXA Studies Anti Factor Xa activity after andexanet Outcome measure: anti Factor Xa activity ANNEXA-4 Study 67 patients with acute major bleeding Connolly et al. N Engl J Med 2016.

14 Additional Pearls Half-life of DOACs is relatively short Anticoagulant effect will wear off if you wait If specific reversal agents for DOACs not available, can use PCC instead Reserve reversal for life-threatening situations Reversal agents might increase thrombotic risk Session Summary Multiple anticoagulant options for AF and VTE Anticoagulants recommended for men with CHA 2 DS 2 -VASc score 1 and women 2 DOACs Now recommended over warfarin for AF Choice individualized on renal function, patient characteristics, and cost Avoid in CKD Stage IV; apixaban may be an option in dialysis patients Summary - continued Summary - continued Provoked VTE should be treated for 3 months Unprovoked VTE should be treated for at least 3 months and considered for extended therapy to prevent recurrence Cancer-associated VTE should be treated with life-long anticoagulation DOACs are reasonable in patients with low bleeding risk To reverse anticoagulation in lifethreatening situations: Warfarin 4-factor PCC Dabigatran Idarucizumab Rivaroxaban and Apixaban Andexnet alfa

15 Useful References: AFib Thank You! Lip GY et al CHEST Guideline and Expert Panel Review: Antithrombotic Therapy for Atrial Fibrillation January CT et al AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation Nishimura RA et al AHA/ACC Focused Update of the 2014 Guideline for the Management of Patients with Valvular Heart Disease Doherty JU et al ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation Tomaselli GF et al ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants Useful References: VTE Useful References: VTE Burnett AE et al. Guidance for the practical management of the direct oral anticoagulants in VTE treatment. J Thromb Thrombolysis 2016, 41: Streiff MB et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis 2016, 41: Kearon C et al. Antithrombotic therapy for VTE disease: CHEST guidelines. CHEST 2016, 149: Simes J. Aspirin for the prevention of recurrent venous thromboembolism. Circulation 2014, 130: Weitz JI et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. NEJM 2017, 376: Raskob GE et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. NEJM 2018, 378: Li A et al. Direct oral anticoagulant versus lowmolecular-weight heparin for treatment of cancer associated thrombosis: A systematic review and metaanalysis. Thromb Res 2018.