Updates in Coagulation Thrombophilia testing and direct oral anticoagulants Kevin Y. Chen, MD Hematology and Medical Oncology October 13, 2017
No conflicts of interest
Introduction to thrombosis
Hemostasis
Coagulation cascade
Virchow s triad
Overview of Acute Venous Thromboembolism Annual incidence in U.S. = 1-2/1000 general population Incidence increases dramatically with age >60 Standard therapy (3 or more months of anticoagulation) Decreases the short-term recurrence rate from ~25% to ~3% Associated with major bleeding (~1-2%/year of treatment with warfarin) Recurrence after stopping anticoagulation 1 year 5years Provoked by surgery ~1% ~3% Provoked by non-surgical reversible risk factors ~5% ~15% (e.g., estrogen, pregnancy, leg injury, flight >8 hours) Unprovoked ~10% ~30% Active cancer ~15%/year
American College of Chest Physicians 2016 Guidelines for Treatment of VTE Kearon C et al., Chest 2012; 141(2 Suppl): e419s-494s (9 th Edition) Kearon C et al., Chest 2016 Feb; 149(2): 315-352 (10 th Edition) Graded recommendations for: Proximal lower extremity DVT and PE PE with hypotension Distal lower extremity DVT Superficial venous thrombosis Upper extremity DVT Post-thrombotic syndrome Catheter-associated thrombosis Splanchnic and hepatic vein thrombosis Chronic thromboembolic pulmonary hypertension Recommendations Strong (Grade 1) Weak (Grade 2) Evidence High-quality (Grade A) Moderate-quality (Grade B) Low-quality (Grade C)
Acute Proximal DVT or PE Initial Treatment For initial treatment with heparin, suggest LMWH or fondaparinux over IV unfractionated heparin (IV UFH preferred in patients with severe renal failure or those undergoing thrombolysis) If using warfarin, initiate therapy on day 1 Continue parenteral AC for 5 days and until the INR 2.0 for 24 h IVC filter Use only in patients with a contraindication to anticoagulation Begin a conventional course of AC if the risk of bleeding resolves (A permanent IVC filter is no longer considered to be an indication for extended AC) Grade 2B/2C 1B 1B 2B
Acute Proximal DVT or PE Choice of Anticoagulant VTE and no cancer Suggest a DOAC over warfarin * In patients not treated with a DOAC, suggest warfarin over LMWH (target INR 2.0-3.0 for all treatment durations) VTE and active cancer Suggest LMWH over warfarin or a DOAC * VTE and pregnancy Suggest LMWH over UFH (warfarin is teratogenic, esp. 1 st TM) Discontinue 24 h prior to induction or C-section Grade 2B 2C 2C 1B 1B * new in 2016 guidelines * new in 2016 guidelines
Duration of Treatment for Acute VTE Depends on estimation of: (1) Risk of recurrence ~1%/y ~15%/y (2) Risk of bleeding Provoked by surgery Provoked by non-surgical reversible risk (e.g., estrogen, pregnancy, leg injury, flight >8 hours) First unprovoked VTE Active cancer/ Second unprovoked VTE
Estimation of Bleeding Risk (not validated prospectively) Risk factors Age >65 Age >75 Previous bleeding Cancer Metastatic cancer Renal failure Liver failure Thrombocytopenia Previous stroke Diabetes Anemia Antiplatelet therapy Poor anticoagulant control Comorbidity and reduced functional capacity Recent surgery Frequent falls Alcohol abuse NSAID use (added in 2016) Bleeding Risk Low factors 0 risk Moderate 1 risk factor High factors 2 risk
Estimation of Bleeding Risk Major Bleeding After VTE (most studies assessed risk on warfarin therapy) Initial 3 Months (%) Extended >3 Months (%/y)
Acute Proximal DVT or PE Duration of Treatment (symptomatic=incidental) VTE provoked by Surgery Non-surgical transient risk factor 1st unprovoked VTE Low/moderate bleeding risk High bleeding risk 2nd unprovoked VTE Low/moderate bleeding risk High bleeding risk VTE and active cancer Low/moderate bleeding risk High bleeding risk VTE during pregnancy 3 months 3 months Indefinite 3 months Indefinite 3 months Indefinite Indefinite Continue until 6 wk postpartum (3 mo minimum) Grade 1B 1B 2B 1B 1B/2B 2B 1B 2B 2C
Hypercoagulable work up Although inherited and acquired thrombophilias are acknowledged to increase the risk of VTE, the majority of patients should not be tested for thrombophilia. Some arguing that these tests should never be performed. NEJM, Connors, 2017
570 patients with first VTE followed prospectively 85% had thrombophilia testing (after anticoagulation stopped) Recurrence rate 11% Recurrence rate not related to inherited thrombophilia status: Hazard ratio 1.5 (.82-2.77)
Case control study of 197 patients who had recurrence after first VTE and 324 control patients Primary endpoint: Odds ratio of recurrent thrombosis based on those tested and those not tested J Thromb Haemost 2008;6:1474
What are the issues with testing? No data supporting benefit of testing to guide secondary or primary prophylaxis Results may not alter management Negative testing does not equate low risk Current tests are insufficient Accuracy of some testing is dependent on timing
Other testing: MPN testing (JAK2, CALR, MPL, BCR-ABL) PNH testing (FLAER) Elevated Factor VIII Elevated Factor IX Elevated Factor XI Elevated plasminogen activator inhibitor -1 (PAI-1) PAI-1 promoter polymorphism MTHFR polymorphism (677C- >T, 1298A->C) NEJM, Connors, 2017
Inherited thrombophila
Clinical characteristics NEJM, Connors, 2017
Antiphospholipid antibody syndrome NEJM, Connors, 2017
Inherited thrombophila and pregnancy
Recommendations
Clinical scenarios A 33 year old male with no medical problems suffers a fractured femur playing football. He has surgery, but 1 week later develops calf swelling and is found to have a DVT. His 65 year old mother was recently found to have PE and was diagnosed with breast cancer.
Clinical scenarios A 23 year old with 2 younger sisters develops a DVT while 28 weeks pregnant. Her mother had a spontaneous PE when she was in her 30s.
Clinical scenarios A 36 year old female in her usual state of health is admitted into the ICU and found to have bilateral PE. She has a depressed EF and is given thrombolytics. Her aunt also had DVTs in her thirties
Algorithm for testing
854 patients randomized to limited cancer screening vs limited cancer screening with body CT Cancer detection: 3.2% vs 4.5% Cancers missed: 4 vs 5 Time to cancer diagnosis: 4.2mos vs 4.0mos Cancer related mortality: 1.4% vs 0.9%
1818 patient with unprovoked DVT treated with coumadin Cox regression to determine factors for recurrence DASH SCORE - D: post-anticoagulation D-Dimer (+2) - A: Age < 50 (+1) - S: Male (+1) - H: Hormone use (-2) Annual risk of recurrence 1 or less: 2.1% 2: 6.4% 3+: 12.3%
3365 patients with VTE and had completed 6-12 months of treatment randomized to 20mg rivaroxaban, 10mg rivaroxaban, 100mg ASA Primary outcome recurrent VTE, safety outcome of major bleeding
Recurrent VTE - 20mg (1.5%) - 10mg (1.2%) - ASA (4.4%) Major Bleeding - 20mg (0.5%) - 10mg (0.4%) - ASA (0.3%) Non major bleeding - 20mg (2.7%) - 10mg (2.0%) - ASA (1.8%)
Take home points Thrombophilia testing is often not indicated May be clinically relevant in select patients (especially APLAB) Testing should not be done at time of acute event Clinical factors more relevant for duration of anti-coagulation Consider age appropriate cancer screening Long term low dose anticoagulation may be an option for intermediate risk patients
Direct oral anticoagulants If these novel breakthrough oral anticoagulant drugs prove to be effective across the broad spectrum of patients in routine care and are conscientiously priced, the worldwide impact will be huge. NEJM, Hylek, 2010
Betrixaban FDA approved 2017
Direct Oral Anticoagulants Bind reversibly to the catalytic sites of their target proteases Thrombin Factor Xa In vivo Rivaroxaban Apixaba n Dabigatran etexilate (prodrug) Dabigatran (active drug) Edoxaban
Coagulation cascade Anthrombin mediated inhibitor of Xa, Iia - UFH - LMWH - Fondaparinaux Vitamin K Antagonist - Warfarin Direct thrombin inhibitor - Argatroban - Bivalrudin - Dabigatran Factor Xa inhibitor - Rivaroxaban - Apixaban - Edoxaban - Betrixiban
Direct Oral Anticoagulants Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Target Thrombin Xa Xa Xa Bioavailability 7% 80% (with food) 60% 60% Peak action 0.5-3 hours 2-4 hours 1-3 hours 1-2 hours Half-life 14-17 hours 7-12 hours 8-15 hours 10-14 hours Renal clearance Interactions Dosing Initial parenteral anticoagulation 80% 33% 25% 50% P-gp Twice daily 5-10 days of heparin/lmwh P-gp CYP3A4 Twice then once daily None P-gp CYP3A4 Twice daily None P-gp Once daily 5-10 days of heparin/lmwh Monitoring None None None None
Dabigatran Dose Stroke prevention in A fib: 110-150 mg bid 110 mg dose not available in US For patients with CrCl 15-30: 75 mg bid Not recommended for CrCl < 15 or dialysis dependent Postop VTE prophylaxis*: 150-220 mg once daily VTE treatment/prevention of recurrent VTE: 150 mg bid (following LMWH or heparin Rx) Less than 10% absorbed; relatively high rate of GI side effects Crosses the placenta do not use during pregnancy Drug may degrade over time after exposure to air must be kept in original packaging
Rivaroxaban Dose: Stroke prevention in nonvalvular Afib: 15-20 mg once daily Post op VTE prophylaxis: 10 mg once daily Acute VTE treatment: 15 mg twice daily Secondary prevention of VTE: 20 mg once daily or 10mg daily after 6 months Acute coronary syndrome*: 2.5-5 mg twice daily Use with caution in moderate renal impairment (CrCL 30-49); 15 mg/day dose recommended Avoid use if CrCl < 30 (not dialyzable) Avoid use in severe liver disease
Apixaban Dose: Stroke prevention in nonvalvular Afib: 5 mg bid 2.5 mg bid if age >80, weight < 60 kg, or serum creatinine > 1.5 Post op VTE prophylaxis: 2.5 mg bid Treatment of acute VTE: 10 mg bid x 7 days, then 5 mg bid Secondary prevention of VTE: 2.5 mg bid after 6 months Lowest dependence on renal excretion of new agents Avoid use in severe liver disease (75% biliary excretion)
Edoxaban Dose: Stroke prevention in Afib: 60 mg/d 30 mg/d if CrCl 15-50 or body wt 60 kg Post op VTE prophylaxis*: 30 mg/d Treatment of acute VTE: 60 mg/d (following LMWH or heparin Rx) Avoid use if CrCl > 95 ml/min (excessive excretion decreases efficacy)
Betrixaban Dose: VTE (prophylaxis): Oral: 160 mg as a single dose on day 1, followed by 80 mg once daily for 35 to 42 days Reduce betrixaban dose (initial and maintenance) by 50% for patients receiving or starting P- glycoprotein inhibitors (eg, amiodarone, azithromycin, clarithromycin, ketoconazole, verapamil). Severe renal impairment: avoid use
Efficacy of DOACs for treatment of acute VTE J Thromb Haemost 2014;12:320
Safety of DOACs for treatment of acute VTE J Thromb Haemost 2014;12:320
DOACS in atrial fibrillation Dabigatran 150 mg bid Rivaroxaban 20 mg qd Apixaban 5 mg bid Edoxaban 60 mg qd Combined Ruff et al, Lancet 2013
DOACs in VTE prophylaxis after total hip arthroplasty Symptomatic VTE Total VTE + All-cause mortality Major bleeding J Thromb Haemost 2014;12:107
Non-valvular a fib stroke prophylaxis FDA-approved Indications Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Betrixaban (Bevyxxa) Initial DVT/PE treatment after 5-10 d heparin Extended-duration DVT/PE treatment Knee replacement VTE prophylaxis Hip replacement VTE prophylaxis Hip fracture VTE prophylaxis after 5-10 d heparin Medical VTE prophylaxis Acute coronary syndrome Heparin-induced thrombocytopenia
Drug effects on coagulation tests PT/INR and PTT are relatively insensitive to the effects of DOACs Reagent-dependent results will vary among labs Normal PT and PTT do not rule out significant blood level of DOAC If PT or PTT elevated assume significant blood levels of DOAC Thrombin time very sensitive to dabigatran effect normal TT implies no drug on board Direct Xa inhibitors do not affect TT
Monitoring Dabigatran: Modified thrombin time assay (Hemoclot ) Rivaroxaban, apixaban, edoxaban: Anti-Xa activity (similar to LMWH assay) Neither assay FDA-approved or widely available now When to consider measuring drug level: Detect/quantify overdose Screen for drug accumulation (eg, impaired renal or liver function) Assure low drug level prior to surgery Limited usefulness for assessing compliance due to short drug half-lives
Reversal agents
Data from 12 RCTs of DOACs involving 102,607 patients Risk Ratios Comparing DOACs to Warfarin RR 0.72 [0.62-0.85] RR 0.53 [0.43-0.64] RR 0.43 [0.37-0.50] RR 0.94 [0.75-1.19] Major bleeding Fatal bleeding Intracranial bleeding Major GI bleeding Blood 2014;124(15):2450-2458
Reversal of Direct Oral Anticoagulants Kaatz et al. Am J Hematol 2012; 87: S141-5 (<2 h) (?) (?)
Reversal of Rivaroxaban by 4-factor PCC (50 IU/kg) in Healthy Volunteers Rivaroxaban PT Dabigatran aptt Dabigatran Thrombin time placebo PCC Eerenberg et al. Circulation 2011; 124(14): 1573-9
Idarucizumab (Praxbind) for Dabigatran Reversal Pollack et al., N Engl J Med 2015 Aug 6;373(6):511-20 Idarucizumab (Praxbind ) is a monoclonal antibody fragment that binds to dabigatran with high affinity (350x that of thrombin) 5 mg of idarucizumab (2 x 2.5 mg vials) completely reverses the anticoagulant effect of dabigatran when the drug is taken at usual recommended doses This effect occurs within minutes of drug administration and restores normal hemostasis (NEJM 2015; 373:511) Idarucizumab approved by FDA in October 2015
503 patients enrolled, 301 uncontrolled bleeding, 202 required urgent procedure Primary end point reversal measure by dilute thrombin time Median maximum percentage reversal was 100% Median time to cessation of bleeding 2.5 hours, median time to procedure 1.6 hours
Idarucizumab (Praxbind) for Dabigatran Reversal
Andexanet alfa for Reversal of Xa Inhibitors Recombinant factor Xa variant Lacks the γ-carboxyglutamic acid domain required for phospholipid binding Alanine substituted for serine in the active site (catalytically inactive) Figures from Nature Medicine 19, 402-4 (2013)
Andexanet alfa for Reversal of Xa Inhibitors Siegal et al., N Engl J Med 2015 Dec 17;373(25):2413-24 Study Design Healthy volunteers (50-75 years old) housed at a study site for 8 days Apixaban study: 5 mg PO BID x 3.5 days, then Andexanet 400 mg IV bolus +/- 4 mg/min continuous IV infusion for 2 h OR placebo Rivaroxaban study: 20 mg PO QD x 4 days, then Andexanet 800 mg IV bolus +/- 8 mg/min continuous IV infusion for 2 h OR placebo Primary outcome: percent change in anti-factor Xa activity
Andexanet alfa for Reversal of Xa Inhibitors Siegal et al., N Engl J Med 2015 Dec 17;373(25):2413-24 Bolus plus infusion
Andexanet alfa for Reversal of Xa Inhibitors Siegal et al., N Engl J Med 2015 Dec 17;373(25):2413-24 Conclusions Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban within minutes Rapid onset and offset of action (provides flexibility of treatment?) No serious adverse events (1 patient with hives) No antibodies against factor X or Xa detected at 43 days
67 patients with acute major bleeding within 18 hours of receiving anti Xa inhibitor Mean time from ED arrival to rx: 4.8 hours Decrease in antixa activity: 89% and 93% (after bolus, during 2hour infusion) 39% and 30% (4 hours after infusion complete) Good/excellent clinical hemostasis 12 hours after: 79% Thrombotic event rate: 18% at 30 days
Transition to DOAC Unfractionated heparin to DOAC: Start DOAC when UFH infusion stopped LMWH to DOAC: Start DOAC 2 h before next scheduled sq dose of LMWH Warfarin to DOAC: When INR < 2.0
Transition from DOAC DOAC to parenteral anticoagulant: CrCl >30: start 12 hours after last NOAC dose CrCl <30: start 24 hours after last NOAC dose DOAC to warfarin: CrCl >50: start warfarin 3 days before NOAC stopped CrCl 31-50: start warfarin 2 days before NOAC stopped CrCl 15-30: start warfarin 1 day before NOAC stopped Remember that NOACs can prolong PT/INR
Perioperative management Stop DOAC at least 3 drug half-lives prior to surgery Dabigatran: 42-51 h Rivaroxaban: 15-27 h Apixaban: 24-48 h Allow more time if: Age > 75 Impaired renal or liver function High bleeding risk
Recurrent VTE While on Anticoagulation Approach to Treatment If recurrence on warfarin or a DOAC Evaluate for true recurrence, compliance, or malignancy Switch to LMWH for at least 1 month * Grade 2C If recurrence on long-term LMWH and patient is compliant Increase dose of LMWH by 25% to 33% * 2C * new in 2016 guidelines
Cost per month Rivaroxaban (20 mg/day) : $290 Dabigatran (150 mg bid): $290 Apixaban (5 mg bid): $147 Warfarin (7.5 mg/day): $31
Patients selection for DOAC Patients who have unstable INR on warfarin not due to poor compliance Adequate renal & hepatic function No mechanical valve Not pregnant (drugs cross placenta) Not at extremes of weight (can t adjust dose) Not at high risk of lower GI bleeding