Judicious Use of Anticoagulation: A Case-Based Approach Michael B. Streiff, MD, FACP Associate Professor of Medicine and Pathology Division of Hematology Medical Director, Johns Hopkins Anticoagulation Management Service and Outpatient Clinics

Disclosures Research Funding Consulting Speaking Honoraria Bristol-Myers Squibb NIH/NHLBI Consulting Sanofi-aventis Eisai, Inc. Daiichi-Sankyo Janssen Healthcare BiO2 Speaking Honoraria Sanofi-aventis Ortho-McNeil Educational Grants Sanofi-Aventis Covidien

Anticoagulation for pregnancy loss 32 year old woman with 2 previous first trimester pregnancy losses asks about LMWH to prevent miscarriages. You advise her to Start therapeutic dose LMWH Start prophylactic dose LMWH Start prophylactic dose LMWH + Aspirin 100 mg Start no antenatal prophylaxis

LMWH does not improve pregnancy outcomes: The ALIFE Study Placebo (N=121) Completed Study (N=103) 364 women with at least 2 pregnancy losses Aspirin 80 mg (N=120) Completed Study (N=97) Aspirin 80 mg + Nadroparin 2850 IU (N=123) Completed Study (N=99) Kaandorp S et al. NEJM 2010

Baseline characteristics Aspirin + LMWH (N=123) Aspirin (N=120) Placebo (N=121) Age (yrs.) 34±5 33±5 Previous miscarriages 3 (2-15) 3 (2-9) 3 (2-12) ≥ 3 miscarriages 73 (59%) 71 (59%) 74 (61%) ≥ 1 late losses 40 (33%) 38 (32%) 35 (29%) Previous live birth 53 (43%) 45 (38%) 46 (38%) Thrombophilia 13 (12%) 17 (17%) Kaandorp S et al. NEJM 2010

LMWH did not increase the live birth rate Kaandorp S et al. NEJM 2010

Thrombophilia did not affect live birth rate Kaandorp SP et al. NEJM 2010

Anticoagulation does not prevent early pregnancy loss Open-label RCT of enox 40 mg/d + ASA 75 mg vs. surveillance alone PMHx ≥ 2 losses 24 weeks or less Begin 7 weeks gestation or less Conclusion- Prophylactic AC does not improve pregnancy outcomes N=294 Clark P et al. Blood 2010

Heparin + Aspirin reduces pregnancy loss in Antiphospholipid Syndrome Metanalysis of 5 RCTs of UFH/LMWH + aspirin versus aspirin Regimens- UFH 5000-20000 units + aspirin 75-81 mg and LMWH 5000 + aspirin 75-81 mg Conclusion- UFH/LMWH + ASA improves live birth rates RR 1.3 Mak A et al. Rheumatol 2010

Anticoagulation- Less or More? A 65 year old man with a St Jude aortic valve is scheduled to undergo a prostatectomy for cancer. When should he resume full-dose anticoagulation? 12 hours post-op 24 hours post-op 36 hours post-op 72 hours post-op

Perioperative AC- Is less more? Metanalysis of 34 studies of 12,278 patients Outcomes- Thromboembolism and Bleeding Limitation- Lack of RCT Conclusion- Value of perioperative bridging unclear Siegal D et al. Circulation 2012

Less is more for perioperative AC Prospective Cohort of 1262 patients Low risk- AVR w/o Afib-prophylactic LMWH High risk- MVR, AVR w/Afib or stroke- Enox 0.7 mg/kg q12h Post-op- resume AC day 1-3 based upon hemostasis Pengo V et al. Circulation 2009

Thromboembolism Risk Stratification Thromboembolic Risk Atrial Fibrillation Mechanical Valve Venous Thromboembolism High CHADS2 score 5 or 6 Any Mitral valve Older valve (Caged-ball, Tilting disk) Recent stroke/TIA Recent (within 3 mos.) VTE Severe thrombophilia Intermediate CHADS2 score 3 or 4 Bileaflet Aortic valve + TE risk factors VTE within 3-12 mos. Recurrent VTE, Active Cancer Non-severe thrombophilia Low CHADS2 score 0-2 Bileaflet Aortic valve w/o TE risk factors VTE > 12 mos. TE risk factors= A fib, Cardiac failure, HTN, DM, Age > 75, Stroke/TIA Douketis JD Blood 2011

Bleeding Risk Assessment Low Bleeding Risk Procedures High Bleeding Risk Procedures Cholecystectomy Abdominal hysterectomy GI Endoscopy ± biopsy or stent Pacemaker insertion, EP testing Dental extractions Carpal tunnel repair Dilatation/currettage Skin Cancer excision Abdominal hernia Hydrocele repair Cataract surgery Bronchoscopy ± biopsy Central Venous Catheter removal Skin, Thyroid, Breast, Lymph node biopsy Cardiac surgery Abdominal aneurysm repair Neurosurgery Urologic surgery Head and Neck surgery Hip/knee replacement Back surgery Kidney biopsy Polypectomy/sphincterotomy Transurethral prostate resection General surgery Vascular surgery Any major surgery (> 45 minutes) Spyropoulos AC and Douketis JD Blood 2012

AC Management Surgical Bleeding risk Pre-operation Post-operation Low Last dose LMWH 24 hours before Resume LMWH 24 hours post-op if hemostasis adequate Start warfarin with LMWH High Resume LMWH 48-72 hours post-op if hemostasis adequate or start prophylactic dose 24 hours post-op or avoid LMWH

Anticoagulation for VTE 65 year old man develops a right femoral-popliteal vein DVT 1 week after right knee replacement. A thrombophilia evaluation reveals he is heterozygous for the factor V Leiden mutation. How long should he be treated? 6 weeks 3 months 12 months Indefinite

Anticoagulation for VTE 48 year old man presents with progressive dyspnea over 1 week and left leg discomfort. CT angiogram identifies bilateral PE. Duplex study finds a left leg DVT. No VTE risk factors are identified. How long should he be treated? 3 months 6 months 12 months Indefinite

Do the Results of Thrombophilia Tests Help to Determine Duration of Therapy? (1.5-2.7) HR 1.8 (1-3.1) HR 1.4 (0.9-2.2) Recurrent VTE (%) HR 1.5 (0.8-2.8) (N= 570) 24 mos. (N=474) 84 mos. (N=267) 46 mos. (N=1626) 50 mos.

Thrombophilia-Assessing the risk High risk thrombophilia Antithrombin deficiency - 1.8 % per year (95% CI 1.1-2.6%) Protein C deficiency - 1.5% per year (1.1-2.1%) Protein S deficiency - 1.9% per year (1.3-2.6%) Moderate risk thrombophilia Factor V Leiden - 0.5% per year (0.4-0.6%) Prothrombin gene mutation - 0.3% per year (0.2-0.5%) Factor VIII - 0.5% per year (0.4-0.5%) Low risk thrombophilia Factor IX - 0.1% per year (0.02-0.2%) Factor XI - 0.2% per year (0.06-0.6%) Hyperhomocysteinemia – 0.1% per year (0.05-0.3%) Lijfering WM et al. Blood 2009

Antiphospholipid syndrome is associated with recurrent thromboembolism Recurrent VTE (%) Months Schulman S , et al. Am J Med 1998; 104: 332-338

VTE recurrence rate varies depending upon initial trigger for the event Cumulative recurrent VTE (%) Time after cessation of therapy (months) Baglin T et al., Lancet 2003

VTE Setting influences recurrence risk Systematic review of prospective cohort studies and RCTs 15 Studies 5159 Subjects Follow up- 3-96 months Conclusion- Setting of thrombosis strongly influences recurrence rate Iorio A et al. Arch Intern Med 2010

D dimer and recurrent VTE D dimer- an indirect marker of activated coagulation PROLONG study (Palareti G et al. NEJM 2006) F/U 1.4 years Systematic Review (Verhovsek M et al. Ann Intern Med 2008) 7 studies, 1888 patients Recurrent VTE- Abnl vs. nl DD (8.9% vs. 3.5% per year) N=608

How do we identify the low risk patient with idiopathic VTE? Prospective cohort study of 665 patients with idiopathic VTE Enrolled at 12 centers, 4 countries prior to DC of warfarin after 5-7 months of therapy Information of 76 laboratory and clinical variables associated with VTE were collected Multivariate analysis used to develop clinical prediction rule for recurrent VTE Results F/U population 600/665 (90%) Mean F/U -18 months (1-47 mos.) Annual risk of recurrent VTE 9.3% per year (7.7%-11.3%) Men 13.7% (10.8%-17%) Women 5.5% (3.7%-7.8%) Rodger MA, et al. CMAJ 2008;179(5):417-26

Clinical prediction rule for recurrent VTE in women Rodger MA, et al. CMAJ 2008;179(5):417-26

Risk stratification for idiopathic VTE: The Vienna Risk Model http://www.meduniwien.ac.at/user/georg.heinze/zipfile/ViennaPredictionModel.html Eichinger S et al. Circulation 2010

Indefinite Anticoagulation: Weighing the risks Thrombosis Bleeding

Assessing Bleeding Risk: The HAS-BLED Score Hypertension (uncontrolled SBP>160) = 1 point Abnormal renal/liver function = 1 or 2 points Stroke = 1 point Bleeding (or anemia) = 1 point Labile INRs (TTR<60%)= 1 point Elderly (Age > 65 years)= 1 point Drugs or alcohol= 1 or 2 points Pisters R et al. Chest 2010; Olesen JB, et al. JTH 2011

Central Venous Catheter Prophylaxis 67 year old man has just had a right subclavian Hickman CVC placed for chemotherapy for recently diagnosed NHL. What should be used for CVC thrombosis prophylaxis? Warfarin 1 mg daily Enoxaparin 40 mg daily Dalteparin 5000 units daily No prophylaxis necessary

CVC Prophylaxis Open RCT of low dose warfarin 1 mg vs. no warfarin Start 3 days before CVC insertion Outcome-Venogram with symptoms or at 90 days Conclusion- Low dose warfarin prevents CVC thrombosis P<0.001 Bern MM et al. Ann Intern Med 1990

Catheter Prophylaxis Study Regimen Outcome assessment DVT (%) P Value Bern et al. 1990 Warfarin 1 mg No treatment Venogram 9.5 37.5 <0.001 Monreal et al. 1996 Dalteparin 2500 6 62 0.002 Reichardt et al. 2002 Dalteparin 5000 Clinical 3.7 3.4 0.9 Couban et al. 2003 Placebo 4.6 4 0.81 Verso et al. 2004 Enoxaparin 40 mg 14.1 18 0.35

Adjusted dose warfarin prevents CVC thrombosis: WARP study A multicenter (N=68) open label study of warfarin CVC prophylaxis (N=1590) Study Arms- No warfarin (404) vs. warfarin 1 mg (408) Warfarin 1 mg (471) vs. warfarin (INR1.5-2.0) ( 473) Conclusion- Dose-adjusted warfarin is required to prevent CVC DVT P=0.002 Young AM, et al. Lancet 2009

Elevated INR- Less vitamin K is more 70 year old man taking warfarin for atrial fibrillation has an INR of 7. He does not have any signs of bleeding. What should you do? Hold warfarin and administer vitamin K 2.5 mg po Hold warfarin and administer vitamin K 2.5 mg IV Hold warfarin and recheck INR in 1-2 days Hold warfarin and administer Vitamin K 2.5 mg and 3 units of FFP

Less vitamin K is more safe RCT of vitamin K 1.25 mg or placebo for pts. with INR 4.5-10 Setting- 14 AC clinics in US, Canada, Italy Outcomes- Symptomatic bleeding or thromboembolism within 90 days Conclusion- Oral Vit K does not improve outcomes with INR 4.5-10 Crowther MA et al. Ann Intern Med 2009

Is less is more? 72 year old man with atrial fibrillation who has been on warfarin 5 mg daily for 3 months. Today his INR is 1.8. No reason identified. What should you do with his warfarin dose? Increase his dose to 7.5 mg MWF, 5 mg ROW (21% dose increase), recheck 1 week Increase his dose to 7.5 mg daily (50% dose increase), recheck 1 week Increase his dose to 7.5 mg W, 5 mg ROW (7% dose increase, recheck 1 week Continue same dose, recheck 1 week

Less dose adjustment=more time in range Observational study of warfarin management Setting- 94 AC clinics, 3961 patients Outcome- Time in therapeutic range Conclusion- Excessive warfarin dose changes lead to poorer INR control Rose AJ et al. J Thromb Haemost 2009

Is less LMWH more? A 65 year old man with an atrial fibrillation (CHADS2 score 3) who has been on warfarin for 4 months has an INR of 1.5. Your nurse asks you for advice. You suggest… LMWH + warfarin dose increase Warfarin dose increase only

Less LMWH is safe Retrospective study of patients in Kaiser CO AC clinics Low INR and therapeutic INR groups Only 13 patients received LMWH Outcomes- Bleeding and TE at 90 days Conclusion- LMWH not necessary for most patients with low INR Clark NP et al. Pharmacother 2008

Conclusions Anticoagulation is not indicated for recurrent early pregnancy loss except perhaps APS Therapeutic AC should be used sparingly in the post-operative period Setting rather than presence of thrombophilia dictates duration of therapy Risk stratification models can help determine the risk of recurrent VTE and bleeding in patients with idiopathic VTE Central venous catheter prophylaxis remains of unproven benefit Studies continue to optimize warfarin management

Questions ?