Judicious Use of Anticoagulation A CaseBased 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 ID: 764414
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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 Bristol-Myers Squibb NIH/NHLBIConsultingSanofi-aventisEisai, Inc. Daiichi-SankyoJanssen HealthcareBiO2 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 LMWHStart prophylactic dose LMWH + Aspirin 100 mgStart no antenatal prophylaxis
LMWH does not improve pregnancy outcomes: The ALIFE Study Placebo (N=121) Aspirin 80 mg (N=120) Aspirin 80 mg + Nadroparin 2850 IU (N=123) Completed Study (N=103) Completed Study (N=97) Completed Study (N=99) 364 women with at least 2 pregnancy losses Kaandorp S et al. NEJM 2010
Baseline characteristics Characteristic Aspirin + LMWH (N=123) Aspirin (N=120)Placebo (N=121)Age (yrs.)34±533±534±5Previous 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%)Thrombophilia13 (12%)17 (17%) 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 alonePMHx ≥ 2 losses 24 weeks or lessBegin 7 weeks gestation or lessConclusion- Prophylactic AC does not improve pregnancy outcomesN=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 ratesMak A et al. Rheumatol 2010 RR 1.3
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-op36 hours post-op72 hours post-op
Perioperative AC- Is less more? Metanalysis of 34 studies of 12,278 patients Outcomes- Thromboembolism and Bleeding Limitation- Lack of RCTConclusion- Value of perioperative bridging unclearSiegal D et al. Circulation 2012
Less is more for perioperative AC Prospective Cohort of 1262 patients Low risk- AVR w/o Afib-prophylactic LMWHHigh 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 FibrillationMechanical ValveVenous ThromboembolismHighCHADS2 score 5 or 6Any Mitral valveOlder valve (Caged-ball, Tilting disk) Recent stroke/TIA Recent (within 3 mos.) VTE Severe thrombophilia Intermediate CHADS 2 score 3 or 4 Bileaflet Aortic valve + TE risk factors VTE within 3-12 mos.Recurrent VTE, Active CancerNon-severe thrombophilia LowCHADS 2 score 0-2Bileaflet 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 ProceduresCholecystectomyAbdominal hysterectomyGI Endoscopy ± biopsy or stentPacemaker insertion, EP testingDental extractionsCarpal tunnel repairDilatation/currettageSkin Cancer excisionAbdominal herniaHydrocele repair Cataract surgery Bronchoscopy ± biopsy Central Venous Catheter removal Skin, Thyroid, Breast, Lymph node biopsy Cardiac surgery Abdominal aneurysm repair Neurosurgery Urologic surgeryHead and Neck surgeryHip/knee replacementBack surgery Kidney biopsyPolypectomy/sphincterotomyTransurethral prostate resection General surgery Vascular surgeryAny major surgery (> 45 minutes)Spyropoulos AC and Douketis JD Blood 2012
AC Management Surgical Bleeding risk Pre-operationPost-operationLowLast dose LMWH 24 hours beforeResume LMWH 24 hours post-op if hemostasis adequateStart warfarin with LMWHHigh Last dose LMWH 24 hours before Resume LMWH 48-72 hours post-op if hemostasis adequate or start prophylactic dose 24 hours post-op or avoid LMWH Start warfarin with 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 months12 monthsIndefinite
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 months12 monthsIndefinite
Do the Results of Thrombophilia Tests Help to Determine Duration of Therapy? HR 1.5 (0.8-2.8) (N= 570)24 mos. (N=474) 84 mos. (N=267) 46 mos. (N=1626) 50 mos. HR 1.4 (0.9-2.2) HR 1.8 (1-3.1) HR 2.0 (1.5-2.7) Recurrent VTE (%)
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 thrombophiliaFactor 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 thrombophiliaFactor 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 P=0.0013
VTE recurrence rate varies depending upon initial trigger for the event Time after cessation of therapy (months) Cumulative recurrent VTE (%) Baglin T et al., Lancet 2003 N = 570
VTE Setting influences recurrence risk Systematic review of prospective cohort studies and RCTs 15 Studies 5159 SubjectsFollow up- 3-96 monthsConclusion- Setting of thrombosis strongly influences recurrence rateIorio 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 yearsSystematic Review (Verhovsek M et al. Ann Intern Med 2008)7 studies, 1888 patientsRecurrent 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 collectedMultivariate analysis used to develop clinical prediction rule for recurrent VTEResultsF/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 Eichinger S et al. Circulation 2010 http://www.meduniwien.ac.at/user/georg.heinze/zipfile/ViennaPredictionModel.html
Indefinite Anticoagulation: Weighing the risks Thrombosis Bleeding
Assessing Bleeding Risk: The HAS-BLED Score HASBLED Hypertension (uncontrolled SBP>160) = 1 point Abnormal renal/liver function = 1 or 2 pointsStroke = 1 pointBleeding (or anemia) = 1 pointLabile INRs (TTR<60%)= 1 pointElderly (Age > 65 years)= 1 pointDrugs 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 dailyEnoxaparin 40 mg dailyDalteparin 5000 units dailyNo 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 daysConclusion- Low dose warfarin prevents CVC thrombosisBern MM et al. Ann Intern Med 1990 P<0.001
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 No treatment Venogram 6 62 0.002 Reichardt et al. 2002 Dalteparin 5000 No treatment Clinical 3.7 3.4 0.9 Couban et al. 2003 Warfarin 1 mg Placebo Clinical 4.6 4 0.81 Verso et al. 2004 Enoxaparin 40 mg Placebo Venogram 14.1 18 0.35
P=0.002 Young AM, et al. Lancet 2009 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 Adjusted dose warfarin prevents CVC thrombosis: WARP study
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 poHold warfarin and administer vitamin K 2.5 mg IVHold warfarin and recheck INR in 1-2 daysHold 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 daysConclusion- Oral Vit K does not improve outcomes with INR 4.5-10Crowther 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 weekIncrease his dose to 7.5 mg W, 5 mg ROW (7% dose increase, recheck 1 weekContinue 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 controlRose 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 LMWHOutcomes- Bleeding and TE at 90 daysConclusion- LMWH not necessary for most patients with low INRClark 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 therapyRisk stratification models can help determine the risk of recurrent VTE and bleeding in patients with idiopathic VTECentral venous catheter prophylaxis remains of unproven benefitStudies continue to optimize warfarin management
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