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Hypercoagulability and Duration of Anticoagulation: How Long is Long Enough? Kathryn Hassell, MD Professor of Medicine Division of Hematology University of Colorado Denver
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Montrose Duration 2014

Jun 12, 2015

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•Assist patients with decision-making about duration of anticoagulation by providing information about:
– risk of recurrent venous thrombosis
– risk of complications of therapy (bleeding)
•Decide if hypercoagulabile testing will be useful for a patient
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  • 1. Hypercoagulability andDuration of Anticoagulation:How Long is Long Enough?Kathryn Hassell, MDProfessor of MedicineDivision of HematologyUniversity of Colorado Denver

2. Disclosures No financial or other conflicts of interest Off label use: discussion not planned 3. Objectives Assist patients with decision-making aboutduration of anticoagulation by providinginformation about: risk of recurrent venous thrombosis risk of complications of therapy (bleeding) Decide if hypercoagulabile testing will be usefulfor a patient 4. 24 year old man with unprovoked PE.No bleeding problems, negative hypercoag testing.How long should he take anticoagulation? 3 months 6 months One year Lifelong 5. 19 year old woman with DVT while on OCPs for 3 years.No bleeding problems, Factor V Leiden positive.How long should she take anticoagulation? 3 months 6 months One year Lifelong 6. 45 year old man with history of 2 clots, (calf, popliteal),each after arthroscopy. No bleeding, negative testingHow long should he take anticoagulation? 3 months 6 months One year Lifelong 7. 60 year old woman with history of PE on tamoxifen formetastatic breast cancer. No bleeding, no testing.How long should she take anticoagulation? 3 months 6 months One year Lifelong 8. 64 year old man with history of PE after bladder cancersurgery 5 months ago. Too much bleeding to takeanticoagulation after surgery, but in your office now.How long should he start anticoagulation for his PE?If yes, for how long? 3 months 6 months One year Lifelong 9. Outline of Presentation Management of current VTE episode Duration of initial/acute therapy (e.g. LMWH) Duration of subsequent/chronic therapy Based on time (e.g. 3 vs. 6 months) Role of other factors (e.g. residual clot or symptoms) Impact of hypercoagulable tests Prevention of subsequent new episodes Balancing risk for recurrent clot vs. bleeding Role of factors which may impact estimate of risk Review major basic principles along the way 10. Principle of Acute Treatment Anticoagulation given to reduce the risk ofnew thrombosis Anticoagulation doesnt actively change an acutethrombus endogenous thrombolysis occurswhether or not someone is on anticoagulation Anticoagulation simply prevents new thrombosisfrom forming In areas of recannalization Extension beyond original 11. Treatment for Acute VTE Risk of no treatment for acute DVT or PE: Untreated PE fatal PE: 26% at 1 year Untreated proximal DVT fatal PE: 5% at 10 days,10% at 30 days No reduction in mortality with IVC filtersYoung, Cochrane Database Sys Rev 17:CD006212, 2010 Judged to be sufficiently high enough to create astandard to treat of all PE/proximal DVT (VTE)unless bleeding is likely to be life-threatening Guidelines favor treatment of even calf DVT 12. Eighth ACCP 2012 DVT or PE Acute Management Subcutaneous LMWH Intravenous or subcutaneous UFH Fondaparinux Rivaroxaban, Apixaban (FDA approved after theguidelines were developed) 13. Eighth ACCP 2012 DVT or PE Other Management Considerations Initiation of VKA (warfarin) on first day (if usingLMWH/heparin/fondaparinux) Continue LMWH/UFH until INR stable and 2.0 for at least 24 hours Treatment with LMWH/UFH for at least 5 days Switch to dabigatran after 5-10 days of LMWH 14. Initial Management of Thrombosis Acute intervention: 5 days of active therapy Active antithrombotic therapy (e.g. heparin/LMWH/neworal agents) Initiation of long-term maintenance (e.g. warfarin/neworal agents) Underlying thrombophilia does not impactselection or intensity of anticoagulation Heparin OK for AT def Warfarin OK for PC/PS deficienciesKearon, Current Opin Hematol 19:1, 2012 15. Warfarin-Induced Skin Necrosis VERY RARE As likely related to acquired/transient protein C/Sdeficiency as inherited state Not a contraindication to initiate warfarin Active anticoagulation(e.g. heparin) protectsagainst the initial furtherdrop in levels with warfarinCrowther, Arch Intern Med 159:46, 1999;Kearon, Current Opin Hematol 19:1, 2012 16. Management of Thrombosis Different INR intensity for APS? No104 patients with APS (Finazzi, J Thromb Haemost 3:848, 2005)2-3 >3Recurrent thrombosis 5.5% 11.1%All bleeding 14.6% 27.8%Major bleeding 3.6% 5.3%INR 2-3 iscurrent standard106 patients with APS (Crowther, NEJM 349:1133, 2003)2-3 3-4Recurrent thrombosis 3% 10.7%Per pt-yr 1.3% 4.1%Major bleeding 4 (19%) 3 (27%)Anticoagulation stopped 13 21 17. Duration of Treatment ForA Given VTE Episode For DVT/PE, 3 months appears to be theminimum time needed HR 1.52 (1.14-2.02) if treated only 1-1.5 monthsvs. 3 months or longerBoutitie, BMJ 342; d3036, 2011 Up to 40% recurrence if anticoagulationinterrupted during the first 3 months 100-fold increase in peri-operative VTE risk ifinterruption in the first monthKearon, NEJM 336:1506, 1997 18. Balancing Risks and Benefits Analysis of rate of fatal events and casefatality rates in the first 3 months on therapyEvent Rate of Fatal Event Case Fatality RateFatal PE 0.4% (0.3-0.6) 11.3% (8.0-15.2)Fatal bleed 0.2% (0.1-0.3) 11.3% (7.5-15.9)Carrier, Ann Intern Med 152:578. 2010Schulman, Sem Thromb Hemost 39:141, 2013 19. Principle: 3 Months of TimeNot 3 Months of Anticoagulation Adequacy of anticoagulation doesnt matterLeiden Thrombophilia Study (2003) 234 patients followed for recurrence afterstopping their anticoagulation Treated for 3, 6, or >6 monthsNo increase in long-term recurrence risk forthose who spent more time out of range No difference in recurrence risk based onduration of therapy, eitherGadisseur, J Thromb Hemostas 5:931, 2007 20. Are longer finite periods better? No evidence to indicate periods longer than 3months is helpful to reduce risk of recurrence Meta-analysis of 7 studies comparing 3, 6, 12, and27 months showed no difference is subsequentrecurrence after therapy stopped Included provoked, unprovoked, DVT and PE Some authors cite trend to increased recurrenceafter 3 vs. 6 months for unprovoked events: HR 1.39 (0.96-2.01)Boutitie, BMJ 342; d3036, 2011; de Jong, BJH 158:433, 2012 21. What if the clot isnt gone? Anticoagulation does not make the clot go away Complete residual occlusion can be asymptomatic DVT doesnt usually go away: e.g. DACUS Study After 3 months of therapy:66.8% had residual veinthrombosis (RVT) >40% of veindiameter The rest could still have clot,just lessSiragusa, Amer J Hematol 86:914, 2011 22. Residual Vein Thrombosis Conflicting evidence about the role of RVTpredicting recurrence (more later) No evidence staying on anticoagulation willimprove resolution of RVT Sustaining anticoagulation because of RVT doesntmake it go away, doesnt change outcomesPrandoni, Ann Intern Med 150:577, 2009 23. What if theres still symptoms? May not be related to residual thrombus Anticoagulation does not change the way the bloodflows; the blood is not thinner Factors are still present, they simply lack carboxylgroups (due to warfarin) or are bound by drug whenactivated (heparin/LMWH/new oral anticoagulants) Remember, anticoagulation doesnt promoteresolution of thrombosis The symptoms will not worsen off anticoagulationunless new clot forms 24. Post-Thrombotic Symptoms Rate of chronic PTS symptoms ~25% de Jong, BJH, 2012 Use of compression stockings: S.O.X. Trial Randomized controlled comparison of graded compressionstocking to placebo stockings (no significant pressureapplied) Started within a mean of 4 days, used up to 2 years 80% of subjects used more than 3 days/week No SAEs related to either stocking 2% had leg rash/itchingKahn, Lancet 383(9920):880, 2014 25. Post-Thrombotic Symptoms No difference between stockings in moderate/severePTS (14-16%), ulceration (3-4%), recurrent VTEKahn, Lancet 383(9920):880, 2014 26. Principles (But No Data) Some people choose to sustain anticoagulationhoping for: Continued recannulization/resorption of clot Symptom improvement with recannulization and/orcollateral formation Role of anticoagulation: prevent new thrombosisfrom undoing the gains made; NOT active therapy Duration individualized: continued until desiredimprovement attained or the best itll be 27. What if they havea hypercoagulable state? They HAVE a hypercoagulable state, asdemonstrated by their episode of thrombosis Most people dont ever clot (1:1000) Most people dont clot even when faced withprothrombotic risk factors Some people who clot with prothrombotic riskfactors may not even know they had a clot Does it matter if we give it a name? 28. An Example: Orthopedic Surgery Even without anticoagulation, only a subset clot, andfewer have symptoms those who do are different0 20 40 60 80 100ArthroscopyTHATKAHip FractureDistal DVT Proximal DVT PE6th ACCP Conf on Antithrombotic and ThrombolyticTherapy; Chest, 2001 29. Testing for ThrombophiliaTEST ABNORMAL RESULTFactor V Leiden (FVL) PresentProthrombin G20210A mutation (PGM) PresentProtein C*/Antithrombin activity* Low (99th %ile 2glycoprotein-1 IgG/IgM >99th %ile Clinical features which may predict thrombosis Other thrombotic risk factors (e.g. OCP use) Co-existent autoimmune disease Suspected but unproven (retrospective, conflicting data) ITP, valvular lesions, history of obstetrical complications,livedo rectiularisBarbhaiya and Erkan, Curr Opin Rheum 13:59, 2011 36. Recurrence Risk in APS Risk factors for thrombosis: History previous thrombosis: 5.4% per pt-yr asymptomatic: 0.95% per pt-yr ACA level >40 GPL: 6.12% per pt-yr 12 hrs) OR 3.6 if clinical VTE risk factors Mostly asymptomatic calf clot by imaging (1-2%) Risk of PE up to 4/million if >12 hour flightPhilbrick, JGIM 22:107. 2007; Kahn, Chest 141 (2)(Suppl):e195, 2012 45. Principle:Lower Risk After Provoked Events Assumes risk factor was transient Persistent malignancy associated with 20+% risk ofrecurrence in first year if anticoagulation stoppedde Jong, BJH 158:433, 2012 Re-use of estrogen-based OCPs after stoppinganticoagulation associated with 8-fold risk ofrecurrence Transdermal estrogen and progesterone-only NOTassociated with increase risk compared to nonusers Risk of recurrence in non-users: 5% in first yearVaillant-Roussel, Contracception 84:e23, 2011 46. Risk of Venous ThrombosisIncreases with AgeOverall risk = 1-2 in 1000/yearAGERISK OF THROMBOSIS200%) May double the risk of recurrence Elevation of other factors (IX, XI) may be weakpredictors of recurrence Current areas of interest: D-dimer Residual vein thrombosis 48. Role of D-Dimer in Predicting VTERecurrence Elevation in D-dimer does not indicate the presenceof an acute thrombosis The only diagnostic value is a negative result whichrules out an acute thrombosisWells, J Thromb Haemost 5 Suppl 1:41, 2007 However, measurement of D-dimer at least onemonth off anticoagulation may risk-stratify Negative D-dimer: 3.5%/year Positive D-dimer: 8.9%/yearVerhovsek, Ann Intern Med 149:481, 2008 Which kit? What is positive? Age adjusted? 49. Role of Residual Vein Thrombosis(RVT) in Predicting VTE Recurrence Inconsistent association of RVT with increased risk ofrecurrent VTE 4 studies suggest increase risk of ~2-fold 5 studies failed to find an associationKearon, Clin Chest Med 31:719, 2010 If there is an association, it likely represents asystemic biological - not mechanical - phenomenon 40-50% of recurrent events are on the opposite leg Difficult to standardize (definition, technique) 50. Combination of Stratifying Factors PROLONG: utilization of RVT and/or D-dimer toguide anticoagulation 619 subjects with first proximal DVT or PE treatedwith anticoagulation for at least 3 months D-dimer measured 30 days after discontinuation Normal D-dimer (n=310): no further anticoagulation Abnormal D-dimer: randomized No further anticoagulation (n=99) Resume anticoagulation for 18 months (n=81) Residual vein thrombosis assessed (as per previousstudy e.g. 2 mm in common femoral/popliteal vein)Cosmi, Eur J Endovasc Surg 39:356, 2010 51. Use of Stratifying Factors Impact on recurrence: D-dimer if anticoagulation discontinued: Normal: 10% (5.5/100 pt-yrs) Abnormal: 19% (12/100 pt-yrs) HR=2.1 RVT: no difference: 11% with vs. 13% withoutCosmi, Eur J Endovasc Surg 39:356, 2010 52. Bottom Line Principle If there were no clear precipitating factors, thelikelihood of recurrence VTE is ~20-25% at 2 years,~50% at 10 years Comparable to having APS, AT deficiency, or a male with afamily history and some other defined states Likely similar for people with persistent recognized riskfactors (e.g. cancer) The weaker the precipitating factor, the higher therisk of recurrence D-dimer might discern lower (higher?) risk group 53. Recurrence Risk on Anticoagulation Risk of recurrence on warfarin therapy Goal INR 2-3: 65-75), renal/liver disease, history of bleeding,anemia, hypertension, use of anti-plt agents, alcohol Studies often in atrial fibrillation (RIETE in VTE) None with sufficient predictive power todistinguish risk groups Low RIETE score may predict a very-low bleeding riskLoewen and Dahri, Amer J Hematol 90:1191, 2011 57. Clot-ability Scale: A Conceptual Model0 10050ME PT #1PREGNANCYPT #2PREGNANCYLONG-HAUL FLIGHT (?)AGEEveryone has number(inherited/acquired)We just cant measure it!WARFARINWARFARINWARFARINANTICOAGULATIONClinicalClottingClinicalBleeding 58. Duration of Anticoagulation:ACCP 2012 Minimum: 3 months for DVT or PE Provoked by transient risk factor = sufficient Unprovoked: favor extended over 3 months If bleeding risk is moderate or high, favor 3months over longer, even if 2nd unprovoked event If extended, annual risk assessment ofrisk/benefitKearon, Chest 141:e419S, 2012 59. What if they havemore than one clot? No evidence recurrent provoked events are worsethan a single provoked event Risk estimate of recurrence is the likely same Some data for multiple unprovoked events30% recurrence2.5 years of follow-upAdapted from Schulman, Am J Med 104:332, 1998Firstunprovokedevent,treated for6 months(n=412)Secondunprovokedevent14%6 monthsIndefinite 3% recurrence 60. Duration: A Review of Principles Anticoagulation does not make clot go away or theblood to flow better The body appears to need 3 months to stabilize thesituation (time, not days on drug) No evidence that more than 3 months is better, butcould reason that some might need more time toheal before potentially have new clots occur A decision to continue otherwise based on moreconcern about new clotting than bleeding 61. Deciding on Extended Anticoagulation Current literature endorses acceptable risk ofrecurrence of up to 5%/1 year or 15%/5 yearsKearon, J Thromb Heamost 8:2313, 2012 Individual should decide what level of risk is OK: Risk of recurrence clotting based on analysis of theinitial clotting event If unprovoked, risk is 25% at 2 years, 50% at 10 years Testing usually doesnt help, D-dimer might Anticoagulation doesnt cause bleeding, but unlucky ifyou have major bleeding while youre on it, because itmight be worse (0.5-2%/year) 62. Pushes off the edge:e.g. surgeryRisk OneThe closer to the edge you are,the less it takes to push you offNormal Risk1-2 : 1000ConceptualModelAnticoagulation 63. 24 year old man with unprovoked PE.No bleeding problems, negative hypercoag testing.How long should he take anticoagulation? 3 months 6 months One year Indefinite 64. 19 year old woman with DVT while on OCPs for 3 years.No bleeding problems, Factor V Leiden positive.How long should she take anticoagulation? 3 months 6 months One year Indefinite 65. 45 year old man with history of 2 clots, (calf, popliteal),each after arthroscopy. No bleeding, negative testingHow long should he take anticoagulation? 3 months 6 months One year Indefinite 66. 60 year old woman with history of PE on tamoxifen formetastatic breast cancer. No bleeding, no testing.How long should she take anticoagulation? 3 months 6 months One year Indefinite 67. 64 year old man with history of PE after bladder cancersurgery 5 months ago. Too much bleeding to takeanticoagulation after surgery, but in your office now.How long should he start anticoagulation for his PE?If yes, for how long? 3 months 6 months One year Lifelong 68. The True Right Answers?Anticoagulation should be given for as long asthe person feels the risks of having a newblood clot are higher or more worrisome thanthe risks/inconveniences of the therapy.