Disclosures. The Yin and Yang of Clotting and Anticoagulation: VTE Management in A New JCAHO Era. Objectives

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1 The Yin and Yang of Clotting and Anticoagulation: VTE Management in A New JCAHO Era Kathryn Hassell, M.D. Professor of Medicine Division of Hematology University of Colorado Denver Health Sciences Center Disclosures No commercial conflicts of interest However, served as a member of the National Quality Forum s national Technical Advisory Panel Objectives Review the National Patient Safety Goal of the Joint Commission In that light, review the practical principals of Diagnosis of DVT and PE Acute Management of DVT and PE Initiation of Chronic Anticoagulation Address specific challenging situations Clotting despite anticoagulation Diagnosis of heparin-induced thrombocytopenia Introduce the (coming) new oral anticoagulants

2 What s Not Covered (Further) Use of thrombolysis Likely reduces post-thrombotic syndrome and anecdotally (but not systematically) saves lives Use of LMWH Which one? Doesn t matter except enoxaparin 1.5 mg/kg q 24 hours may not be enough Obesity: don t cap the dose Renal dysfunction: avoid if GFR<20 ml/min Cancer and Pregnancy: LMWH > warfarin Hypercoag testing: Don t exceptions will be discussed Eighth ACCP Consensus Guidelines Chest 133(6), Supplement June 2008 All bleeding stops

3 If it bleeds, we can kill it! NPSG 3E Anticoagulant Therapy Requirement: Reduce the likelihood of patient harm associated with the use of anticoagulation therapy. Rationale: Anticoagulation is a high risk treatment, which commonly leads to adverse drug events due to the complexity of dosing these medications, monitoring their effects, and ensuring patient compliance with outpatient therapy. The use of standardized practices that include patient involvement can reduce the risk of adverse drug events associated with the use of heparin (unfractionated), low molecular weight heparin (LMWH), warfarin, and other anticoagulants. Implementation Expectations for 3E 1. The organization implements a defined anticoagulant management program to individualize the care provided to each patient receiving anticoagulant therapy. 2. To reduce compounding and labeling errors, the organization uses ONLY oral unit dose products and pre-mixed infusions, when these products are available

4 Implementation Expectations for 3E 3. The hospital uses approved protocols for the initiation and maintenance of anticoagulation therapy appropriate to the medication used, to the condition being treated, and to the potential for drug interactions. M D 4. For patients being started on warfarin, a baseline International Normalized Ratio (INR) is available, and for all patients receiving warfarin therapy, a current INR is available and is used to monitor and adjust therapy. Implementation Expectations for 3E 5. When dietary services are provided by the organization, the service is notified of all patients receiving warfarin and responds according to its established food/drug interaction program M 6. When heparin is administered intravenously and continuously, the organization uses programmable infusion pumps. Implementation Expectations for 3E 7. The organization has a policy that addresses baseline and ongoing laboratories tests that are required for heparin and low molecular weight heparin therapies. D 8. The organization provides education regarding anticoagulation therapy to prescribers, staff, patients, and families. M NOTE: Patient/family education includes the importance of follow-up monitoring, compliance issues, dietary restrictions, and potential for adverse drug reactions and interaction.

5 Implementation Expectations for 3E 9. The organization evaluates anticoagulation safety practices (medical management plan as per MM.8.10) Objectives Review practical aspects of the diagnosis of DVT and PE Diagnosis of VTE Imaging is the mainstay SEE THE CLOT When to image: clinical prediction models Likely setting for VTE e.g. they re in the hospital! Clinical findings, in absence of a better explanation When NOT to image: (-) D-dimer testing Positive test is NOT a justification for imaging Validity on anticoagulation not well established

6 Diagnosis of VTE: Delay in Imaging Empiric anticoagulation should be given when until imaging is available Remember half-life of drug if using s.q. therapy Enoxaparin, UFH given every 12 hours Dalteparin, Fondaparinux given every 24 hours (Enoxaparin every 24 hours in selected subsets) Assure prompt follow-up for outpatients The Shadow of NQF/CMS National Quality Forum (NQF) now lists VTE after hip/knee surgery as a never event Medicaid/Medicare may not pay for VTE care Should drive appropriate prophylaxis Imperfect at best!! Be really sure it s a clot Objectives Review practical aspects of acute treatment of DVT and PE

7 Treatment of VTE Treatment is HEPARIN, not warfarin Minimum time is 4-5 days Binds activated factors, preventing clot propagation Warfarin does not control activated factors After 5-7 days of administration, reduces pool of activatable factors to 25-30% Unaffected factors can still be activated and contribute to active thrombosis Minimum overlap: 24 hours with INR>2.0 Antithrombotic Choices Acute treatment Unfractionated heparin i.v. or s.q. Low molecular weight heparin s.q. Enoxaparin (Lovenox) Dalteparin (Fragmin) Tinzaparin (Innohep) Fondaparinux (Arixtra) s.q. Chronic treatment: Warfarin p.o. The Heparin Family All work through antithrombin (III) N-acetyl glucosamine 6-O-sulfate Glucuronic acid N-sulfated glucosamine 3,6-O-disulfate Iduronic acid 2-O-sulfate N-sulfated glucosamine 6-O-sulfate UFH LMWH PENTASACCHARIDE (Fondaparinux)

8 Antithrombotic Characteristics Drug UFH (sq q 8-12 hrs) LWMH (sq q hrs) Fondaparinux (sq q 24 hrs) Warfarin (po q day) Duration of effect 8-12 hrs hrs 24 hrs hrs Renal clearance? No Yes (>30 ml/min) Yes (>30 ml/min) No Reversal Protamine ±Protamine (40-70%) None (VIIa conc?) FFP Vitamin K Implementation Expectations for JCAHO The hospital uses approved protocols for the initiation and maintenance of anticoagulation therapy appropriate to the medication used, to the condition being treated, and to the potential for drug interactions. M D Considerations: 1. Heparin nomogram 2. Orders written q12 or q24, not BID or q day for LMWH Implementation Expectations for JCAHO The organization has a policy that addresses baseline and ongoing laboratories tests that are required for heparin and low molecular weight heparin therapies. D Considerations: 1. Baseline laboratory studies (aptt, PT/INR, platelet count; creatinine for LMWH) 2. Platelet monitoring protocol

9 Eighth ACCP Consensus Conference If risk of HIT is >0.1%, platelet count monitoring is recommended Heparin Use Therapeutic UFH Therapeutic LMWH Risk of HIT 1% 0.1-1% Recommendations (Grade 2C) at least every 2-3 days until day 14 or until UFH stopped it may be impractical to obtain monitoring, less frequent (or none) may be appropriate With start of UFH or LMWH in patients who have received heparin in the last 100 days Check platelet count at baseline Check platelet count at 24 hours after first dose If acute systemic reaction occurs, check platelet count immediately Warkentin and Grienacher, Chest 133: S, 2008 Treatment of DVT/PE Recurrent DVT/PE Major Bleed Drug/Dose LMWH UFH LWMH UFH Enoxaparin 5.3% 6.7% 2.0% 1.2% (1 mg/kg q 12 hrs) Dalteparin 4.9% 2.9% 3.9% 1.9% (200 U/kg q 24 or 100 U/kg q 12 hrs) Tinzaparin 2.8% 6.9% 0.5% 5.0% (175 U/kg q 24 hrs) Fondaparinux 3.8% 5.0% 1.3% 1.1% (5, 7.5, or 10 mg q 24hrs) UFH S.Q. 3.4% 3.8% 1.4% 1.1% (333 U/kg first dose, then 250 U/kg q 12 hrs) Kearon, JAMA 296:935, 2006 Outpatient Management of VTE Patients still need daily follow-up for INR to assess/adjust warfarin Advise patients of 5% recurrence risk, 1-2% major bleeding risk, 0.5% mortality Includes deaths during first week of therapy in PE (and some DVT) studies

10 Other Acute Management Considerations Conversion from iv heparin to LMWH: give s.q. injection and turn off drip at same time Start warfarin on same day as heparin 3-4 hours after first s.q. LMWH After documenting therapeutic aptt for iv heparin Objectives Review practical aspects of initiation chronic anticoagulation for VTE Anticoagulation with Warfarin Mechanism Suppresses production of carboxylated ( sticky ) factors Does not treat active clotting Dosing: start with excepted daily dose Commonly 5 mg/day Loading of unclear benefit, potential harm Still need 5 days of heparin Need to establish stable dosing

11 Effect of Warfarin on Factor Activity Factor VII Factor IX Factor X Factor II 100 Factor activity (%) Days Therapeutic INR once ALL factors suppressed Effect of Warfarin on Factor Activity Factor activity (%) Factor VII Factor IX Factor X Factor II Protein C Protein S Days Protein C and protein S fall before all procoagulant factors transient HYPERcoagulable state Pharmacogenetics and Warfarin Genetic polymorphisms may affect warfarin metabolism and effects CYP2C9 converts to more potent S-enantiomer *2 and *3 associated with lower doses, more bleeding VKORC1 is the enzyme inhibited by warfarin 1173TT associated with lower doses, more bleeding Awareness of genotype of no proven benefit for anticoagulation management Limdi, Pharmacotherapy 28:1084, 2008

12 Pharmacogenetics and Warfarin Two prospective randomized studies Shorter time to goal INR Most driven by aggressive dosing in those with wild-type genes (not those with the variants) No difference in % of INRs within range No consistent difference in bleeding complications Ongoing randomized study of 2000 subjects may clarify a role for testing Caraco, Clin Pharmacol Ther 83:460; Anderson, Circulation 116:2563 Implementation Expectations for JCAHO For patients being started on warfarin, a baseline International Normalized Ratio (INR) is available, and for all patients receiving warfarin therapy, a current INR is available and is used to monitor and adjust therapy. Considerations: 1. Baseline INR if new start 2. INR monitoring even if admitted on warfarin Implementation Expectations for JCAHO The hospital uses approved protocols for the initiation and maintenance of anticoagulation therapy appropriate to the medication used, to the condition being treated, and to the potential for drug interactions. M D Considerations: Documentation of sufficient overlap between acute therapy (heparin) and warfarin

13 Implementation Expectations for JCAHO The organization provides education regarding anticoagulation therapy to prescribers, staff, patients, and families. M Considerations: Patient/family education includes compliance issues dietary advice follow-up monitoring arrange appt for first outpt INR potential for adverse drug reactions and interactions Warfarin and Vitamin K Abstinence from vitamin K not possible and ill-advised Consistency more than content is most helpful Try to achieve daily RDA (1 ug/kg) Labile INRs may be stabilized by vitamin K supplementation Once daily supplement 150 ug vs. placebo 16% increase in warfarin dose with vit K 2-fold _ in SD of INR ( stabilized ) in 33/35 Sconce, Blood 109:2419, 2007 Chronic Anticoagulation Minimum duration: 3 months Avoid interruption especially within 1 st month, if possible for all 3 months Aggressive bridging if interruption unavoidable Unclear if longer is better Often big DVTs treated for 6 months Often PE treated for 6-12 months Goal INR 2-3

14 Challenging Situations Clotting Despite Anticoagulation (Warfarin) 38 year old discharged last week with DVT on LMWH and warfarin; presents with worsened leg swelling just like the first DVT INR = 2.8 Ultrasound = partially recannulized clot?distal propogation Anticoagulation Failure? Actually not a new thrombosis Symptoms cannot be used to diagnose a new thrombosis A positive D-dimer does NOT mean there is active thrombosis A negative D-dimer may not rule-out thrombosis in present of anticoagulation Uncertainty with imaging Old vs. new thrombosis Solution: resist the temptation to assume Failure to Anticoagulate IS NOT Anticoagulation Failure

15 Failure to Anticoagulate INR on day of diagnosis of thrombosis of unclear significance Thrombosis likely began to form before patient presents with symptoms Rapid change in FVII _ rapid change in INR May reflect extra doses or return to compliance after symptoms started, rather than true degree of anticoagulation at time thrombosis started Consumption of factors with acute thrombosis Solution: careful, gently persistent history-taking Failure to Anticoagulate Failure to adequately overlap heparin and warfarin therapy Minimum duration of heparin (-like) therapy: 5 days INR should be >2.0 for at least 24 hours before stopping heparin (-like) therapy Solution: appropriate use of anticoagulation Limitations of Vitamin K Antagonism (Warfarin) Some failure expected at therapeutic INR Br J Cardiology 10:370 Increase in thrombotic risk with relatively modest fall below therapeutic range Mayo Clin Proc 79:904

16 Challenging Situations Clotting Despite Anticoagulation (Warfarin) If truly a new thrombosis despite therapeutic INR, then switch to LMWH Consider reversing warfarin if INR high If truly a new thrombosis despite subtherapeutic INR Still need to treat new thrombosis with heparin/heparin-like agent for 5 days Stop only when INR therapeutic x 24 hrs. Challenging Situations Clotting Despite Anticoagulation (Heparins) 68 year old admitted for last week for CHF and DVT (significant pain precluded discharge, ESRD prevented LMWH use). On iv UFH, leg not better and develops new hypoxia, SOB, chest pain aptt = sec over last week V/Q scan = moderate probability for PE Failure to Anticoagulate aptt of seconds may not represent therapeutic heparin effect Therapeutic range varies per heparin lot, lab reagents and instrumentation Lab should standardize against standard heparin curve Heparin contamination in sample Line draws: Don t Marked elevated in Factor VIII may shorten aptt Most common example: pregnancy Baseline aptt may be altered Lupus anticoagulant phenomenon Solution: measure heparin (anti-xa) level

17 Failure to Anticoagulate Unmonitored LMWH Dosing is every 12 or 24 hours, NOT BID or q day Inappropriate orders/completion of orders Skipped/delayed dose Relative heparin resistance missed Solution: measure heparin (anti-xa) level at peak e.g. 3-4 hours after last dose LMWH Monitoring: Heparin Assay Levels drawn 3-4 hours after subcutaneous dose Test method Prophylaxis Treatment Chromogenic Low risk: U/ml High risk: Monitoring recommended in pregnancy, with renal insufficiency or obesity Meaning of anti-xa levels for fondaparinux unclear Harenberg, Sem Thromb Hemost, 19:79, 1993 Once-daily enoxaparin less effective in obesity and cancer 900 pts with DVT (32% also had confirmed PE) Enoxaparin UFH 1.5 mg/kg/day 1.0 mg/kg BID Number of pts Recurrent VTE 4.3% 4.4% 3.1% Major bleeding 2.1% 1.7% 1.3% Recurrent VTE Cancer pts 6.7% 12.2% 6.4% Obesity 2.5% 7.3% 3.4% Merli, et al, Ann Intern Med 134:191, 2001

18 Limitations of Subcutaneous Heparins Next dose J Invasive Card 15:536 Anti-Xa levels fall out of the therapeutic range 9-10 hours after a subcutaneous dose Challenging Situations Clotting Despite Anticoagulation (Heparins) If truly new thrombosis despite heparin: Check anti-xa level Consider heparin-induced thrombocytopenia If not HIT, and truly new thrombosis Despite appropriate LMWH: switch to iv UFH Despite therapeutic iv UFH: panic Consider i.v. direct thrombin inhibitor Maybe, maybe consider an IVC filter IVC Filters Recommended if anticoagulation fails e.g. i.v. heparin fails to control thrombosis 10%-43% risk of venous thrombosis at site of insertion (without anticoagulation) Long-term impact of IVC filters (h/o DVT): Time Recurrence Filter No Filter Day 12 PE 1.1% 4.9% Year 2 PE DVT 3.4% 20.9% 6.3% 11.9% Year 8 PE DVT 6.2% 35.7% 15.1% 27.5%

19 True Anticoagulation Failures Cancer: a topic for another day Multiple impacts on clotting system described Antibody-Mediated Hypercoagulable States Antiphospholipid Antibody Syndrome (APS) Heparin-Induced Thrombocytopenia (HIT) Laboratory Criteria for APS Immune therapy for clotting despite anticoagulation Mod-High Titer Anticardiolipid Antibodies (ACA) IgG, IgM Lupus anticoagulant (LA) -at least 2 methods Mod-High Titer β 2 glycoprotein-1 Antibodies (β 2 GP-1) IgG, IgM Classic HIT 1. Thrombocytopenia 50% drop in platelet count from baseline onset 5 14 days after starting any dose, any type, or any route of heparin exposure 2. Exclusion of other causes of thrombocytopenia 3. With or without thrombotic complications plus A positive serologic test for HIT

20 HIT and Seroconversion Exposure to heparin results in antibody formation without clinical HIT (<2% HIT reported in these situations): Adult by-pass Pediatric by-pass Ortho prophylaxis (UFH) Ortho prophylaxis (LWMH) Med prophylaxis (UFH) Neurology prophylaxis (UFH) PCI (cath-ufh) Chronic hemodialysis Vascular surgery ED for chest pain/vte (in hosp in last 6 months) 50% % 15% 8% 3% 20% 12% 12% 32% 6.9/9.2% Blood 96:1703 Anesth Analg 107:371 Blood 96:1703 Blood 96:1703 Blood 101:2955, 2003 Neurology 62:657, 2004 Thromb Res 115:475, 2005 Kidney Int 73:713, 2008 J Vasc Surg 48:377 Am J Emer Med 25:279 HIT and Seroconversion HIT antibodies can develop in ABSENCE of heparin exposure ED patients who had not been to the hospital in the last 6 months Having chest pain: 6.9% ELISA positive Having other thrombosis: 4.7% ELISA positive Am J Emerg Med 25:279, 2007 APS patients without history of heparin exposure 9% of apl (+) SLE patients HIT ELISA positive Ann Rheum Dis 67:395, 2008 Spontaneous HIT reported acute systemic rxn Am J Med 121:632, Time Course for HIT Classic HIT HIT with Reexposure Unlikely HIT _ _ Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

21 Fall Timing Pre-Test Probability of HIT High: 6-8 Moderate: 4-5 Low: 0-3 Thrombocytopenia Nadir (x10 9 /L) Recent heparin No prev heparin Thrombosis, ASR, skin lesions Other cause for _ plt Points (0, 1, or 2), Maximum = >50% 1 dy 5-10 dys New event after heparin None % 1 dy Unclear or >10 dys Progressive or possible new thrombosis/event Possible 0 <10 <30% 4 days None Definite Diagnosis of HIT 100 consecutive cases evaluated for HIT Definition Classic Liberal Modified conservative EIA-GTI OD EIA-IgG OD 0.45 Not considered Not considered SRA % release 50% Not considered Not considered 4T Pretest category Intermediate or high Low, intermediate or high Intermediate or high Amer J Hematol 81:1037, 2007 Diagnosis of HIT 100 consecutive cases evaluated for HIT Definition Treated Alternative SRA + Thrombosis Bleeding Classic (n=16)* 100% 100% 68.8% 0% Liberal (n=16) 50% 6.3% 6.3% 18.8% HIT test negative (n=68) 50% 0% 7.4% 16.2% *If use modified criteria (OD>1.2) _ identify the same 16 as classically defined, but don t need SRA Potential for 100% over-diagnosis if use a weakly positive EIA to confirm and ignore pretest probability Amer J Hematol 82:1037, 2007

22 Objectives Introduce the (coming) new oral anticoagulants New Oral Anticoagulant Agents DRUG ACTION HALF-LIFE VTE DOSING Rivaroxaban FXa Inhibitor 9 hrs 20 mg q day Apixaban FXa Inhibitor 9-14 hrs mg BID Dabigatran Etexilate Thrombin Inhibitor hrs 150 mg BID No monitoring (but drug interactions can occur) No sustained effect (missed dose _ loss of effect) Renal clearance (GFR<50-60 ml/min affect half-life) Irreversible effect (no antidote) Gross and Weitz, Arteriscler Thromb Vasc Biol 28:380, 2008 Summary Treatment of VTE has been well-studied and standardized JCAHO will now enforce appropriate practice Complications occur if it s not done right Atypical and challenging situations occur Few studies provide guidance; still the art of medicine built on basic principals New anticoagulants will solve some old challenges but create/emphasize new ones