What we all Needs to Know about New and Old Anticoagulant and Antiplatelet Drugs. None related to this presentation 11/22/2012

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1 What we all Needs to Know about New and Old Anticoagulant and Antiplatelet Drugs Marvin A Wayne, MD, FACEP, FAAEM Associate Clinical Professor University of Washington, EMS Medical Director Whatcom County, Attending ED PeaceHealth St. Joseph Medical Center Bellingham, WA Objectives Review advantages / pitfalls of vitamin K antagonists / heparins Discuss uses and limitations of Direct Thrombin Inhibitors and Factor Xa Inhibitors Discuss uses and limitations of newer antiplatelet agents The Ideal Agent has 100% efficacy in preventing and/or treating thromboembolism is free of bleeding complications.can be administered either by mouth or by injection does not require dose adjustment in any situation Commercial Disclosures None related to this presentation Introduction Thromboembolic disease causes more deaths than breast cancer, prostate cancer, AIDS, and MVC combined Venous disease: anticoagulants Arterial disease: antiplatelet The Ideal Agent does not require monitoring of anticoagulant effect is cost effective has no unexpected toxicity is reversible if patient exsanguinating does not exist (not even close) 1

2 Vitamin K Antagonists Vitamin K Antagonists Vitamin K Antagonists Vitamin K-dependent Clotting Factors Name Function Half-life Protein C Anticoagulant 8 hours Protein S Anticoagulant 30 hours Factor VII Procoagulant 7 hours Factor IX Procoagulant 24 hours Factor X Procoagulant 36 hours Factor II Procoagulant 50 hours Vitamin K Antagonists Difficult to manage Monthly monitoring recommended Interact: foods rich in vitamin K Interact: hundreds of medications At any given time only ½ the people taking it are appropriately anticoagulated Warfarin: still the gold standard Essential for synthesis of procoagulant factors II, VII, IX, X Essential for synthesis of anticoagulant Proteins C & S Other coumarin derivatives same Do They Work? Yearly incidence of stroke in patients with atrial fibrillation ~5% ~5 x higher than population without atrial fibrillation Stroke rate reduced 2/3 by using oral anticoagulants Vitamin K Antagonists Must keep INR to be effective without risk of bleeding MVR For every one point in INR, risk of bleeding doubles 50% of patients outside range ~14% have INR >3.0 2

3 Concept of Bridging During first 2 3 days of VKA therapy rapid increase in INR Reflects only reduction of shorter half-life of factors VII and IX Clinically significant reductions of factors X and II take several days Advantages / Disadvantages Advantages and Disadvantages of VKAs Advantages Disadvantages Proven high effectiveness Monitoring of INR Therapeutic window known Antidote(s) established Long action: low thrombosis risk with poor compliance Drug interactions Food interactions Slow action onset High bleeding risk Major Bleeding: Vitamin K Withhold VKA ~1 week for INR to return to baseline Vitamin K: shortens to 24 hours Oral and subcutaneous: slow onset, unpredictable response IV: ~3/100,000 risk anaphylaxis, several deaths reported Concept of Bridging FII (prothrombin) has longest T½ Optimal potential of VKAs only after final clearance of factor II (50+ hours) Therefore bridge with heparin therapy for 4 5 days Major Bleeding Care in anticoagulation clinic: <2% Usual medical care: 4 5% Major Bleeding: FFP Need >1L FFP to reverse high INR down to ~1.5 Thawing takes 30 to 45 minutes Difficult to infuse quickly Small risk of transfusiontransmitted infection 3

4 Major Bleeding: FFP Normal INR , depending on your lab FFP will not reliably INR below ~1.7, as FFP itself has INR ~1.6 Below that point, patient needs normal temperature and good perfusion to drop INR further Major Bleeding: PCCs PCC (prothrombin complex concentrates): vitamin Kdependent factors ~25 x more concentrated than in FFP Volume required for reversal ~4% FFP volume Ideal dose adjusted to body weight and desired reduction of INR Major Bleeding: PCCs Major Bleeding: PCCs PCCs work!! Study #1: 10 hemorrhaging patients with median INR >20 May be contraindicated in DIC Many brands available worldwide USA: Beriplex and Octaplex After PCC: median INR to 1.1 at 30 minutes, bleeding stopped Study #2: mean INR 6.1 to 1.5 within 10 minutes of administration Major Bleeding: FVIIa Caution! Recombinant FVIIa may correct INR, since PT is most sensitive to reductions in FVII Gives false sense of security that bleeding diathesis is corrected Factors IX, X, and II all have T½ >3 times that of factor VII Heparins 4

5 Introduction Hepar: Greek, liver Extracted from pig intestines or cow lungs Unfractionated heparin (UFH) Low-molecular-weight heparins (LMWH) Heparinoids Introduction Bind to antithrombin (AT) Indirectly inactivate FIIa (thrombin) and FXa To lesser degree, inhibit FIXa, FXIa, and FXIIa Efficacy as selectivity for FXa LMWHs superior to UFH Introduction UFH binds to platelets, plasma proteins, macrophages, and endothelial cells Unpredictable response LMWHs have binding to these elements More predictable dose response Each LMWH is different Heparin and Bleeding Major bleeding in 0.8% of patients receiving full-dose UFH with low-dose SQ heparin LMWH may cause bleeding, but this finding not consistent Bleeding rates vary with product, indication, patient population, dose Heparin and Protamine Heparin and Protamine UFH infusion: steady state within 4-6 hours Stop infusion coagulation normalizes after 4 hours If necessary: protamine sulfate 1 mg per 100 units of UFH received in previous 2 hours Converts heparin stable salt Removed from body by reticuloendothelial system Binds preferentially to larger heparin molecules: not as effective in reversing LMWHs 5

6 Parenteral DTIs Direct Thrombin Inhibitors Come and Gone: Exanta Ximelagatran: oral DTI Did not require anticoagulant monitoring or dose adjustments More effective than or comparable to warfarin Post market: liver toxicity in 6% Discontinued in 2006 D = Dabigatran W = Warfarin D W All 1o outcomes MI Mortality Major bleeding ICH Net clinical benefits RE-LY End points (%) NNT / 150 bid INR 2 3 NNH Used during PCI or to treat / prevent thrombosis in patients with HIT Lepirudin (Refludan), bivalirudin (Angiomax), and argatroban Derivatives of leech saliva 2010: Pradaxa Dabigatran etexilate has single indication: to reduce risk of stroke in patients with nonvalvular atrial fibrillation Off-label uses to treat / prevent VTE with mixed results Beware!! Apparently does not affect Protein C / Protein S End Result Noninferior to warfarin when given 150mg twice daily Also studied was 110mg bid, but this dose not approved by FDA 6

7 Some Advantages No dose adjustment needed No monitoring required Rapidly absorbed: reaches serum peak in ~1 hour May eliminate heparin bridge ~80% excreted in urine T½ 12 to 17 hours b.i.d. dosing Some Disadvantages Rapidly deteriorates when open: discard unused after 60 days Cannot monitor anticoagulation TT and ECT demonstrate linear response, neither in widespread use INR of no value Normal aptt excludes significant anticoagulation Some Disadvantages Reversal Twice daily drug Short T½: forgetting more than one dose prothrombosis GI intolerance: D/Ced in ~10% Slight risk of MI Drug interactions, known/unknown Cost No antidote available No good studies If consumed within 2 hours of presentation activated charcoal (GOBSAT) Vitamin K: will not work Reversal Reversal FFP: won t work drug will inhibit thrombin in the transfused plasma Prolonged clotting times in patients taking dabigatran are reflection of thrombin inhibition and not a clotting factor deficiency Cryoprecipitate will not work rviia: animal studies suggest can reduce bleeding time and aptt, human evidence mixed PCC: improve clotting times, 4 factor better?thrombogenic DDAVP, aprotinin, tranexamic acid and aminocaproic acid do not work in rat models 7

8 Reversal Emergency dialysis can remove up to 62% of dabigatran at 2 hours Sticking a dialysis catheter in a patient who is over anticoagulated is scary Conclusion Jury still out HeartWire: 260 fatal bleeds in patients taking dabigatran How many fatal bleeds in patients taking VKAs during same period? Safety advisories issued in Japan, New Zealand, others Fondaparinux Factor Xa Inhibitor, Indirect Fondaparinux (Arixtra): only drug in category thus far Heparins indirect FXa inhibitors, but also inactivate FIIa Fondaparinux does not inhibit bound Factor Xa Seems to offer no advantages over standard heparins Reversal Long-term use limited by requirement of SQ injection Major bleeding at about same rate as seen with patients treated with LMWHs Protamine not effective to reverse Factor Xa Inhibitor Direct 8

9 Direct FXa Inhibitors xabans act directly on FXa without using AT as mediator Currently available: Rivaroxaban (Xarelto ) Under study: apixaban (Eliquis), betrixaban, edoxaban, otamixaban Rivaroxaban (Xarelto ) Oral, direct, reversible, rapid, dose-dependent Works on free FXa / bound FXa Rapid absorbed peak plasma concentrations in hours T½ 6 to 7 hours dosed b.i.d. Rivaroxaban (Xarelto ) Indication #1: prophylaxis of DVT in patients undergoing knee or hip replacement surgery Indication #2: reduce risk of stroke in patients with nonvalvular atrial fibrillation Same as dabigatran (Pradaxa) R = Rivaroxaban W = Warfarin ROCKET AF 1o outcomes (noninferiority) R W P NNT < Non-CNS embolism Vascular death / stroke / CNS embolism Ischemic stroke Reversible? rfviia seems to partially reverse rivaroxaban in both human and rats, but thus far only abstracts PCC in healthy subjects given drug immediate reversal of prolonged PT protein bound no dialysis Lab Studies? Exert effects at junction of coagulation pathways prolong both PT and aptt PT can show some linearity, but INR system is not recommended aptt also prolonged, but even less sensitive than PT ECT and TT not affected 9

10 Aspirin NSAIDS (lesser degree) Clopidogrel (Plavix) ADP receptor Prasugrel (Effient) inhibitors Ticagrelor (Brilinta) Ticlopidine (Ticlid) Phosphodiesterase Cilostazol (Pletal) inhibitors Glycoprotein IIB/IIIA Abciximab (ReoPro) inhibitors Eptifibatide (Integrilin) (Intravenous only) Tirofiban (Aggrastat) Adenosine reuptake Dipyridamole inhibitors (Persantine) COX-1 Anti-Platelet Agents Aspirin PO immediately absorbed Irreversibly binds to COX-1 PLT life span 8 to 10 days Normal bone marrow releases about 10% of its PLT daily Stop ASA for 2 days 50,000/ L functionally adequate PLT Aspirin Spontaneous bleed rare with functional PLT >20,000/ L Significant bleeding can occur in trauma and surgery with counts of 20,000/ L 50,000/ L Clinical resistance in ~10% to 30% NSAIDs ADP Receptor Inhibitors NSAIDs bind to COX-1 reversibly for only 6 to 8 hours and are not considered antiplatelet agents NSAID ingestion several hours prior to ASA ineffective Prevent binding to and activating GP IIb/IIIa receptors Ticlopidine (Ticlid): first ADP receptor inhibitor risk of TTP and neutropenia, so seldom used COX-1 receptors temporarily occupied by NSAID 10

11 Clopidogrel Clopidogrel Clopidogrel (Plavix): prodrug metabolized by cytochrome P450 Daily dose of 75 mg shows effects within 24 hours, but maximal effect not reached for 4 to 7 days Loading dose of 300 to 600 mg shows effect within 2 to 4 hours C = Clopidogrel P = Placebo C P NNT outcome CV death MI Stroke Refractory ischemia Major bleeds Life-threatening bleed NNH PCI CURE Any 1o CHARISMA C + ASA P + ASA P NNT 371 (4.8%) 374 (4.8%) (3.1%) 229 (2.9%) MI (nonfatal) 147 (1.9%) 159 (2.0%) Ischemic CVA (nonfatal) 132 (1.7%) 160 (2.1%) CVA (nonfatal) 149 (1.9%) 185 (2.4%) Hospital for USA, TIA, revascularize 866 (11.1%) Death from any cause Death from CV cause 957 (12.3%) Clopidogrel in Unstable Angina to Prevent Recurrent Events: unstable angina without STelevation but with dynamic EKG changes and / or troponin elevation clopidogrel in addition to aspirin for 3 to 12 months PCI CURE Not So Sick Patients in CURE and PCI-CURE were sick What if they re not so sick? Stopping clopidogrel Discontinuation causes major increases in stent occlusion >30 x occlusion rate when clopidogrel is discontinued within 6 months of insertion of a drug-eluting stent 6x occlusion rate when discontinued beyond 6 months 11

12 Prasugrel (Effient ) Ticagrelor = Brilinta Similar to clopidogrel Prodrug metabolized by cytochrome P450 Loading dose of 60mg followed by daily dose of 10mg Significantly more bleeding, both major and minor T = Ticagrelor; C = Clopidogrel PLATO N = 1261 patients 1o composite end point at % 13.1% months Total mortality 4.7% 9.7% Cardiovascular 4.1% 7.9% death Noncardiovascular 0.7% 2.0% death T C Faster onset than clopidogrel / prasugrel (not a prodrug) Resistance far less likely Binds reversibly to platelets Shorter T½ twice-daily dosing Better with 81mg/day ASA vs 325mg/day ASA (???) Measuring PLT Activity P NNT 40 < < Reversing PLT Activity Evidence for patients taking APAs in setting of spontaneous ICH: unclear Most neurosurgeons / neurointensivists recommend aggressive reversal of APAs in setting of spontaneous ICH Several platelet function assays Older methods: bleeding time, platelet aggregometry Newer: thromboelastograph platelet mapping, PFA-100, VerifyNow Aspirin assay, VerifyNow PLAVIX assay Reversing PLT Activity Traumatic ICH taking APA:??? Some studies: no difference Others: mortality up to 30% Treatment results:??? Only 1 study compares patients taking APAs who had traumatic ICH and did or did not receive platelets: death rates same (17.5% vs 16.7%) 12

13 Reversing PLT Activity Numerous recommendations say transfuse PLT Standard dose of PLT for adult transfusion of one apheresis unit OR 6 units of pooled donor PLT harvested from whole blood Both contain ~ 4 6 x 1011 PLT Reversing PLT Activity Transfusion of one standard dose should raise PLT count in patent with a BSA of 2.0 m2 by ~30,000/ L at 10 minutes to one hour after transfusion This is enough to prevent spontaneous bleeding Traumatic / Spontaneous Intracranial Hemorrhage Reversing PLT Activity Desmopressin (DDAVP) also recommended, but no RCTs Case reports of patients undergoing emergent surgery who received a single dose of DDAVP 0.3 g/kg and did fine 1. Vitamin K 5-10 mg slow IV Warfarin / 2. PCC 4000 IU (or weight) VKAs 3. FFP if no PCC available 1. Stop infusion UFH 2. Protamine 1mg / 100U 2h LMWH Protamine 1mg / mg LMWH* 1. PCC/FIEBA/Kanokad 2. DDAVP 0.3 g/kg* DTI 3. Consider cryoprecipitate* 4. Consider rfviia g/kg* 1. PCC/FIEBA FXa inhibitors 2. rfviia g/kg* Aspirin alone Any thienopyridine Large ICH Small ICH DDAVP + Transfuse 1 Transfuse 2 2 standard dose standard dose standard dose PLT, then PLT PLT 2 PLT q12h x 48h 1. 1 pack PLT transfusion 2. Consider DDAVP 0.3 g/kg* Aspirin 3. Consider rfviia 3090 g/kg* 1. 2 pack PLT transfusion 2. Consider DDAVP 0.3 g/kg* ADP Inhibitors 3. Consider rfviia 3090 g/kg* NOTE: 1 pack PLT = 1 apheresis unit or 6 units of pooled donor platelets harvested from whole blood (~4 6 x 1011 platelets) * Not based on evidence (GOBSAT) 13

14 New Data on reversal of Diabagatran and Rivaroxaban, Apixaban Rivaroxaban FIEBA Dabagatran Kanokad,FIEBA 14