The Brave New (Anticoagulant) World

Transcription

1 The Brave New (Anticoagulant) World Diane M. Birnbaumer, M.D., FACEP Emeritus Professor of Medicine University of California, Los Angeles Senior Clinical Educator Department of Emergency Medicine Harbor-UCLA Medical Center Disclosure Dr. Birnbaumer has no financial relationships to disclose The Agony and The Ecstasy of Platelets and Clotting The Ecstasy We can change how people clot, so We can prevent strokes in atrial fibrillation We can prevent DVT and PE We can improve cardiac outcomes in ACS 1

2 The Agony and The Ecstasy of Platelets and Clotting The Agony Variable efficacy Narrow therapeutic index Potential drug / food interactions Potential need for monitoring Bleeding risk Presence (or absence) of antidotes in cases of severe bleeding The Agony and The Ecstasy of Platelets and Clotting There are new drugs out there But are they better??? Newer is Better Right? Depends on what type of glasses you are looking through As a cardiologist? As a neurologist? As an emergency physician? Or as a patient? 2

3 Antiplatelet Agents Aspirin Tried and true Poisons platelet for life of the platelet 5-10 days Can reverse with (and/or) Platelet concentrate DDAVP ( µg/kg) Reversal in minutes Antiplatelet Agents Clopidigrel and Prasugrel Thienopyridine derivatives Block ADP receptor on platelet Can be effectively combined with aspirin in some cases Increases bleeding risk signficantly Therefore, in some cases the combination overall is not worth the risk Antiplatelet Agents Clopidigrel and Prasugrel Clopidigrel (Plavix ) vs. Prasugrel (Effient ) Prasugrel has stronger antiplatelet effect In general More effective than clopidigrel More major bleeding events than clopidigrel 3

4 Antiplatelet Agents Clopidigrel and Prasugrel Can reverse with (and/or) Platelet concentrate (15-30 minutes) Maybe add DDAVP ( µg/kg) Reversal in minutes : Vitamin K Antagonists Vit K Antagonists: Warfarin Long experience with its use Blocks production of vitamin K dependent coagulation factors (II, VII, IX, X and Proteins S, C and Z) Induces a factor deficiency state To reverse VKAs we Restore and Replenish Risk of major bleeding 0.5-1% per year Risk of ICH is % per year 4

5 Vit K Antagonists: Warfarin Risk of bleeding directly related to height of INR Over 3.0, incidence doubles when compared to INR of Risk of bleeding increases with co-administration of antiplatelet agents Elderly have two-fold increased risk of ICH Vit K Antagonists: Warfarin Hemostasis after cessation: hours Reversal Vitamin K (dosing varies) IV: Reversal in hours PO: Reversal in 24 hours FFP large amounts needed; may be prohibitory PCCs reversal is immediate What is a PCC? Prothrombin Complex Concentrate Derived from pooled human plasma Therefore a blood product (important for patients with religious objections to blood products) Virus inactivated Minimal infectious risk Come in powder form Immediate reconstitution; smaller volume 5

6 What is a PCC? Prothrombin Complex Concentrate Contain multiple factors Profilnine, Bebulin 3 factors (II, IX and X) Kcentra, Briplex, Octaplex 4 factors (II, VII, IX and X) Some also contain Proteins S, C and Z Most are inactivated (added unfractionated heparin or antithrombin) Some are activated (Factor VII is activated) (FEIBA) What is a PCC? Prothrombin Complex Concentrate Have more prothrombin than FFP Useful for bleeding in patients on warfarin Kcentra (4-factor, inactivated) only PCC FDA approved for VKA reversal Useful in bleeding with other agents? What is a PCC? Concerns May be thrombogenic Especially activated forms May cause heparin-induced thrombocytopenia May cause DIC Not a panacea Weigh their use with care 6

7 Warfarin Reversal Guidelines INR Bleeding? Intervention Monitoring Supratherapeutic but < 4.5 No Lower or omit next VKA dose Recheck INR next day No Omit next 1-2 VKA doses (No routine Vit K) 10 No Vit K mg PO Omit next 1-2 VKA doses Reduce subsequent doses Recheck INR next day Recheck INR next day Serious bleed with ANY INR ELEVATION Yes Vit K 5-10 mg slow IV 4-factor PCCs (no FFP unless PCCs unavailable) Recheck INR Redose PCCs if needed Recheck INR q 6 hr Repeat PCCs for persistent INR elevation : The xabans EXTRINSIC PATHWAY INTRINSIC PATHWAY Rivaroxaban Apixaban a Prothrombin 7

8 The xabans Oral Factor Xa inhibitors Rivaroxaban Xarelto (approved 7/11/11) Apixaban Eliquis (approved 12/30/12) Rapid onset of action May obviate the need for parenteral anticoagulant bridge The xabans Routine monitoring of anticoagulation not required Can monitor special aptt assay if need to monitor activity (similar to one used to monitor LMWH activity) Cannot reliably measure anticoagulant effect with usual testing The xabans Rivaroxaban Xarelto (approved 7/11/11) Surgical DVT prophylaxis (hip/knee) Stroke prevention in nonvalvular AF DVT/PE treatment Reduction of risk for recurrent DVT/PE after initial therapy (ACS coming down the pike?) 8

9 The xabans Apixaban Eliquis (approved 12/30/12) Stroke prevention in nonvalvular AF DVT/PE treatment Reduction of risk for recurrent DVT/PE after initial therapy Edoxaban Savaysa (approved January 2015) Treatment of DVT and PE Stroke prevention in nonvalvular atrial fibrillation The xabans Rivaroxaban Xarelto Half-life 5-13 hours Apixaban Eliquis Half-life 9-14 hours Edoxaban - Savaysa Half-life 9-10 hours The xabans General efficacy / safety data (so far) Compared with LMWH (DVT prophylaxis) Lower bleeding risk Similar efficacy Compared with warfarin (stroke in AF) Noninferior to warfarin Apixaban may be superior Lower rate of bleeding (2.1 % vs 3%) 9

10 The xabans - potential issues They still have drug interactions Particularly the azoles, carbamazepine, rifamycins, St. John s wort Renal dysfunction Not recommended if CrCl < 30 ml/min Contraindicated if CrCl < 15 ml/min, significant hepatic impairment The xabans - potential issues Age Not for use if less than 18 years of age Contraindicated in pregnancy Not for anticoagulation in patients with mechanical valves The xabans - potential issues Neuraxial anesthesia recommendations Resume drug > 24 hours after traumatic puncture Catheter should not be removed sooner that 24 hours after last dose Next dose should not be administered until at least 6 hours after catheter removal What does this mean for emergent lumbar punctures? 10

11 Consider benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromoboprophylaxis Monitor patients frequently for signs and symptoms of neurologic impairment. If neurological compromise is noted, urgent treatment is necessary Xabans have a black box warning WARNING: Discontinuing (Xarelto, Eliquis) in patients with nonvalvular atrial fibrillation increases risk of stroke So do you ever board patients in your ED? Do those patients ever miss doses of their home meds? Huge potential for malpractice exposure here Rivaroxaban has an additional warning WARNING: Premature discontinuation of Xarelto increases the risk of thrombotic events Includes systemic embolism Xabans should be taken WITH FOOD Efficacy decreased if not taken with food 11

12 What is the ISMP Data? Institute for Safe Medication Practices First quarter 2012 rivaroxaban data 356 adverse events 158 serious thrombus (e.g. PE) 121 associated with hemorrhage Raises two issues Possible suboptimal anticoagulation Increased risk of bleeding Reversal in bleeding No antidotes available to date Factor Xa inhibitor antidotes would be useful, being investigated but not available to date Andexanet alfa a Factor Xa inhibitor antidote Highly protein bound; not dialyzable PCCs recommended based on teeny animal studies or small studies of healthy young volunteers : Direct Thrombin Inhibitors 12

13 EXTRINSIC PATHWAY INTRINSIC PATHWAY a Dabigatran Prothrombin Direct Thrombin (IIa) Inhibitors Hirudin was prototype (= leech spit) Dabigatran Pradaxa (appr. Oct 2010) Competitive, direct thrombin inhibitor Approved for Stroke prevention in A Fib (2010) DVT prophylaxis after surgery Half-life hours (normal renal function) Direct Thrombin (IIa) Inhibitors Dabigatran Pradaxa Benefits over warfarin Anticoagulation immediate No transient hypercoagulable state Does not require blood testing to monitor 13

14 Direct Thrombin (IIa) Inhibitors Dabigatran Pradaxa Minimal interactions with food/drugs * Does interact with Rifampin, quinidine, ketoconzole, verapamil, amiodarone, clarithromycin Not recommended in renal failure or in patients with impaired hepatic function ** Direct Thrombin (IIa) Inhibitors Dabigatran Pradaxa For stroke prevention As effective as warfarin Risk of major bleeding same or less than warfarin (around 3%) Older patients have higher risk of bleeding (Note: These rates were in trials; we ll see what happens in the real world ) Direct Thrombin (IIa) Inhibitors Issues for emergencies Cannot follow blood testing for anticoagulation effect (non-linear effect) Results often normal at trough of drug effect INR specifically NOT recommended Coagulation studies are elevated, but do not correlate with bleeding risk aptt that is NORMAL indicative of no SUPRATHERAPEUTIC anticoagulant effect 14

15 Direct Thrombin (IIa) Inhibitors Issues for emergencies Treatment of bleeding Supportive measures CRUCIAL prbcs IV fluids (maintain renal perfusion) Stop bleeding by direct means Discontinue drug (gone in hours) Discontinue any other drugs that would potentiate bleeding Direct Thrombin (IIa) Inhibitors Issues for emergencies Treatment of bleeding Consider activated charcoal Binds highly to charcoal Consider in recent ingestion of drug (2 hours) Remove dabigatran One third protein bound; potentially dialyzable 2 hours of dialysis removes about 60% of the drug Activating thrombin Direct Thrombin (IIa) Inhibitors Issues for emergencies Treatment of bleeding Activating thrombin May be impossible FFP has minimal prothrombin not likely useful PCCs may be useful but poorly studied to date rviia not adequately studied and unlikely useful Not useful Cryoprecipitate, protamine, DDAVP, tranexamic acid, aminocaproic acid 15

16 But wait there s hope on the horizon! A dabigatran antidote is in the pipeline Idarucizumab (Who comes up with these names?) FDA granted Breakthrough Therapy designation But wait there s hope on the horizon! Phase 1: Immediate, complete, sustained reversal in healthy humans 5-minute infusion All sounds great, right? Hmmm. But wait there s hope on the horizon! Phase 1: Immediate, complete, sustained reversal in healthy humans 5-minute infusion Optimal dose unclear (1, 2 and 4 gm being studied) 16

17 Direct Thrombin (IIa) Inhibitors An interesting twist Meta-analysis of 7 RCTs (comparing dabigatran to warfarin, enoxaparin or placebo) Significantly higher risk of AMI or ACS 1.19 vs % (OR 1.33; CI ) Now Here s The REAL Ugly BMJ July 2014 B-I withheld data showing benefit to following drug levels as a predictor of risk of bleeding To date, Boehringer-Ingelheim has agreed to pay $650 million to settle 4,000 lawsuits over the drug Now Here s The REAL Ugly BMJ July 2014 B-I withheld data showing benefit to following drug levels as a predictor of risk of bleeding To date, Boehringer-Ingelheim has agreed to pay $650 million to settle 4,000 lawsuits over the drug 17

18 The New Unanswered questions for the cardiologist / neurologist When should I use these agents? How do I start them in patients already on warfarin? How do I start them as a de novo agent? What if I need to stop the agent and try something else? The New Unanswered questions for the EP How are they faring used in the general population? What if NSAIDs, ASA are used in conjunction? What if we miss giving a dose in the ED? Xabans missed doses increase risk of stroke and other thromboembolic events? What do we do if we need to do a procedure such as a lumbar puncture in these patients? Issues with the New Agents Can we measure their activity if we need to? Normal aptt no supratherapeutic dabigatran Currently no ready access to thrombin time, ecarin clotting time Keep an eye out for factor Xa activity testing 18

19 Issues with the New Agents What do we do in cases of overdose? Dabigatran Check aptt at both 6 and 12 hours Normal both times? Probably can discharge Abnormal at all? Admit Xabans who knows What if the patient is having an acute ischemic stroke? No thrombolytics Issues with the New Agents What if the patient is having a STEMI? No thrombolytics Consider PCI Must weigh the risks and benefits What if the patient has minor head trauma? Admit for observation Issues with the New Agents Can we reverse their effects in cases of bleeding requiring emergency care? 19

20 Approach to the Severely Bleeding Patient: VKAs Supportive measures Fluids / blood Local measures to stop bleeding Consult appropriate services (IR, surgery) Avoid ASA / NSAIDs / stop warfarin Vitamin K 5-10 mg slow IV 4-factor PCCs (or may consider 3-factor PCCs, rfviia, FFP all suboptimal) Approach to the Severely Bleeding Patient: Xabans Supportive measures / try to stop the bleeding / no exacerbating drugs Stop xaban Get consultants involved Consider charcoal 4-factor PCCs likely useful Keep an eye out for Xa reversal agents in the future Approach to the Severely Bleeding Patient: Dabigatran Supportive measures / try to stop the bleeding / no exacerbating drugs Stop dabigatran Get consultants involved Consider activated charcoal Consider dialysis Consider 4-factor PCC Reversal agents being tested 20

21 Thank You for your Attention! Any Questions? 21