Managing Anticoagulation in the Hospitalized Patient

Transcription

1 Managing Anticoagulation in the Hospitalized Patient TRACY MINICHIELLO, MD CHIEF, ANTICOAGULATION& THROMBOSIS SERVICE-SAN FRANCISCO VAMC PROFESSOR OF MEDICINE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO Financial Disclosures-NONE 1

2 Objectives Develop approach to patient bleeding on DOAC Know when to restart anticoagulation after a bleed Reduce overuse of double and triple therapy Review recommendations for isolated subsegemental PE, thrombolysis in DVT and extended duration DVT prophylaxis for the medical patient Case 75 yo man with HTN, remote CAD s/p PCI/DES in 2015, NVAF on metoprolol, rivaroxaban 20 mg QD and ASA 81 mg daily presents with syncope. He was in his usual state of health until the morning of admission when he suddenly fainted on his way from the kitchen to the bathroom. He recalls feeling urgency to move his bowels then woke up on the floor. He was able to get himself to the bathroom where he had black tarry stools. His wife called 911 and he is brought to the ED. 2

3 Management of Bleeding on AC Summary of Pathway 2017 by American College of Cardiology Writing Committee et al. JACC 2017;j.jacc

4 Defining Bleeding Severity Major bleeding if 1 of factors apply Bleeding in critical site Hemodynamic instability Overt bleeding with HGB drop 2g/dL or admin 2 u PRBCs Nonmajor bleeding None of the factors apply Writing Committee et al. JACC 2017;j.jacc Critical Site Bleeding Table 1 Writing Committee et al. JACC 2017;j.jacc

5 Case In the ED his BP is 110/70, HR 110, O2 sat 99% On exam his lungs are clear, heart is tachy irregular rhythm without murmur; abdomen is soft and non tender, he has no peripheral edema, rectal exam show melena His HGB/HCT is 7.5 g/dl/24 %. his baseline is Major bleeding if 1 of factors apply 12g/dL/36 %. Bleeding in critical site Creatinine is 1.3 mg/dl, baseline Hemodynamic 0.8 mg/dl, instability LFTS are normal Overt bleeding with HGB drop 2g/dL or admin 2 u PRBCs INR 1.9 PT 18.7 Bleeding on DOAC Is drug still present? What is the t ½ of the agent When was last dose of drug? What is patient s renal function? Will laboratory data help? 5

6 Assessing Residual DOAC Efect Property Dabigatran 1 Rivaroxaban 2 Apixaban 3 Edoxaban 4 Est t ½ hrs Crcl > CrCl CrCl Renal clearance of absorbed dose Approximate anticoagulation resolution a (nml renal fxn) 80% 35% 27% 50% Day after last dose Day after last dose Day 1 2 after last dose Day after last dose a Estimated as the time it takes for 5 half-lives to elapse since the last dose 11 Suggestions for Lab Measurement of DOACs Writing Committee et al. JACC 2017;j.jacc

7 Suggestions for Lab Measurement of DOACs if Specialized Tests Available-Table 3 ISTH recommends consideration of reversal for patients with serious bleeding and DOAC level > 50 ng/ml and severe bleeding;> 30 ng/ml is high risk bleeding and invasive procedure Writing Committee et al. JACC 2017;j.jacc Assessing Bleed Severity/Management 2017 by American College of Cardiology Writing Committee et al. JACC 2017;j.jacc

8 Recent Regulatory Trials of Approved Reversal Agents Pivotal Study Reversal agent Anticoagulant Number Hemostatic Efficacy (95% CI) Thrombotic Event Rate (95% CI) Total % ICH Total ICH Total ICH ANNEXA-4 * REVERSE-AD Sarode 2013 Sarode 2013 Andexanet FXa Inhibitors Idarucizumab Dabigatran 4F-PCC Warfarin Plasma Warfarin % (76-89) 81% (72-90) 11% (7-16) % a NR b 5% (3-8) % (64-81) 65% (56-75) 42% (15-72) 58% (28-85) 8% (3-15) 6% (3-13) 4F PCC = Four factor prothrombin complex concentrate; CI = Confidence interval; ICH = Intracranial hemorrhage; NR = Not reported a 68% had investigator determined, non adjudicated time to hemostasis within 24 hours b Time to hemostasis not calculated in ICH patients 12% (7-19) 6% (2-13) NR NR Case In the ED he receives 3 u lactated ringers and 2 u PRBCs. His BP is 100/60. He continues to have melena.gi is called for urgent evaluation and he is transferred to the ICU. His last dose of rivaroxaban was at 6 am this morning with breakfast. It is now 11 am. Should he receive a reversal agent? a) Yes b) No c) Maybe? 8

9 Guidance for Administering Reversal Agent 2017 by American College of Cardiology Writing Committee et al. JACC 2017;j.jacc Specific Reversal Agents for DOACs Idarucizumab 1 FDA approved Reverses dabigatran Andexanet alfa 2 FDA approved Reverses factor Xa inhibitors Approved Oct 2015 for patients who need rapid reversal of dabigatran for emergency procedures or life-threatening or uncontrolled bleeding 3 Approved March 2018 for reversal of apixaban and rivaroxaban in patients with life threatening bleeding PDUFA, Prescription Drug User Fee Act 1. Praxbind (idarucizumab) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 10/ Portola Pharmaceuticals. [news release]. 1/8/ Accessed 3/15/ Perosphere. Accessed 3/15/

10 Andexanet alfa: Recombinant Modified Human Factor Xa GLA domain removed to prevent anticoagulant effect Factor Xa Decoy High affinity S419A S419A Factor Xa Inhibitor Gla Catalytic Domain N terminal residues retained to reduce immunogenicity Nature Medicine, Volume 19, April 2013 S S Activity eliminated to prevent thrombin generation ANNEXA-4 Study Design Patient Screening Patient with acute major bleeding ~ 60% ICH Within 18 hours of last dose of FXa inhibit or Efficacy Outcomes Change in anti-fxa activity Clinical hemostatic efficacy through 12 hours Bleeding and Laboratory Assessment Andexanet Safety follow-up IV 2-hour After end visit Bolus IV Infusion of infusion 1 hr 4 hr 8 hr12 hr Day 1 Day 3 Day 30 Safety Measurements Thrombotic events Antibodies to FX, FXa, andexanet 30-day mortality Connolly NEJM

11 ANNEXA-4 Dose Selection Acute major bleeding 18 hours of last dose of apixaban, edoxaban, rivaroxaban, or enoxaparin Andexanet IV bolus and 2 hour infusion Pts on apixaban or rivaroxaban >7 h from last dose Bolus 400 mg + Infusion mg/min Pts on enoxaparin, edoxaban or Pts on enoxaparin apixaban or edoxaban or 7 7 h from last rivaroxabandose Bolus 800 mg + Infusion mg/min There was a median reduction in anti-factor Xa inhibitor activity of 88 percent for patients taking rivaroxaban, 91 percent for patients taking apixaban and 75 percent for patients taking enoxaparin. Very few patients in the study had received edoxaban Anti-factor Xa Activity: Rivaroxaban n= 75 Anti factor Xa Activity (ng/ml) RIVAROXABAN 0 Baseline End of Bolus End of Infusion 4 Hr 8 Hr 12 Hr Median Percent Change 88% 87% 42% 49% 60% (95% CI) ( 92 to 82) ( 89 to 82) ( 46 to 33) ( 53 to 45) ( 65 to 53) Enox

12 Idarucizumab Mechanism of Action Boriani et al Dove Medical Press 2018 Grp A-45% GIB, 32% ICH, 33% trauma 12

13 Repeat Doses of Idarucizumab The most likely explanation for a recurrent elevation in clotting time, which was seen mainly between 12 and 24 hours in 114 patients is redistribution of unbound dabigatran from the extravascular to the intravascular compartment.however only TEN patients rebled. Therefore, among patients with a recurrent elevation in clotting time (67), only those with new-onset or recurrent bleeding should be considered for a second dose of idarucizumab. Case The patient undergoes urgent EGD which reveals a bleeding gastric ulcer. The ulcer is cauterized. He is started on high dose PPI. His BP improves to 115/80 and heart rate decreases to 90s. HGB remains steady at 9.5 ng/dl. Should he be restarted on anticoagulation and if so, when? a) Now b) 2 weeks c) Never d) We think it is best to defer this complicated decision that requires multidisciplinary input and intimate knowledge of this event and findings of GI evaluation to his PCP during their 11.5 minute follow up visit weeks and weeks from now 13

14 Considerations After GIB on AC Reassess risk benefit of anticoagulation secondary prevention of VTE therapy, low CHADS-vasc Assess risk of rebleeding from source identifiable source, treatable lesion? Take steps to decrease risk of bleeding related to AC regimen Consider control of warfarin poor TTR DOAC Not DOAC candidate, increase INR monitoring Reconsider need for antiplatelet therapy If ongoing strong indication for AC determine best time to restart therapy in multidisciplinary meeting with proceduralist Indications for Anticoagulation with High Thromboembolic Risk-Table 6 Writing Committee et al. JACC 2017;j.jacc

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16 AC FORUM Clinical Guidance Antithrombotic Therapy for VTE IN THE EVENT OF GI BLEED WE SUGGEST WAITING AT LEAST 7 DAYS WITHOUT EVIDENCE OF ACTIVE BLEEDING AND AFTER ENDOSCOPIC TX BEFORE REINITIATING AC Considerations After GIB on AC Reassess risk benefit of anticoagulation secondary prevention of VTE therapy, low CHADS-vasc Assess risk of rebleeding from source identifiable source, treatable lesion? Take steps to decrease risk of bleeding related to AC regimen Consider control of warfarin poor TTR DOAC Not DOAC candidate, increase INR monitoring Reconsider need for antiplatelet therapy If ongoing strong indication for AC determine best time to restart therapy in multidisciplinary meeting with proceduralist 16

17 In patients with prior unprovoked bleeding, warfarin associated bleeding or at high risk of bleeding we suggest using apixaban, edoxaban or dabigatran 110 mg BID if available as all demonstrate significantly less major bleeding compared to warfarin CHEST AFIB GUIDELINES 2018 DOAC Onset of Action Anticoagulation FULLY therapeutic within 1-2 hours Only dabigatran has a reversal agent 17

18 Considerations After GIB on AC Reassess risk benefit of anticoagulation secondary prevention of VTE therapy, low CHADS-vasc Assess risk of rebleeding from source identifiable source, treatable lesion? Take steps to decrease risk of bleeding related to AC regimen Consider control of warfarin poor TTR DOAC Not DOAC candidate, increase INR monitoring Reconsider need for antiplatelet therapy If ongoing strong indication for AC determine best time to restart therapy in multidisciplinary meeting with proceduralist Restarting Anticoagulation-Figure by American College of Cardiology Writing Committee et al. JACC 2017;j.jacc

19 AFIB PCI Antithrombotic Therapy Angiolillo et al. Circulation 2018 AFIB PCI Antithrombotic Therapy 19

20 AFIB PCI Antithrombotic Therapy In AF patients requiring OAC undergoing elective PCI/stenting, where bleeding risk is high (HASBLED 3), we suggest triple therapy for 1 month, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) for 6 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). Considerations After GIB on AC Reassess risk benefit of anticoagulation ISSPE, calf vein DVT, secondary prevention of VTE therapy, low CHADS-vasc Assess risk of rebleeding from source identifiable source, treatable lesion? Take steps to decrease risk of bleeding related to AC regimen poor TTR DOAC Not DOAC candidate, increase INR monitoring Reconsider need for antiplatelet therapy If ongoing strong indication for AC determine best time to restart therapy in multidisciplinary meeting with proceduralist 20

21 Case-Finale The patient continues to do well with no signs of recurrent bleeding. The team discusses anticoagulation with GI, anticoagulation and cardiology services. It is decided that he should no longer be on antiplatelet therapy and that he will resume anticoagulation with apixaban after 2 weeks at follow up with PCP, provided he remains stable without recurrent bleeding. TO TREAT OR NOT TO TREAT This Photo by Unknown Author is licensed under CC BY-SA-NC 21

22 Subsegmental PE A 77 yo man had undergoes colectomy for recurrent bleeding from diverticulosis. On POD # 3 he becomes tachycardic to the 110s. WBC is elevated.the surgical team orders an abdominal CT which shows a fluid collection concerning for early abscess. It also shows an isolated RLL subsegmental PE. A dedicated CTa shows a single isolated RLL subsegmental PE. Do you anticoagulate this patient? a) Sure, it is a PE. b) No this is incidental. Let s pretend we don t know it is there. Should I Treat This Isolated Subsegemental PE? Kearon et al. Chest. 2016;149(2):

23 Subsegemental PE 1 st IS IT REAL? good scan, multi defects, central, sx, + d-dimer 2 nd Consider risk of recurrence if not treated Hospitalized, reduced mobility, CA, no reversible risk factor 3 rd Consider bleeding risk 4 th Make an individualized plan High risk recurrence-treat Low cardiopulm reserve or no alternative etiology of sx-consider treating Low risk recurrence or high bleeding risk- get U/S lower extrem (& upper if CVC). IF + DVT treat If NO DVT serial u/s Subsegmental PE A 77 yo man had undergoes colectomy for recurrent bleeding from diverticulosis. On POD # 3 he becomes tachycardic to the 110s. WBC is elevated.the surgical team orders an abdominal CT which shows a fluid collection concerning for early abscess. It also shows an isolated RLL subsegmental PE. A dedicated CTa shows a single isolated RLL subsegmenral PE. Do you anticoagulate this patient? a) Sure, it is a PE. b) No this is incidental. Lets pretend we don t know it is there 23

24 Thrombolysis for DVT A 55 year old man presents with swelling and pain of his RIGHT lower extremity. On exam his RLE is swollen ~ 3.5 cm> LLE with erythema. Pulses are 2+. U/S shows occlusive DVT in his common femoral and non occlusive DVT in his external iliac vein. Should this patient receive thrombolysis for his DVT to prevent post thrombotic syndrome? 1) Yes 2) No 3) Can t decide, getting close to snack time. Should Patients with Proximal DVT Have Catheter-Directed Thrombolysis? NO, not usually Vedantham et al. ATTRACT trial NEJM

25 Should Medical Patients Receive Extended duration DVT Prophylaxis? NO, not usually A value <1 indicates that harm from a given AE exceeds clinical benefit of outcome Yami et al J Blood Med 2018 ASA for VTE Prevention in High Risk Ortho Surgery A 65 year old man with PMHx of obesity (BMI 32, weight 105 kg), HTN, OA has left total knee arthroplasty. Which is the most effective DVT prophylaxis regimen for him? 1. Rivaroxaban 10 mg QHS for 14 days 2. Rivaroxaban 10 mg QHS for 5 days- ASA 81 mg daily for 2 weeks 3. ASA (81 mg BID to 325 mg BID) QD for 14 days 4. Honestly, who knows. But ortho wont listen to me anyway. 25

26 Current ACCP VTE Prophylaxis Guidelines in Orthopedic Surgery ASA vs Rivaroxaban for VTE prevention after Hip or Knee Arthroplasty Starting on POD#6 ASA is as safe/effective as rivaroxaban Few patients with obesity cancer prior VTE Patients on higher dose ASA had higher bleed rates-use low dose ASA Anderson DR et al. N Engl J Med

27 ASA for VTE Prevention in High Risk Ortho Surgery A 65 year old man with PMHx of obesity (BMI 32, weight 105 kg), HTN, OA has left total knee arthroplasty. Which is the most effective DVT prophylaxis regimen for him? 1. Rivaroxaban 10 mg QHS for 14 days 2. Rivaroxaban 10 mg QHS for 5 days- ASA 81 mg daily for 2 weeks 3. ASA (81 mg BID to 325 mg BID) QD for 14 days 4. Honestly, who knows. But ortho wont listen to me anyway. Take Home Points Consider renal function and timing of last dose to determine residual anticoagulant effect in patient bleeding on DOAC. Use reversal agents judiciously in patients with life threatening and critical site bleeding After GIB on AC-reconsider risk benefit of therapy; reconsider anticoagulation regimen, eliminate dual and triple therapy whenever possible, multidisciplinary approach to determining if/when to restart AC after bleeding event should be conducted during hospitalization Consider ISSPE on case by case basis. Witholding anticoagulation if no DVT and opting for serial u/s may be reasonable in select population Extended duration VTE prophylaxis in medical patients-not sure who will benefit most yet ASA for DVT prophylaxis in high risk ortho patients-yes 27

28 WORKSHOP IVC filters Thrombolysis for DVT Does this patient need to be bridged? Calf vein thrombosis, superficial vein thrombosis PICC line thrombosis ASA for DVT prophylaxis And more! 28