10/20/16 1 MANAGEMENT OF ANTICOAGULATION IN THE HOSPITALIZED PATIENT Tracy Minichiello, MD Professor of Medicine University of California,, San Francisco Chief, Anticoagulation & Thrombosis Service San Francisco VA Medical Center Disclosures • none Cases • How do I choose the best anticoagulant for my patient with NVAFIB? • How do I switch a patient from warfarin to DOAC? • What do I need to do for a patient being discharged on a DOAC • Should this patient on anticoagulation with GI bleed restart anticoagulation and if so when? • Should this patient be on BOTH ASA and anticoagulation? • How do I manage this patient who is bleeding on a DOAC? Case #1 An 81 year old 70 kg man with CKD, Cr= 1.6, CrCl 35 ml/min, remote GI bleed presents with new AFIB. Which anticoagulant do you recommend? 1. Dabigatran 150 mg BID 2. Rivaroxaban 20 mg QD 3. Rivaroxaban 15 mg QD 4. Apixaban 5 mg BID 5. Apixaban 2.5 mg BID 6. Edoxaban 30 mg QD 7. Warfarin
Transcript
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MANAGEMENT OF ANTICOAGULATION IN THE HOSPITALIZED PATIENT
Tracy Minichiello, MDProfessor of MedicineUniversity of California,, San FranciscoChief, Anticoagulation & Thrombosis ServiceSan Francisco VA Medical Center
Disclosures
• none
Cases• How do I choose the best anticoagulant for my patient
with NVAFIB? • How do I switch a patient from warfarin to DOAC?• What do I need to do for a patient being discharged on
a DOAC• Should this patient on anticoagulation with GI bleed
restart anticoagulation and if so when?• Should this patient be on BOTH ASA and
anticoagulation?• How do I manage this patient who is bleeding on a
DOAC?
Case #1
An 81 year old 70 kg man with CKD, Cr= 1.6, CrCl 35 ml/min, remote GI bleed presents with new AFIB. Which anticoagulant do you recommend?1. Dabigatran 150 mg BID2. Rivaroxaban 20 mg QD 3. Rivaroxaban 15 mg QD 4. Apixaban 5 mg BID5. Apixaban 2.5 mg BID6. Edoxaban 30 mg QD7. Warfarin
From: DIRECT COMPARISON OF DABIGATRAN, RIVAROXABAN, AND APIXABAN FOR EFFECTIVENESS AND SAFETY IN NONVALVULAR ATRIAL FIBRILLATIONJ Am Coll Cardiol. 2016;67(13_S):692-692. doi:10.1016/S0735-1097(16)30693-3
riva dabiriva
apix
dabi
dabi apix
riva
dabi
rivaapix apix
Stroke and SEapix=dabi=riva
Major bleeding apix<dabi<riva
DOAC Selection Clinical Considerations: NVAFa
These suggestions are debatable in the absence of head-to-head trials.
High overall bleeding risk
apixaban>dabi>riva
High GI bleeding risk
GI upsetapixaban
Age > 75apixaban > dabigatran >
rivaroxaban
Patient adherence/ QD
preferencerivaroxaban QD
edoxaban QD
Edoxaban
Rivaroxaban Apixaban
High stroke risk low bleed risk
rivaroxaban, dabigatran
CrCl < 50 ml/minapixaban, edoxaban
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Renal Function and DOACs for NVAF
• Most DOACs not recommended in severe renal impairment (CrCl <15 mL/min)
• All DOACs require dose adjustment for renal impairment in NVAF◼ Dabigatran1: 75 mg BID if CrCl 15‒30 mL/min ◼ Rivaroxaban2: 15 mg QD if CrCl 15‒50 mL/min◼ Apixaban3: 2.5 mg BID with ≥2 of following:
▫ Age ≥80 y▫ Weight ≤60 kg▫ Creatinine ≥1.5 mg/dL
◼ Edoxaban4: 30 mg QD if CrCl 15‒50 mL/min
1.. Connolly SJ et al. N Engl J Med. 2010;363:1875-1876. 2. Patel MR et al. N Engl JMed. 2011;365:883-891. 3.Granger CB et al. N Engl J Med. 2011;365:981-992. 4. Giugliano RP et al. N Engl J Med. 2013;369:2093-2104.
SHOULD HAVE TWO CRITERIA FOR DOSE REDUCTION!
DOACs: Potential for Drug InteractionsCYP3A4
Inducers Inhibitors
Carbamazepine Amiodarone Itraconazole
Efavirenz Aprepitant Ketoconazole
Glucocorticoids Cimetidine Nefazodone
Nevirapine Clarithromycin Protease inhibitors
Phenobarbital Cyclosporine Verapamil
Phenytoin Diltiazem Voriconazole
Primidone Erythromycin
Rifampin Fluconazole
Rifapentine Fluoxetine
St. John’s wort Fluvoxamine
P-Glycoprotein
Inducers Inhibitors
Midazolam Amiodarone Dronaderone
Nifedipine
Nifedipine Ceftriaxone Propranolol
Phenobarbital Clarithromycin Quinidine
Phenytoin Cyclosporine Tacrolimus
Rifampin Diltiazem Verapamil
St. John’s wort Dipyridamole
Erythromycin
Hydrocortisone
Itraconazole
Ketoconazole
www.NOACforAF.eu
http://depts.washington.edu/anticoag/home/
Optimal Candidates for DOAC for NVAF
◼ Have difficulty getting INR testing or, despite adherence have low ‘time-in-range’
◼ Can afford (or arrange to get) them◼ Are not taking medications known to interact
with the new anticoagulants◼ Have normal renal function or only moderate
stable renal insufficiency
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NOT GOOD CANDIDATES FOR DOACS
• Have severe renal insufficiency or likely spurious decline in renal function
• Are likely to skip doses• Have reservations about the lack of antidote• Extremes of weight (?)
Case #1
• An 81 year old 70 kg man with CKD, Cr= 1.6, CrCl 35 ml/min, remote GI bleed presents with new AFIB. Which anticoagulant do you recommend?
• Access to DOAC(affordability)• If SNF-is DOAC on formulary?• Patient/caregivers know it is AC• DOAC education done• Number of who to call with questions• Handoff to provider-
indication/duration/DOAC schedule• Time of next dose• Clearly outlined planned dose change• Follow-up arrangedBurnett et al J Thromb Thrombloysis 2016
DOAC Therapy Follow-up: EHRA 2015 Recommendations
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q Adherence?◼ Patients to bring
remaining medicationq TE events?q Bleeding events?q Other side effects?q Concomitant
medications ◼ Including OTC
(eg, ASA, NSAIDs)
Blood Sampling
• Anticoagulation level monitoring is not required
• Annually: Hb, renal, liver function
• If >75‒80 y (especially if dabigatran) or frail: 6-mo renal function
• If CrCl ≤60 mL/min: Recheck interval = CrCl/10
• Consider co morbidites-liver, renal, interacting meds
Heidbuchel H et al. Europace. 2015;17(10):1467-1507.
Checklist for Each VisitChecklist for EACH Visit
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Case #2
A 75 year old man with NVAF is on rivaroxaban for stroke prevention. He is admitted with CHF and is found to have AKI with CrCl in the 30s (baseline in the 50s) as well as congestive hepatopathy with transaminitis. The team is concerned about medication adherence, flucuatating renal function, liver function and decides to transition him to warfarin.
Burnett, A.E., et al. J Thromb Thrombolysis (2016)
Transitioning Between DOACS and other Anticoagulants
Per AC Forum: As a general rule, we suggest that as INR drops below 2.5, a DOAC can be started;As a general rule, we suggest that each DOAC can be started within 30 min after stopping (iv) UFH
Hein Heidbuchel et al. Eur Heart J 2016
Transitioning Between DOACS Case #3
76 y/o man with CAD (NSTEMI 2006), AFIB CHADS-Vasc=4on warfarin and ASA is admitted with UGIB. INR is 3.0. He requires 3u PRBCs, vit K and FFP. EGD shows peptic ulcer disease. He is started on high dose PPI therapy, bx for H Pylori done. When should his anticoagulation be restarted?a) Neverb) In one weekc) In three months d) Let the primary provider deal with this one
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Outcomes after GIB in AFIB
WITT et al Arch Intern Med. 2012
Risk of death 3x lower if restart↑ GIB (ns)-none fatalHighest risk time day 1-7
% alive
% without recurrent GIB
% without thrombosis
Nearly 50% of pts with GIB on ASA also
↓ TE 0.4% vs 5.5% -3 fatalIf resumed within 14 days no thrombosis
Qureshi Amer J of Cardiol 2014
Outcomes Stratified by Duration of Warfarin Interruption
----< 7 days___ no warfarin
Freedom from GIBCumulative Survival
Freedom from TE
1-7 days
Outcomes After GIB In AFIB
Staerk BMJ 2015
GIBs: DOACs vs Warfarin
Di Minno et al. Blood Reviews 2015.
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GIBs: DOACs vs Warfarin
Di Minno et al. Blood Reviews 2015.
GIBs: DOACs vs Warfarin
Di Minno et al. Blood Reviews 2015.
Resumption of DOACs
Anticoagulation FULLY therapeutic within 1-2 hoursOnly dabigatran has a reversal agent
Considerations After GIB on AC1. reassess risk benefit of anticoagulation
◼ Secondary prevention of VTE therapy, low CHADS-vasc,2. assess risk of rebleeding from source
identifiable source, treatable lesion?3. Take steps to decrease risk of bleeding related to AC regimen
reconsider need for concomitant antiplatelet therapy if on warfarin-was INR in range, is control good?spurious elevation in INR or poor TTRàDOACincrease INR monitoring-home POC INR?
4. if ongoing strong indication for anticoagulation determine best time to restart therapy in multidisciplinary meeting with proceduralist - Remember DOAC immediately active
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Case #3
76 y/o man with AFIB CHADS-Vasc=5 on anticoagulation with warfarin is admitted with UGIB. INR is 3.0. He requires 3u PRBCs, vit K and FFP. EGD shows peptic ulcer disease. He is started on high dose PPI therapy, bx for H Pylori done. When should his anticoagulation be restarted?a) Neverb) In one weekc) In three months d) Let the primary provider deal with this one
Case #3a
76 y/o man with CAD (NSTEMI 2006), AFIB CHADS-Vasc=4on warfarin and ASA is admitted with UGIB. INR is 3.0. He requires 3u PRBCs, vit K and FFP. EGD shows peptic ulcer disease. He is started on high dose PPI therapy, bx for H Pylori done. He will be restarted on warfarin in one week. Should he restart his ASA? a) Yes b) No c) Let the primary provider deal with this one
Risk of Bleeding With Single, Dual, or Triple Therapy With Warfarin, Aspirin, and Clopidogrel in Patients With AFIB
Hansen M et al. Arch Intern Med. 2010
warfarin + asa= up to 2xwarfarin + asa + clopidigrel=3x
NEW CHEST GUIDELINES
“For patients taking warfarin we suggest AVOIDING concomitant antiplatelet therapy except where benefit is likely to be greater than harm: valves, ACS, stents, CABG” (2C)
Holbrook A et al. CHEST 2012 (Suppl);
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Is ASA in addition to Warfarin Necessary?
Indication for ASA Risk/benefit RegimenPrimary CAD Warfarin superior to
ASA (20% lower risk of CV event and death)
Anticoagulation only
Remote secondary CAD
Warfarin at least as good as ASA at↓future CV events
Consider anticoagulation only
Secondary ischemic stroke prevention
Warfarin and ASA provide similar benefit
Anticoagulation only
Recent ACS; DES; BMS
Anticoagulation plus antiplatelet (per cards)
CABG; mechanical heart valve
Anticoagulation plus antiplatlet (per cards)
Dentali etal. Arch Intern Med 2007Lamberts M et al. Circulation. 2014;129:1577-1585 Mohr et al. N Engl J Med. 2001
Case #3a
76 y/o man with CAD (NSTEMI 2006), AFIB CHADS-Vasc=4on warfarin and ASA is admitted with UGIB. INR is 3.0. He requires 3u PRBCs, vit K and FFP. EGD shows peptic ulcer disease. He is started on high dose PPI therapy, bx for H Pylori done. He will be restarted on warfarin in one week. Should he restart his ASA? a) Yes b) Noc) Let the primary provider deal with this one
Case #4
A 65 year old man with AFIB CHADS-Vasc=5 on rivaroxaban for stroke prevention presents with melena, BP 120/80, HR 99, HCT 30 (baseline 40). PT 18. INR 1.5.How do you manage his anticoagulation?
1. hold rivaroxaban and transfuse PRBCs & IVfluids as needed2. hold rivaroxaban and administer PCC3. hold rivaroxaban and transfuse FFP and vitamin K4. I knew we should have had a protocol for this. Didn’t she mention at last years conference??
Bleeding on DOAC
• Is drug still present?◼ When was last dose of drug?◼ What is patient’s renal function? ◼ Will laboratory data help?
aEstimated as the time it takes for 5 half-lives to elapse since the last doseSlide adapted: courtesy of Chalres Pollack, MD
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Interpreting Lab Tests on DOACS
Burnett et al. J Thromb Thrombolysis 2016Samuelson et al Blood Reviews 2016
Dabigatran-an elevated aPTT signifies clinically significant drug levelsa normal PTT rules out supratherapeuticdrug levels but does not rule out clinically significant residual AC effect.A normal dTT rules out residual dabigatranRivaroxaban/apixaban/edoxabanan elevated PT signifies clinically significantdrug levels (riva only)a normal PT rules out supratherapeuticdrug levels but does not rule out clinically significant residual AC effect.In the absence of a drug-specific calibrated anti Xa level the use of a curve calibrated for UFH or LMWH is a reasonable surrogate for excluding drug levels ≥ 25–30 ng/mL (below trough)
Managing DOAC Bleeding: EHRA 2015 Recommendations
MILD BLEEDING§ Delay/discontinue
next dose§ Reconsider
concomitant medication, especially antiplatelets
MODERATE TO SEVERE BLEEDING
Supportive measures§ Mechanical compression§ Endoscopic hemostasis if
GI bleed§ Surgical hemostasis§ Fluid replacement
(colloids if needed)§ RBC substitution if
needed§ FFP (as plasma
expander)§ Platelet substitution if
platelet count ≤60 x 109/L
LIFE-THREATENING BLEEDING
Consider§ PCC (eg, CoFact®)
50 U/kg; +25 U/kg if indicated
§ aPCC (Feiba®) 50 U/kg; max 200 U/kg/d
§ rFVIIa (NovoSeven®) 90 µg/kg (no data about additional benefit)
§ For dabigatran, administeridarucizumab 5 g IV
Heidbuchel H et al. Europace. 2015. 43
Case #4
• A 65 year old man with AFIB CHADS2=2 (DM/HTN) on rivaroxaban for stroke prevention presents with melena, BP 120/80, HR 90, HCT 30 (baseline 40). PT 18. How do you manage his anticoagulation?
• 1. hold rivaroxaban and transfuse PRBC IV fluids as needed
• 2. hold rivaroxaban and administer PCC• 3. hold rivaroxaban and transfuse FFP and vit K
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Case Study
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76-year-old man presents to the ED with GI hemorrhage
• Dabigatran 150 mg BID started in 2014 for NVAF◼ Last dose 8 h before
admission
• No prior major bleed
• History of hypertension, CHF
BP: 105/71 mm HgPulse: 128 bpm
Massive, ongoing hematochezia
Hemodynamic status: Unstable
Slide courtesy of Dr Charles Pollack
Case Study: Additional Assessment
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Test Result ULNaPTT (s) 57.4 40
TT (s) 114.0 14dTT (s) 47.2 36ECT (s) 98.1 42
Baseline Blood Results
Slide courtesy of Dr Charles Pollack
Idarucizubab
Prelim results –approx 90 patientsVery ill patients (18 deaths)Major bleeding or urgent surgeryNo control armCorrection of lab coagulopathy d TT
80-90 % normalization of dTT in minutes5 TE while off AC,1 within 3 days25% had nml dTT when entered10% patients had rebound elevationIn dTT at 12-24 hours
• Consider organ fxn, age, meds, bleeding risk to guide DOAC selection
• Assure smooth and safe transitions on patients on DOACs
• After GIB on AC-reconsider risk benefit of therapy; multidisciplinary approach to determining when to restart AC after bleeding event
• Consider renal function and timing of last dose to determine residual anticoagulant effect in patient bleeding on DOAC. No evidence-based reversal agents with exception of idarucizumab for dabigatran
• Have institutional protocol for reversal of all anticoagulants
• Reassess risk benefit of concomitant ASA in all patients on anticoagulation-discuss with cardiology
WORKSHOP
• IVC filters• Thrombophilia work up• Recurrent VTE while on anticoagulation• Who to bridge• Management of calf vein thrombosis, superficial
