Pennsylvania Academy of Family Physicians Foundation & UPMC 43rd Refresher Course in Family Medicine CME Conference March 10-13, 2016

Transcription

1 Pennsylvania Academy of Family Physicians Foundation & UPMC 43rd Refresher Course in Family Medicine CME Conference March 10-13, 2016 Disclosures: Anticoagulatns New Agents, Reversal and Bridging William Sonnenberg, MD Speaker has no disclosures and there are no conflicts of interest. The speaker has attested that their presentation will be free of all commercial bias toward a specific company and its products. The speaker indicated that the content of the presentation will not include discussion of unapproved or investigational uses of products or devices.

2 William R. Sonnenberg, MD, FAAFP 1 Disclosure The speaker has no conflict of interest, financial agreement, or working affiliation with any group or organization. 2 DVT and PE Kills 4-5 times as many as breast cancer 300,000 deaths per year Number one preventable cause of hospital related deaths 10% of hospital deaths #1 killer of pregnant women 3 1

3 THE OLD GUARD 4 Warfarin 5 mg. per day 10 mg. may work 1.4 days sooner INR months Not in pregnancy Teratogen 1 st trimester Antepartum bleeding 3 rd trimester 5 Warfarin Necrosis Typically in first several days Mainly in Protein C deficiency Inhibition of Protein C stronger than K-dependent coagulation factors Protein C is anticoagulant 6 2

4 Warfarin Drug Interactions Potentiate Antibiotics/Antifungals Sulfa, ciprofloxacin, tetracycline, metronidazole, all azoles, isoniazid, macrolides CV Agents Amiodarone, disopyramide, propafenone Others Cimetidine, ASA, NSAIDs, allopurinol, omeprazole Reduce Antibiotics/Antifungals Rifampin, nafcillin, dicloxacillin Anticonvulsants Phenytoin, brbiturates Others Sucralfate, cholestyramine, colestipol, chlorodiazeopxide, trazadone 7 Warfarin Herbal Interactions Ginkgo increase bleeding St. John Wort interfere with warfarin Ginseng increase bleeding Garlic not dietary, only supplement; increase bleeding Ginger increase bleeding St. John Wort 8 Warfarin Duration Event First with reversible risk factor Minimum Duration Strength of Recommendation 3 months A First embolic episode 6 months A Recurrence 12 months B Continuing Risk Factor 12 months B Isolated calf vein thrombosis 6-12 weeks A 9 3

5 D-dimer for Warfarin Duration? D-dimer abnormal in 223/608 pts one month after stopping warfarin for PE or DVT Resumption of warfarin or placebo in + D- dimer group 15% events in stopped group 2.9% events in treated group Hazard ratio of 4.26 N Engl J Med Dec 28;355(26): Fall Risk in Elderly and Anticoagulation? Risk of subdural hematoma from fall is small Pt with 5% annual stroke risk from AF would need to fall 300 times/year to outweigh risk reduction from stroke Sellers MB, Newby LK. Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients. Am Heart J. 2011;161(2): NEWER ANTICOAGULANTS 12 4

6 Novel (Target-Specific) Anticoagulants 13 General Comments Reduce hemorrhagic strokes by 50% Tissue factor in CSF?? No dietary interaction Less food and genetic effects Rapid onset (within 2 hours) All are non-inferior to warfarin 14 Effect on Labs Direct thrombin inhibitor (dabigatran) PTT Variable Normal excludes therapeutic level Direct factor Xa inhibitor PT Variable Normal excludes therapeutic levels 15 5

7 Dabigatran Apixaban Rivaroxaban Edoxaban Mechanism of Action Direct thrombin inhibitor Direct factor Xa inhibitor Atrial Fibrillation Approved DVT prophylaxis, recurrent Yes After 6 months of RX Hip, knee DVT treatment After parenteral Rx for 5-10 days yes yes After parenteral Rx for 5-10 days Oral Bioavailability Low (6.5%) Moderate (60%) Moderate (70%) Moderate (60%) Dosing Twice daily Twice daily Once daily Once daily 16 Reasons NOT to treat acute PE/DVT with NOACs Severe renal insufficiency (Cr Cl < 30 ml/min) Weight > 120 kg or < 50 kg tpa use contemplated PATIENT CANNOT AFFORD MEDICATION Known pro-thrombotic state HIT, cancer, antiphospholipid syndrome 17 Advantages and Disadvantages Advantages No lab monitoring Rapid onset, no bridging Once or twice daily dosing Less major bleeding, especially intracranial Disadvantages No reversal agent Lack of lab monitoring Higher cost More GI bleeding Contraindicated in mechanical valves or severe renal impairment 18 6

8 Nonvalvular Atrial Fibrillation All 4 NOADS More effective at preventing stroke Less hemorrhagic stroke or intracranial bleed Higher risk of GI bleeding Worse with dabigatran Overall bleed risk no worse than warfarin 19 Mechanical Heart Valves?? More thrombotic and bleeding complications with dabigatran 5% stroke v. none Twice bleeding (major bleed pericardial) Not indicated in NOADS Eikelboom JW et al. N Engl J Med 2013;369: NOADS in Acute Coronary Syndrome 7 published studies, 30,866 patients NOAD + ASA reduced major coronary event HR 0.70 Increased bleeding HR 1.79 Eur Heart J Jun;34(22):

9 DABIGATRAN 22 Dabigatran Approved for stroke prevention in Afib and treatment of VTE (after LMWH or heparin) Lowest bioavailability and highest GI bleed risk Prodrug Unstable Keep in original packaging and discard unused tablets after 120 days Good for only 30 days after bottle opened Surrounded by tartaric acid 23 Pharmacology - Dabigatran 24 8

10 Dabigatran v. Coumadin Studies RECOVER -DVT 30% lower risk of any bleed No difference in major bleed 3% dyspepsia 30 deaths v. 27 deaths in warfarin RELY a-fib Stroke or embolism 2.21% v. 3.35% (NNT 88) All-cause mortality 7.2% v. 8.1% Major bleeding NS Life-threatening bleeding 2.9% v. 3.5% 25 Afib and Stroke Reduction Placebo v. ASA = 19% ASA v. warfarin = 30% Placebo v. warfarin 62% Dabigatran v. warfarin 34% 26 Dabigatran and MI? 7 studies (Uchino, K. et al) increased risk of MI OR 1.3 Meta-analysis (Douxifils J. et al) - 32% increase over comparator Larsen study HR 40% at 150 mg BID 27 9

11 RE-LY Dabigatran 150 mg. bid Mean CHADS 2 score = 2.1 Dabigatran better Warfarin better D150 W P Efficacy outcomes %/y Stroke / systemic embolism < Stroke < Ischemic stroke Hemorrhagic stroke < Myocardial infarction All-cause mortality Safety outcomes ICH < Major bleeding Major GI bleeding < Any bleeding Hazard ratio Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2009;361: Connolly SJ, Ezekowitz MD, et al. N Engl J Med. 2010;363: Idarucizumab for Dabigatran Reversal Monoclonal antibody fragment binds dabigatran 350x more than thrombin Complete reversal in 88% 98% of patients within minutes 1/90 patients had thrombotic event within 72 hours Approved Oct 2016 $3500 per dose June 22, 2015 Pollack C.V., Reilly P.A., Eikelboom J., et al /nejmoa Dabigatran in a Nutshell Twice daily dosing Renally cleared (CrCl < 50 may be issue) Dyspepsia most common side effect Increased risk of GI bleed Mildly increase risk of MI Predictable anticoagulant effect with CrCl > 50 Decreased risk of intracranial bleeding Non-inferior for VTE treatment 30 10

12 RIVAROXABAN 31 Rivaroxaban Stroke prevention in afib, prophylaxis and treatment of VTE qday for afib and prevention of VTE BID for recent VTE Mostly renal excretion, some liver 15 mg in renal impairment Must take with food 32 Rivaroxaban: Pharmacology 33 11

13 Rivaroxaban Dosing Atrial fibrillation VTE Treatment Recurrent VTE VTE 20 mg daily 15 mg. daily CrCl mg bid then 21 days, then 20 mg daily 20 mg. daily 10 mg daily for 35 days after hip surgery 10 mg daily for 12 days after knee surgery 34 Rivaroxaban v. Coumadin Studies EINSTEIN -DVT Recurrent VTE 2.1% v. 3% (HR 0.68) Major bleeding 0.8% v. 1.2% (NS) ROCKET a-fib Stroke or embolism 2.1% v. 2.4% Bleeding, major and nonmajor 14.9% v. 14.5% Intracranial hemorrhage 0.5% v ROCKET AF: Rivaroxaban Mean CHADS 2 score = 3.5 Rivaroxaban better Warfarin better Riva W P Efficacy outcomes %/y Stroke / systemic embolism < 0.001* Stroke Ischemic stroke Hemorrhagic stroke Myocardial infarction All-cause mortality Safety outcomes ICH Major bleeding Major GI bleeding < Major and CRNM bleeding Hazard ratio *Noninferiority Patel MR, et al. N Engl J Med. 2011;365:

14 Rivaroxaban in a Nutshell dose for CrCl Once daily dosing Increased risk of GI bleeding Increase risk after discontinuation Predictable anticoagulant effect Decreased risk of intracranial hemorrhage 37 APIXABAN 38 Apixaban Approved for stroke prevention, and prophylaxis and treatment of VTE Twice daily dosing Less renal excretion than others Avoid in severe liver disease 75% biliary excretion 39 13

15 Apixaban Dosing Atrial fibrillation VTE Treatment VTE prophy 5mg. BID 2.5 mg. BID for age > 80, wt < 60 kg, Cr > mg BID then 7 days, then 5 mg BID daily 2.5 mg. BID daily for 35 days after hip surgery & 12 days after knee surgery 40 Apixaban Pharmacology 41 Apixiban v. Coumadin Studies AMPLIFY - DVT Composite bleeding 4.3% v. 9.7% Relative risk for death 0.84 ARISTOTLE - a-fib stroke and systemic embolism 21% major bleeding 31% mortality 11% Fewer discontinuations than warfarin 42 14

16 ARISTOTLE: Apixaban Mean CHADS 2 score = 2.1 Apixaban better Warfarin better D150 W P Efficacy outcomes %/y Stroke / systemic embolism Stroke Ischemic stroke Hemorrhagic stroke < Myocardial infarction All-cause mortality Safety outcomes ICH < Major bleeding < Major GI bleeding Any bleeding < Hazard ratio Granger al. N EnglJ Med. 2011;365: CB, et 43 Apixaban in a Nutshell Lower dose for Cr 1.5, Age 80, Weight 60kg Major hemorrhage risk similar to Aspirin Benefits persist in patients aged 75 Twice a day dosing Multiple routes of elimination Reliable predictable anticoagulant effect Non-inferior for VTE treatment (AMPLIFY) 44 EDOXABAN 45 15

17 Edoxaban Stroke prevention in nonvalvular afib and treatment of acute VTE and PE (after heparin or LMWH for 5-10 days) Primarily renal excretion Avoid if creatinine clearance > 95 ml/min 46 Edoxaban Pharmacology 47 Edoxaban v. Coumadin Studies HOKUSAI - VTE Recurrent VTE 3.2% v. 3.5% (noninferior) Major or relevant nonmajor bleeding 8.5% v. 10.3% (NNT 56) No significant different in major bleeding or death ENGAGE - a-fib Stroke or systemic embolism 1.18%/1.61% v. 1.50% Major bleeding 2.75%/1.61% v. 3.43% CV causes 2.74%/2.71% v. 3.17% 48 16

18 Edoxaban in a Nutshell Lower dose for CrCl30-50, Weight 60kg Once daily dosing Mortality and major hemorrhage risk benefits Increased risk of GI bleeding (poor oral bioavailability) Reliable predictable anticoagulant effect Non-inferior for VTE treatment (Hokusai- VTE) Both once-daily edoxaban doses were noninferior to warfarin on the prevention of stroke 49 Meta-Analysis: NOACS VS Warfarin RELATIVE RISK TO WARFARIN (%) Hemorrhagic Stroke Intracranial Hemorrhage All-Cause Mortality Major GI Hemorrhage Hemorrhage Adapted from Ruff CT, et al. Lancet 2013 Online; S (13) Prevention of Stroke 51 17

19 Bleeding Risk 52 Mortality 53 Treatment of VTE Comparable to warfarin Fewer pts experience bleeding complications Rivaroxaban and Apixaban monotherapy Dabigatran and edoxaban after five day course of heparin and LMWH Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database of Systematic Reviews 2015, Issue 6. Art. No.: CD DOI: / CD pub

20 Reversal Agents? Aripazone D-arginine compound Apixaban, edoxaban, rivaroxaban, dabigatran, heparin, LMWH Single injection Andexanet modified factor Xa molecule Apixaban, Edoxaban, Rivaroxaban Sops up anti-xa anticoagulant Works in 2-5 minutes Idarucizumab antibody fragment against dabigatran 55 Andexanet Modified Factor Xa Molecule Factor Xa Andexanet 56 Long Term Aspirin After Discontinuation of Anticoagulation Meta-analysis of 2 trails, 1225 patients 100 mg aspirin after warfarin Recurrent DVT 1/3 lower in aspirin group 5.1% vs. 7.5% recurrent DVT No difference in bleeding Less MI, CVA or CV death in aspirin group Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation. 2014;130(13):

21 Anticoagulant Choice by Pt. Pt Characteristic Choice Reason MVR or Valve disease Warfarin No data (dabigatran) Cancer Warfarin No data Liver disease Warfarin NOADS require liver metabolism Poor Adherence Warfarin Worse consequences with NOADS CrCL < 30 Warfarin Little data with NOADS CrCL Rivar or Pixy Less effect than dabigatran UGI Symptoms Rivar or Pixy 10% dyspepsia with dabigatran Recent GI bleed Recent ischemic CVA on warfarin Pixy Dabigatran bleeding with dabigatran or rivaroxaban than warfarin risk of ischemic bleeding than warfarin Recent ACS Rivaroxaban or pixy? MI with dabigatran 58 Switching Anticoagulants Agents VKA NOADS NOADS VKA Parenteral to NOADS UFH LMWH NOAD parenteral Recommendations INR < 2.0 immediate INR immediate or next day INR > 2.5 Wait till INR < 2.5 Administer concomitantly till INR appropriate Re-test 24 hours after last dose of NOAD Start once when UFH stopped: caution renal Start when next dose would be given Start when next NOAD dose due Heidbuchel H, Verhamme P, et al. EP Europace 2013;15: ANTICOAGULATE BRIDGING 60 20

22 Risk Balance Thromboembolism Bleeding During Procedure 61 Decision Approach Estimate thromboembolic risk Estimate bleeding risk Determine timing of anticoagulant interruption Bridging anticoagulation 62 High Risk for Thromboembolism Stroke or embolic event within 12 weeks Mechanical mitral valve Mechanical aortic valve with stroke risk factors Afib with CHAD 2 score of 5-6 VTE within 12 weeks Recent stenting Previous thromboembolism during anticoagulation interruption 63 21

23 Bleeding Risk High Risk CABG Kidney biopsy Procedure > 45 minutes Low Risk Dental extraction Minor skin surgery Cholecystectomy Carpal tunnel repair Abdominal hysterectomy 64 ACP Guidelines High Risk Recommended Therapeutic-does SQ LMWH IV Heparin Moderate Risk Proposed Therapeutic-does SQ LMWH IV Heparin Low-dose SQ LMWH Low Risk Recommended Low-dose SQ LMWH No bridging 8th and 9th edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 65 Coronary Stents Bare metal stents Surgery within 6 weeks Continue aspirin and clopidrogrel perioperatively Drug-eluding stents Surgery within 12 months Continue aspirin and clopidrogrel perioperatively 66 22

24 Other Procedures Minor dental procedures Continue VKAs Coadminister oral prohemostatic agent Minor skin procedures or cataract removal Continue VKAs perioperatively 67 Perioperative Bridging in Atrial Fibrillation? BRIDGE Trail 1884 patients with afib on Coumadin randomized to SQ LMWH or placebo Warfarin held 5 days before surgery, restarted in 24 hours Mean CHADS 2 score 2.3 (mild to moderate risk) Douketis JD et al. N Engl J Med 2015;373: BRIDGE Trail Results Incidence of Arterial Thromboembolism Major Bleeding 0.40% 3.20% 0.30% 1.30% Heparin Placebo Heparin Placebo Douketis JD et al. N Engl J Med 2015;373:

25 Bridging with the NOADS Stop 2-3 days before surgical procedure Most bridging unnecessary except for very high risk Rapid offset and onset Restart when hemostasis achieved 70 Dwight White (1949-June 6, 2008) Steel Curtain in 70 s First safety in Super Bowl history with sack of Fran Tarkenton in Super Bowl IX "Dwight was going to make life miserable for anybody who didn't have our jersey on," Back surgery May 12, 2008 PE several weeks later 71 THE END 72 24

26 RE-COVER: Dabigatran versus Warfarin in Acute DVT 30% lower risk of any bleed No difference in major bleed 3% dyspepsia INR therapeutic 60% of time 30 deaths v. 27 deaths in warfarin Schulman S et al. N Engl J Med 2009;361: Recurrent DVT and Death Schulman S et al. N Engl J Med 2009;361: Dabigatran v. Warfarin Bleeding Risk Schulman S et al. N Engl J Med 2009;361:

27 RELY Study: Dabigatran v. Coumadin in A-fib 18,113 pts with afib & risk factors, F/U 24 months 150 mg. v warfarin Stroke or embolism 2.21% v. 3.35% (NNT 88) All-cause mortality 7.2% v. 8.1% Major bleeding 6.57% v. 6.99% (NS) Life-threatening bleeding 2.9% v. 3.5% (NNT 200) MI 1.6% v. 1.25% Connolly SJ et al. N Engl J Med 2009;361: RELY Study: Outcome for Stroke or Embolism Connolly SJ et al. N Engl J Med 2009;361: EINSTEIN: Rivaroxaban for DVT Randomized, double blind 15 mg PO q12 hr for 21 days with food, then 20 mg PO qday for 6 months Recurrent VTE 2.1% v. 3% (HR 0.68) Major bleeding 0.8% v. 1.2% (NS) Bauersachs R, Berkowitz SD, et al. N Engl J Med 2010 Dec 23;363(26):

28 Rivaroxaban v. VKA for DVT The EINSTEIN Investigators. N Engl J Med 2010;363: Safety Outcome in Einstein The EINSTEIN Investigators. N Engl J Med 2010;363: ROCKET Study: Rivaroxabon v. Coumadin in Nonvalvular Afib Non-inferiority trial, 14, 264 pts, follow up 22 months Results: Stroke or embolism 2.1% v. 2.4% (significant for non-inferiority, NS for superiority) Bleeding, major and nonmajor 14.9% v. 14.5% (NS for superiority) Intracranial hemorrhage 0.5% v. 0.7% (significant for superiority) Patel MR, Mahaffey KW, Garg J, et al. N Engl J Med 2011;365(10):

29 AMPLIFY: Apixaban v. VKA in DVT or PE Randomized, double-blind 10 mg bid x 7 days, then 5 mg bid for 6 months SQ enoxaparin followed by heparin Composite bleeding 4.3% apixabon 9.7% VKA Relative risk 0.84 for death or recurrent DVT Agnelli G et al. N Engl J Med 2013;369: AMPLIFY: Apixaban v. VKA Agnelli G et al. N Engl J Med 2013;369: Aristotle Study: Apixaban v. Coumadin in Afib 18,201 pts with afib and at least one more risk factor 1.8. year follow-up 84 28

30 Aristotle: Primary Efficacy and Safety Outcomes Granger CB et al. N Engl J Med 2011;365: Aristotle: Summary Reduces stroke and systemic embolism by 21% Reduces major bleeding by 31% Reduces mortality by 11% Fewer discontinuations than warfarin Granger CB, Alexander JH, McMurray JJ, et al. N Engl J Med 2011;365(11): Hokusai: Edoxaban v. Coumadin in VTE pts with acute VTE. Non-inferiority study. 59% DVT, 41% PE LMWH or UFH for 5 days initially Results: edoxaban v. Coumadin Recurrent VTE 3.2% v. 3.5% (noninferior) Major or relevant nonmajor bleeding 8.5% v. 10.3% (NNT 56) No significant different in major bleeding or death Buller HR, Decousus H, Grosso MA, et al. N Engl J Med 2013;369(15):

31 Edoxaban Efficacy and Safety Giugliano RP et al. N Engl J Med 2013;369: