Dabigatran Warfarin RE-LY trial (atrial fibrillation) 150 mg bid P-value

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1 The Best of Chest Highlights of the 9 th edition ACCP guidelines for antithrombotic therapy and prevention of thrombosis Sidney V. Keisner, Pharm.D., BCPS Central Arkansas Veterans Healthcare System Little Rock, Arkansas Objectives Recognize changes in the approach to the development of the guideline Summarize major updates relevant to health system pharmacists Apply guideline recommendations to patient cases 2 Methodology Changes More summary tables DVT diagnosis Structure Changes Stricter rules for financial/intellectual conflicts New insights into evidence More emphasis on patient preference Reorganized venous thromboembolism (VTE) prevention Non-Surgery Orthopedic surgery Non-orthopedic surgery Omission of acute coronary syndrome sections Guyatt et al. CHEST. February 2012;141(2_suppl):53S-70S. doi: /chest New Anticoagulant Agents Direct thrombin inhibitor dabigatran etexilate Dabigatran etexilate Direct thrombin inhibitor FDA Indication: non-valvular atrial fibrillation Factor Xa inhibitor rivaroxaban apixaban RE-LY trial (atrial fibrillation) Primary endpoint: stoke or systemic embolism Dabigatran 150 mg bid n=6,076 (% per year) Warfarin n=6,022 (% per year) P-value <0.001 Major bleeding Not significant Hemorrhagic stroke <0.001 Gastrointestinal bleeding < Connolly et al. N Engl J Med 2009;361:

2 Dabigatran etexilate Dabigatran etexilate Postoperative VTE prophylaxis (not FDA approved) RE-MODEL and RE-NOVATE trials Primary endpoint: asymptomatic or venographic VTE and mortality Dabigatran (220 mg OR 110 mg once daily) noninferior to enoxaparin 40 mg once daily Treatment of VTE (not FDA approved) RE-COVER trial Primary endpoint: VTE recurrence and related deaths at 6 months Dabigatran 150 mg bid noninferior to warfarin Eriksson et al. Lancet Sep 15;370(9591): Eriksson et al. J Thromb Haemost Nov;5(11): Schulman et al. N Engl J Med 2009; 361: Dabigatran etexilate Dabigatran etexilate Pharmacokinetics Absorption Rapid Protein binding 35% Metabolism Bioavailability 3-7% Half life Excretion Urine (80%) Hydrolyzed to active form by plasma and hepatic esterases dabigatran Hepatic glucuronidation to active isomers Average: hours Elderly: hours Mild-to-moderate renal impairment: hours Severe renal impairment: 28 hours Dosing: 150 mg bid (atrial fibrillation) Renal impairment Cl cr ml/min: 75 mg twice daily Cl cr <15 ml/min or hemodialysis: not studied Non-bleeding adverse effects Dyspepsia, gastritis like symptoms, anemia 9 10 Factor Xa inhibitor FDA-approved indications postoperative VTE prophylaxis (hip and knee) non-valvular atrial fibrillation 11 VTE prophylaxis after hip replacement RECORD 1 (n=4541) 10 mg daily vs enoxaparin (both x35d) RECORD 2 (n=2509) 10 mg daily x35d vs. enoxaparin x10-14d RECORD I (%) Enoxaparin (%) P value Primary endpoint: VTE + all cause mortality <0.001 Major bleeding Not significant RECORD II Primary endpoint: VTE + all cause mortality <0.001 Major bleeding Not significant Eriksson et al. N Engl J Med Jun 26;358(26): Kakkar et al. Lancet 2008; 372:

3 VTE prophylaxis after knee replacement RECORD 3 (n=2531) 10 mg daily x14d vs enoxaparin x14d RECORD III (%) Enoxaparin (%) P value Primary endpoint: VTE + all cause mortality <0.001 Non-valvular atrial fibrillation not addressed in 2012 atrial fibrillation recommendations ROCKET AF trial Primary endpoint: stroke and non-cns embolism 20 mg daily noninferior to warfarin Major bleeding Not significant Lassen et al. N Engl J Med 2008; 358: Patel et al. N Engl J Med, 2011, 365(10): Treatment of VTE (not FDA approved) EINSTEIN trial Primary endpoint: recurrent VTE noninferior to vitamin K antagonist (VKA) dose: 15 mg bid for 3 weeks, then 20 mg once daily Pharmacokinetics Absorption Rapid Protein binding 92-95% Metabolism CYP 3A4/5 and CYP2J2 Bioavailability 10 mg dose: ~80% to 100% 20 mg dose: ~66% (fasting; increased with food) Half life Excretion Terminal: 5-9 hours; Elderly: hours Urine: (66%; 36% as unchanged drug; 30% as inactive metabolites) Feces : (28%; 7% as unchanged drug; 21% as inactive metabolites) Bauersachs et al. N Engl J Med Dec 23;363(26): Dosing Atrial fibrillation: 20 mg once daily Postoperative VTE prophylaxis: 10 mg once daily Dosing Renal impairment (atrial fibrillation) Cl cr ml/minute: 15 mg once daily Cl cr <15 ml/minute: Avoid use Renal impairment (postoperative VTE prophylaxis) Cl cr ml/minute: No dosage adjustment; use with caution Cl cr <30 ml/minute: Avoid use Avoid in moderate-severe hepatic impairment

4 Apixaban Apixaban Factor Xa inhibitor Not FDA approved Addressed in postoperative VTE prophylaxis guideline Postoperative VTE prophylaxis Primary endpoint: DVT, nonfatal pulmonary embolism, and death from any cause ADVANCE 1 (knee): Apixaban NOT noninferior to enoxaparin ADVANCE 2 (knee): Apixaban superior to enoxaparin ADVANCE 3 (hip): Apixaban superior to enoxaparin 19 Lassen et al. N Engl J Med 2010;363: Lassen et al. N Engl J Med 2009;361: Lassen et al. Lancet 2010, 375(9717): Apixaban Atrial fibrillation ARISTOTLE trial Primary endpoint: ischemic or hemorrhagic stroke or systemic embolism Apixaban superior to warfarin with less major bleeding and fewer deaths Pharmacokinetics Absorption Rapid Protein binding 87% Metabolism Bioavailability 50% Half life Excretion Apixaban Predominantly via CYP3A4/5 to inactive metabolites; substrate of P glycoprotein and breast cancer resistant protein 8 hours Urine (27% as parent drug) Feces (25% recovered as metabolites) Granger et al. N Engl J Med 2011;365: Apixaban Dosing (per trials) Postoperative VTE prophylaxis: 2.5 mg bid Atrial fibrillation: 5 mg bid Renal impairment Severe impairment: excluded from trials Hepatic impairment Pt with active hepatobiliary disease excluded from ADVANCE trials Grading of recommendations Strength of Quality of recommendation evidence 1A Strong high 1B Strong moderate 1C Strong Low/very low 2A Weak high 2B Weak moderate 2C Weak Low/very low Benefit vs Risk and Burdens Benefits clearly outweigh risk and burdens or vice versa Benefits closely balanced with risks and burden Uncertainty in the estimates of benefits, risks, and burden; benefits, risk, and burden may be closely balanced

5 AC is a 65 year old woman admitted for total hip arthroplasty PMH HTN, hyperlipidemia, osteoarthritis of left hip Medications Scenario 1 simvastatin, lisinopril, acetaminophen No known drug allergies 25 Vital signs/pe: normal Scenario 1 Laboratory: CMP, CBC, PT, PTT within normal limits Hip X-ray: severe arthritis with a shallow acetabulum (hip socket) and nearly dislocated hip joint AC undergoes successful THA without immediate complications 26 Questions VTE prevention: hip replacement What agents are recommended for prevention of postoperative VTE? When should antithrombotic therapy be initiated? What is the optimal duration of antithrombotic therapy? Low molecular weight heparin (LMWH; 1B) Fondaparinux (1B) Adjusted-dose VKA (1B) (1B) Dabigatran (not FDA approved; 1B) Apixaban (not FDA approved; 1B) Low dose unfractionated heparin (LDUH; 1B) Aspirin (1B) Intermittent pneumatic compression (IPC; 1C) VTE prevention: hip replacement Consider LMWH over other alternatives (2B/2C) lack of long term safety data with new agents Possible bleeding with fondaparinux, rivaroxaban, VKA possible efficacy with LDUH, VKA, aspirin, IPC VTE prevention: hip replacement May consider adding IPC to pharmacologic prophylaxis during hospital stay (2C) If increased bleeding risk or contraindication to both pharmacologic and mechanical prophylaxis, suggest against using IVC filter (2C) Falck-Ytter et al. CHEST. February 2012;141(2_suppl):e278S-e325S. doi: /chest Falck-Ytter et al. CHEST. February 2012;141(2_suppl):e278S-e325S. doi: /chest

6 VTE prevention: hip replacement Scenario 1 Questions When to initiate prophylaxis LMWH Start either 12 hours or more before surgery OR 12 hours or more after surgery (1B) Not specifically addressed for other agents Duration of prophylaxis Minimum of days (1B/1C) Option of extending up to 35 days (2B) Falck-Ytter et al. CHEST. February 2012;141(2_suppl):e278S-e325S. doi: /chest What agents are appropriate for AC for prevention of postoperative VTE? When should antithrombotic therapy be initiated for AC? What is the optimal duration of antithrombotic therapy for AC? 32 VTE prevention: other orthopedic surgeries Knee replacement: Similar recommendations as hip replacement Hip fracture surgery: Similar recommendations as for hip and knee replacement except dabigatran, rivaroxaban, apixaban have not been studied for this indication Falck-Ytter et al. CHEST. February 2012;141(2_suppl):e278S-e325S. doi: /chest Scenario 2 AC was given enoxaparin 40 mg sc daily starting 12 hours after her hip replacement surgery. Five days later, she experienced pain behind right knee that extends to calf. Denies sob, chest pain. PE: right calf tight, warm to touch, tender, 1+ pretibial pitting edema VS: normal 34 D Dimer: 10 mcg/ml Scenario 2 Lower extremity venous duplex ultrasonography: acute DVT of right femoral, popliteal, and peroneal veins Questions When should treatment be initiated for acute DVT of lower leg based on level of suspicion of diagnosis? What options for anticoagulation are recommended for acute DVT of lower leg? What is the optimal duration of anticoagulation for acute DVT of lower leg?

7 Acute Lower Extremity DVT Acute Lower Extremity DVT Initiation of parenteral anticoagulation (all 2C) High clinical suspicion: treat while awaiting test results (same as old guideline; 2C)) Intermediate clinical suspicion: do not treat unless test results will be delayed >4h (2C) Low clinical suspicion: treat if test results will be delayed >24 hours (2C) Initial Treatment options: LMWH, fondaparinux, UFH (no change; 1B) Suggest LMWH or fondaparinux over UFH (2B/2C) Suggest once daily over twice daily LMWH dosing only if total daily dose is the same (2C) Start VKA early (if used); continue parenteral anticoagulation for >5 days AND until INR >2 (1B) Acute Lower Extremity DVT Acute Lower Extremity DVT Isolated distal DVT of leg Option of serial imaging instead of anticoagulation if not high risk for extension or severely symptomatic (2C) Risk factors for extension: Positive D-dimer, thrombosis that is extensive or close to proximal veins, no reversible risk factor for DVT, active cancer, history of VTE, inpatient status Inferior vena cava (IVC) filter Only if contraindication to anticoagulation (1B) If contraindication resolves, conventional course of anticoagulation (2B) Permanent filter is not an indication for anticoagulation Acute Lower Extremity DVT Duration of therapy Longer term therapy No cancer: VKA (2C) Second choice: LMWH Cancer: LMWH (2B) Second choice: VKA Third choice [cancer (2B) or no cancer (2C)] dabigatran, rivaroxaban Duration of anticoagulation (DVT and/or PE) Provoked VTE (surgical or non-surgical risk factor) Unprovoked VTE First unprovoked VTE Second unprovoked VTE VTE and active cancer 3 months At least 3 months; after 3 months, reevaluate risk vs benefit of further therapy Isolated distal DVT: 3 months All others: -Low to moderate bleed risk: extended therapy -High bleed risk: 3 months Low or moderate bleed risk: extended treatment High bleed risk: 3 months extended treatment Extended treatment= therapy beyond 3 months without a scheduled stop date

8 Scenario 2 Questions Acute pulmonary embolism What are treatment options are for AC s acute DVT? Similar treatment recommendations as DVT except for role of thrombolysis/thrombectomy What is the optimal duration of treatment of AC s acute DVT? Other VTE Upper extremity DVT Treat if axillary or more proximal veins affected (1B) Duration of treatment: 3 months (same) If catheter not removed, treat for as long as it remains (1C) Superficial Vein Thrombosis Treat if lower limb, >5 cm Prophylactic dose LMWH or fondaparinux x45 d (2C) Suggest fondaparinux over LMWH due to higher quality evidence (2C) 45 Scenario 3 5 years later, AC (now 70 y/o) presents to the emergency room with complaints of heart palpitations and dizziness for the past 5 days PMH: HTN, hyperlipidemia, osteoarthritis of left hip s/p total hip replacement complicated by acute proximal DVT Current Medications: simvastatin, acetaminophen, lisinopril 46 Scenario 3 VS/PE within normal limits except for irregular heart rhythm and tachycardia Laboratory: CBC, CMP normal ECG: atrial fibrillation, HR=150 Questions How is risk for stroke assessed in patients with atrial fibrillation? Who should be started on antithrombotic therapy to prevent stroke due to atrial fibrillation? If indicated, what antithrombotic agents are recommended for patients with atrial fibrillation?

9 Analysis of stroke risk CHADS 2 score CHF, HTN, Age >75 y, DM, Stroke/TIA CHADS 2 score >2 Treat with oral anticoagulation (1B) Oral anticoagulation = VKA or dabigatran CHA 2 DS 2 -VASc score CHF, HTN, Age >75 y, DM Stroke/TIA/Systemic embolism Vascular disease (CAD, MI, PAD, aortic plaque) Age y Sex category: female If contraindication to oral anticoagulation (other than bleeding risk) aspirin+clopidogrel recommended over aspirin alone (1B) CHADS 2 score=1 Treat with oral anticoagulation rather than aspirin or aspirin+clopidogrel (2B) If contraindication to oral anticoagulation (other than bleeding risk): aspirin+clopidogrel rather than aspirin (2B) CHADS 2 score=0 Suggest no therapy (2B) If patient opts for antithrombotic therapy: Aspirin alone (2B) Patients managed with rhythm control Anticoagulate according to risk regardless of apparent rhythm (2C) Cardioversion planned: A fib duration <48 hours LMWH or UFH prior to cardioversion (2C) New anticoagulants Suggest dabigatran 150 mg bid over VKA (2B) Caution: renal impairment, no antidote A fib duration > 48 hours (or unknown) LMWH, warfarin, or dabigatran x3 weeks prior to cardioversion (1B) After successful cardioversion, anticoagulate for 4 weeks. Then, treat based on stroke risk

10 Scenario 3 Questions Should antithrombotic therapy be initiated to reduce stroke risk due to atrial fibrillation for AC? If indicated, what antithrombotic agents are recommended for AC? Coronary stent placement CHADS 2 >2 Initial period post stent BMS: Triple therapy x1 mo (2C) DES: Triple therapy x3-6 mo (2C) After initial period up to 12 months VKA+ single antiplatelet (2C) CHADS 2 =0-1 dual antiplatelet tx (regardless of stent type; 2C) Triple therapy: VKA + aspirin + clopidogrel Acute coronary syndrome without stent >12 months after stent or ACS without stent CHADS 2 >1 CHADS 2 =0 First 12 months after event VKA+single antiplatelet (2C) Dual antiplatelet tx (2C) If stable CAD and if oral anticoagulation chosen to reduce stroke risk due to atrial fibrillation VKA alone rather than combination of VKA and aspirin (2C) Stable CAD: no PCI, ACS, CABG in one year (angina okay) Honorable Mentions Honorable Mentions Warfarin loading dose at initiation of therapy 10 mg daily x2 days, then adjust based on INR (2C) VKA monitoring frequency If stable INR, extend follow up to every 12 weeks (2B) Single subtherapeutic INR (previously stable) No bridge required (2C) Recommend against routine vitamin K supplementation (2C) Previously stable, single INR out of range by <0.5 Keep same dose and recheck within 1-2 weeks (2C) Holbrook et al. CHEST. February 2012;141(2_suppl):e152S-e184S. doi: /chest Holbrook et al. CHEST. February 2012;141(2_suppl):e152S-e184S. doi: /chest

11 Honorable Mentions Vitamin K for high INR INR value Action without bleeding No vitamin K recommended (2B) Honorable Mentions Mechanical heart valve Add aspirin ( mg/g) to VKA regardless of risk factors (1B) >10 without bleeding Oral vitamin K (2C) Any INR, major bleeding PCC=prothrombin complex concentrate 4 factor PCC+ Vitamin K 5-10 mg IV (2C) *PCC suggested rather than plasma (2C) Holbrook et al. CHEST. February 2012;141(2_suppl):e152S-e184S. doi: /chest Acute coronary syndrome Ticagrelor/aspirin OR clopidogrel/aspirin x12 mo (1B) Prasugrel/aspirin x12 mo (stent patients only) (1B) Suggest ticagrelor/aspirin over clopidogrel/aspirin (2B) Vandvik et al. CHEST. February 2012;141(2_suppl):e637S-e668S. Whitlock et al. CHEST. February 2012;141(2_suppl):e576S-e600S. 62 Honorable Mentions Anterior MI with LV thrombus No stent Bare metal stent Drug eluting stent Initial period After initial period up to 12 months Warfarin + aspirin x3 mo (1B) Triple therapy x1 mo (2C) Triple therapy x3-6 mo (2C) Dual antiplatelet tx Warfarin + single antiplatelet x2 mo, then dual antiplatelet therapy (2C) Dual antiplatelet tx Questions Triple therapy: VKA + aspirin + clopidogrel Vandvik et al. CHEST. February 2012;141(2_suppl):e637S-e668S References 1. Bauersachs R, Berkowitz SD, Brenner B et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med Dec 23;363(26): Epub 2010 Dec Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: Eriksson BI, Borris LC, Friedman RJ et al. versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med Jun 26;358(26): Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, doubleblind, non-inferiority trial. Lancet Sep 15;370(9591): Eriksson BI, Dahl OE, Rosencher N et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost Nov;5(11): Falck-Ytter F, Francis CW, Johanson NA et al. Prevention of VTE in Orthopedic Surgery Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST. February 2012;141(2_suppl):e278S-e325S. doi: /chest Granger CB, Alexander JH, McMurray JJV et al. Apixaban versus Warfarin in Patients with. N Engl J Med 2011;365: Guyatt GH, Norris SL, Schulman S et al. Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. CHEST. February 2012;141(2_suppl):53S-70S. doi: /chest References 9. Hirsh J, Guyatt G, Albers GW et al. Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). CHEST. June 2008;133(6_suppl):71S-109S. doi: /chest Holbrook A, Schulman S, Witt DM et al. Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST. February 2012;141(2_suppl):e152S-e184S. doi: /chest Kakkar AK, Brenner B, Dahl OE et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372: Kearon C, Akl EA, Comerota AJ et al. Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST. February 2012;141(2_suppl):e419S-e494S. doi: 13. Lassen MR, Ageno W, Borris LC et al. versus Enoxaparin for Thromboprophylaxis after Total Knee Arthroplasty. N Engl J Med 2008; 358: Lassen MR, Gallus A, Raskob GE et al. Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement. N Engl J Med 2010;363: Lassen MR, Raskob GE, Gallus A, et al. Apixaban Versus Enoxaparin for Thromboprophylaxis After Knee Replacement (ADVANCE-2): A Randomised Double-Blind Trial. Lancet 2010, 375(9717):

12 References 16. Lassen MR, Raskob GE, Gallus A et al. Apixaban or Enoxaparin for Thromboprophylaxis after Knee Replacement. N Engl J Med 2009;361: Comp, Inc.; September 5, Patel MR, Mahaffey KW, Garg J et al. versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med, 2011, 365(10): Schulman S, Kearon C, Kakkar AK et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med 2009; 361: Vandvik O, Lincoff AM, Gore JM et al. Primary and Secondary Prevention of Cardiovascular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST. February 2012;141(2_suppl):e637S-e668S. doi: /chest Whitlock RP, Sun JC, Fremes SE et al. Antithrombotic and Thrombolytic Therapy for Valvular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST. February 2012;141(2_suppl):e576S-e600S. doi: /chest You JJ, Singer DE, Howard PA et al. Antithrombotic Therapy for : Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST. February 2012;141(2_suppl):e531S-e575S. doi: 67 12