Management for Deep Vein Thrombosis and New Agents

Transcription

1 Management for Deep Vein Thrombosis and New Agents Mark Malesker, Pharm.D., FCCP, FCCP, FASHP, BCPS Professor of Pharmacy Practice and Medicine Creighton University 5 th Annual Creighton Cardiovascular Symposium Omaha, Nebraska, December 6, 2013 Objective 2 Identify issues and new agents in the management and treatment of deep venous thrombosis (DVT) 1

2 Faculty Disclosure 3 Mark A. Malesker, Pharm.D. Dr. Malesker has listed no financial interest/arrangement that would be considered a conflict of interest Outline 4 Describe the current American College of Chest Physicians (ACCP) recommendations for the treatment of DVT Clinical pharmacology of new oral anticoagulants Clinical trial data for new oral anticoagulants in the treatment of DVT 2

3 Ignatian Values Related To This Topic 5 Cura Personalis Care of the whole person Special concern for those most in need Economic Consequences of DVT and PE 6 DVT/PE has a substantial economic impact per patient Estimated average cost of management of DVT: $10,072 Estimated average cost of management of DVT with PE: $14,649 Hospital readmission may occur in 5-14% of patients Mean cost for a readmission for recurrent DVT: $11,862 Mean cost for PE readmission: $14,722 Over half of readmissions are within 90 days of initial hospitalization Pharmacoeconomics 2002;20:603-15, J Manag Care Pharm 2007;13:

4 7 Public Reporting and Consumer Choice Data on VTE hospital measures is publicly available Hospital Compare (Medicare) Quality Check (Joint Commission) The Leapfrog Group Advances in AC Therapy in the United States 1940s Heparin available commercially Injectable Agents 1998 First commerciallyavailable DTI 1993 First commerciallyavailable LMWH Warfarin available commercially Oral Agents 56 Years 2001 First commerciallyavailable synthetic factor Xa inhibitor 2010 Oral DTI 2011 Oral Xa 4

5 Inhibition of Coagulation Factors by Traditionally-Used Anticoagulants Intrinsic XII Extrinsic XI Tissue Factor Injectable UFH AT Injectable LMWH AT IX VIII X V VII II Oral Warfarin Fibrinogen UFH = unfractionated heparin. AT = antithrombin. Hirsh. Chest. 2001;119:64S-94S. Fibrin Clot Inhibition of Coagulation Cascade by New Anticoagulants Intrinsic XII Extrinsic Xa Inhibitors XI AT IX VIII X VII Tissue Factor V II DTIs Fibrinogen Weitz et al. Chest. 2001;119:95S-107S. Fibrin Clot 5

6 12 ACCP Antithrombotic Guidelines 9 th Edition Supplement in February 2012 issue of CHEST Executive Summary Introduction to Ninth Edition Methodology Complete guidelines available online ( via iphone, and ipad More than 600 recommendations for the prevention, diagnosis, and treatment of thrombosis Living Guideline Model Systematically developed, evidence-based, and continually updated recommendations 6

7 ACCP Grading System 13 Reflects system adopted for all ACCP guidelines The strength of any recommendation depends on two factors: The trade-off between benefits, risks, burdens, costs, and level of confidence in estimates of those benefits and risks The quality of the evidence upon which the recommendations are based (A, B, C) If benefits do (or do not) outweigh risks, burdens, and costs, a strong (Grade 1) recommendation is used. If there is less certainty about magnitude of benefits and risks, burdens, and costs, a weak (Grade 2) recommendation is used The phrase we recommend is used for strong recommendations (Grade 1A, 1B, 1C) and we suggest for weak recommendations (Grade 2A, 2B, 2C) Antithrombic Therapy for VTE 14 For acute DVT or PE, we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban CHEST 2012;141(2)(Suppl):e419S-e494S 7

8 15 Initial Anticoagulation for Patients With Acute DVT of the Leg In patients with acute DVT of the leg treated with VKA therapy, we recommend initial treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such initial treatment (Grade 1B) In patients with acute DVT of the leg, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) CHEST 2012;141(2)(Suppl):e419S-e494S Timing of Initiation of VKA and Duration of Parenteral Anticoagulant Therapy 16 In patients with acute DVT of the leg, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2.0 or above for at least 24 h (Grade 1B) CHEST 2012;141(2)(Suppl):e419S-e494S 8

9 Parenteral Anticoagulants 17 Heparin Weight based protocol LMWH Enoxaparin (Lovenox) Dalterparin (Fragmin) Factor Xa inhibitor Fondaparinux (Arixtra) Oral Anticoagulants 18 Warfarin Direct thrombin inhibitor Dabigatran etexilate (Pradaxa) Xa inhibitors Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban N Engl J Med 2013;369:

10 Future Management of VTE 19 Best Practice & Research Clinical Haematology 2013;26: Warfarin (Coumadin) million receive a dose daily in USA Gold standard oral anticoagulant for over 50 years Use limited by close monitoring to keep INR 2-3 At best, 60% of patients have INR within therapeutic range Half life is approximately 40 hours Genetic variations in metabolism account for variability in the therapeutic dose Slow onset/offset of action Potential for food interactions Many drug interactions exist 10

11 21 Advantages of Newer Oral Anticoagulants vs VKA Advantage Rapid onset of action Predictable anticoagulant effect Specific coagulation enzyme target Low potential for food interactions Low potential for drug interactions Clinical Implications No need for bridging No need for routine coagulation monitoring Low risk of off-target adverse effects No dietary precautions Few drug interactions Annu Rev Med 2011;62: Targeted Indications for New Oral Anticoagulants Prophylaxis of VTE (hip, knee, medically ill) Stroke prevention in atrial fibrillation Treatment of VTE Secondary prevention of VTE Acute coronary syndromes HIT 11

12 Dabigatran Etexilate (Pradaxa) 23 Direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation Dabigatran etexilate is prodrug of dabigatran and a substrate of p-glycoprotein (Pgp) Avoid concurrent use of rifampin (inducer) Oral bioavailability is 6%, peak plasma concentration achieved 2-3 h after administration Dialyzable because of low protein binding CHEST 2012;141(Suppl)e44s-e88s, Dabigatran Dose 24 Based upon renal function CrCl > 30 ml/min: 150 mg PO twice daily CrCl ml/min: 75 mg PO twice daily CrCl < 15 ml/min: not recommended Do not chew, break, or open capsules If dose not taken at scheduled time, the dose should be taken as soon as possible the same day the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose Never double the dose to make up missed dose CHEST 2012;141(Suppl)e44s-e88s, 12

13 Other Dabigatran Considerations 25 Storage Store in original package to protect from moisture Once opened use within 120 days, keep bottle tightly closed Side effect Dyspepsia Post-market reports of serious bleeding events and reports from FDA VTE studies: RE-COVER, RE-MEDY, RE-SONATE Arch Intern Med 2011;171: , Circulation 2011;123: , trials.gov RE-COVER Study 26 Objective: To compare the effectiveness and safety of dabigatran (D) with warfarin (W) therapy for treatment of VTE Methods: A randomized, double-blind, noninferiority trial was conducted, involving patients with acute VTE who were initially given parenteral anticoagulation for 8-11 days, and then randomized to D 150 mg twice daily or W with a therapeutic INR range of N Engl J Med 2009;361:

14 RE-COVER Results 27 A total of 1274 patients were randomized to D and 1265 received W therapy The number of recurrent thromboembolism was similar (2.4% with D vs. 2.1% with W, non-inferiority p <0.001) Major bleeding occurred in 1.6% of patients on D vs. 1.9% on W (HR for dabigatran 0.82, 95% CI ) The number of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in both groups Adverse events occurred in 9% patients on D vs. 6.8% on W (p=0.05), leading to discontinuation of the drug N Engl J Med 2009;361: RE-COVER Conclusion 28 D is as effective/safe as W for the treatment of acute VTE This drug does not need monitoring as compared to W N Engl J Med 2009;361:

15 Rivaroxaban (Xarelto) 29 Orally active factor Xa inhibitor approved for prevention of DVT in knee or hip replacement At least as effective as enoxaparin in clinical studies Approved for thromboembolism (stroke) prevention in atrial fibrillation Comparable to warfarin in efficacy, lower hemorrhagic stroke, higher rate of GI bleed Approved for the treatment of VTE and to reduce the risk of recurrent DVT and PE As effective as enoxaparin and VKA combination Bioavailability of 80%, max anticoagulant effects in 2-4 hours The most common adverse reaction (>5%) was bleeding CHEST 2012;141(Suppl)e44s-e88s, Xarelto Product Information. Nov 2012 Rivaroxaban (Xarelto) Dosing 30 Non-valvular atrial fibrillation For patients with CrCl > 50 ml/min: 20 mg once daily with evening meal For patients with CrCl ml/min: 15 mg once daily with the evening meal Prophylaxis of DVT following hip or knee replacement surgery Dose is 10 mg once daily for 35 days (hip replacement) Dose is 10 mg once daily for 12 days (knee replacement) 15

16 Rivaroxaban (Xarelto) Dosing 31 Treatment of DVT or PE 15 mg twice daily with food for first 21 days, then 20 mg once daily with food for remaining treatment Reduction in the risk of recurrence of DVT and PE 20 mg once daily with food following initial 6 months treatment for DVT/PE Rivaroxaban (Xarelto) 32 Mechanism of excretion: (1/3 unchanged via kidneys, 1/3 via liver CYP3A4, 1/3 metabolized in liver with inactive renal metabolites) Avoid use when CrCl < 15 ml/min Use with caution when CrCl 30 to < 50 ml/min Avoid use with Child-Pugh B-C or with hepatic disease associated coagulopathy Available as 10mg, 15mg, 20mg tablets VTE studies: EINSTEIN, EINSTEIN EXT, EINSTEIN PE CHEST 2012;141(Suppl)e44s-e88s,

17 Rivaroxaban (Xarelto) 33 No relevant effects of extreme body weight, age or gender Avoid use with combined P-gp and strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, lopinavir/ritonavir, indinavir/ritonavir, conivaptan, clarithromycin) Avoid use with combined P-gp and weak or moderate CYP3A4 inhibitors unless the benefit outweighs the bleeding risk in patients with renal dysfunction (erythromycin, verapamil, diltiazem, dronedarone) Avoid use with combined P-gp and strong CYP3A4 inducers (phenytoin, rifampin, carbamazepine, St. John s wort) Avoid use with clopidogrel unless the benefit outweighs risk CHEST 2012;141(Suppl)e44s-e88s, EINSTEIN DVT Study 34 Objective: To determine the safety and efficacy of rivaroxaban (R) for treatment of acute VTE as compared to warfarin (W) Methods: An open-label, randomized, event-driven, noninferiority study comparing oral R (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with SC enoxaparin followed by VKA The investigators also conducted a superiority study, that randomized patients to R (20 mg once daily) or placebo for an additional 6-12 months, after completing 6 to 12 months of VTE treatment N Engl J Med 2010;363:

18 EINSTEIN DVT Results 35 R was non-inferior to enoxaparin and VKA in terms of primary outcome of recurrent VTE (2.1% R vs. 3.0% in other group, p< for non-inferiority) Major bleeding occurred in 0.8% of the patients on R vs. 1.2% in the VKA group (HR 0.65, 95% CI ) Non-major bleeding was also similar in both groups (HR 0.97, 95% CI ) In the continued-treatment study, R demonstrated superior efficacy (1.3% vs. 7.1% in placebo group; HR 0.18, 95% CI ) N Engl J Med 2010;363: N Engl J Med 2010;363:

19 EINSTEIN DVT Conclusions 37 R was non-inferior to W in the initial treatment of acute VTE, with a similar safety profile R was also safe and effective for continued treatment of VTE N Engl J Med 2010;363: Apixaban (Eliquis) 38 Rapid absorption with onset of 1-3 hours Half-life is 8-15 hours Lower peak-to-trough concentration ratios seen with twice daily dosing Apixaban and metabolites are excreted by multiple elimination pathways (renal 25%, hepatic metabolism via CYP3A4 and intestinal excretion 55%) Can be used in presence of hepatic or renal dysfunction Avoid concurrent potent CYP3A4 inhibitors VTE trials: AMPLIFY, AMPLIFY EXT 19

20 AMPLIFY Study 39 Objective: To compare the efficacy and safety of apixaban (A) with conventional therapy (CT) in patients with acute symptomatic VTE Methods: A randomized, double-blind noninferiority trial compared A (10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (SC enoxaparin (1 mg/kg) q 12 hours for at least 5 days, followed by warfarin begun concomitantly for 6 months) N Engl J Med 2013; 369: AMPLIFY Results 40 A total of 2691 were randomized to A and 2704 received CT The primary efficacy outcome of recurrent symptomatic VTE or death related to VTE occurred in 2.3% with A and 2.7% in CT (p<0.001 for non-inferiority) Major bleeding occurred in 0.6% who received A vs. 1.8% who received CT (p<0.001 for superiority) The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% with A and 9.7% with CT (p<0.001 for superiority) N Engl J Med 2013; 369:

21 AMPLIFY Conclusions 41 A fixed-dose regimen of apixaban alone was non-inferior to conventional therapy for acute treatment of VTE and was associated with significantly less bleeding N Engl J Med 2013; 369: N Engl J Med 2013; 369:

22 Comparison of New Anticoagulants 43 Parameter Dabigatran Rivaroxaban Apixaban Target Thrombin Factor Xa Factor Xa Oral bioavailability 7% 60-80% 80% Dosing Fixed, 1D or 2D Fixed, 1D or 2D Fixed, 2D Time to Peak (h) Half-life (h) Routine coagulation No No No monitoring Renal clearance 80% 66%, half is 25% inactive drug Drug interactions Rifampin, quinidine, amiodarone, P-gp inhibitors 3A4 inhibitors, P-gp inhibitors 3A4 inhibitors Involvement of CYP No CYP3A4 CYP3A4 Annu Rev Med 2011;62:41-57, Chest 2012;141(2)(Suppl):e120s-e151s 44 Disadvantages of Newer Oral Anticoagulants Short half-life Potential for increased risk of stroke or systemic embolism with poor drug adherence No coagulation assay easily available to precisely measure anticoagulation effect Cannot titrate dose Cannot assess cause for failure of therapy (poor adherence vs. failure) Cannot easily assess degree of coagulation inhibition in emergent situations such as the need for urgent surgery or in the setting of life-threatening bleeding Circulation 2012;125:

23 45 Disadvantages of Newer Oral Anticoagulants No routine coagulation monitoring required Potential for increased risk of stroke or systemic embolism with poor drug adherence No antidote or well-established procedure for reversing anticoagulation in emergent situations Cost Circulation 2012;125: Components of a Protocol For Use of New Anticoagulants in Acute VTE Patient preference (informed treatment options) Patient selection (derived from clinical trials) Drug interactions (should be considered) Compliance (treatment contract) Follow-up (less intense vs. traditional treatment) Monitoring (document outcomes, report ADRs to P&T) N Engl J Med 2013;369:

24 Conclusions 47 Traditional treatment for acute VTE is bridging anticoagulation therapy from parenteral agent to VKA, which requires laboratory monitoring Clinical data exist for the use of new oral coagulants to treat VTE Only rivaroxaban is approved for this use These agents do not require laboratory monitoring More information needed on reversal Further clinical data needed for the routine use of these agents and head to head trial data is lacking ACCP AT10 is in progress 24