New Anticoagulation Agents

Transcription

1 New Anticoagulation Agents Use of New and Older Therapeutic Agents in the Treatment Regimen Michelle Geddes

2 Case 1 40 year old woman with idiopathic proximal DVT. Previous heparin allergy (wheals, hives) when given LMWH prophylaxis around abd surgery What initial treatment option would you use? A) LMWH +/- benadryl B) IV heparin +/- benadryl C) fondaparinux D) danaparoid sc E) other

3 Case 2 80 year old man in nursing home with atrial fibrillation, on longstanding warfarin Difficult venous access: family does not want to continue with blood draws as they feel it is onerous on the patient Do you have any oral options available that do not require monitoring?

4 Oral Characteristics of the ideal Reversible anticoagulant Minimal adverse effects/wide therapeutic margins Predictable anticoagulation effect No monitoring Inexpensive

5 Overview of Anticoagulants Inhibit initiation of thrombosis Target tissue factor/viia complex Prevent clot propagation Inhibit IXa or Xa, or cofactors VIIIa or Va Direct Xa inhibitors inhibit both free and platelet-bound Xa Indirect inhibitors catalyze free Xa inhibition by antithrombin eg fondaparinux Alter fibrin production Target thrombin Platelet activation, fibrin formation, fibrinolysis inhibition, cellular effects

6 Coumadin Fondaparinux (Idraparinux) Rivaroxaban Apixaban Heparin LMWH Warfarin Argatroban Hirudin Bivalirudin (Ximelagatran) Dabigatran Heparin Warfarin

7 Heparin Rapid effect Narrow therapeutic window Requires monitoring Differences in bioavailability Nonspecific or competitive obstruction of binding sites by plasma proteins, PF4, acute phase reactants Reduced inactivation of thrombin bound to fibrin and Xa bound to activated plts within clot IV or sc only

8 AT Thrombin HEPARIN AT Xa HEPARIN and LMWH

9 Warfarin Available for >50y Oral, half-life 36-42h Narrow therapeutic window Multiple drug interactions CYP2C9, protein binding Requires monitoring

10 Mechanism of Warfarin Bloodjournal library.org

11 Can we make warfarin and heparin dosing safer?

12 Warfarin Pharmacogenetics August 2007 FDA changed the label for warfarin Black box warning regarding bleeding Lower initiation doses should be considered for patients with certain genetic variation in CYP and VKORC1 enzymes genotyping not required CYP2C9 genotype affects stable warfarin dose Alters warfarin metabolism patients with 1 variant alleles had greater INRs, time to stabilize, bleeds VKORC1 genotype (target) alters stable warfarin dose and predicts warfarin resistance Retrospective studies show haplotype assoc with dose and genotype associated with >70 mg/week warfarin

13 New Anticoagulants Xa inhibitors Fondaparinux, SSR236517, rivaroxaban, apixaban Direct thrombin inhibitors Dabigatran Argatroban Bivalirudin Ancrod

14 Fondaparinux Synthetic pentasaccharide analog of the antithrombinbinding pentasaccharide on heparin and LMWH Indirect Factor Xa inhibitor Catalayze antithrombin inhibition of Xa Once daily injection Not currently reversible Renal clearance accumulates in patients with renal insufficiency (<30ml/min) underweight patients AT Xa

15 Fondaparinux and VTE PE 2213 patients randomized to fondaparinux vs. UFH x5d or until INR>2 with warfarin, then 3m warfarin Similar recurrence VTE 3.8% fondaparinux and 5.0% UFH Major bleed 1.3% vs 1.1% (7.7% vs 3.6% if CrCl <30mL/min) Major or clinically relevant bleed 4.5% vs 6.3%, death 5.2 vs 4.4% DVT 2205 patients randomized to fondaparinux vs enoxaparin bid x5d until INR >2, then 3m warfarin Similar 3m recurrence VTE 3.9% fondaparinux v 4.1% enox Major bleed similar 1.1 vs 1.2%, mortality 3.8% vs 3.0% NEJM 2003; 349:1695, Ann Int Med 2004;140:871

16 Fondaparinux Prophylaxis in Medical Patients ARTEMIS: randomized double-blind placebocontrolled trial of fondaparinux VTE prophylaxis in 849 patients >60y hospitalized for medical illness with moderate VTE risk, bedridden 4d Fondaparinux 2.5 mg sc daily 6-14d Reduced radiographic VTE from 10.5% placebo to 5.6% (RRR 47%, 95% CI 8-69) Major bleed 0.2% each group BMJ 2006; 332(7537): 325

17 Fondaparinux prophylaxis in Orthopedics Study Surgical Site N DVT (%) RR EPHESUS Elective Hip 2309 FPX 5% LMWH 9% PENTATHLON Elective Hip 2275 FPX 6% LMWH 8% PENTAMAKS Knee 1049 FPX 13% LMWH 28% PENTHIFRA Hip Fracture 1711 FPX 8% LMWH 19% 56% 25% 55% 56% Meta-analysis: day 11 DVT 13.7% LMWH vs 6.8% fondaparinux No difference in symptomatic VTE. PE, fatal PE, or death Major bleed 2.7 vs 1.7% Arch Int Med 2002; 162:1833

18 Fondaparinux Alternative to heparin and LMWH for treatment of acute PE and DVT No data for long term therapy Licensed for VTE prevention in high-risk orthopedic surgery patients ACS NSTEMI or unstable angina; use in STEMI in patients on thrombolytics or no reperfusion tx Risk of catheter thrombosis if no concurrent heparin Health Canada

19 New Pentasaccharides Second and third generation synthetic pentasaccharides include longer half-life (once weekly injection) and biotinylated variant (rapidly reversed with IV avidin) SSR Long-acting pentasaccharides are being compared with warfarin for extended treatment in phase III trials Safety and efficacy are not yet established Pentasaccharide-containing hexadecasaccharide Accelerates the antithrombin-induced inhibition of Xa and thrombin Better bioavailability than heparin by sc injection Less likely to cause HIT, renally cleared

20 Direct Xa Inhibitors Oral agents and parenteral small-molecule direct inhibitors of factor Xa and thrombin Reversibly block active site of Factor Xa No effective antidote for acute bleeding

21 Coumadin Fondaparinux (Idraparinux) Rivaroxaban Apixaban Heparin LMWH Warfarin Argatroban Hirudin Bivalirudin (Ximelagatran) Dabigatran Heparin Warfarin

22 Rivaroxaban 80% oral bioavailability, half-life 9h Renal and fecal clearance Changes in renal function must be considered Safety data not available for CrCl < 30mL/min Health Canada approval for VTE prophylaxis for THR or TKR surgery Phase III trials underway for afib, VTE treatment, VTE prevention in medically hospitalized patients and ACS Health Canada

23 Rivaroxaban THR Prophylaxis Trial (n) Therapy VTE% P Major Bleeding % P RECORD1 THR (2531) RECORD2 THR (2509) 10mg QDx35d; 6-8h postop Enox 40mg QD x 35d; preop 10mg QDx35d; 6-8h postop Enox 40mg QD x 10-14d; preop 1.1 < NS < NS NEJM 2008; 358:2765, Blood 2007;110: 97a

24 Rivaroxaban TKR Prophylaxis Trial (n) Therapy VTE% P Major Bleed % P RECORD3 TKR (2531) RECORD4 TKR (3148) 10mgQD x 10-14d; 6-8h postop Enox 40mg x 10-14d; pre-op 10mgQD x 10-14d; 6-8h postop Enox 30mg bid x 10-14d; 12-24h post-op 9.6 < NS Blood 2007; 110:97a-98a, Blood 2008; 112:35a

25 Treatment of DVT Phase III trials ongoing (MAGELLAN study) Two dose-ranging trials randomized patients with proximal DVT to 3m rivaroxaban (doses 10 mg bid 40 mg qd) vs UFH/LMWH + coumadin N=613 patients: endpoint reduced thrombus burden on 21d U/S 43.8% rivaroxaban vs 59.2% conventional N=543 patients: Composite endpoint VTE-related death, DVT, PE, plus increase in thrombus by serial U/S and V:Q 6% in rivaroxaban vs 9.9% conventional therapy Circulation 2007; 116:131, Blood 2008; 112:2242

26 Rivaroxaban and Atrial Fib ROCKET study: Rivaroxaban 20mg daily Xa inhibition vs. Warfarin (N=14264) Stroke or systemic embolism non-inferior (1.7%/y vs. 2.2%/y, p<0.001 for non-inferiority) Major and nonmajor clinically relevant bleeding 14.9%/y vs 14.5%/y Intracranial hemm 0.5% vs 0.7%, (p=0.02) and fatal bleeding less (0.2% vs. 0.5%, p=0.003) Patel NEJM epub Aug 10, 2011

27 Apixaban Oral Xa Inhibitor Oral bioavailability, half life 12h (bid ) Fecal and renal (25%) excretion Undergoing FDA evaluation in US Ongoing phase III studies orthopedic surgery, hospitalized medical patients, VTE tx

28 J Thromb Haem 2007; 5:2368, J Thromb Haem 2008; 6:1313 Apixiban Phase II study prophylaxis in knee replacement: N=1,238 comparing apixiban 5, 10, 20mg 1-2x/d with enoxaparin 30 mg bid or warfarin Composite total VTE and all-cause mortality lower with apixaban in all doses Total bleeding lower than conventional treatment at 2.5 mg bid or 5 mg qd dosing, but higher at 10-20mg doses Phase II DVT treatment: Dose-ranging study N=520 symptomatic DVT treated 84-91d with one of 3 apixaban doses or LMWH + VKA Endpoint worsening US or symptomatic recurrence apixaban 4.7% vs 4.2%, no difference bleeding

29 ADVANCE-1 Trial Apixaban Phase III, N=3195 Patients with TKR randomized to apixaban 2.5 mg q12h or enoxaparin 30 mg bid 12d treatment starting 12-24h postop VTE endpoint apixaban 8.99% vs 8.85% Barely failed to meet noninferiority criteria Low event rate in enoxaparin arm influenced statistical results; clinical significance? Bleeding 2.88% vs 4.28%? surgical bleeding Blood 2008; 112:31a

30 ARISTOTLE Trial Apixaban 5mg bid vs warfarin for INR 2-3 in atrial fibrillation (phase III, N= 18201) Patients with afib and 1 additional CVA risk factor Apixaban superior to warfarin risk of CVA or systemic embolism by 21% 1.27%/y vs 1.60%/y (HR 0.79, CI ) risk of major bleeding 31% Hemm CVA 0.24%/y vs 0.47%/y death from any cause 11% For every 1000 patients treated 1.8y, prevented stroke in 6 patients, major bleeding in 15 patients, death in 8 patients Granger NEJM epub Aug 28, 2011

31 Thrombin Inhibitors: Inhibitors of Fibrin Formation Thrombin converts fibrinogen to fibrin in final step of clot formation Indirect thrombin inhibitors catalyze heparin cofactor II Direct thrombin inhibitors bind thrombin and interfere with substrate interaction Predictable - do not bind plasma proteins Clot-bound and free fibrin Do not find platelet factor 4 found near platelet thrombi Hirudin, argatroban, and bivalirudin licenced Ximelagatran withdrawn from market due to potential hepatotoxicity

32 Dabigatran Etexilate Prodrug, 5-6% GI bioavailability in acid environment Half-life 8h, increases to 17h after multiple doses Possibility of once or twice daily oral dosing 80% renally excreted contraindicated if CrCl<30ml/min; half life can be greater than 24h Approved by Health Canada for prophylaxis in TKR and THR Ongoing phase III trials for VTE treatment

33 Dabigatran Phase III Trials Orthopedic Surgery Trial (n) Dose Sched VTE% P Major bleed% RE- NOVATE THR/TKR (3494) RE-MODEL TKR (2076) RE- MOBILIZE TKR (2615) 220 mg Qdx28-35d, 6.0 NI mg 1-4h postop ½ dose 8.6 NI 1.3 Enox 40 mg Qdx28-35d, 12h preop mg Qdx6-10d; 1-4h postop 36.4 NI mg 40.5 NI 1.3 Enox 40 mg Qdx6-10d; 12h preop mg Qdx12-15d; mg 6h postop ½ dose 33.7 < Enox 30mg BID; 12-14h postop J Thromb Haem 2007; 5:2178, Lancet 2007: 370:949, J arthroplasty 2009; 24:1

34 Dabigatran in Atrial Fib: RE-LY Dabigatran 150 mg bid compared to warfarin Stroke (ischemic or unspecified) (1.1%/y vs 1.7%/y, p<0.001 for superiority) Rate of bleeding not different (3.1% vs 3.6%) Increased GI bleeding Dabigatran 110 mg bid compared to warfarin CVA rate similar (1.53%/y vs. 1.69%/y) Lower major bleeding compared to warfarin (2.7%, p=0.003), hemm CVA 0.38%/y vs 0.12%/y Connolly NEJM 2009; 361:1151

35 Dabigatran in VTE RE-COVER study: N=2539 patients with VTE Dabigatran 150 mg bid vs warfarin for 6m Noninferior to prevent symptomatic VTE and death: 2.4% with dabigatran vs 2.1% warfarin HR 1.10 (CI ) Major bleeding in 1.6% with dabigatran vs 1.9% warfarin (any bleeding 16.1 vs 21.9%) Not yet approved for this indication

36 Cost and availability 1 week drug supply Drug Dose Available Cost at FMC? Enoxaparin 40 mg/d Yes $ Warfarin 3 mg/d Yes $14.58 Fondaparinux 7.5 mg/d Yes $ Dabigatran 150 mg/d No Rivaroxaban 10 mg/d Yes $79.92 Apixaban 5mg bid No

37 Conclusions Options for prophylaxis of VTE in orthopedic surgery Other indications are being investigated Renal insufficiency and lack of reversibility are areas of concern Not yet time to replace heparin and warfarin Await results of further studies and costeffectiveness

38 Case 1 40 year old woman with idiopathic proximal DVT. Previous heparin allergy (wheals, hives) when given LMWH prophylaxis around abd surgery What initial treatment option would you use? A) LMWH and benadryl B) IV heparin C) fondaparinux D) darbopoietin sc E) other

39 Case 2 80 year old man in nursing home with atrial fibrillation, on longstanding coumadin Family does not want to continue with blood draws; feels onerous on the patient Do you have any oral options available that do not require monitoring?