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Advancements In Anticoagulation

Advancements In Anticoagulation. John Devlin, Pharm D Feb 4, 2009 . Agenda. Unmet needs in anticoagulation Niche for new anticoagulants Dabigatran Etexilate Evidence for efficacy and safety from phase 3 randomized trials Implications for clinical practice Comparing agents

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Advancements In Anticoagulation

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  1. Advancements In Anticoagulation John Devlin, Pharm D Feb 4, 2009

  2. Agenda Unmet needs in anticoagulation Niche for new anticoagulants Dabigatran Etexilate Evidence for efficacy and safety from phase 3 randomized trials Implications for clinical practice Comparing agents Future developments

  3. Currently available anticoagulants Parenteral Agents Heparins UFH LMWH (3 agents) Heparinoids Anti-Xa Fondaparinux DTIs Bivalirudin / hirudin Argatroban • Oral Agents • VKA’s • Warfarin • Acenocoumarol

  4. Place in therapy Venous thrombosis • Prevention • In-hospital • Out-of-hospital • Treatment • Initial • Long term Arterial thrombosis • Treatment • ACS • Prevention • Stroke (AF, CHF, Prosthetic valves) • Post MI • PCI / HD

  5. The “Magic Bullet” Oral Dosage Form Little or no monitoring required Equally efficacious and safe to current treatments Consistent dosing regimen (wide therapeutic window) Predictable PK and PD Free from alcohol and food interactions Free from drug interactions Un phased by genetic factors (VKOR, CYP2C9) Un phased by organ dysfunction Reversibility Rapid onset and offset Inexpensive

  6. Urgent Need to Replace Warfarin!

  7. Where Can We Improve? Venous thrombosis • Prevention • In-hospital • Out-of-hospital • Treatment • Initial • Long term Arterial thrombosis • Treatment • ACS • Prevention • Stroke (AF, CHF, Prothestic heart valves) • Post MI • PCI / HD

  8. VTE Prevention“Call to Action” on DVT and PE September 15, 2008 (Washington, DC) - The Office of the Surgeon General called today for a coordinated, multifaceted plan to reduce the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the us. The “call to action” is intended to increase awareness about these silent conditions and emphasize the importance of evidence based practices in the management of DVT.

  9. Out of HospitalUnderuse of Extended Prophylaxis after major Orthopedic Surgery ACCP guidelines for extended prophylaxis: Hip fracture 1A Hip arthroplasty 1A Knee arthroplasty 2B Reasons for underuse Need for subcut injection Need for monitoring and dose adjustment of VKA therapy Coordinating drug coverage

  10. VTE PreventionNon Traditional Prophylaxis Medical patients (EXCLAIM trial) 4000 patients 6-14 days vs 1 month with LMWH > 14 days? Knee arthroscopy (KANT trial) 1800 patients Nadroparin 3800 units vs elastic stockings for 7 days 0.9% vs 3.2 % Thalidomide associated VTE

  11. Long TermSecondary VTE Prophylaxis Duration of anticoagulation for first unprovoked VTE Proximal DVT or PE, no bleeding risk factors, and good monitoring is available Those with permanent risk factors (ie Cancer) Unprovoked VTE with strong preference for less frequent monitoring.

  12. Aterial ThrombosisUnderuse of Warfarin in AF

  13. New Oral Agents

  14. New Oral Agents Feature Dabigatran Etexilate Rivaroxaban Apixiban Target Thrombin Factor Xa Factor Xa Prodrug Yes No No Dosing Fixed, b.i.d. Fixed, o.d. Fixed, b.i.d Bioavailability 6% 80% 50% Monitoring No No No Half-life (h) 12-17 5-9 12 Renal clearance 80% 65% 25% Interactions P-gp inhibitor Combined P-gp Potent CYP3A4 and CYP3A4 inhibitors inhibitors Indications VTE prevention VTE prevention None Trials ongoing AF, ACS, VTE AF, ACS, VTE AF, ACS, VTE treatment treatment prevent/treat Pradax Product Monograph 2008; Xarelto Product Monograph 2008; Turpie Eur Heart J 2008; Gross, Weitz. Arterioscler Thromb Vasc Biol 2008

  15. New Oral Anticoagulant Targets Initiation Phase TF/ VII XII IX X XI Platelet Surface Amplification Propagation Phase VIII Rivaroxaban Apixaban Xa Thrombin Activity Common Pathway Dabigatran Etexilate Thrombin Fibrinogen Fibrin

  16. Anti-Xa or Anti-IIa? Hirudin Bivalirudin Argatroban Ximelagatran Dabigatran Etexilate Fondaparinux Idraparinux Rivaroxaban Apixaban Dalteparin Enoxaparin Nadroparin Reviparin Unfractionated Heparin Anti-IIaAnti-Xa

  17. Anti-Xa or Anti-IIa?Pharmacologic Considerations

  18. Dabigitran Etixilate

  19. The Molecule

  20. Key Characteristics Indicated for prevention of VTE post THR & TKR Dose 110 mg 1-4 hours post surgery followed by 220 mg daily

  21. Dabigatran Pharmacokinetics Absorption Oral Bioavailability: ~ 6.5% Time to peak: 0.5-2 hours, delayed 2 hours by food Distribution Linear kinetics ~35% protein bound Vd = 60-70L

  22. Dabigatran Pharmacokinetics Metabolism Hepatic glucuronidation to active metabolite Elimination Excreted in urine (85%, primarily as unchanged drug); fecal (6% of total dose) t1/2 = 12-17 hours

  23. Drug Interactions Avoid concomitant use with p-glycoprotein inhibitors & inducers Verapamil, Clarithromycin, *Quinidine Rifampicin, St. Jonh’s Wort, Tenofovir) Antacids diminished clinical effect; avoid within 24 hours after surgery Amiodarone Adjust dosing to 150 mg daily dabigatran with amiodarone Pantoprazole Co-administration with Dabigatran may diminish clinical effect

  24. Special Considerations Contraindications Severe renal impairment (CrCl < 30 mL/min) Concomitant treatment with strong P-Glycoprotein inhibitors (Quinidine) Antidote Switching agents Special Patient Populations Age Pregnancy Weight End organ dysfunction

  25. Dabigatran Etixilate &Phase 3 Trials REVOLUTION

  26. Dabigatran Phase III Studies: REVOLUTION • Enoxaparin • 40 mg QD* OR • 30 mg BID # Start evening before surgery* OR 12-24 hours post-operatively# Dabigatranetexilate 75 / 150 mg QD R Start 1-4 hours* OR 6-12 hours# post-operatively Dabigatranetexilate 110 / 220 mg QD Follow-up 12–14 weeks Venography Within 12 hours of last dose *RE-MODEL and RE-NOVATE #RE-MOBILIZE Design: Non-Inferiority in Modified Intention-To-Treat Population Eriksson et al. J ThrombHaemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132

  27. Methods - Procedures • Primary efficacy outcome: • Composite of total venous thromboembolic events (VTE) (symptomatic or venographic DVT and/or pulmonary embolism [PE]), and all-cause mortality during treatment • Secondary efficacy outcomes: • Composite of major VTE (proximal DVT and PE) and VTE-related mortality • Proximal DVT • Incidence of total VTE and all-cause mortality during follow-up • Individual components of the primary outcome Eriksson et al. J ThrombHaemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132

  28. Methods - Procedures • Primary safety outcome: • Major bleeding events • Associated with ≥2 g/dL drop in haemoglobin or required transfusion of ≥2 units blood • Fatal, retroperitoneal, intracranial, intraocular, or intraspinal • Warranted treatment cessation or re-operation • Clinically relevant non-major bleeding events • Minor bleeding events • Events were classified by an independent, expert adjudication committee Eriksson et al. J ThrombHaemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132

  29. Baseline characteristics

  30. Primary Efficacy Outcome: Total VTE or All-Cause Mortality Enoxaparin P=0.0003 for non-inferiority P<0.0001 for non-inferiority Dabigatran P=0.017 for non-inferiority P<0.0001 for non-inferiority P=0.02 * P=0.0009 * RE-MODEL RE-MOBILIZE† RE-NOVATE (Hip) (Knee) * P-value that the margin of 9.2% as the upper limit of the 95% CI for ARD was exceeded † Confidence intervals not reported Eriksson et al. J ThrombHaemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007

  31. Safety Outcome: Major Bleeding Events Enoxaparin No significant differences between either dose of dabigatran etexilate and enoxaparin. Dabigatran RE-MODEL RE-MOBILIZE* RE-NOVATE * Confidence intervals not reported Eriksson et al. J ThrombHaemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007

  32. Interpretational Considerations Failure to demonstrate non-inferiority of dabigatran in Re-Mobilize • Factors that may have contributed • Higher dose of enoxaparin (30 mg BID vs 40 mg QD in RE-MODEL) • Comparator event rate was lower than anticipated (25.3% versus 37.7% in RE-MODEL) • Different median duration of treatment • Delayed initiation of dabigatran dosing

  33. Efficacy by Timing of Initiation of Dabigatran Total VTE Rate (%) P = 0.0005 (70/498) (121/539) A post-hoc analysis from BISTRO II (THR & TKR patients) Eriksson et al. J ThrombHaemost2005

  34. Meta-Analysis of RE-MODEL, RE-MOBILIZE, RE-NOVATE: Total VTE & All-Cause Mortality Dabigatranetexilate 220 mg QD n/N Enoxaparin n/N RR [95% CI] RR Study or sub-category RE-MOBILIZE 188/604 163/643 RE-MODEL 183/503 193/512 RE-NOVATE 53/880 60/897 1.23 [1.03, 1.47] 0.97 [0.82, 1.13] 0.90 [0.63, 1.29] Total events: 424 (dabigatranetexilate), 416 (enoxaparin) Test for heterogeneity: Chi2 = 4.73, df = 2 (P=0.09), I2 = 57.7% Random Effects Analysis Total (95% CI) 1987 2052 Test for overall effect: Z = 0.47 (P = 0.64) 1.05 [0.87, 1.26] 0.1 0.2 0.5 1 2 5 10 Favours DabigatranEtexilate Favours Enoxaparin Analysis is based on the 220 mg QD dose of dabigatranetexilate. Wolowaczet al. ThrombHaemost2009

  35. The “Magic Bullet”……. Oral Dosage Form Little or no monitoring required Equally efficacious and safe to current treatments Consistent dosing regimen Predictable PK and PD Free from alcohol and food interactions Free from drug interactions Un phased by genetic factors (VKOR, CYP2C9) Un phased by organ dysfunction Reversibility Rapid onset and offset Inexpensive

  36. …..Not entirely yet much better! Oral Dosage Form  Little or no monitoring required  Equally efficacious and safe to current treatments  Consistent dosing regimen  Predictable PK and PD  Free from alcohol and food interactions  Free from drug interactions X Un phased by genetic factors (VKOR, CYP2C9)  Un phased by organ dysfunction X Reversibility X Rapid onset and offset  Inexpensive 

  37. Implications for Clinical Practice Dabigatran etexilate is safe and effective for prevention of VTE in patients undergoing hip or knee arthroplasty Potential to replace LMWH or fondaparinux Major unmet need is out of hospital prophylaxis Potential to improve guideline adherence and reduce VTE disease burden

  38. Summary Massive unmet need for new oral anticoagulant Dabigatran etexilate Simple Convenient, unmonitored Safe Effective First in AF (September 2009) Closing the care gap – more patients treated appropriately with improved quality of life. Excellent replacement for warfarin

  39. Questions? Questions?

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