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Advancements In Anticoagulation John Devlin, Pharm D Feb 4, 2009 Agenda 1. 2. 3. 4. Unmet needs in anticoagulation Niche for new anticoagulants Dabigatran Etexilate Evidence for efficacy and safety from phase 3 randomized trials 5. Implications for clinical practice 6. Comparing agents 7. Future developments Currently available anticoagulants Parenteral Agents Heparins UFH LMWH (3 agents) Heparinoids Anti-Xa Fondaparinux DTIs Bivalirudin / hirudin Argatroban Oral Agents • VKA’s – Warfarin – Acenocoumarol 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 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 Urgent Need to Replace Warfarin! 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 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. Out of Hospital Underuse 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 VTE Prevention Non 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 Long Term Secondary 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. Aterial Thrombosis Underuse of Warfarin in AF AFASAK II 60 EAFT SPAF II SPINAF SPAF III Oral Anticoagulant % on Medication Aspirin 50 SPAF I CAFA 40 30 BAATAF AFASAK I 20 10 0 Visit Year LASAF PATAF Japanese NVAF study New Oral Agents New Oral Agents Feature Dabigatran Etexilate Rivaroxaban Apixiban Target Prodrug Dosing Bioavailability Monitoring Half-life (h) Renal clearance Interactions Thrombin Yes Fixed, b.i.d. 6% No 12-17 80% P-gp inhibitor Factor Xa No Fixed, b.i.d 50% No 12 25% Potent CYP3A4 inhibitors Indications Trials ongoing VTE prevention AF, ACS, VTE treatment Factor Xa No Fixed, o.d. 80% No 5-9 65% Combined P-gp and CYP3A4 inhibitors VTE prevention AF, ACS, VTE treatment None AF, ACS, VTE prevent/treat Pradax Product Monograph 2008; Xarelto Product Monograph 2008; Turpie Eur Heart J 2008; Gross, Weitz. Arterioscler Thromb Vasc Biol 2008 New Oral Anticoagulant Targets Initiation Phase Contact TF/ VII XII IX XI Amplification Propagation Phase Thrombin Activity X Platelet Surface VIII Rivaroxaban Apixaban Xa Common Pathway Dabigatran Etexilate Thrombin Fibrinogen Fibrin Anti-Xa or Anti-IIa? Hirudin Bivalirudin Unfractionated Argatroban Heparin Ximelagatran Dabigatran Etexilate Anti-IIa Dalteparin Enoxaparin Nadroparin Reviparin Fondaparinux Idraparinux Rivaroxaban Apixaban Anti-Xa Anti-Xa or Anti-IIa? Pharmacologic Considerations Anti-Xa Anti-IIa “Gatekeeper of the coagulation cascade” “Final Common Pathway” Block thrombin generation Block thrombin activity Selective “targeted” effect Block Contact Activation Maintain -ve feedback Block +ve feedback Platelet Inhibition Dabigitran Etixilate The Molecule Key Characteristics Indicated for prevention of VTE post THR & TKR Dose 110 mg 1-4 hours post surgery followed by 220 mg daily 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 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 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 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 Dabigatran Etixilate & Phase 3 Trials REVOLUTION Dabigatran Phase III Studies: REVOLUTION Enoxaparin 40 mg QD* OR 30 mg BID # Start evening before surgery* OR 12-24 hours post-operatively# R Dabigatran etexilate 75 / 150 mg QD Start 1-4 hours* OR 6-12 hours# post-operatively Dabigatran etexilate 110 / 220 mg QD Venography Follow-up Within 12 hours of last dose 12–14 weeks *RE-MODEL and RE-NOVATE #RE-MOBILIZE Design: Non-Inferiority in Modified Intention-To-Treat Population Study Therapy Duration Enoxaparin Dose (mg) RE-MODEL Knee 6-10 days 40 QD RE-NOVATE Hip 28-35 days 40 QD Knee 12-15 days 30 BID RE-MOBILIZE Eriksson et al. J Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132 Methods - Procedures Trial RE-MODEL RE-NOVATE RE-MOBILIZE Countries Europe, Australia, South Africa US , Canada, Mexico, UK # Sites Sample Size 105 2101 115 3494 58 2615 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 Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132 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 Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132 Baseline characteristics RE-MOBILIZE RE-MODEL RE-NOVATE Patient Characteristics Age (mean) - years 66 68 64 Females - % 58 66 56 Weight (mean) – kg 88 83 79 53 38 31 Time to first oral dose* (mean) – h 9.5 3.5 3.4 Treatment duration (median) – d 13 8 33 Anesthetic Details General - % Study Drug Administration Primary Efficacy Outcome: Total VTE or All-Cause Mortality Enoxaparin P=0.0003 for non-inferiority Dabigatran P=0.017 for non-inferiority P=0.02 * P<0.0001 for non-inferiority P<0.0001 for non-inferiority P=0.0009 * RE-MODEL † Confidence intervals not reported 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 Eriksson et al. J Thromb Haemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007 Safety Outcome: Major Bleeding Events No significant differences between either dose of dabigatran etexilate and enoxaparin. Enoxaparin Dabigatran RE-MODEL RE-MOBILIZE* RE-NOVATE * Confidence intervals not reported Eriksson et al. J Thromb Haemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007 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 Efficacy by Timing of Initiation of Dabigatran Total VTE Rate (%) P = 0.0005 (70/498) Eriksson et al. J Thromb Haemost 2005 (121/539) A post-hoc analysis from BISTRO II (THR & TKR patients) Meta-Analysis of RE-MODEL, RE-MOBILIZE, RENOVATE: Total VTE & All-Cause Mortality Dabigatran etexilate Study or 220 mg QD Enoxaparin sub-category n/N n/N RR [95% CI] RR RE-MOBILIZE 188/604 163/643 1.23 [1.03, 1.47] RE-MODEL 183/503 193/512 0.97 [0.82, 1.13] 53/880 60/897 0.90 [0.63, 1.29] RE-NOVATE Total events: 424 (dabigatran etexilate), 416 (enoxaparin) Test for heterogeneity: Chi2 = 4.73, df = 2 (P=0.09), I2 = 57.7% Random Effects Analysis Total (95% CI) 1987 1.05 [0.87, 1.26] 2052 Test for overall effect: Z = 0.47 (P = 0.64) 0.1 0.2 Analysis is based on the 220 mg QD dose of dabigatran etexilate. Wolowacz et al. Thromb Haemost 2009 0.5 Favours Dabigatran Etexilate 1 2 5 10 Favours Enoxaparin 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 …..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 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 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 Questions? Questions?