Are there sufficient indications for switching to new anticoagulant agents

Are there sufficient indications for switching to new anticoagulant agents Meyer Michel Samama et Gregoris Gerotziafas Groupe Hémostase-Thrombose Hôtel-Dieu, Hôpital Tenon, Paris & Biomnis Ivry/seine, France

Mechanism of blood coagulation Blood borne TF* Vascular lesion Atherosclerotic plaque r-tfpi r-napc2 VIIai Tissue Factor VII X Xa VIIa IX IXa Anti IXa Anti Xa First traces of thrombin Activation of platelets, FV FVa, FVIII FVIIIa Amplification of thrombin formation Anti-IIa * Activated monocytes-macrophages

Antithrombotic anticoagulants Multi target drugs Single target drugs Proven antithrombotic activity Proven antithrombotic activity Anti-Xa + Anti-IIa Heparins and LMWH > 20 y.o. (ultra low MWH) Vitamin K Antagonists F II, VII, IX, X, PC, PS > 40 y.o. Selective Anti-Xa or Anti-IIa activity (free and bound activities) Fondaparinux, Idrabiotaparinux Hirudin and Bivalirudin Parenteral Otamixaban New agents - Rivaroxaban, Apixaban, Edoxaban - Dabigatran Oral

Heparins (UFH, LMWH) Fondaparinux and Idrabiotaparinux UFH LMWHs* Pentasaccharide FONDAPARINUX Binding site of AT * Ultra Low Molecular Weight Heparin (semuloparin) Idrabiotaparinux

Oral Anticoagulants Limitations of VKA Novel anticoagulants Slow onset and offset Fast onset and offset Iatrogenicity Greater antithrombotic activity at similar rate of bleeding Need of laboratory monitoring No predictable response No routine coagulation monitoring Predictable pharmacodynamics and pharmacokinetics Narrow therapeutic window Broad therapeutic window Prolonged half-life Short half-life Level of anticoagulation frequently outside the therapeutic range Minimal influence of comedications and food

A new Era with novel anticoagulants Main objective To overcome some of the limitations of VKA and heparins Obtained by chemical synthesis (different from animal derived substances) No heparin induced thrombocytopenia No need for routine anticoagulant monitoring Minimal or no influence of comedications and diet Cost of treatment?

Potential drawbacks of new oral anticoagulants Lack of specific antidote for most drugs Rebound hypercoagulation? Less active than VKA in the prevention of acute MI (Dabigatran RELY Study) Problem of compliance and reduced medical follow-up patients education and physician information No indications in pregnancy and breast feeding mothers, in pediatrics and in patients with mechanical cardiac valves

RE-VOLUTION Clinical Trial Programme with Dabigatran in major orthopedic surgery (8000 patients) No significant differences were detected between Dabigatran etexilate and Enoxaparin in any of the endpoints analysed. Meta-analysis of all 3 trials found no significant differences between treatments in any of the endpoints analysed.

Dabigatran in Total Hip or Knee Arthroplasty RE-MODEL Knee RE-MOBILIZE Knee RE-NOVATE Hip N patients 2101 2615 3494 Duration of prophylaxis (days) 6-10 12-15 28-35 220 x 1 150 x 1 220 x 1 150 x 1 220 x 1 150 x 1 Half-dose 1-4 h after surgery Half-dose 6-12 h after surgery Half-dose 1-4 h after surgery 40 mg x 1 30 mg x 2 40 mg x 1 0.97 (0.82-1.13) 1.23 (1.03-1.47) 0.90 (0.63-1.29) Trial Doses First dose Dabigatran Comparator Enoxaparin (mg) R.R total VTE and all cause mortality

Pooled analysis design 1e efficacy outcome Day 12* (10-14) Day 1 2e efficacy outcome (end of study medication) Day 35 (31-39) Follow-up Day 65 (61-65) RECORD 1 Rivaroxaban Follow-up Hip Enoxaparin Follow-up RECORD 2 Rivaroxaban Follow-up Hip Enoxaparin RECORD 3 Rivaroxaban Follow-up Knee Enoxaparin Follow-up Placebo Day 12* (10-14) * 2-week time point; # Follow-up Follow-up Day 42# (42-47) 5-week time point Conclusion : Symptomatic VTE + all-cause mortality at 2 weeks - RIVA. 0.4% versus ENOXA. 0.8% (p=0.005)

RECORD 4 Design Double-blind Day 1 Rivaroxaban 10 mg OD 6-8 hours after wound closure or adequate haemostasis 12-24 hours after wound closure or adequate haemostasis Mandatory bilateral venography Follow-up R S U R G E R Y Enoxaparin 30 mg BID Day 13 ± 2 Last dose, day before venography Day 42 +5

Rivaroxaban in Total Knee Replacement in US (RECORD 4) 12 10 RRR 31% 10.1% Enoxaparin 30 mg x 2/d Incidence (%) Rivaroxaban 10 mg /d 8 6.9% 6 4 2.0% 2 1.2% 1.2% 0.7% 0.3% 0.7% 0 Total VTE p=0.012 Major VTE p=0.124 Symptomatic VTE p=0.191 All p-values based on absolute weighted risk differences Major bleeding p=0.110

Progress in anticoagulant therapy Main advantages of new oral anticoagulants in major orthopedic surgery Rivaroxaban Dabigatran - More efficacious than Lovenox - As efficacious as Lovenox - Similar bleeding rate? - Similar bleeding rate - Single dosage 10 mg once a day - Two differents dosages 150 or 220 mg once a day Remark - More convenient for prolonged treatment

Long term treatment with new oral anticoagulant drugs Non valvular atrial fibrillation Treatment of acute VTE Secondary prevention in patients with VTE Acute coronary syndrome (treatment during and post)

Dabigatran Phase 3 Program Orthopedics Surgery Prophylaxis DVT Re-Novate Stroke Prevention in AF Treatment / Re-Ly Re-Cover Re-Model Secondary Prevention DVT Re-Medy Re-Mobilize 8000 Patients 15 000 Patients 5000 Patients Other Potential Indications ACS?

RE-LY Study in atrial fibrillation Dabigatran etexilate (Outcome % per year) Warfarin 150 mg X 2 110 mg X 2 INR 2-3 Stroke 1.11 1.53 1.69 Intracranial hemorrhage 0.12 0.10 0.38 Myocardial Infarction 0.72 0.74 0.53

AVERROES trial stopped early AVERROES : Primary and secondary end point Outcomes Apixaban Aspirin Relative risk (95% CI) (n=2809) (n=2791) Stroke or systemic embolic event 1.6 3.6 0.46 (0.33-0.64) Stroke, embolic event, MI, or vascular death 4.1 6.2 0.66 (0.53-0.83) Total death 3.4 4.4 0.79 (0.62-1.02) AVERROES : Bleeding events Outcomes Apixaban Aspirin Relative risk (95% CI) (n=2809) (n=2791) Major bleeding 1.4 1.2 1.14 (0.74-1.75) Clinical relevant non major bleeding 3.0 2.6 1.18 (0.88-1.58)

Results of Phase III clinical trials in acute DVT and in secondary prevention of VTE with Dabigatran Etexilate and Rivaroxaban

RE-COVERTM Trial DesignObjectiveconfirmationof VTEER30 daysfollow up Initial parenteraltherapy Single-dummyperiod Double-dummy period72 h6 monthsend of treatmentuntil INR 2.0 attwo consecutivemeasurements(811 days)warfarinwarfarin(inr 2.0 3.0)Dabigatran etexilate placebo bidwarfarin placebodabigatran etexilate 150 mg bidwarfarinplaceboe= enrolmentr= randomization Vasc Health Risk Manag. 2010; 6:339-349

Secondary prevention DVT / PE EINSTEIN EXTENSION After initial treatment during 6 to 12 months (mean 8 months) Rivaroxaban 20 mg once a day (mean 190 days) versus Placebo Randomised double-blind superiority study DVT PE non fatal PE fatal Rivaroxaban (n=602) Placebo (n=594) 8 (1.3%) 42 (7.1%) 0.3% 0.2% 0 0.2% Linear rate of recurrences during the 6 months study (NNTT 15 Pts)

Secondary prevention DVT / PE EINSTEIN EXTENSION Rivaroxaban (n=602) Placebo (n=595) 4 (0,7%) 0 (p=0,10) Gastro intestinale bleeding 3 0 Clinically significant bleeding 32 7 5,4% 1,2 Major bleeding Urogenital bleeding Liver enzymes > 3 fold normal (Transient increase) 6 1

ASC Stockholm, H. Buller 31/08/2010

ASC Stockholm, H. Buller 31/08/2010

ASC Stockholm, H. Buller 31/08/2010

ASC Stockholm, H. Buller 31/08/2010

Conclusions In patients who had acute symptomatic proximal DVT, without symptomatic PE, rivaroxaban showed : Non-inferiority to LMWH/VKA for efficacy : HR=0.68 (0.44-1.04); p<0.0001 for non-inferiority Similar findings for principal safety outcome : HR=0.97 (0.76-1.22); p=0.77 Consistent efficacy and safety results irrespective of age, body weight, gender, creatinine clearance and cancer No evidence for liver toxicity

Conclusions Oral rivaroxaban, 15 mg twice-daily for 3 weeks followed by 20 mg once-daily, could provide clinicians and patients with a simple, single-drug approach for the acute and continued treatment of DVT that potentially improves the benefit-risk profile of anticoagulation.

Progress in anticoagulant therapy Laboratory monitoring Standardized coagulation assays are available for some clinical settings Documented response of usual tests for rivaroxaban and dabigatran Specific anti-xa and anti-iia tests and global tests : PT, aptt, Ecarin clotting time

Progress in anticoagulant therapy Laboratory monitoring Routine coagulation monitoring was not used in clinical trials New therapeutic approach and improved patients quality of life However as bleeding is an inherent risk associated with all anticoagulants, one could raise the question : Could the bleeding events observed in clinical trials hav been rduced if occasional monitoring has been used?

CONCLUSION

New anticoagulants ready to challenge WARFARIN / LMWHs Indications Dabigatran, rivaroxaban Versus standard treatment Major orthopedic surgery (THR, TKR) More convenient and effectiveness and safety Treatment of acute VTE Positive results : simple single drug approach for rivaroxaban Secondary prevention of VTE Positive results Prophylaxis in medical patients Ongoing studies Atrial fibrillation Dabigatran > warfarin Apixaban > aspirin Acute coronary syndrome Increased bleeding, new ongoing studies