Are there sufficient Are there sufficient indications for switching - PowerPoint PPT Presentation

Are there sufficient Are there sufficient indications for switching to indications for switching to new anticoagulant agents 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 Mechanism of blood coagulation Blood borne TF* Blood borne TF* Vascular lesion Atherosclerotic plaque Vascular lesion Atherosclerotic plaque  r-TFPI Tissue Factor Tissue Factor  r-NAPc 2 VII VIIa VII VIIa  VIIa i  Anti IXa X Xa IX IXa X Xa IX IXa  Anti Xa First traces of thrombin First traces of thrombin Activation of platelets, FV  FVa, FVIII  FVIIIa Activation of platelets, FV  FVa, FVIII  FVIIIa  Anti-IIa Amplification of thrombin formation Amplification of thrombin formation * Activated monocytes-macrophages

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

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

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

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

Pooled analysis design 1 e efficacy 2 e efficacy outcome outcome (end of study medication) Follow-up Day 1 Day 12* Day 35 Day 65 (10 - 14) (31 - 39) (61 - 65) RECORD 1 Rivaroxaban Follow-up Hip Follow-up Enoxaparin RECORD 2 Rivaroxaban Follow-up Hip Enoxaparin Placebo Follow-up RECORD 3 Rivaroxaban Follow-up Knee Enoxaparin Follow-up Follow-up Day 12* Day 42 # (10 - 14) (42 - 47) * 2-week time point; # 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 Rivaroxaban 10 mg OD S S U U Follow-up Follow-up 6 - 8 hours after wound closure R R Mandatory or adequate haemostasis R G G bilateral 12 - 24 hours after wound E E venography closure or adequate haemostasis R R Y Y Enoxaparin 30 mg BID Day 1 Day 13 ± 2 Day 42 + 5 Last dose, day before venography

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

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

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

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

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

Results of Phase III Results of Phase III clinical trials in clinical trials in acute DVT and in secondary acute DVT and in secondary prevention of VTE prevention of VTE with Dabigatran Etexilate with Dabigatran Etexilate and Rivaroxaban 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(8- 11 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 Secondary prevention DVT / PE EINSTEIN EXTENSION   After initial treatment during 6 to 12 months (mean 8 months) After initial treatment during 6 to 12 months (mean 8 months) Rivaroxaban 20 mg once a day (mean 190 days) versus Placebo Rivaroxaban 20 mg once a day (mean 190 days) versus Placebo  Randomised double-blind superiority study  Randomised double-blind superiority study Rivaroxaban Placebo Rivaroxaban Placebo (n=602) (n=594) (n=602) (n=594) • DVT • DVT 8 (1.3%) 42 (7.1%) 8 (1.3%) 42 (7.1%) • PE non fatal 0.3% 0.2% • PE non fatal 0.3% 0.2% • PE fatal 0 0.2% • PE fatal 0 0.2% Linear rate of recurrences during the 6 months study Linear rate of recurrences during the 6 months study (NNTT 15 Pts) (NNTT 15 Pts)

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

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