Are there sufficient Are there sufficient indications for switching [PDF]

SLIDE 1

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

SLIDE 2

X Xa X Xa IX IXa IX IXa

First traces of thrombin First traces of thrombin Activation of platelets, FV  FVa, FVIII  FVIIIa Activation of platelets, FV  FVa, FVIII  FVIIIa Amplification of thrombin formation Amplification of thrombin formation

Tissue Factor VII VIIa Tissue Factor VII VIIa Atherosclerotic plaque Atherosclerotic plaque Blood borne TF* Blood borne TF* Vascular lesion Vascular lesion * Activated monocytes-macrophages

r-TFPI
r-NAPc2
VIIai
Anti IXa
Anti Xa
Anti-IIa

Mechanism of blood coagulation Mechanism of blood coagulation

SLIDE 3

Antithrombotic anticoagulants

Single target drugs Single target drugs

Proven antithrombotic activity

Selective Anti-Xa or Anti-IIa activity

(free and bound activities)

New agents

Rivaroxaban, Apixaban, Edoxaban
Dabigatran…

New agents

Rivaroxaban, Apixaban, Edoxaban
Dabigatran…
Fondaparinux, Idrabiotaparinux
Hirudin and Bivalirudin
Otamixaban

Parenteral Parenteral Oral Oral

Multi target drugs Multi target drugs

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. Proven antithrombotic activity

SLIDE 4

Binding site of AT

LMWHs UFH Pentasaccharide

FONDAPARINUX

Idrabiotaparinux

Heparins (UFH, LMWH) Fondaparinux and Idrabiotaparinux

* * Ultra Low Molecular Weight Heparin (semuloparin)

SLIDE 5

Oral Anticoagulants

Limitations of VKA

Slow onset and offset
Iatrogenicity
Need of laboratory monitoring
No predictable response
Narrow therapeutic window
Prolonged half-life
Level of anticoagulation frequently
utside the therapeutic range

Novel anticoagulants

Fast onset and offset
Greater antithrombotic activity

at similar rate of bleeding

No routine coagulation monitoring
Predictable pharmacodynamics

and pharmacokinetics

Broad therapeutic window
Short half-life
Minimal influence of comedications

and food

SLIDE 6

Main objective

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 ?

A new Era with novel anticoagulants

 To overcome some of the limitations of VKA and heparins

SLIDE 7

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…

SLIDE 8

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.

SLIDE 9

Dabigatran in Total Hip or Knee Arthroplasty

Trial

N patients
Duration of

prophylaxis (days)

Doses
First dose Dabigatran
Comparator

Enoxaparin (mg)

R.R total VTE and

all cause mortality RE-MODEL Knee 2101 6 -10 220 x 1 150 x 1 Half-dose 1 - 4 h after surgery 40 mg x 1 0.97 (0.82-1.13) RE-MOBILIZE Knee 2615 12 -15 220 x 1 150 x 1 Half-dose 6 - 12 h after surgery 30 mg x 2 1.23 (1.03-1.47) RE-NOVATE Hip 3494 28 -35 220 x 1 150 x 1 Half-dose 1 - 4 h after surgery 40 mg x 1 0.90 (0.63-1.29)

SLIDE 10

Pooled analysis design

Rivaroxaban Rivaroxaban Rivaroxaban Enoxaparin Enoxaparin Enoxaparin RECORD 1 RECORD 2 RECORD 3

Hip Hip Knee

Follow-up Follow-up Follow-up Follow-up Placebo Follow-up Follow-up Day 1 1e efficacy

utcome

Day 12* (10 - 14) 2e efficacy outcome (end of study medication) Day 35 (31 - 39) Follow-up Day 65 (61 - 65) Day 12* (10 - 14) Follow-up Day 42# (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)

SLIDE 11

RECORD 4

Design

S U R G E R Y S U R G E R Y

R

Rivaroxaban 10 mg OD

6 - 8 hours after wound closure

r adequate haemostasis

Enoxaparin 30 mg BID

12 - 24 hours after wound closure or adequate haemostasis

Day 1

Follow-up Follow-up Mandatory bilateral venography

Day 42 + 5 Day 13 ± 2 Last dose, day before venography

Double-blind

SLIDE 12

All p-values based on absolute weighted risk differences

2 4 6 8 10 12 Incidence (%)

Enoxaparin 30 mg x 2/d Rivaroxaban 10 mg /d

6.9% 10.1% 2.0% 1.2% 1.2% 0.7% 0.3% 0.7%

RRR 31%

Rivaroxaban in Total Knee Replacement in US (RECORD 4)

Symptomatic VTE p=0.191 Major VTE p=0.124 Major bleeding p=0.110 Total VTE p=0.012

SLIDE 13

SLIDE 14

Progress in anticoagulant therapy Progress in anticoagulant therapy

Main advantages of new oral anticoagulants in major orthopedic surgery Rivaroxaban

More efficacious than Lovenox
Similar bleeding rate ?
Single dosage 10 mg once a day

Dabigatran

As efficacious as Lovenox
Similar bleeding rate
Two differents dosages

150 or 220 mg once a day

Remark

More convenient for prolonged treatment

SLIDE 15

Long term treatment with new oral anticoagulant drugs 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)

SLIDE 16

Orthopedics Surgery

Prophylaxis

DVT Treatment /

Secondary Prevention

DVT Other Potential Indications ACS ? Re-Novate Re-Model Re-Mobilize Re-Novate Re-Model Re-Mobilize Re-Cover Re-Medy Re-Cover Re-Medy 8000 Patients 8000 Patients 5000 Patients 5000 Patients

Dabigatran Dabigatran

Phase 3 Program

Stroke Prevention in AF Re-Ly Re-Ly 15 000 Patients 15 000 Patients

SLIDE 17

SLIDE 18

SLIDE 19

SLIDE 20

150 mg X 2 1.11 0.12 0.72 110 mg X 2 1.53 0.10 0.74  INR 2-3 1.69 0.38 0.53

Stroke
Intracranial hemorrhage
Myocardial Infarction

Dabigatran etexilate Warfarin

RE-LY Study in atrial fibrillation RE-LY Study in atrial fibrillation

(Outcome % per year)

SLIDE 21

AVERROES trial stopped early AVERROES trial stopped early

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

SLIDE 22

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

SLIDE 23

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

SLIDE 24

SLIDE 25

EINSTEIN EXTENSION

Secondary prevention DVT / PE Secondary prevention DVT / PE

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

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

Rivaroxaban (n=602) 8 (1.3%) 0.3% Rivaroxaban (n=602) 8 (1.3%) 0.3% Placebo (n=594) 42 (7.1%) 0.2% 0.2% Placebo (n=594) 42 (7.1%) 0.2% 0.2%

DVT
PE non fatal
PE fatal
DVT
PE non fatal
PE fatal

Linear rate of recurrences during the 6 months study (NNTT 15 Pts) Linear rate of recurrences during the 6 months study (NNTT 15 Pts)

SLIDE 26

Rivaroxaban (n=602)

4 (0,7%) 3 32 5,4%

Rivaroxaban (n=602)

4 (0,7%) 3 32 5,4%

Placebo (n=595)

0 (p=0,10) 7 1,2

Placebo (n=595)

0 (p=0,10) 7 1,2

Major bleeding
Gastro intestinale bleeding
Clinically significant bleeding
Urogenital bleeding
Major bleeding
Gastro intestinale bleeding
Clinically significant bleeding
Urogenital bleeding

Liver enzymes > 3 fold normal (Transient increase) Liver enzymes > 3 fold normal (Transient increase) 6 6 1 1

EINSTEIN EXTENSION

Secondary prevention DVT / PE Secondary prevention DVT / PE

SLIDE 27

ASC Stockholm, H. Buller 31/08/2010

SLIDE 28

ASC Stockholm, H. Buller 31/08/2010

SLIDE 29

ASC Stockholm, H. Buller 31/08/2010

SLIDE 30

ASC Stockholm, H. Buller 31/08/2010

SLIDE 31

Conclusions 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

f age, body weight, gender, creatinine clearance

and cancer  No evidence for liver toxicity

SLIDE 32

Conclusions 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

f DVT that potentially improves the benefit-risk

profile of anticoagulation.

SLIDE 33

Progress in anticoagulant therapy 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

SLIDE 34

Progress in anticoagulant therapy 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 ?

SLIDE 35

CONCLUSION CONCLUSION

SLIDE 36

New anticoagulants ready to challenge WARFARIN / LMWHs New anticoagulants ready to challenge WARFARIN / LMWHs

Indications

Major orthopedic surgery

(THR, TKR)

Treatment of acute VTE
Secondary prevention of VTE
Prophylaxis in medical patients
Atrial fibrillation
Acute coronary syndrome

Dabigatran, rivaroxaban

Versus standard treatment

More convenient and ≥ effectiveness

and safety

Positive results : simple single drug

approach for rivaroxaban…

Positive results
Ongoing studies
Dabigatran > warfarin

Apixaban > aspirin

Increased bleeding, new ongoing

studies