Are there sufficientindications for switching tonew anticoagulant agents

Are there sufficientindications for switching tonew anticoagulant agents

Meyer Michel Samama et Gregoris GerotziafasGroupe Hémostase-Thrombose

Hôtel-Dieu, Hôpital Tenon, Paris & Biomnis Ivry/seine, France

X XaX Xa IX IXaIX IXa

First traces of thrombinFirst traces of thrombin

Activation of platelets, FV FVa, FVIII FVIIIaActivation of platelets, FV FVa, FVIII FVIIIa

Amplification of thrombin formationAmplification of thrombin formation

Tissue FactorVII VIIa

Tissue FactorVII VIIa

Atherosclerotic plaque Atherosclerotic plaque Blood borne TF*Blood borne TF*

Vascular lesionVascular lesion

* Activated monocytes-macrophages

r-TFPI r-NAPc2

VIIai

Anti IXa Anti Xa

Anti-IIa

Mechanism of blood coagulationMechanism of blood coagulation

Antithrombotic anticoagulants

Single target drugsSingle target drugsProven 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

ParenteralParenteral

OralOral

Multi target drugsMulti target drugs

Anti-Xa + Anti-IIaHeparins and LMWH

> 20 y.o.(ultra low MWH)

Vitamin K Antagonists

F II, VII, IX, X, PC, PS> 40 y.o.

Proven antithrombotic activity

Binding site of AT

LMWHsUFH PentasaccharideFONDAPARINUX

Idrabiotaparinux

Heparins (UFH, LMWH)Fondaparinux and Idrabiotaparinux

*

* Ultra Low Molecular Weight Heparin (semuloparin)

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 outside 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

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

Potential drawbacks of new oralanticoagulants

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 medicalfollow-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 Dabigatranin major orthopedic surgery (8000 patients)

No significant differences weredetected between Dabigatran etexilateand Enoxaparin in any of theendpoints analysed.

Meta-analysis of all 3 trials foundno significant differences betweentreatments in any of theendpoints analysed.

Dabigatran in Total Hip or KneeArthroplasty

Trial

N patients

Duration of prophylaxis (days)

Doses

First dose Dabigatran

Comparator Enoxaparin (mg)

R.R total VTE and all cause mortality

RE-MODELKnee

2101

6 -10

220 x 1150 x 1

Half-dose 1 - 4 hafter surgery

40 mg x 1

0.97 (0.82-1.13)

RE-MOBILIZEKnee

2615

12 -15

220 x 1150 x 1

Half-dose 6 - 12 hafter surgery

30 mg x 2

1.23 (1.03-1.47)

RE-NOVATEHip

3494

28 -35

220 x 1150 x 1

Half-dose 1 - 4 hafter surgery

40 mg x 1

0.90 (0.63-1.29)

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-upPlacebo

Follow-up

Follow-up

Day 1

1e efficacyoutcomeDay 12*(10 - 14)

2e efficacy outcome(end of study medication)

Day 35(31 - 39)

Follow-upDay 65

(61 - 65)

Day 12*(10 - 14)

Follow-upDay 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)

RECORD 4Design

SURGERY

SURGERY

R

Rivaroxaban 10 mg OD

6 - 8 hours after wound closureor adequate haemostasis

Enoxaparin 30 mg BID

12 - 24 hours after woundclosure or adequate haemostasis

Day 1

Follow-up

Follow-up

Mandatorybilateral

venography

Day 42+ 5

Day 13 ± 2

Last dose, daybefore venography

Double-blind

All p-values based on absolute weighted risk differences

0

2

4

6

8

10

12

Inci

denc

e (%

)

Enoxaparin 30 mg x 2/dRivaroxaban 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 Replacementin US (RECORD 4)

Symptomatic VTEp=0.191

Major VTEp=0.124

Major bleedingp=0.110

Total VTEp=0.012

Progress in anticoagulant therapyProgress in anticoagulant therapy

Main advantages of new oral anticoagulantsin 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

Long term treatment with new oralanticoagulant drugs

Long term treatment with new oralanticoagulant drugs

Non valvular atrial fibrillation

Treatment of acute VTE

Secondary prevention in patients with VTE

Acute coronary syndrome (treatment during and post)

OrthopedicsSurgery

ProphylaxisDVT

Treatment / Secondary

PreventionDVT

Other Potential

Indications ACS ?

Re-Novate Re-ModelRe-Mobilize

Re-Novate Re-ModelRe-Mobilize

Re-CoverRe-MedyRe-CoverRe-Medy

8000 Patients8000 Patients 5000 Patients5000 Patients

DabigatranDabigatranPhase 3 Program

Stroke Prevention

in AF

Re-LyRe-Ly

15 000 Patients15 000 Patients

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 fibrillationRE-LY Study in atrial fibrillation

(Outcome % per year)

AVERROES trial stopped earlyAVERROES trial stopped early

Apixaban(n=2809)

1.6

4.1

3.4

Outcomes

Stroke or systemic embolic event

Stroke, embolic event, MI, orvascular 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)

Results of Phase IIIclinical trials in

acute DVT and in secondaryprevention of VTE

with Dabigatran Etexilateand Rivaroxaban

Results of Phase IIIclinical trials in

acute DVT and in secondaryprevention of VTE

with Dabigatran Etexilateand 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

EINSTEIN EXTENSIONSecondary prevention DVT / PESecondary 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%

0

Rivaroxaban(n=602)

8 (1.3%)

0.3%

0

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)

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)

0

7

1,2

Placebo(n=595)

0 (p=0,10)

0

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)

66 11

EINSTEIN EXTENSIONSecondary prevention DVT / PESecondary prevention DVT / PE

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

ConclusionsConclusions 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 irrespectiveof age, body weight, gender, creatinine clearanceand cancer

No evidence for liver toxicity

ConclusionsConclusions

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 therapyProgress in anticoagulant therapy

Laboratory monitoring

Standardized coagulation assays are available forsome clinical settings

Documented response of usual tests for rivaroxabanand dabigatran

Specific anti-Xa and anti-IIa testsand global tests : PT, aPTT, Ecarin clotting time

Progress in anticoagulant therapyProgress in anticoagulant therapy

Laboratory monitoring

Routine coagulation monitoring was not usedin clinical trials New therapeutic approach andimproved patients quality of life

However as bleeding is an inherent risk associatedwith all anticoagulants, one could raise the question :

Could the bleeding events observed in clinical trialshav been rduced if occasional monitoring has beenused ?

CONCLUSIONCONCLUSION

New anticoagulants ready tochallenge WARFARIN / LMWHsNew 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, rivaroxabanVersus 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