AZ. ST. JANSCOLLOQUIA FLASHAVOND ETHIEK EN ECONOMIE 12-11-2013.

Economische reflecties bij nieuwe anticoagulantia voor de behandeling

van DVT en longembolen

Dr. Veerle Ringoet

Coagulation cascade

2012 ACCP guidelines: recommended agents for VTEx

Extended

Phases of anticoagulation

Long-term Initial

Kearon C et al. Chest 2012

0 to ~7 days

Therapeutic UFH, LMWH, fondaparinux or rivaroxaban

>3 months to indefinite withperiodic (eg. annual) risk assessment

Up to 3 months

VKA (INR2.0-3.0) or LMWH, dabigatran or rivaroxaban

VKA (INR2.0-3.0) or LMWH, dabigatran or rivaroxaban

Recommended anticoagulants

Traditional anticoagulants: drawbacks

• UFH1

– Parenteral administration IV

– Monitoring and dose adjustment required

– Risk of HIT

• LMWH1

– Parenteral administration s.c.

– Weight-adjusted dosing

– (HIT)

• Oral VKAs2

– Narrow therapeutic window

– Interaction with food and drugs

– Frequent monitoring and dose adjustment required

1. Hirsh J et al. Chest 2008;133;141S–159S; 2. Ansell J et al. Chest 2008;133;160S–198S

“New anticoagulants: NOAC’s”

Direct Factor Xa inhibitorsThrombin inhibitors

Direct Factor Xa inhibition

Rivaroxaban Apixaban Edoxaban Betrixaban Darexaban

Adapted from Spyropoulos AC. Expert Opin Investig Drugs 2007;16:431–440

Inactive factor

Active factor

Transformation

Catalysis

Clot formation

Initiation

Propagation

Thrombin inhibitors Dabigatran (Argotraban)

Fibrinogen Fibrin

Prothrombin

X IX

II

VIITF

IXa

IIa

VIIa

Xa

Rivaroxaban EINSTEIN phase III: Trial designs

15 mg bid

Confirmed acute

symptomatic DVT without symptomatic

PE

N=3,449Rivaroxaban

Day 1 Day 21

Enoxaparin 1.0 mg/kg bid for at least 5 days, followed

by VKA to start ≤48 hours, target INR range 2.0–3.0

Confirmed acute symptomatic PE with or without symptomatic

DVT

EINSTEIN DVT1 and EINSTEIN PE2 (non-inferiority studies)Treatment period of 3, 6 or 12 months

20 mg od

N=4,845

Rivaroxaban

R

1. The EINSTEIN Investigators. N Engl J Med 2010; 2. The EINSTEIN–PE Investigators. N Engl J Med 2012

30

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Confirmed symptomatic

DVT or PE completing 6 or 12 months

of rivaroxaban or VKA

Rivaroxaban 20 mg od

PlaceboDay 1

N=1,197

EINSTEIN Extension1 (superiority study)Treatment period of 6 or 12 months

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30

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EINSTEIN DVT and PE: exclusion criteria

• Thrombectomy, insertion of a caval filter or use of a fibrinolytic agent to treat current DVT and/or PE

• Indication for VKA other than DVT and/or PE

• >48 hours prerandomization treatment with therapeutic dosages of anticoagulant treatment or more than a single dose of VKA prior to randomization

• Creatinine clearance <30 ml/min• Significant liver disease or ALT

>3× ULN• Life expectancy <3 months

• Active bleeding or high risk for bleeding • Systolic blood pressure >180 mm Hg

or diastolic blood pressure >110 mm Hg

• Childbearing potential without proper contraceptive measures, pregnancy or breast feeding

• Bacterial endocarditis• Participation in another

pharmacotherapeutic study within 30 days before screening

• Concomitant use of strong CYP3A4 inhibitors or inducers

The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; The EINSTEIN–PE Investigators. N Engl J Med 2012; 366:1287-1297; EINSTEIN Integrated Protocol/Study number 11702/Version no 2.0/08Jun2009, incl. Amend 2, 3, 4

EINSTEIN DVT and PE: study outcomes

Primary efficacy outcome*

• Symptomatic recurrent VTE: composite of recurrent DVT, non fatal PE or fatal PE

Principal safety outcome*

• Combination of major and non-major clinically relevant bleeding

*Adjudicated by a central independent and blinded adjudication committee

1. The EINSTEIN Investigators, N Engl J Med 2010;363:2499–2510; 2. The EINSTEIN–PE Investigators. N Engl J Med 2012; 366:1287-1297

EINSTEIN DVT: primary efficacy

outcome analysisRivaroxaban

(n=1,731)Enoxaparin/VKA

(n=1,718)

n (%) n (%)First symptomatic recurrent VTE 36 (2.1) 51 (3.0)

Recurrent DVT 14 (0.8) 28 (1.6)

Recurrent DVT + PE 1 (<0.1) 0 (0.0)

Non-fatal PE 20 (1.2) 18 (1.0)

Fatal PE/unexplained death wherePE cannot be ruled out 4 (0.2) 6 (0.3)

ITT population

p<0.001 for non-inferiority (one-sided)

1.00 0

0.44 1.040.68

HRRivaroxaban

superiorRivaroxaban non-inferior

Rivaroxaban inferior

p=0.08 for superiority (two-sided)

2.00

The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510

EINSTEIN DVT: principal safety

outcome analysisRivaroxaban

(n=1,718)Enoxaparin/VKA

(n=1,711)HR (95% CI)

n (%) n (%) p-value

First major or non-major clinically relevant bleeding

139 (8.1) 138 (8.1)0.97 (0.76–1.22)

p=0.77

Major bleeding 14 (0.8) 20 (1.2)0.65 (0.33–1.30)

p=0.21

Contributing to death 1 (<0.1) 5 (0.3)

In a critical site 3 (0.2) 3 (0.2)

Associated with fall in haemoglobin 2 g/dl and/or transfusion of 2 units

10 (0.6) 12 (0.7)

Non-major clinically relevant bleeding 126 (7.3) 119 (7.0)

Safety population


EINSTEIN DVT: Key secondary and other outcomes

Outcome

Rivaroxaban Enoxaparin/VKAHR

(95% CI)n/N (%) n/N (%)

Net clinical benefit: (primary efficacy outcome plus major bleeding)

51/1,731 (2.9) 73/1,718 (4.2)

0.67 (0.47–0.95)

p=0.03

Total mortality 38/1,731 (2.2) 49/1,718 (2.9)0.67

(0.44–1.02)

Cardiovascular events

12/1,718 (0.7) 14/1,711 (0.8) 0.79(0.36–1.71)

The EINSTEIN Investigators. N Engl J Med 2010 (Supplementary Appendix)

EINSTEIN PE:Primary efficacy outcome analysis

Rivaroxaban (N=2419)

Enoxaparin/VKA(N=2413)

n (%) n (%)First symptomatic recurrent VTE 50 (2.1) 44 (1.8)

Recurrent DVT 18 (0.7) 17 (0.7)

Recurrent DVT + PE 0 2 (<0.1)

Non-fatal PE 22 (0.9) 19 (0.8)

Fatal PE/unexplained death wherePE cannot be ruled out 10 (0.4) 6 (0.2)

ITT population

Rivaroxaban superior

Rivaroxaban non-inferior

Rivaroxaban inferior

p<0.0026 for non-inferiority (one-sided)

p=0.57 for superiority (two-sided)

1.00 0 2.00

0.75 1.12 1.69

The EINSTEIN–PE Investigators. N Engl J Med 2012; 366:1287-1297

Primary efficacy outcome: time to first event

ITT population

3.0

2.5

2.0

1.5

1.0

0.0

0.5

0 30 60 90 120 150 180 210 240 270 300 330 360

Number of patients at risk

Rivaroxaban 2419 2350 2321 2303 2180 2167 2063 837 794 785 757 725 672

Enoxaparin/VKA 2413 2316 2296 2274 2157 2149 2053 837 789 774 748 724 677

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%)

Time to event (days)

RivaroxabanN=2419

Enoxaparin/VKAN=2413

HR=1.12; p<0.0026 (non-inferiority)


Principal safety outcome analysis:major or non-major clinically relevant bleeding

Rivaroxaban(N=2412)

Enoxaparin/VKA (N=2405) HR (95% CI)

p-valuen (%) n (%)

First major or non-major clinically relevant bleeding event

249 (10.3) 274 (11.4)0.90 (0.76–1.07)

p=0.23

Major bleeding 26 (1.1) 52 (2.2)0.49 (0.31–0.80)

p=0.0032

Contributing to death 2 (<0.1) 3 (0.1)

In a critical site 6 (0.2) 27 (1.1)


18 (0.7) 26 (1.1)

Non-major clinically relevant bleeding

228 (9.5) 235 (9.8)

Safety population


Key secondary and other outcomes

Outcome

Rivaroxaban Enoxaparin/VKAHR

(95% CI)n/N (%) n/N (%)

Net clinical benefit* 83/2419 (3.4) 96/2413 (4.0) 0.85 (0.63–1.14)

Total mortality 58/2419 (2.4) 50/2413 (2.1) 1.13 (0.77–1.65)

On-treatment CV events 35/2412 (1.5) 37/2405 (1.5) 0.94 (0.59–1.49)

Stroke/TIA 12/2412 (0.5) 13/2405 (0.5)

MI/UA 15/2412 (0.6) 21/2405 (0.9)

Other 8/2412 (0.3) 3/2405 (0.1)

Off-treatment CV events#

Stroke/TIA 2/2206 (<0.1) 1/2197 (<0.1)

MI/UA 3/2206 (0.1) 2/2197 (<0.1)

Other 4/2206 (0.2) 0/2197

*Primary efficacy outcome plus major bleeding#30-day follow-up

Recurrent VTE and bleeding in fragile and non fragile patients

Fragile* Non-fragile HR (95% CI)

n/n (%) n/n (%)

Recurrent VTE 31/987 (3.1) 63/3845 (1.6) 1.97 (1.28–3.04)

Major bleeding 31/984 (3.2) 47/3833 (1.2) 2.72 (1.72–4.29)

Clinically relevant bleeding

144/984 (14.6) 379/3833 (9.9) 1.62 (1.34–1.97)

*Fragile patients defined as age >75 years, weight ≤50 kg and/or creatinine clearance <50 ml/min

Recurrent VTE and bleeding in fragile patients

Rivaroxaban Enoxaparin/VKAHR 95% CI

n (%) n (%)

Recurrent VTE 14/510 (2.8) 17/477 (3.6) 0.75 (0.37–1.52)

Major bleeding 7/508 (1.4) 24/476 (5.0) 0.26 (0.11–0.61)

Clinically relevant bleeding

64/508 (12.6) 80/476 (16.8) 0.72 (0.52–0.99)

Conclusion

• There is no evidence to support a rivaroxaban dose adjustment in fragile patients

EINSTEIN Extension: study objective

Primary objective

• Is rivaroxaban superior to placebo in the long-term prevention of recurrent symptomatic VTE in patients with symptomatic DVT or PE who completed 6 or 12 months of treatment with a VKA or rivaroxaban ?


EINSTEIN Extension: study design

Randomized, double-blind, placebo-controlled, event-driven (n=30), superiority study

Rivaroxaban 20 mg od

Placebo

N=1,197

30-d

ay

ob

serv

ati

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p

erio

d


DVT or PE completing

6 or 12 months of

rivaroxaban or VKA in

EINSTEIN VTE programme

R

Treatment period of 6 or 12 monthsDay 1


DVT or PE completing

6 or 12 months

of VKA

~53%

~47%


EINSTEIN Extension: primary efficacy outcome and individual components

Rivaroxaban(n=602)

Placebo(n=594)

n (%) n (%)

Symptomatic recurrent VTE* 8 (1.3)# 42 (7.1)

Recurrent DVT 5 (0.8) 31 (5.2)

Non-fatal PE 2 (0.3) 13 (2.2)

Fatal PE 0 (0) 1 (0.2)

Unexplained death (where PE cannot be excluded)

1 (0.2) 0 (0)

ITT population; *Some patients experienced more than one event; #p<0.001


EINSTEIN Extension: major bleeding

Rivaroxaban(n=598)

Placebo(n=590)

n (%) n (%)

Major bleeding 4 (0.7)* 0 (0)

Bleeding contributing to death 0 (0) 0 (0)

Bleeding in a critical site 0 (0) 0 (0)


4 (0.7) 0 (0)

Gastrointestinal bleeding 3 (0.5) 0 (0)

Menorrhagia 1 (0.2) 0 (0)

Safety population; *p=0.11


EINSTEIN Extension: non-major clinically relevant bleeding

Rivaroxaban(n=598)

Placebo(n=590)

n (%) n (%)

Non-major clinically relevant bleeding 32 (5.4) 7 (1.2)

Urogenital/uterus 12 (2.0) 2 (0.3)

Nasal 8 (1.3) 1 (0.2)

Rectal/anal 6 (1.0) 2 (0.3)

Skin 4 (0.7) 2 (0.3)

Ear 1 (0.2) 0 (0)

Gastrointestinal 1 (0.2) 0 (0)

Surgical site 1 (0.2) 0 (0)

Safety population; some patients experienced more than one event


Summary and conclusion of the EINSTEIN study program

EINSTEIN DVT and PE: rivaroxaban vs standard therapy showed:1,2

Non-inferiority for efficacy

Similar findings for the principal safety outcome

EINSTEIN DVT: rivaroxaban vs standard therapy showed:1

Favourable prespecified net clinical benefit

EINSTEIN PE: rivaroxaban vs standard therapy showed:2

Superiority for major bleeding

EINSTEIN Extension study: rivaroxaban showed:1

– 82% RRR in the recurrence of VTE

– Low incidence of major bleeding ; modest increase in non-major clinically relevant bleeding compared with placebo

1. The EINSTEIN Investigators. N Engl J Med 2010; 2. The EINSTEIN-PE Investigators. N Engl J Med 2012

Oral rivaroxaban provides a simple, single-drug approach for the acute and continued treatment of DVT and PE

Oral rivaroxaban provides a simple, single-drug approach for the acute and continued treatment of DVT and PE

EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding

Number of patients at risk

Rivaroxaban 4130 3921 3862 3611 3479 3433 2074 1135 1095 1025 969 947 499

Enoxaparin/VKA 4116 3868 3784 3525 3394 3348 1835 1109 1065 990 950 916 409

0.5

3.0

2.5

2.0

1.5

1.0

0.0

RivaroxabanN=4130

Enoxaparin/VKAN=4116

0 30 60 90 120 150 180 210 240 270 300 330 360

Time to event (days)

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%)

First major bleeding

Rivaroxabann/N (%)

Enoxaparin/VKAn/N (%)

HR (95% CI)p-value

40/4130 (1.0)

72/4116(1.7)

0.54 (0.37–0.79) p=0.002

Safety population Buller HR, for the EINSTEIN Investigators. ASH, December 2012

EINSTEIN DVT and PE pooled analysis: conclusions

In acute symptomatic DVT and/or PE, rivaroxaban showed: Non-inferiority versus enoxaparin/VKA for efficacy Similar incidence rates to enoxaparin/VKA for the principal

safety outcome Superiority for major bleeding Consistent efficacy and safety results irrespective of age,

body weight, gender, renal function, cancer, and severity of DVT/PE

Single-drug approach for treatment of acute DVT, PE and secondary prevention

CONCLUSIONS RIVAROXABAN

Advantages:-Fixed dose-No laboratory monitoring-Einstein studies , many pts-Short half-life

stop 24-48 hrs before surgery


Drawbacks:-No long term experience-Limited duration of treatment (reimbursement)( max.12 months)-Insufficient data in cancer pts-Surgical intervention: stop 24-48 hrs-Einstein-DVT/PE :

* open-label design* absolute benefits small


Contra-indications:-Renal insufficiency ( cr. cl. ≤ 30 mL/’)-Significant hepatic impairment-Pregnancy

No ( not yet…) specific antidoteBut: *short half-life 5-9 hrs

*Activated or unactivated protein concentrate may be effective

APIXABAN

• Direct Xa inhibitor

• Prevention DVT knee-/hip prosthesis

• ADVANCE 2 ( knee) and 3 ( hip)

• Versus enoxaparine s.c. 40 mg: – Combined endpoint prevention VTE, non-fatal

PE, & death: – RR 0,62 , NNT11 ( knee)– RR 0,36 , NNT 40 ( hip)

• Safety: no significant difference

DIRECT THROMBIN INACTIVATOR

DABIGATRAN

• Oral direct thrombin inactivator• Can inactivate fibrin-bound thrombin• High affinity and specificity• Prodrug ( liver) drug• 80 % renal excretion• Half-life 12-14 hrs ( longer in elderly,↓renal function)• No monitoring• Surgical intervention: stop Dabi 24-48 hrs ( if creat

clear < 50 mL/’: 48-72 hrs).

DABIGATRAN

• Drawbacks:– Dose reduction :* > 75-80 yrs

* moderate/severe renal impairment

– Low body weight ? Morbidly obese ?– No monitoring– Interactions

• Interactions:– Food: no– CYP 450: no– Substrate for efflux transporter P-glycoprotein drug

interactions !

Inhibitors of P-gp efflux transporter Increased dabigatran concentration : Abiraterone, alfentanil, amiodarone, atorvastatin, azithromycin•, boceprevir•, carvedilol, clarithromycin, cobicistat containing coformulations, conivaptan•, crizotinib, cyclosporine, darunavir, diltiazem•, dipyridamole, dronedarone, duloxetine•, erythromycin, fenofibrate•, grapefruit and grapefruit juice¥, indinavir•, itraconazole, ivacaftor, ketoconazole, lapatinib, lomitapide, lopinavir, lovastatin•, mefloquine, mifepristone•, nelfinavir, nicardipine, nifedipine•, nilotinib, posaconazole•, progesterone, propafenone•, propranolol, quinidine, quinine•, ranolazine, reserpine, ritonavir, ritonavir containing coformulations, saquinavir, sunitinib, tacrolimus, tamoxifen, telaprevir, telithromycin•, ticagrelor•, tolvaptan•, ulipristal, vandetanib, vemurafenib, verapamil

Inducers of P-gp efflux transporter Decreased dabigatran concentration (significant effect) : Carbamazepine, dexamethasone, doxorubicin, nefazodone, pentobarbital•, phenobarbital•, prazosin, rifampin◊, St. John's wort, tenofovir§, tipranavir, trazodone, vinblastine.

Antacids Decreased dabigatran concentration (moderate effect) : H2 antagonists, PPIs

DABIGATRAN

• Contra-indications:

– Renal insufficiency : kreat clear ≤ 30 mL/’

– Pregnancy

– Avoid rifampicin, amiodarone, quinidin, ketoconazole,clarithromycin…

DABIGATRAN• If bleeding:

– Stop dabigatran

– Dialysis

– Activated coal ( if ingestion ≤ 2 hrs)

– If life threatening: prothrombin complex concentrate, recombinant human factor VIIa

– Antidote : aDabi-Fab

DABIGATRAN

• Dabigatran versus warfarin in the treatment of acute venous thromboembolism. Schulman S, Kearon C, Kakkar AK, et al. RE-COVER Study Group . N Engl J Med. 2009;361(24):2342.

• Double blind RCT , non-inferiority, n=2539 pts• Parenteral antico mean 9 d,then:

dabigatran warfarin INR 2-3

DABIGATRAN

WARFA DABI HR P

Recurrent venous thromboembolism

2,1% 2,4% 1,1 <0,001

Major bleeding 1,9% 1,6% 0,82

Any bleeding 21,9% 16,1% 0,71

Discontinuation drug 6,8% 9% 0,05

DABIGATRAN

• Dabigatran versus warfarin in the treatment of acute venous thromboembolism. Schulman S, Kearon C, et al RE-COVER Study Group .

• Conclusion:

– Fixed dose dabigatran as effective as warfarin

– Similar safety profile

– No laboratory monitoring

DABIGATRAN

• N Engl J Med. 2013 Feb 21;368(8):709-18. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism.Schulman S, Kearon C, Kakkar AK, et al.;

RE-MEDY Trial Investigators;

RE-SONATE Trial Investigators.• Double blind RCT , pts completed ≥ 3 months of

therapy; then active control study ( dabigatran vs warfarin) / placebo control study ( dabigatran vs placebo)

RE-MEDY & RE-SONATE trials

DABI WAR HR P

Recurrent venous thromboembolism

1,8 % 1,3 % 1,44 0,01

Major bleeding 0,9 % 1,8 % 0,52

ACS 0,9 % 0,2 % 0,02

DABI PLAC HR P

Recurrent thromboembolism

0,4 % 5,6 % 0,08

COST/1day treatment Warfarin=Marevan®:1 co/d=0,24 €; 0,25 co/d=0,06 €Enoxaparin=Clexane:2x80mg/d=10,3€/d;2x120mg/d=15,8€

Apixaban=Eliquis®:(Prophylactic dose) 2x2,5mg/d=2,88 €/dRivaroxaban=Xarelto®:2x15 mg/d= 5,1 €/d1x20 mg/d=2,54 €/dDabigatran=Pradaxa®:2x110 or 2x150 mg/d=2,67 €/d

But:

Warfarin: -cost INR-consultation physician-blood drawing -Costs ( major ) bleeding

LMWH:-cost nurse-cost hospitalisation ( acute PE/DVT)

TERUGBETALING BELGIE 11/2013

• Eliquis®: – Cat Bf: preventie CVA bij non-valvulaire VKF + ≥1

risicofactor– Preventief na heup-en knievervangende OP

• Pradaxa®:– Preventie CVA bij non-valvulaire VKF + ≥1 risicofactor– Preventief na heup-en knievervangende OP

• Xarelto® : – preventie CVA bij non-valvulaire VKF + ≥1 risicofactor– Behandeling DVT, preventie recidief DVT/PE na acute DVT– Preventie VTE bij orthopedische chirurgie heup/knie

II - Elementen te bevestigen door de behandelende arts:Ik ondergetekende, behandelende arts, verklaar dat de bovenvermelde volwassen patiënt met DVT (diep veneuze trombose) eenbehandeling nodig heeft met Xarelto 15 mg 2 maal daags gedurende de eerste 3 weken voor de initiatie (2 per daggedurende 3 weken), gevolgd door eenmaal daags Xarelto 15 mg of Xarelto 20 mg gedurende de voortgezette behandelingvan diep veneuze trombose (DVT) en preventie van recidief DVT en pulmonale embolie (PE) na een acute DVT.De duur van de vergoeding hangt samen met de behoeften van de behandeling per DVT, namelijk een korte behandelingsduurvan maximaal 3 maanden na voordoen van risicofactoren van voorbijgaande aard en een langere behandelduur (6 tot12 maanden) gebaseerd op permanente risicofactoren of idiopathische DVT.Datum van DVT: / /De specialiteit zal worden toegediend met een dosis van tweemaal daags 15 mg gedurende de eerste drieweken, gevolgd door eenmaal daags 20 mg erna.Staatsblad 21/08/2013.

BIJ WIE NOAC’s ?• Wel:

– Bijwerkingen op VKA– Contra-indicatie VKA– Geneesmiddeleninteracties– Problematische INR controles

• Niét : – ptn zonder VKA problemen– Contra-indicaties NOAC

MELDEN BIJWERKINGEN BELGIE 11/2013

• BCGH:-Papieren gele fiche FAGG

-www.gelefiche.be

[email protected]

• Eliquis®

-Bristol-Myers Squibb:

-email:safety [email protected]

-tel 023527172

MELDEN BIJWERKINGEN BELGIE 11/2013

• Pradaxa® :-Boehringer Ingelheim

-email:pv local [email protected]

-tel. 027733438

• Xarelto®

-Bayer

-email:[email protected]

-tel 025356393

AZ. ST. JANSCOLLOQUIA FLASHAVOND ETHIEK EN ECONOMIE 12-11-2013.

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Transcript of AZ. ST. JANSCOLLOQUIA FLASHAVOND ETHIEK EN ECONOMIE 12-11-2013.