Nuovi anticoagulanti a confronto:

i risultati dei trials clinici

Walter Ageno Dipartimento di Medicina Clinica e Sperimentale

Università dell’Insubria – Varese

ACCP 2012 Treatment of VTE

2012

Real-life treatment of acute VTE:

RIETE registry

Treatment PE±DVT Isolated DVT p

(n=20,543) (n=21,283)

Thrombolytics 0.9% 0.1% <0.001

UFH 12% 2.9% <0.001

LMWH 85% 95% <0.001

Fondaparinux 1.3% 1.6% 0.036

VKA 73% 67% <0.001

Lecumberri R et al Thromb Haemost 2013

*Or unfractionated heparin or fondaparinux

BID = twice daily; LMWH = low molecular weight heparin; OD = once daily; s.c. = subcutaneous; VKA = vitamin K

antagonist

dabi bid / edo OD

RE-COVER + RE-COVER II

DABIGATRAN (publ . 2009/2013)

EINSTEIN-DVT + EINSTEIN-

PE RIVAROXABAN (publ 2010/2012)

VKA

AMPLIFY

APIXABAN (publ. 2013)

Day 1

Day 1

Day 1

At least 3 months

At least 3 months

Day 5–11

LMWH s.c.

At least 3 months

Current standard of care

LMWH or

Fonda s.c.*

HOKUSAI-VTE

EDOXABAN (publ. 2013)

Day 5–11

riva 15 mg BID 3 wk, then 20 mg OD

api 10 BID 1 wk, then 5 mg BID

Venous thromboembolism:

drugs and strategies

iv UFH / VKA versus VKA alone:

VTE: optimal treatment for acute initial period

Brandjes et al. N Engl J Med 1992;327:1485-9.

VTE recurrences at 3 months: 7 % 20 %

0

2

4

6

8

D1-7 D7-14 D15-30

Ximelagatran alone

LMWH / VKA

Nu

nb

er o

f re

curr

ence

s

THRIVE II-V study. Fiessinger et al. JAMA 2005;293:681-9.

HR = 2.09 [ 1.2 – 3.6 ]

Van Gogh PE study. N Engl J Med 2007;357:1094-104.

Idraparinux ow alone

LMWH / VKA

Acute initial phase: period at risk requiring intensive parenteral treatments

0

0,5

1

1,5

2

2,5

3

3,5

4

RE-COVER EINSTEIN AMPLIFY Hokusai-VTE

Pati

ents

(%

) Phase III VTE trials – Recurrent VTE

1.6% 1.9%

2.3% 2.2% 2.1%

2.3% 2.3%

2.7%

1. Schulman et al. N Engl J Med 2009;361:2342–2352

2. EINSTEIN Investigators. N Engl J Med 2010; 3. EINSTEIN–PE Investigators. N Engl J Med

4. Agnelli et al. N Engl J Med 2013; 5. The Hokusai-VTE Investigators. N Engl J Med 2013

*

* On Treatment

NOAC

Control

Dabigatran Rivaroxaban Apixaban Edoxaban

0

0,5

1

1,5

2

2,5

3

3,5

4

RE-COVER EINSTEIN AMPLIFY Hokusai-VTE

Pati

ents

(%

) Phase III VTE trials – Major Bleeding

1.4% 1.6%

1.4%

2.0%

1.0%

1.7%

0.6%

1.8%

1. Schulman et al. N Engl J Med 2009;361:2342–2352

2. EINSTEIN Investigators. N Engl J Med 2010; 3. EINSTEIN–PE Investigators. N Engl J Med

4. Agnelli et al. N Engl J Med 2013; 5. The Hokusai-VTE Investigators. N Engl J Med 2013

NOAC

Control

Dabigatran Rivaroxaban Apixaban Edoxaban

RE-

COVER1#

(Dabigatran)

EINSTEIN

DVT2

(Rivaroxaban)

EINSTEIN PE3

(Rivaroxaban)

AMPLIFY4

(Apixaban)

Hokusai-

VTE5

(Edoxaban)

Patients, N 2539 3449 4832 5395 8292

Age (yrs) 55 56 58 57 56

Female (%) 42 43 47 41 43

Creatinine

clearance

<50 mL/min (%)

NR 7 8 6 7

DVT (%) 69 99 - 65 59

PE±DVT (%) 31 0.6 100 35 40

Unprovoked (%) NR 62 65 90 65

Cancer (%) 5 6 5 3 9†

Previous VTE 26 19 19 16 18

NOAC VTE trials:

Baseline characteristics

NR=not reported; #RECOVER II is still only available as an abstract and therefore is not included in the table †Data from Hokusai-VTE are for history of cancer; active cancer was observed in 2.4% of patients overall

1. Schulman et al. N Engl J Med 2009;361:2342–2352

2. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 3. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297

4. Agnelli et al. N Engl J Med 2013;369:799–808; 5. The Hokusai-VTE Investigators. N Engl J Med 2013

EINSTEIN PE 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

Cu

mu

lati

ve

even

t ra

te (

%)

Time to event (days)

Rivaroxaban

N=2419

Enoxaparin/VKA

N=2413

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

The EINSTEIN Investigators. N Engl J Med 2012

44 (1.8%)

50 (2.1%)

EINSTEIN PE Principal safety outcome: major or non-major clinically relevant bleeding

Safety population

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

15 14

10

13 12 11

9 8 7 6 5 4 3 2 1

0

Number of patients at risk

Rivaroxaban 2412 2183 2133 2024 1953 1913 1211 696 671 632 600 588 313

Enoxaparin/VKA 2405 2184 2115 1990 1923 1887 1092 687 660 620 589 574 251

Cu

mu

lati

ve

even

t ra

te (

%)

Time to event (days)

Rivaroxaban

N=2412

Enoxaparin/VKA

N=2405

The EINSTEIN Investigators. N Engl J Med 2012

11.4% (Major 2.2%*)

10.3% (Major 1.1%*)

* 0.49 (0.31-0.79)

Hokusai study:

Subgroup analysis in PE patients with

NT-proBNP ≥500 pg/mL

15/454 30/484

HR=0.52 (95% CI, 0.28-0.98)

3.3%

6.2%

The Hokusai-VTE Investigators. N Engl J Med 2013

ACCP 2012 Treatment of VTE

2012

RE-MEDY™ study design

S, screening; R, randomization.

*Original protocol, 3–6 months of pre-treatment, then 18 months on study drug; amendment

allowed 3–12 months of pre-treatment, then up to 36 months on study drug.

Confirmed

VTE

Anticoagulant

therapy

3–12 months*

S R

0–7 days until

INR ≤2.3

Screening/

baseline

Dabigatran etexilate 150 mg bid

Warfarin placebo

Warfarin (INR 2.0–3.0)

Dabigatran placebo

Up to 36 months*

End of treatment

Follow up

30 days Treatment period

and “increased

risk of

recurrence”

26/1430

Recurrent symptomatic VTE and VTE-related deaths

1.8%

1.3%

Risk difference 0.38 (95% CI: -0.50–1.25); p < 0.0001 (non-inferiority).

HR 1.44 (95% CI: 0.78–2.64)

18/1426

Perc

en

tage

p = 0.027 (non-inferiority)

0

0,5

1

1,5

2

2,5

3

Dabigatran 150 mg bid Warfarin13/1430

Major bleeding

0.9%

1.8%

HR 0.52 (95% CI: 0.27–1.02)

25/1426

Per

cen

tage

p = 0.058

On treatment

48%

RRR

RRR, relative risk reduction.

Eleggibilità da piano terapeutico

per Xarelto

• Prevenzione della TVP recidivante e dell’EP

dopo TVP PROSSIMALE acuta nell’adulto

• Diagnosi confermata mediante ecografia

ARTI INFERIORI nelle 48 ore precedenti

• Oppure

• Terapia con EBPM o ENF o fondaparinux

• Insufficienza grave (clearance creatinina < 30

mL/min-15 mL/min per alcuni farmaci?)

• Insufficienza epatica moderata-grave (Child-Pugh

B-C); epatite acuta

• Terapia con farmaci non associabili (es.

antiretrovirali)

• Gravidanza e allattamento

• Neoplasia attiva con indicazione a EBPM a lungo

termine

• Concomitante EP con instabilità emodinamica

Pazienti non candidabili ai nuovi

anticoagulanti orali

I nuovi anticoagulanti nella terapia del

TEV: conclusioni

• Studi di fase III 27.100 pazienti con TVP ed EP dimostrano efficacia comparabile al trattamento standard e sicurezza complessivamente superiore

• Non vi sono segnali di differenze nei vari sottogruppi, soprattutto di pazienti più fragili

• I vantaggi pratici sono indiscutibili

• Siamo in attesa di dati da studi osservazionali/fase IV (Xalia)

I nuovi anticoagulanti nella terapia del

TEV: conclusioni 2

• E’ fondamentale la selezione dei pazienti idonei per ciascun trattamento

• E’ fondamentale un’adeguata istruzione dei pazienti

• E’ fondamentale un adeguato follow-up

• Aree incerte:

• Embolia polmonare con disfunzione ventricolare dx

• Neoplasia attiva (vs EBPM)

• Sedi inusuali