Quali sono gli elementi predittivi di recidiva?

Gualtiero PalaretiU.O. di Angiologia e Malattie della Coagulazione

“Marino Golinelli”Policlinico S. Orsola-Malpighi

Bologna

Recurrence after DVT and PE.A population based cohort study.

Olmsted County, Minnesota, Missouri. 106.470 inhabitants

Heit JA et al. Arch Intern Med 2000.

Prevalenza di recidive nel tempo

• 17,5% a 2 a

• 24,6% a 5 a

• Circa 30% a 10 a

Tipologia dei fattori di rischio di recidiva

• Intervallo dal primo evento• Età e sesso• Tipo del 1° evento

(presentazione come TVP o EP, TVP prox o dist)• Natura del 1° evento

(idiopatico, secondario a causa rimuovibile o non)• Adeguata terapia del 1° evento• Patologia associata (cancro, pat. flogistica, ecc)• Trombofilia (congenita, acquisita)• Familiarità• Persistenza residuo trombotico• D-dimeri• Altro

L’intervallo dal primo evento

(From Keeling, Blood Review 2006, 20: 174)

Età e incidenza di TEV

0

2

4

6

8

10

12

14in

cid

enza

per

100

0/an

no

<20 20-39 40-59 60-74 >74 anni

Donne

Uomini

(EPI-GETBO Study Group, Thromb Haemost, 2000)

(McRae et al. Lancet 2006)

Tipo del primo evento

Embolia polmonareTVP prossimaleTVP distale isolata

(from Eichinger S et al, Arch Intern Med 2004; 164: 94)

3 or 6 m. OAT after a first episode of proxymal DVT/PE 6 or 12 w. OAT after isolated calf DVT

(DOTAVK; Pinede et al., Circulation 2001)

(from Schulman et al., NEJM 1997)

La natura del primo evento è predittiva del rischio di recidiva

(from Levine et al., Throm Haemost 1995)

VTE recurrences during follow-up (Palareti et al. T&H 2002)

Type of index VTE Rate % pts % pt-y

Idiopathic 10.8 6.9

Permanent risk factor 34 ** 24.7 ***

Transient risk factor 4.3 * 2.6 *

La qualità del trattamento anticoagulante (specie nei primi 3 mesi)

influenza il rischio di recidiva

Cumulative incidence of recurrence during follow-up according to the % of time spent at INR values <1.5

during the first 90 days of OAT course

5th quintile = continuous line 1st-4th quintiles = dashed line HR = 2.77 (95%CI 1.75–8.40)

(Palareti et al., J Thromb Haemost 2005)

TAO a bassa intensità (INR 1,5-1,9)o a normale intensità (INR 2,0-3,0)

LONG TERM LOW-INTENSITY WARFARIN TREATMENT (the ELATE study)

(Kearon et al., NEJM 2003)

1,90

0,60 0,96 0,93

4,9

3,6

0,00

1,00

2,00

3,00

4,00

5,00

6,00

7,00

8,00

9,00

10,00

% pt-y

rVTE Maj. Bleed Maj +min bleed

Rates of recurrent VTE and bleedinglow intensity

conventionalintensity

Trombofilia congenita e rischio di recidiva

From Baglin et al.Lancet 2003

Recurrence in subjects with/without thrombophilia(Palareti et al. Circulation 2003)

Ho et al, Arch Intern Med 2006

Risk of recurrence incommon thrombophilia

Presenza di residuo trombotico e rischio di recidiva

Residual vein thrombosis (RVT) and risk of recurrences

(Prandoni et al., Ann Intern Med 2002)

CUS normal if ø < 2.0 mm o < 3.0 mm in 2 visits

• CUS normal in:38.8% at 6 m58.1% “ 1 y69.3% “ 2 y73.8% “ 3 y

• 58 recurrences41 in pts with RVT17 in pts without RVT

• Cox proportional hazard model: 2.9 (95%CI 1.6-5.2; p=0.001)

Residual Venous Thrombosis as a Predictive Factor of Recurrent Venous Thromboembolism

Prandoni, Annals Intern Med, 2002.

0

2

4

6

8

10

12

14

16

18

N

Trombofilia Idiopatica Secondaria

58 recidive

CUS NORMTV RESIDUA

D-Dimer test to predict the risk of VTE recurrence

Rate of abnormal D-d results in pts on AVK treatment, 1 m. and 3 m. after this was stopped

(Palareti et al., T&H 2002)

05

101520253035404550

% of pts with abnormal D-d

on treat. 1 m. 3 m.

Cumulative probability of recurrencehazard ratio= 2.45 (1.28-4.53; p< 0.01)

(Palareti et al. T&H 2002)  

(from Eichinger et al., JAMA 2003)

(from Shrivastava et al, J Thromb Haem, 2006;4:1210)

D-d carried out 1 month after OAT interruption and recurrences (Palareti et al., Circulation 2003)

0 250 500 750 10000.0

0.1

0.2

0.3

0.4

Thrombophilic alterationsand altered D-Dimer

Thrombophilic alterationsand normal D-Dimer

Hazard ratio = 8.34(95%CI: 2.72-17.43)

Days

Cum

ula

tive p

robabili

ty o

fre

curr

ence

Cumulative recurrence in pts with idiopathic events according to combination of D-dimer

and RVO (Cosmi et al., T&H 2005;94:969)

A= normal D-dimer without RVO B= RVO and normal D-dimer C= abnormal D-dimer without RVO D= abnormal D-dimer and RVO

Può il D-dimero essere usato per determinare il rischio individuale di

recidiva?

Lo studio prospettico, randomizzatoPROLONG

PROLONG: flow-chart of pts

627 enrolled pts in 30 Centres

Excluded3 pts no consensus5 pts had VTE before inclusion

619 pts included

392 (63.3%) = normal D-d 227 (36.7%) = abnormal D-d

yes VKA 103(2 pts excluded for LA)

randomized to

no VKA 120(2 pts excluded for LA)

No VKA 385(7 pts excluded for LA)

Outcomes Normal-Dd

n 385

Abnormal-Dd No VKA

n 120

Abnormal-Dd+VKA

No. 103

n/n total

n/100 person-yr

6.2%

4.4

15.0%

10.9

2.9%

2.0

Prolong: outcomes in 608 pts(during 864.8 y follow up)

(Palareti et al., NEJM 2006)

(Palareti et al., NEJM 2006;335:1780-9)

The Prolong studyresults in the subgroup of pts with P.E.

• 227 patients [105 males; 67 y (19-84)]

• Isolated PE n = 118

• PE+DVT n = 109

• Total follow-up period = 321.0 y

The Prolong studyoutcomes in patients with P.E.

Normal-Dd

N=144

Abnormal-Dd No VKA

N=47

Abnormal-Dd VKA

N=36

No. (%) of VTE recurrence

5 (3.5%) 8 (17.0%) 1 (2.8%)#

No./100 patient/yr

2.4 12.3 1.9

# = major bleeding

The Prolong study cumulative incidence of outcomes in pts with P.E.