Prognosi e follow-up

della TVP

Milano FCSA, 21-10-2016

Paolo Prandoni Università di Padova

Teatro Anatomico Università di Padova

Presentation includes discussion of the following off-label use of a drug or medical device: N/A

Disclosures of: Paolo Prandoni

Employment No conflict of interest to disclose

Research support No conflict of interest to disclose

Scientific advisory board No conflict of interest to disclose

Consultancy Bayer, Pfizer, Sanofi-Aventis, Daiichi-Sankyo

Speakers bureau No conflict of interest to disclose

Major stockholder No conflict of interest to disclose

Patents No conflict of interest to disclose

Honoraria No conflict of interest to disclose

Travel support No conflict of interest to disclose

Other No conflict of interest to disclose

Late events after DVT

• (Severe) PTS • Recurrent VTE

§ Arterial thrombotic events

§ Overt cancer

Kahn SR, Shrier I, Julian JA, et al

Determinants and time course of the postthrombotic syndrome after acute

deep-venous thrombosis

Ann Intern Med 2008;149:698-707

Cumulative risk of the PTS in the study cohort

Independent predictors of the PTS

Additional risk factors of PTS

l Superficial vein insufficiency

l D-dimer, CRP and other biomarkers of inflammation

l Inadequate oral anticoagulant therapy

l Persistent venous obstruction

The impact of residual thrombosis on the long-term outcome of patients

with deep venous thrombosis treated with conventional anticoagulation

Paolo Prandoni et al.

Semin Thromb Haemost 2015

Rate of RVT Ø Recruited patients 869

Ø RVT at 3 months after DVT 429 (49.4%)

Risk of Recurrent VTE

adjusted HR 2.03; 95% CI, 1.40 to 2.94

Risk of PTS

STRATEGIES FOR PREVENTION OF PTS

THOMBOLYTIC THERAPY

Cavent Study

Catheter-directed thrombolysis

(n=90)

n % (95%CI)

Standard treatment

(n=99)

n %(95%CI)

P

Veins recanalization after 6 months

58 65.9% (55.5-75.0)

45 47.4% (37.6-57.3)

0.012

PTS after 6 months 27 30.3% (21.8-40.5)

32 32.2% (23.9-42.1) 0.77

PTS after 24 months 37 41.1% (31.5-51.4)

55 55.6% (45.7-65.0) 0.047

Enden et al, Lancet 2011

Lancet Hematol 2016

Bleeding complications

CDT (no=90)

ST THERAPY (no=99)

MAJOR BLEEDING 3 0

CLINICALLY RELEVANT BLEEDING 5 0

MINOR BLEEDING 12 0

Enden et al, Lancet 2011

JAMA Intern Med 2014

Observational study of patients with a principal discharge diagnosis of proximal or caval DVT from 2005 to 2010 in the Nationwide Inpatients Sample (NIS) database in the U.S.A

Key baseline characteristics in propensity-matched groups

ATTRACT (NCT00790335)

Acute venous thrombosis: thrombus removal with adjunctive catheter-directed thrombolysis

(ATTRACT). Clintrials Gov 2010; NCT00790335.

Available at: http://www.clinicaltrials.gov

COMPRESSION STOCKINGS

Prandoni P, Frulla M, Marchiori A, et al

Below-knee compression elastic stockings for prevention of PTS in patients with proximal DVT

Ann Intern Med 2004

Cumulative Incidence of PTS

Months

72 66 60 54 48 42 36 30 24 18 12 6 0

Pro

porti

on o

f pat

ient

s w

ith P

TS

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

Controls

Stockings

Prandoni et al, ISTH 2003

The Lancet 2013

The Lancet 2013

Ginsberg index

Villalta scale

Optimal duration of CES

Durata individualizzata dell’uso della calza elastica in base allo score Villalta: 6 mesi vs 2 anni dopo la TVP

AHA Consensus Statement Circulation 2014

The effectiveness of ECS to prevent PTS is

uncertain, but ECS may be reasonable to

consider after diagnosis of proximal DVT

to reduce swelling (Class IIb; Level of

Evidence A).

ADEQUACY OF ANTICOAGULANT THERAPY

Van Dongen CJJ, Prandoni P et al. “Relation between quality of anticoagulation treatment and the development of the PTS”, JTH

2005

PTS is more likely to occur (3-fold more frequent) in patients who spend more than 50% of time below the desirable intensity of anticoagulation (INR below 2.0) during the first three months after the qualifying DVT episode.

Post thrombotic syndrome in patients treated

with rivaroxaban or enoxaparin/vitamin K

antagonists for acute deep vein thrombosis

Cheung W, Middeldorp S, Prins MH, Pap AF,

Lensing AWA, ten Cate-Hoek AJ,

Villalta S, Prandoni P for the Einstein PTS

Investigators Group

PTS cumulative incidence

Rivaroxaban

Unadjusted HR 0.71 (95%CI 0.48-1.03), p=0.07

After adjustment

HR 0.76 (95%CI 0.51-1.13), p=0.18

Enoxaparin/VKA

PTS development

Rivaroxaban 45 (28%) Enoxaparin/VKA 66 (38%)

0 84 72 60 48 36 Months 24 12

Cum

ulat

ive

Eve

nt R

ate

Number of subjects

R 162 119 110 106 83 43 8 0

VKA 174 124 109 99 81 37 8 0

0

0.1

0.3

0.4

0.2

0.5

VKAs

Thrombolytic treatment

Compression elastic stockings

DOACs

Optimal prevention of recurrent DVT

Strategies for prevention of PTS

PREVENTION OF RECURRENT DVT

Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, Iotti M, Tormene D, Simioni P, Pagnan A

The risk of recurrent VTE after discontinuing anticoagulation in patients with acute proximal

DVT or PE

Haematologica 2007; 91: 199-205

Adjusted HR = 2.30 (95% CI, 1.82 - 2.90)

The clinical course of 1626 patients with DVT and/or PE

Prandoni, Hematologica 2007

Finite durations of anticoagulation

Extending anticoagulation with VKA

Alternative scenarios?

1. DOAC

2. Aspirin or sulodexide

3. Post-baseline parameters (RVT/DD)

Amplify Extension

42

Kaplan–Meier: Non-fatal and fatal VTE

100

80

60

40

20

0 0 1 2 3 4 5 6 7 8 9 10 11 12

Cum

ulat

ive

even

t rat

e (%

)

Months

12 11 10 9 8 7 6 5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9

10

Baseline 840 813 826

Month 3 836 807 796

Month 6 825 799 768

Month 9 818 791 743

Month 12 533 513 471

No. at risk Apixaban 2.5 mg Apixaban 5 mg Placebo

Placebo Apixaban 2.5 mg Apixaban 5 mg

Cum

ulat

ive

even

t rat

e (%

)

43

Kaplan–Meier: Major or Clinically relevant non major bleeding

100

80

60

40

20

0 0 1 2 3 4 5 6 7 8 9 10 11 12

Cum

ulat

ive

even

t rat

e (%

)

Months

12 11 10 9 8 7 6 5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9

10

Baseline 840 811 823

Month 3 786 751 749

Month 6 759 716 687

Month 9 737 689 651

Month 12 354 331 298

No. at risk Apixaban 2.5 mg Apixaban 5 mg Placebo

Placebo Apixaban 2.5 mg Apixaban 5 mg

Cum

ulat

ive

even

t rat

e (%

)

Reduced-dosed rivaroxaban and standard-dosed rivaroxaban versus ASA in the long-term prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic DVT and/or PE

Einstein Choice

Low-dose aspirin/sulodexide

Meta-analysis of the WARFASA and ASPIRE studies

Andreozzi et al, Circulation 2015

Combination of D-dimer and

residual vein thrombosis

Palareti G, Cosmi B, Legnani C, Antonucci E, Erba N, Ghirarduzzi A, Poli D, Testa S, Tosetto A, Pengo V,

Prandoni P

Blood 2014

D-dimer to guide the duration of anticoagulation

in patients with venous thromboembolism

A management study

Proximal DVT 3-12 months VKA

Popliteal/femoral CUS

RVT Recanalization

D-dimer

Continuing VKA up to

a maximum of 1 year

Negative Positive

Stop VKA

Serial DD repetition

Negative Positive

No VKA Resuming VKA Resuming VKA

Continuing VKA

Main Study Results Ø Proportion of subjects with persistently

negative D-Dimer among eligible patients 51.2%

Ø Annual incidence of recurrent VTE in this

patients’ group (mean f-up, 2 years) 3.0%

Residual vein thrombosis and serial D-dimer for the management of patients

with unprovoked DVT

The MORGAGNI study

Submitted

Proximal DVT 3-12 months VKA

Popliteal/femoral CUS

RVT Recanalization

D-dimer

Continuing VKA Negative Positive

Stop VKA

Repeat DD after 1 and 3 months Repeat CUS after 6-12-18-24 months

RVT Recanalization

Continuing VKA

Negative Positive

No VKA Resuming VKA

Features Patients (no = 620)

Age

- mean + SD 61.2 + 17.9

- median (range) 65 (19 - 93)

Male gender 345 (55.6)

Nature of DVT

- of unknown origine 493 (79.5)

- associated with weak risk factors 127 (20.5)

Simultaneous PE symptoms 144 (23.2)

Localization of DVT

- popliteal only 284 (45.8)

- common femoral only 120 (19.4)

- both sites 216 (34.8)

Family history of VTE 97 (15.6)

Anticoagulation period before recruitment (months)

- up to 6 380 (61.3)

- up to 12 240 (38.7)

Overall duration of follow-up (months)

- mean (+ SD) 35.4 + 13.1

- median (range) 36 (3 - 75)

Main Study Results Ø Proportion of subjects meeting the Morgagni criteria

among eligible patients 65.0%

Ø Proportion of patients in whom anticoagulation could

be discontinued 80.0%

Ø Annual incidence of recurrent VTE in this

patients’ group (mean f-up, 3 years) 3.6%

Possible scenario

Unprovoked proximal DVT

3-12 months VKA or NOA

High risk for recurrent VTE

YES NO

Indefinite anticoagulation Dulcis/Morgagni criteria

YES

Stopping anticoagulation

NO

Apixaban 2.5 mg x 2

Rivaroxaban 10 mg?

THE DISCOVERY OF HEPARIN