Long-term management of idiopathic VTE:

individualised approach vs DOAC for everybody

Prof. Gualtiero Palareti

Cardiovascular Diseases University of Bologna

“Arianna Anticoagulazione” Foundation

Education course of Swiss Society of Hematology

Lausanne, 10-11 November 2017

ACCP 2016

Duration of AC in patients with VTE

- All the patients with an acute VTE event should receive not < 3 months of anticoagulation

From Blondon & Bounameaux, Circulation 2015

Initial Long-Term Extended

From Kearon et al., Chest 2016

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.

Risks of VTE recurrences and

treatments

• Recurrences = 17,5% (at 2 y); 24,6% (at 5 y); about

30% (at 10 y)

• VKAs (INR 2.0-3.0) = highly effective with a risk

reduction 90%; major bleeding ≈ 2%

• DOACs = all non-inferior for efficacy and safety vs

VKA (very good safety results in some trials)

Couturaud et al.

JAMA 2015

Whatever the duration of anticoagulation, the

protection against recurrences persists only

during treatment

The risk of recurrence is not the same for

all patients

- Nature and site of the index event

- Characteristics of the patients

Arch Intern Med 2010

Criteria for short anticoagulation

Isolated distal DVT

The “provoked” events

• VTE post major surgery (within 3 months)

• VTE post bed resting (≥ 4 d)

• VTE post major trauma (within 3 months)

• VTE post plasters or immobilization (within 3

months)

High bleeding risk

Criteria for extended anticoagulation

• > one documented VTE episodes (proximal DVT and/or

PE)

• Active cancer or hematologic disease

• Antithrombin deficiency

• Antiphospholid antibody syndrome (Sydney criteria)

• PE with shock or life-threatening prolonged hypotension

• Different indications for anticoagulation (>PAP)

• Severe Cardio-Respiratory insufficiency (NYHA 3 or 4)

Example of distribution of VTE patients examined

for deciding the duration of treatment

All VTE Pts

Provoked VTE,

short AC

25%

Criteria

for extended AC

25% Unprovoked VTE

~50%

In patients with a first unprovoked proximal DVT or PE

and who have a:

(i) low or moderate bleeding risk, we suggest extended AC therapy

(no scheduled stop date) (Grade 2B)

(ii) high bleeding risk, we recommend 3 months of AC therapy over

extended therapy (Grade 1B)

All patients who receive extended AC therapy should be reassessed

at periodic intervals (e.g. annually).

2016

2010

Case-fatality rates of:

• Recurrent VTE events after AC is stopped:

3.6% pt/y

• Bleeding event during AC (6 mo):

11.0% pt/y

T&H 2013

The case-fatality rate of recurrent VTE decreases over time during

anticoagulation, while that of major bleeding remains stable

Only 50% of patients with unprovoked

VTE are expected to have

recurrences in 10 y (Prandoni et al. Haematologica 2007)

Should we give indefinite AC to 100% of

these patients?

Recurrent VTE or VTE-related death in recent

extension studies in placebo-treated

Trials Placebo group

Resonate (6 mo; 18 mo) (dabig.) 5.6%; ~10%

Inspire (4 y) (ASA) 18.4%

Amplify extension (1 y) (apix.) 8.8%

SURVET (2 y) (sulodex.) 9.7%

The target of our clinical studies:

to identify subjects at high or low risk

of recurrence and to give or avoid them

indefinite AC

D-dimer after AC is stopped

Palareti et al,

NEJM, 2006

Elevated D-dimer levels after AC is

stopped are associated with increased

risk of VTE recurrence

Pooled analysis of ~1,900 patients with 1st unprovoked

VTE and ~4,500 patient-yrs follow-up

Annual risk for recurrent VTE in patients with…

•-ve D-dimer = 3.5% (2.7-4.3)

•+ve D-dimer = 8.9% (5.8-11.9)

2010

Cumulative incidence of recurrence and HR of main

outcomes according to D-dimer time course from the 3th

to the 13th month (Cosmi et al, Blood 2010)

Group 1 = D-dimer normal at T90 and afterwards (66.0%)

Group 2 = D-dimer abnormal at T90 and persistently abnormal (13.7%)

Group 3 = D-dimer sometimes abnormal after T90 (20.3%)

2016

Remarks:

Patient sex and D-dimer level measured a month after stopping AC

therapy may influence the decision to stop or extend anticoagulant

therapy.

Scores to assess the individual risk of

VTE recurrence

Rodger et al., CMAJ 2008

The Vienna nomogram to estimate the probability of recurrence

(Eichinger et al., Circulation 2010);

recently validated (Marcucci et al., JTH 2015)

Individual patient data meta-analysis of 7 prospective studies,

1818 pts

DASH score= points

Abnormal D-dimer after stopping anticoagulation 2

Age < 50 years 1

Male sex 1

VTE associated with hormonal therapy (in women) -2

JTH

2012

External validated of

DASH Score

Tosetto et al.

JTH in print

Blood 2014

NEJM 2013

Amplify Extension

(Agnelli et al. NEJM 2013)

Patients included if:

• treated for 6 to 12 months with standard AC therapy

• there was clinical equipoise about the continuation or

cessation of AC therapy

• Unprovoked 93.2%

• Transient or reversible risk factor 6.7%

The Einstein-Choice trial

Weitz et al. NEJM 2017

Three recent studies for

secondary prevention

Studies Recurrences

During AC vs

control

% pt/y

Major Bleeds

During AC vs

control

% pt/y

DULCIS (2014)

(management based on DD)

VKA vs no therapy

0.7 vs 3.0 2.3 vs 0

AMPLIFY Extension (2013)

(randomized trial)

Apixaban 2.5 mg x 2, vs placebo

1.7 vs 8.8 0.2 vs 0.5

EINSTEIN CHOICE (2017)

(randomized trial)

Rivaroxaban 10 mg x 1 vs ASA 100 mg x 1

1.2 vs 4.4 0.4 vs 0.3

Einstein Choice (Weitz et al. NEJM 2017)

Patients included:

• Treated for 6 to 12 months with standard AC

therapy

• Unprovoked (42.6%); bleeds: 1.9%

• Provoked (57.4%); bleeds: 2.8% (with the 10 mg/d dose, M+CRNMB)

The Apidulcis study (multicenter, management)

Promoted by the

“Arianna Anticoagulazione” Foundation

(Bologna, Italy)

Palareti G. & Prandoni P.

Apidulcis

• Patients (< 75 y age) with a first unprovoked (or

WRF) VTE

• After 12 m AC (whatever the drug)

• Serial DD assessment (during and after AC is

stopped)

• Apixaban 2.5 mg bd for 18 m at first positive DD

• No AC if DD persistently negative

D-dimer Test

Patients with First VTE episode Exclusion criteria Inclusion

criteria Screening

Negative value

D-dimer Test

D-dimer Test

D-dimer Test

Apixaban 2,5 mg x2/die 18 months

Follow up 18 months

T1

T2

T3

Negative value

Anticoagulation (for 12-18 Months)

Positive value

T0

Informed Consent Signature/Patient Enrollment

Negative value

Negative value

Stop AC

Apidulcis

• DD = using commercial assays

• Timing = during AC, and 15, 30, 60 d after AC is

stopped

• Cut-off (FEU) =

Males: 350 mg/mL

Females: 500 mg/mL

Apidulcis

• FU = 18 m.

Targets

• About 40% of patients excluded from indefinite

AC

• HR < 3 vs the rate of events (recurr. + bleeds) in

the apixaban treated patients

Apidulcis:

50 Italian centres

1200 pts will be included

1st patient expected January 2018

Thank you