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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
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