VENOUS THROMBOEMBOLISM:

THE PRESENT

P.M. Mannucci

IRCCS Ca’ Granda Maggiore Policlinico

Hospital Foundation and University of Milano

DISCLOSURES

Honoraria for lectures as speaker or chair at

symposia organized by Bayer, Biotest, Grifols,

Kedrion, LFB, Novo Nordisk and Pfizer.

He also acted as scientific consultant for Bayer

and Kedrion

BACKGROUND

• Venous thromboembolism (VTE) is the third most

common cardiovascular disease (2-3/1000 each year)

• There is a markedly positive age gradient for its main

clinical manifestations: deep vein thrombosis (DVT)

and pulmonary embolism (PE)

• More patients die from PE than from breast and

prostate cancer, AIDS and traffic accidents combined

• Anticoagulant drugs have been extensively employed

as the mainstay of VTE treatment

PRINCIPLES OF ACUTE AND EXTENDED

VTE TREATMENT

TO

TOTO

THE BIG ISSUE OF VTE RECURRENCE

• After cessation of anticoagulants, 10% of

patients experience recurrent VTE within 12

months

• Up to 30% of patients experience recurrence

within 10 years

Prandoni et al. Haematologica 2007; 92: 199

Pharmacological

• Unfractionated heparin (UFH)

• Low molecular weight heparins (LMWHs)

• Fondaparinux

• Vitamin K antagonists (VKAs)

• Direct oral anticoagulants (DOACs) (dabigatran, rivaroxaban,

apixaban, edoxaban)

• Thrombolysis (only for hemodynamically severe PE)

Non pharmacological

• Surgery (embolectomy, thrombectomy)

• Interventional radiology (mechanical fragmentation,

thrombosuction)

• Vena cava filters (IVCFs)

VTE TREATMENT WEAPONS

Unpredictable response

Routine coagulation monitoring needed

Slow onset/offset

of action

Risk of bleeding

complications

Warfarin therapy

has several

limitations Numerous drug-drug interactions

Numerous food-drug interactions

Frequent dose adjustments

Narrow therapeutic window

(INR range 2-3)

VITAMIN K ANTAGONISTS – MAJOR DRAWBACKS

MAIN FEATURES OF “NEW” DIRECT ORAL ANTICOAGULANTS (DOACs)

Dabigatran Rivaroxaban Apixaban Edoxaban

Target IIa (thrombin) Xa Xa Xa

Hours to Cmax 1.25-3 2-4 3-4 1-2

Half-life 14-17 h 7-11 h 8-15 h 8-10 h

Administration

frequencyTwice daily Once daily Twice daily Once daily

Renal elimination 80% 60% 25% 35%

Liver metabolism Minimal Yes Yes Minimal

TREATMENT OF ACUTE VTE WITH DIRECT ORAL

ANTICOAGULANTS: POSSIBLE OPTIONS

• Initiation of therapy with standard parenteral

drugs (i.e. LMWHs) before the subsequent oral

use of VKAs or DOACs

• Initiation with an intensive regimen of DOACs

for the first few weeks (“single drug oral

approach”), followed by lower maintenance

doses of DOACs

EXTENDED TREATMENT OF VTE

• In some instances, anticoagulant therapy

is prolonged for more than the 3-6 months

of acute management

• This is named extended VTE treatment

SUMMARY OF THE MAIN PHASE III NON-INFERIORITY TRIALS REGARDING

ACUTE AND EXTENDED TREATMENT OF VENOUS THROMBO-EMBOLISM

Low-molecular-weight heparin has to be given upfront for the initiation of the treatment with dabigatran and edoxaban (A), while a

single-drug approach drives the treatment with rivaroxaban and apixaban both in the initiation and the early maintenance phases

(B).

Fontana P , EHJ 2014

+ LMWH

or

or

Main results (summarized by a meta-

analysis) of non-inferiority trials comparingVKA and DOACs for acute VTE treatment

PRIMARY EFFICACY END POINTS:

EARLY RECURRENT VTE OR VTE-RELATED DEATH

Van Es N, et al. Blood 2014

0.2

PRIMARY SAFETY END POINT:

MAJOR BLEEDING EVENTS

Van Es N, Blood 2014

0.1

INTRACRANIAL, MAJOR GASTROINTESTINAL, FATAL, AND

CLINICALLY RELEVANT NON MAJOR (CRNM) BLEEDING

Van Es N, Blood 2014

0.1

PATIENTS AGED ≥ 75 YEARS

RISK OF EARLY RECURRENCE AND MAJOR BLEEDING

Van Es N, Blood 2014

0.1

VTE RECURRENCE

• After cessation of anticoagulants, 10% of

patients experience recurrent VTE within

12 months

• Up to 30% of them experience recurrent

VTE within 10 years

• Hence, evaluation of extension therapies

is warranted after the acute phase

Prandoni et al. Haematologica 2007; 92: 199

Schulman S, et al. N Engl J Med 2009; Agnelli G, et al. N Engl J Med, 2013; Prins M, et al.

Thromb J, 2013; Hokusai VTE, N Engl J Med, 2013

EXTENSION STUDIES: RECURRENT VTE AND

RECURRENCE RELATED MORTALITY

1.750.50 0.75 1.00 1.25 1.50

Dabigatran

HR

(95% CI)

Rivaroxaban

Apixaban

P-value

(non-inferiority)

<0.001

<0.001

<0.001

Edoxaban <0.001

Favors NOAC Favors Warfarin

ACCP RECOMMENDATIONS

Kearon C, Chest 2016

• In patients with proximal DVT or pulmonary

embolism (PE), we recommend long-term (>3

months) anticoagulant therapy over no such

therapy (Grade 1B)

• In patients with DVT of the leg or PE and no cancer,

as long-term anticoagulant therapy we suggest

dabigatran, rivaroxaban, apixaban or edoxaban

over vitamin K antagonist (VKA) therapy (all Grade

2B)

Efficacy in PE patients?

DVT AND PE ARE THE SAME DISEASE

• Share the same risk factors

• Diagnostic approach similar (D dimer +

imaging)

• Prognosis comparable

• Treatment strategy identical (except for

massive PE with hemodynamic impairment)

Dentali F, Intern and Emerg Med 2015

Dentali F, Intern and Emerg Med 2015

FOREST PLOT OF THE PRIMARY EFFICACY OUTCOME

(RECURRENT VTE OR DEATH RELATED TO VTE) IN PATIENTS

RECEIVING DOACs OR VKAs

DOAC UNCERTAINTIES

• Cancer

• Antiphospholipid syndrome

• Heparin induced thrombocytopenia

• Atypical sites

ACCP RECOMMENDATIONS FOR

CANCER-ASSOCIATED VTE

Kearon C, Chest 2016

• In patients with DVT of the leg or PE and

cancer, as long-term anticoagulant therapy we

suggest LMWH over VKA therapy (Grade 2B),

dabigatran (Grade 2C), rivaroxaban (Grade 2C),

apixaban (Grade 2C),or edoxaban (Grade 2C)

VTE TREATMENT:

TWO DECISION POINTS

Schulman S, Seminar TH 2015

The treatment of VTE can formally be divided

into two decision points, at which a choice

must be made regarding treatment regimen:

- at the time of diagnosis

- at 3 to 6 months from index event

Schulman S, TH 2015

AT THE TIME OF DIAGNOSIS

• Low-risk patients can be offered outpatient

treatment

• Today, this can be done with one of the

DOACs, but

• with a few exceptions for certain patient

subsets:

• UFH (severe renal failure)

• LMWH (active cancer)

Schulman S, TH 2015

THREE TO SIX MONTHS FROM ACUTE EVENT

Does one limit the anticoagulant treatment duration or continues

it indefinitely?

Extended treatment should be considered for:

- males (and females) with unprovoked VTE even after the first

event

- patients with recurrent VTE or severe forms of thrombophilia

(antithrombin deficiency, homozygosity for factor V Leiden,

or combined defects)

- patients with massive PE

This choice has become more attractive with the increased safety

and convenience of the direct oral anticoagulants

Conclusions

• All the DOACs are at least as efficacious of

warfarin

• They can be used with no laboratory

monitoring

• All the DOACs have a smaller risk of severe

bleeding (particularly intracranial) than

warfarin

• DOACs simplify anticoagulant therapy in

VTE and cause less bleeding than warfarin

• The personalized choice of each DOAC for

each patient should aim to maximize

advantages and minimize risks

MAIN FEATURES OF “NEW” DIRECT ORAL ANTICOAGULANTS (DOACs)

Dabigatran Rivaroxaban Apixaban Edoxaban

Target IIa (thrombin) Xa Xa Xa

Hours to Cmax 1.25-3 2-4 3-4 1-2

Half-life 14-17 h 7-11 h 8-15 h 8-10 h

Administration

frequencyTwice daily Once daily Twice daily Once daily

Renal elimination 80% 60% 25% 35%

Liver metabolism Minimal Yes Yes Minimal

ANTIDOTES

• Antidotes are seldom needed (except for life

threatening bleeding episodes), owing to the

very short half-life of all DOACs

• A monoclonal antibody (idarucizumab) is

licensed as a specific reversal agent for

dabigatran

• An antidote for all the factor Xa inhibitors

(rivaroxaban, apixaban, edoxaban) will be soon

available (Andexanet)

Thank you for listening

DIFFERENCES AND SIMILARITIES

• Hokusai/Recover I/II used initially low

molecular weight heparins before edoxaban or

dabigatran

• Mostly DVT and PE combined

• Duration of treatment/follow-up variable, but:

• Comparable definition of efficacy and safety

outcomes

REAL-LIFE POST-MARKETING

OBSERVATIONAL STUDIES

• XALIA compared in 5142 patients the efficacy

and safety of rivaroxaban compared with VKA

• No difference between rivaroxaban and VKA in

the acute and extension phase of treatment

Lancet Hematology. 2016; 3:e12-21

Caratteristiche Scelta del farmaco Razionale

Interferenza con altrifarmaci

Dabigatran(edoxaban)

Minore interferenza con altri farmaci

Terapia a lungo terminein pazienti ad alto rischio

Dabigatran Studio di confronto con warfarina

CrCl 30-50 ml/min Inibitori del XaMeno condizionati dall’IR neiconfronti di dabigatran

Dispepsia o disordinidelle prime vie digestive

Inibitori del XaDispepsia con dabigatran fino al 10% dei pazienti

Significativa CHD Inibitori del Xa Debole segnale con dabigatran

Terapia tutta orale Apixaban o rivaroxabanNon richiedono iniziale terapia parenterale

Caratteristiche Scelta del farmaco Razionale

Scarsa compliance alladoppia dose

Edoxaban o rivaroxabanConsentono la mono-somministrazione

EP (associata ad IVD)Rivaroxaban o Edoxaban

Selettività di dati in pazienti con EP (complicata da IVD)

Terapia a lungo termine in pazienti a basso rischio Apixaban

Dati a sostegno di una dose dimezzata

Recente emorragiagastrointestinale

Apixaban o edoxabanDabigatran e rivaroxaban aumentano il rischio nei confrontidella warfarina

Terapia iniziale di pazientifragili

EdoxabanIl solo con dati a sostegno di unadose dimezzata

Trombosi in neoplastici Edoxaban Vantaggio in sottogruppi

EINSTEIN_

EXT1

AMPLIFY_EXT2 RE-MEDY*3 RE-SONATE3

Study drug Rivaroxaban Apixaban Dabigatran Dabigatran

Study design Double-blind Double-blind Double-blind Double-blind

Comparator

drug

Placebo Placebo Warfarin Placebo

Dose 20 mg OD 2,5 mg BID

5 mg BID

150 mg BID 150 mg BID

Randomized

population

1,197 2,482 2,866 1,353

Treatment

duration

6 or 12 months 12 months 6-36 months 6 months

VTE: DESIGN OF DOAC EXTENSION STUDIES

1. Einstein Investigators N Engl J Med 2010;363:2499-510; 2. Agnelli et al. N Engl J Med 2013;368:699-708;

3. Schulman et al. N Engl J Med 2013;368:709-18.

43

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

ula

tive e

vent

rate

(%

)

Months

1211109876543210

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

ula

tive e

vent

rate

(%

)

Benefits of DOACs vs warfarin in patients with PE have been demonstrated across Phase III studies

Study Primary endpointHR*/RR†

(95%CI)

RECOVER 1+2 (Index PE)Recurrent symptomatic VTE or fatal VTE

1.09 (0.76–

1.57)

EINSTEIN-PE Recurrent VTE1.12*

(0.75–1.68)

AMPLIFY (Index PE)Recurrent VTE / VTE-related death

0.90†

(0.50–1.61)

HOKUSAI (Index PE) Recurrent VTE0.73*

(0.50–1.06)

HOKUSAI (Severe PE)(ProBNP ≥500 pg/mL)

Recurrent VTE0.52*

(0.28–0.98)

EINSTEIN-PE Investigators N Engl J Med 2012;366:1287–97; Agnelli G et al. N Engl J Med 2013;369:799–808;Hokusai-VTE Investigators N Engl J Med 2013;369:1406–15

TREATMENT RECOMMENDATIONS FOR PE PATIENTS WITHOUT SHOCK OR HYPOTENSION (INTERMEDIATE OR LOW-RISK)

Recommendations Class Level

Anticoagulation: direct oral anticoagulants

As an alternative to the combination of parenteral anticoagulation and a VKA, anticoagulation with rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) is recommended

I B

As an alternative to the combination of parenteral anticoagulation and a VKA, anticoagulation with apixaban (10 mg twice daily for 7 days, followed by 5 mg twice daily) is recommended

I B

As an alternative to VKA treatment, administration of dabigatran (150 mg twice daily, or 110 mg twice daily for patients >80 years of age or those under concomitant verapamil treatment) is recommended following acute phase parenteral anticoagulation

I B

As an alternative to VKA treatment, administration of edoxaban* is recommended following acute-phase parenteral anticoagulation I B

New oral anticoagulants (rivaroxaban, apixaban, dabigatran, edoxaban) are not recommended in patients with severe renal impairment III A

*Edoxaban is currently subject to regulatory review for the treatment of venous thromboembolism in the European Union

PE + DVT vs DVT ONLY:

RISK OF EARLY RECURRENCE

Van Es N, Blood 2014

0.2