Prevention of DVT Recurrence.

A Practical Approach

Andrew Nicolaides

Emeritus Prof. of Vascular Surgery, Imperial College, London, UK

Honorary Prof. of Surgery,

Nicosia University Medical School, Cyprus

Disclosures

Received Honoraria for lectures from:

Covidien/Medronic

Servier

Alpha Wasserman

Pierre Fabre

Recurrent VTE Following Cessation of Anticoagulation

Unprovoked

Provoked

11%

30%

40%

Prandoni et al Haematologica 1997; 82:423

Are there any markers of recurrence?

CompressionNo Compression

B-mode Ultrasound

Normal vein

Residual Vein Thrombus (DACUS study)

Siragusa S et al Blood 2008;112:511-515

Residual Thrombus(N=180)

No RVT(N=78)

Siragusa S et al Blood 2008; 112:511-515

Residual Thrombus in CF and/or Popliteal Vein and Recurrent DVT

DACUS Study

Ultrasound

First Episode DVT

(N=258)

AnnualRecurrence

0.63% 12.8%

p<0.001

3 Months VKA

D-dimer and Recurrence of DVT

Idiopathic VTE

(N=619)

Randomized

No Anticoagulation

(N=385)

Normal D-dimer

(N=385)

Elevated D-dimer

(N=227)

Resume Anticoagulation

(N=105)

No Anticoagulation

(N=122)

D-dimer 1 Month after

Anticoagulation Discontinued

15.0%6.2% 2.9%Events at 18 months

(VTE or Bleed)

Palareti G et al NEJM 2006;355:1780

NEJM 2012; 366:1959

NEJM 2012; 367:1979

WA

RF

AS

AA

SP

IRE

Brighton TA et al NEJM 2012;367:1979

Recurrent VTE/Death

Ris

k

Months

p=0.001 p=0.03

11.5%

5.6%

0.4%

7.6%

Extended Use of Dabigatran

Schulman S et al NEJM 2013;368:709

Any

Bleeding

Months

P<0.003

10.5 %

5.9 %

Extended Use of Dabigatran

Major or

CRNMB

5.3 %

1.8 %

P<0.001

Schulman S et al NEJM 2013;368:709

Extended Use of Rivaroxaban in VTERecurrent VTE

Major or CRNMB

1.2 %

6.0 %

P<0.001

EINSTEIN Investigators NEJM 2010;363:2499

RRR 75%

After completion of 6-12 months anticoagulant therapy, 2486 patients

were randomized 1:1:1 to:

(a) Placebo

(b) 2.5mg apixaban

(c) 5.0mg apixaban

for 12 months

Extended Use of Apixaban in VTE(Amplify-Extension Study)

Agnelli G et al NEJM 2013;368:699-708

RRR = 81%

P<0.001

Recurrent VTE / VTE Death8.8 %

1.7 %

Extended Use of Apixaban in VTE(Amplify-Extension Study)

Agnelli G et al NEJM 2013;368:699-708

P=NS

4.3 %

3.2 %2.7 %

Extended Use of Apixaban in VTE(Amplify-Extension Study)

Major or CRNMB

Agnelli G et al NEJM 2013;368:699-708

Sulodexide: Multicenter RCT615 patients with 1st unprovoked VTE after completion of VKA therapy

Efficacy: 54% reduction in VTE Bleeding

No Major bleeding

2 patients in each group had

clinically relevant bleeding

episodes

Andreozzi MA et al. The SURVET Study: Circulation 2015;132:1891-7

Current Thinking

1. “One approach fits all” is not appropriate

2. Can we balance risk of recurrence vs. risk of bleeding?

Risk of VTE Recurrence after 1st Episode

High (one or more risk factors)Unprovoked 2 or more VTE Episodes

Iliofemoral DVT

Residual thrombus (>40%)

Active cancer

Serious thrombophilia

D-dimer > 500 1-3 months after stopping

anticoagulation

Life threatening PE

Inflammatory bowel disease

Moderate (one risk factor)Unprovoked isolated calf DVT

Male

Obesity

Low (one transient risk factor)Post major surgery or bed rest for > 4 days.

Post POP or post major trauma

Post estrogen therapy or pregnancy

Risk of Bleeding during Anticoagulant Therapy

HighHistory of major bleeding

Platelet count < 50,000

Need for double antiplatelet therapy

Portal hypertension (Bleeding esoph.

varices)

History of stroke or cerebral changes

Metastatic Carcinoma

Renal insufficiency

Liver failure

Diabetes

Age > 75

ModerateHistory of clinically relevant non-major

bleeding

One antiplatelet drug

Platelet count 50,000- 100,000

Age 65-75

LowNo history of bleeding

No bleeding during previous antig. Therapy

No associated pro-hemorrhagic drugs

Age < 65

BLEEDING RISKRefused or

Contraindication

to DOAsLOW MODERATE HIGH

DVT RISK HIGH ≥ 20%

in 2 years

Rivaroxaban or

Apixaban

Apixaban Sulodexide or

Apixaban

Sulodexide

DVT RISK MODERATE

5-20% in 2 years

Rivaroxaban or

Apixaban

Sulodexide or

Apixaban

Sulodexide or

Apixaban

Sulodexide

DVT RISK LOW < 5%

in 2 years

Sulodexide or

Aspirin*

Sulodexide* Sulodexide* Sulodexide or

Aspirin*

* If patient would like to have cover

The Evidence for DVT Reduction in Cancer Patients

LMWH vs VKA in Cancer Patients: Efficacy

LMWH vs VKA in Cancer Patients: Major Bleeding

DOAC vs LMWH in Cancer Patients: Efficacy

LMWH

DOAC vs LMWH in Cancer Patients: Major Bleeding

LMWH

Conclusions

Reduction in recurrent VTE without any increase in bleeding is

now possible; it should contribute to the reduction in PTS

In patients with active cancer:➢ LMWH are more effective than VKA in preventing VTE recurrence

without any increase in bleeding

➢ DOAC are more effective than LMWH in preventing VTE recurrence

but caused more major bleeding (6.5% vs 3.7%).

➢ More studies with DOAC are needed.