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Recurrent Deep Vein Thrombosis

Case 159-year-old man presented for pain and swelling of Lt calf. 3 years ago diagnosed with posterior tibial vein thrombosis treated with warfarin for several months. PE: Tenderness and warmth of the calf and increase in calf diameters of 3 cm compared with the other leg. Deep palpation of the calf muscles was painful. Recurrent DVT was suspected.What are the next diagnostic step?

Recurrent DVT: Strong risk factors

- Recent surgery- Trauma- Prolonged bed rest- Active cancer- Previous VTE

Recurrent DVT ½ occur in the unaffected contralateral leg

Lindmarker P, et al. J Intern Med 2000;247:601-6.

Diagnosis of 1st DVT- D-dimer- Compression ultrasonography (CUS)

CUS gold standard for diagnosis 1st DVTSensitivity >90% (proximal)

60% (distal) Specificity 100%

Goodacre S, et al. BMC Med Imaging 2005;5:6.

Diagnosis of recurrence DVT• Venography• Compression ultrasonography• CT venography • MR direct thrombus imaging

Venography- Invasive- Associated serious complications - Technical problem- Expertise declined

Diagnosing recurrent DVT in a previously affected vein segment - Increase in thrombus diameter of at

least 4 mm on serial CUS- Combination with D-dimer measurement

Proximal CUS should be performed at time of withdrawal of anticoagulation to obtain a baseline measurement

Suspected Recurrent DVT

Perform clinical assessment and measure D-Dimer

Full compressibility Non-diagnostic

Exclude DVT Treat

Re-consider clinical assessment

Whole-leg Compression Ultrasonography

Non-compressibility of vein not affected by 1st DVT

Likely Unlikely

D-Dimer+ D-Dimer- D-Dimer-D-Dimer+

Treat Exclude DVTConsider serial CUSor alternative imaging

Case 1• High clinical likelihood of recurrent DVT• Whole leg CUS, non compressibility of

femoral vein and popliteal vein • D-dimer positive supported thrombosis

What are the treatment options for a patient with a recurrent DVT?

Confirmed Diagnosis of Recurrent DVT

Start DOACs Consider of all-oral regimen if admission is not required

Evaluate duration of anticoagulation after 3 months

DVT triggered by a transient risk factor

DVT unprovoked

Start LMWH/VKADo not use VKA in cancer/pregnancy

Discontinue Continue

DVT triggered by a persistence risk factor

Continue as long as risk factorpersist and/or it is safe to do so

Anticoagulant treatment of recurrent DVT

How to estimate the bleeding risk?• Evaluate the bleeding risk before and

regular interval there after

• Estimation of bleeding risk relies on treating physician rather than on scientific evidence

How to estimate the bleeding risk?• Long-term major bleeding risk <1%->65% depend on

- advanced age- previous bleeding- cancer- thrombocytopenia- antiplatelet therapy- recent surgery- previous stroke- other comorbidities

Which anticoagulant regimen should be used for acute treatment?

• Similar to the first DVT• Immediate and intensive• UH, LMWH, or fondaparinux followed by

VKA• DOACs

- Direct Xa inhibitor: rivaroxaban,apixaban edoxaban

- Direct thrombin inhibitor: dabigatran

DOACs1. Apixaban 10 mg twice daily for 1 week

followed by 5 mg twice daily for month then 2.5 mg twice daily

2. Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily

3. LMWH once or twice daily at therapeutic dose for at least 5 days followed by dabigatran 150 mg twice daily or edoxaban60 mg once daily

Pregnancy• LMWH at therapeutic dose until 24 hours

before induction of labor or caesareansection, and restart LMWH at reduced dose

Cancer• LMWH at therapeutic dose reduced to about

75% at 4 weeks for 6 months or as long as itis safe to do so

Transient risk factors

Surgery, trauma, prolonged bed rest, oral contraceptives, HRT, pregnancy/puerperium

Discontinue anticoagulants after 3 months

Persistent risk factors:- Inflammatory bowel syndrome- APS- Nephrotic syndrome- PNH- MPN - Behcet syndrome- Post thrombotic syndrome- Congenital venous malformation

Continue as long as risk factor persists and/or it is safe to do so

What is the optimal duration of anticoagulant?- Depend on risk of recurrent VTE- 1st provoked recurrent < 1st unprovoked- Transient risk 3-6 months- Persistent risk long-term

anticoagulant as long as bleeding riskdose not increase

1st unprovoked VTE have recurrence risk 30% over 5 years after discontinue anticoagulants

Prandoni P et al. Haematologica 2007;92:199-205.Rodger MA, et al. CMAL 2008;179:417-26.

Kyrle PA, et al. Lancet 2010;376:2032-9.

2nd unprovoked VTE recurrent >1.5 time of 1st unprovoked VTE 50% over 5 years

KearonC, et al. Chest 2012 141:e419S-e494S.

Unprovoked VTE• Treat 6 months --- recurrence 20.7%

one major bleeds• Treat infinitely --- recurrence 2.6%

2 fatal bleeds and 8 major bleeds

Long-term anticoagulant treatment• Patient’s preferences and concerns• Major life-style implications • Regular follow-up• Evaluate the quality of anticoagulation

and the adherence to treatment• Capture the appearance of new risk

factors of bleeding

Which anticoagulant regimen should be used for long-term treatment?

• DOACs conferred substantial riskreductions 64% - 92% comparedwith placebo

• DOACs effectively preventrecurrent VTE at an acceptablebleeding risk

• DOACs are alternative to VKA

The patient was healthy and no risk of bleeding, no need to admission, an all-oral DOAC regimen was started

The patient consented to long-term anticoagulant therapy after having been informed his 2nd unprovoked VTE with high risk of recurrent DVT and low bleeding risk

Adviced to take medicine regularly missing dose could result in thrombus progression, embolization or recurrent

Case 2 Recurrent DVT during anticoagulant therapy

A 27-years-old presented with swelling and pain of the right leg. PE: Revealed warmth, edema from the distal thigh downward to the ankle and tenderness on palpation of the calf. He often traveling by plane over long distances.

Case 2 Recurrent DVT during anticoagulant therapy

The D-dimer was elevated and CUS showed femoral vein thrombosis. He had already diagnosed with unprovoked proximal DVT of left leg 1 year earlier and long-term anticoagulation had been recommended. At the time of presentation he was still on VKA treatment.

What could be the reason for a recurrent DVT during anticoagulation?

• Insufficient intensity of anticoagulation• Non adherence to the medication• DOACs have short half-life missing dose

may increase the susceptibility forrecurrence

Possible underlying conditions for recurrent VTE during anticoagulation

• Insufficient intensity of anticoagulation

• Active cancer

• Anatomical abnormalities (M-T syndrome)*

• Myeloproliferative neoplasms (PV, ET)*

• Paroxysmal nocturnal hemoglobinuria*

• Phospholipid antibody syndrome*

• Heparin-induced thrombocytopenia

* Low level of scientific evidence

Recurrent VTE during VKA treatment1st step• Asses the quality of treatment by checkingINR at the time and earlier • ผปวยอาจหยดกนยาและมากนตอนทมาพบแพทย

ใหคา INR ด• Hypercoagulability risk factor potent

enough to over come the usual intensity of anticoagulation

• Cancer patient have more 3 foldshigher risk of recurrent VTE thannon cancer

- >80% occurred at therapeutic range- VKA recurrent 17%- LMWH recurrent 9%

• Unknown hidden malignancy

Recurrent DVT during anticoagulationWhile on VKA at INR <2 or on DOACs• Start LMWH once or twice daily at therapeutic

dose (at least 5 days) then VKA INR 2-3• Apixaban 10 mg twice daily for 1 week then

5 mg twice daily• Rivaroxaban 15 mg twice daily for 3 weeks

then 20 mg once daily• LMWH once or twice daily at therapeutic dose

for at lest 5 days then 150 mg dabigatran twicedaily or edoxaban 60 mg once daily

At INR ≥ 2• Vitamin K 10 mg orally or IV• LMWH once or twice daily at therapeutic dose

together with VKA INR 2.5-4.0 continue LMWH until a stable INR has reached (at least 5 days)

• LMWH once or twice daily at therapeutic dosetogether with VKA INR 2.0-3.0 and aspirin 100 mg one daily and continue LMWH until a stable INR reach (at least 5 days)

• LMWH once or twice daily at therapeutic dose• Fondaparinux weight-adjust at therapeutic dose

Recurrent DVT During Anticoagulation

While on VKA While on DOACs While on LMWH

INR < 2 INR < 2

StartLMWH/VKA

StartDOAC

GiveVitamin K

StartLMWH/VKA

High-dosaLMWH

Start LMWH/High intensity VKA

Start LMWH/VKAPlus aspirin

Start LMWH

Start Fondaparonux

While on LMWH• LMWH one or twice daily dose increase

by ~ 25%

Case 2INR 1.4The patient had stopped INR monitoring several months before. He refused to take VKA any longer→ DOAC regimen