Unprovoked DVT in a young patient Cecile du Toit Groote Schuur Hospital + UCT

Introduction Venous thromboembolism (VTE) which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) has an annual incidence of 0.1 -0.27% 5% of population affected by VTE Current management decisions rest on a balance of risk and benefit of treatment options

Introduction 3 phases of treatment to consider -acute (first 5-10days) -long-term –first 3 months -extended – beyond 3 months 3Etiology groups -provoked -unprovoked -malignancy

Introduction The diagnosis and treatment for acute and long-term phases is the same for all cases of VTE not associated with malignancy Etiology and specifically the unprovoked VTE becomes important in the extended phase Differences in the management of young patients with DVT also centre around the extended phase – will be discussed there

Diagnosis of DVT A certain diagnosis can only be established with imaging It is good practice to rule out DVT using D-Dimer and a standardised clinical probability assessment - reduces the required number of imaging in a cost and staff constrained health system Both tests should be used 40% of cases presenting as possible DVT can be ruled out Very poor adherence to the guidelines – most patients have D-dimer test and imaging and clinical decision rules are either not used or not acted on.

Diagnosis of DVT D-dimer The D-dimer can be positive in many conditions other than VTE and is only useful to exclude DVT or PE The higher the sensitivity of a specific D-dimer test , the lower the risk of a false negative No D-dimer test has 100% sensitivity – us only in patients with a low clinical probability assessment Clinical decision rule The best validated of the clinical decision rules in DVT remains the Wells rule

Diagnosis of DVT

Diagnosis of DVT Imaging Contrast venography is not used any more Compression ultrasonography (CUS) is the imaging of choice particularly for proximal vein DVT Non- compressibility of the femoral or popliteal vein by CUS is diagnostic of a first proximal DVT with a sensitivity of 94% and specificity of 98% CT or MR venogram can be used where the CUS cannot be used or is less reliable : casts, morbid obesity or if DVT of the illiac veins or IVC is suspected

Treatment of DVT – acute and long-term phases If there is a high probability of DVT and imaging is delayed – start empiric therapy Acute treatment prevents extension of the DVT as well as PE and relieves symptoms

Treatment of DVT – acute and long-term phases Thrombolysis Thrombolysis may restore the vein patency and prevent postthrombotic syndrome (PTS) A meta-analysis of IV thrombolysis suggested a decrease in PTS but with a risk of major bleeding and no reduction in recurrence ,PE or death

Treatment of DVT – acute and long-term phases Thrombolysis Catheter –directed thrombolysis was compared to standard therapy for illio-femoral DVT – doubled vein patency at 6 months an decreased PTS – more bleeding – same recurrence and mortality May be considered for young well patients with symptoms less than 14 days and low bleeding risk Should be used for threatened limbs

Treatment of DVT – acute and long-term phases Vena Cava filters Vena cava filters in the acute situation should be reserved for patients with an absolute contraindication to anticoagulation – eg cerebral bleed Carry a risk of thrombosis of the filter Start anticoagulation as soon as the contraindication resolves

Treatment of DVT – acute and long-term phases Standard treatment LMWH once daily is the treatment of choice with Enoxiparin given at 1.5mg/kg Unfractionated heparin only for very unstable patients where rapid reversal may be needed or if creatinine clearance <20ml/min

Treatment of DVT – acute and long-term phases Standard treatment Warfarin is started after the LMWH – in young well patients 10mg daily x 2days is safe Pharmakogenetic testing definitely not indicated in our setting Treatment continues for at least 3 months INR 2-3 for all indications

Treatment of DVT – acute and long-term phases New oral agents Rivaroxiban – direct factor X inhibitor can be used as monotherapy for all phases of DVT treatment Non-inferior to LMWH/VKA interms of bleeding and recurrence of VTE No need to monitor, few drug interactions –easier than warfarin

Treatment of DVT – acute and long-term phases New oral agents Pivotal trials did not include patients with creatinine clearance <30ml/min and only 5% with 30-50ml/min Not reversible Not for the non-compliant patient Main limiting factor in our setting is cost

Treatment of DVT – acute and long-term phases Other management issues Compressions stockings improve pain and edema as well as the later symptoms of PTS, but no proof in RCT that it prevents PTS Early mobilisation is recommended and a meta-analysis indicated that it may reduce the severity of PTS Outpatient management of DVT is safe and improves QOL with decreased cost Outpatient management may not be possible in poor social circumstances and patients with severe symptoms as well as severe renal impairment

Extended phase Management depends on the etiology Cancer –associated – LMWH continued while active cancer Provoked with clear secondary cause– stop after 3 months Unprovoked – evaluate risk of recurrent thrombosis vs risk of bleeding

Unprovoked DVT DVT without any identifiable thrombotic risk factor Recurrence rate of 10% after one year (12% for men and 8% for women) and 30% at 5 years Extended if not lifelong anticoagulation may be required Guidelines favour indefinite anticoagulation over just extending to 6 months Indefinite anticoagulation should be done in “all” cases with a second unprovoked VTE

Unprovoked DVT The risk of VTE and it consequences must be weighed up against the bleeding risk The case fatality rate of a major bleed is 12% vs 4% for recurrent DVT and 8 % for PE The recurrence risk must be high to justify extended or long –term anticoagulation Patient preference must also be considered

Unprovoked DVT Base line factors predicting risk of recurrent VTE Inherited thrombophilia and family history -deficiency of AT,protC,protS and patients with hyperhocysteienemia may have higher recurrence when stopping VKA -not conclusive that family history increases recurrence risk -? Do thrombiphilia screen in young patient with unprovoked DVT if family history is strong or thrombosis in unusual site

Unprovoked DVT Male gender -confirmed by meta-analysis of VTE that male gender is associated with higher recurrence rate when anticoagulation is stopped Age -associated with higher recurrence than younger patients Obesity -higher risk of recurrence Fibrate lipid lowering drugs -higher risk of recurrence

Unprovoked DVT Post- baseline factors predicting risk for recurrent VTE Residual vein thrombosis -residual thrombosis on ultrasound in a proximal DVT is a powerful independent risk for recurrent thrombosis D-dimer - positive / negative D-dimer at time of stopping anti-coagulation is a strong predictor of risk of recurrence or not -can stop for a month and recheck then -can be used to make decision to stop VKA or not Early development of PTS -May predict for higher risk of recurrence Study now ongoing using D-dimer and residual thrombosis to determine recurrence risk and decide on indefinite anticoagulation

Patients with VTE who should be treated for 3 months and who should be treated indefinitely. Patients with VTE who should be treated for 3 months and who should be treated indefinitely. Use of d-dimer testing to guide treatment decisions in patients with a first unprovoked proximal DVT or PE is optional. If d-dimer is not used, the decision is based on risk of bleeding and patient preference (estimated risk of recurrence in the first year of 12% for men and 8% for women). Kearon C , and Akl E A Blood 2014;123:1794-1801 ©2014 by American Society of Hematology

Unprovoked DVT New Scenarios for indefinite prevention of recurrent VTE Low dose aspirin -shown in 2 recent studies to decease the risk of recurrence of VTE by 30% vs 90% with anticoagulation -bleeding risk significant New oral agents for indefinite anticoagulation -recent studies using Rivaroxiban or other oral agents compared to LMWH/VKA for VTE -during extended use new oral agents were non-inferior in preventing VTE recurrence and resulted in fewer major bleeds

Conclusion Unprovoked VTE is associated with as much as 50% recurrence over years Ideally these patients should all have indefinite anticoagulation Extending the anticoagulation from 3 -6months does not give significant benefit Risk of bleeding needs to be weighed up against the thrombosis risk

Conclusion Gender ,D-dimer test and CUS to determine of the vein is occluded are the best predictors of risk of recurrence Consider patient’s wishes New oral agents offer an effective ,safe alternative to warfarin – COST Aspirin is less effective than warfarin and has a significant bleeding risk