What is the appropriate duration of treatment for VTE? Any advances in predicting recurrence?

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1 What is the appropriate duration of treatment for VTE? Any advances in predicting recurrence? Beverley Hunt Thrombosis & Haemostasis, King s College Guy s & St Thomas Trust Medical Director of Lifeblood: the thrombosis charity

2 Major issue- short term or long term anticoagulation after VTE Risk of recurrent VTE is 30% at 10 years Risk of post thrombotic sydrome is 30% at 10 years What are the risk factors?

3 Provoked VTE Triggered by recent events Recent surgery or trauma Temporary reduced mobility Pregnancy Oestrogen containing medication Baglin et al. Lancet 2003; 362: 523 Prospective study of 570 patients after VTE Without malignancy or antiphospholipid syndrome. After 2 years 0% recurrence in those with VTE after surgery 19% if unprovoked

4 Duration of anticoagulation therapy after an unprovoked VTE: from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Unprovoked VTE account for 25-50% of all VTEs Guidance does not apply to unusual situations such as cerebral or splanchnic or cancer-related. Definitions Initial anticoagulation: 3-6 months Long-term (indefinite anticoagulation: > 3-6 months of Rx with no definite stop time which could be either lifelong or until perceived bleeding risk precludes continution of anticoagulation)

5 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Evidence At least 3 months of therapeutic intensity anticoagulation is required to prevent thrombus extension/recurrence after first PE or proximal VTE (i.e. involvement of popliteal or more proximal veins) 6 months Rx after unprovoked PE or proximal DVT gives a lower risk of recurrence Distal (calf) DVT have a lower risk of recurrence

6 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Guidance Statements We suggest that patients with unprovoked calf DVT should be treated for 3 months We recommend that patients with unprovoked PE or proximal DVT should be treated for 3-6 months

7 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Continued anticoagulation after 3-6 months? Evidence Unprovoked VTE risk of recurrence is >5% per year (provoked risk is <1%) This risk exceeds risk of bleeding Therefore they should be considered for long-term anticoagulation Unprovoked calf VTE have a lower risk of recurrence

8 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Guidance Statements on continued anticoagulation We suggest that unprovoked calf DVT do not require therapy for longer than 3 months We suggest that unprovoked PE and proximal DVT should be considered, as long as the perceived risk of anticoagulant-related bleeding is not so high as to preclude continued treatment We suggest that in provoked PE or DVT anticoagulant therapy after 3 months is not required

9 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Hormone-associated PE or DVT i.e COC or oestrogen containing HRT are the only risk factors Evidence 50% lower risk of recurrence than those with unprovoked VTE If there is a need to continue oestrogens then despite absence of clinical trials, it is usual to continue therapeutic anticoagulation

10 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Hormone-associated PE or DVT Guidance statements We recommend that anticoagulation for more than 3 months is not required for women with hormoneassociated VTE if hormone therapy is stopped at the time of diagnosis We recommend that women with hormone-associated VTE stop hormonal RX before stopping anticoagulation: premenopausal women require an to avoid the potential toxicity of early fetal warfarin exposure We suggest that hormonal Rx can be continued in selected patients if there is a strong clinical indication for such Rx but anticoagulant therapy should be continued for the duration of hormonal therapy

11 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Risk of bleeding and quality of anticoagulant therapy Evidence Determinants of bleeding risk are: age; previous bleed; increased intensity;comorbidities such as renal and hepatic impairment; use of other antithrombotics. Thus risk is low in 1 Target INR of Age <70 3. Those not taking other antithrombotics 4. Those who have NOT had a bleed in the first 3-6 months of therapy VKA-bleeding in patients with VTE in meta-analysis 9% per annum in initial 3 months 2.7% per year after initial RX Intracranial bleeds 1.48% per 100 patient years in first 3 months 0.65% per 100 patient years after this?is time in range during the initial 30 days predictive of future INR control/bleeding risk?

12 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Other factors to predict risk of recurrence 1. D dimer 2. Residual vein occlusion 3. Post thrombotic syndrome 4. Thrombophilia 5. Male gender 6. Mode of presentation

13 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: D-dimer Lower risk of recurrence with a low D-dimer 3-4 weeks after completion of initial VKA therapy compared with those with a high D-dimer (~4% vs 9%) BUT exactly how D-dimer is used is under investigation. Different assays have different performance characteristics and only those validated by clinical studies should be used.

14 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Residual vein occlusion. As detected by USS does not predict a likelihood of recurrent DVT to a degree that is clinically useful. Post thrombotic syndrome A prospective cohort study showed PTS associated with 2.6 x increased rate of recurrent DVT. Similar to D-dimers and PTS is assocaited with high D-dimer.

15 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Male gender 1.8 fold higher risk of recurrence after unprovoked VTE. Mechanism?? Mode of presentation Initial PE- 3-4 x increased risk to suffer a recurrence as PE, than if present with DVT Risk of fatal PE 2-3x greater if present with PE vs DVT

16 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Guidance statements 1. Not possible to give definite guidance in an individual! 2. Favour long-term: a) Male b) Moderate to severe PTS c) Ongoing dyspnoea d) Satis INR control e) Elevated D-dimers in a study-validated assay

17 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Guidance statements 3 Favour stopping: Female No or mild PTS Poor INR control Low D-dimer based on study-validated assay

18 The uselessness of thrombophilia tests!

19 Definitions of thrombophilia USA individuals who appear to have a predisposition to develop venous thromboembolism UK the familial or acquired disorders of the haemostatic mechanisms which are likely to predispose to (venous) thrombosis

20 The rise and fall in the popularity of thrombophilia screening among haematologists Increasing popularity 20011/2 Time Decreasing popularity

21 Why has thrombophilia screening had such a bad press recently? Changing evidence, uncertainty Requested imprudently - A lack of education about what should be in a thrombophilia screen, who should be screened, when & why A fear that more psychological harm than good occurs The cost

22 Thrombophilia screening requested inappropriately Especially Screening prior to COC/HRT Arterial/atheroscle rotic disease First trimester pregnancy loss and infertility

23 THROMBOPHILIA TESTING IN APRIL 2012 Full blood count (MPD) Antiphospholipid antibodies (LA & ACL) Fibrinogen Antithrombin Protein C Protein S APCR/Factor V Leiden Prothrombin In rare cases CD59 N.B Arterial risk factors Full blood count Antiphospholipid antibodies Fibrinogen Lipids Lipoprotein (a) Homocysteine/MTHFR

24 Can thrombophilia assays be used for screening? The intention of screening is to identify disease in a community early, thus enabling earlier intervention and management in the hope to reduce mortality and suffering from a disease. Although screening may lead to an earlier diagnosis, not all screening tests have been shown to benefit the person being screened. Overdiagnosis, misdiagnosis and creating a false sense of security are potentially adverse effects. For these reasons, a test used in a screening program, especially for a disease with low incidence, must have good sensitivity in addition to acceptable specificity

25 SENSITIVITY OF INHERITED THROMBOPHILIA TESTS? If 100 patients with VTE and strong family history of VTE Only 50-60% will have a positive thrombophilia assay. e.g 17 year old wants to use COC. Mother had a VTE. Negative thrombophilia testing does not exclude a hereditary thrombophilia

26 SPECIFICITY? Prevalence of heterozygous Factor V Leiden is 5% in the Caucasian population Most NEVER have a VTE..

27 Inherited thrombophilia Only Caucasian populations widely studied Factor V Leiden and prothrombin are not seen outside of Caucasians?Defects in Eastern & African populations?

28 PREVALENCE OF FV LEIDEN 5% Caucasians (1 in 1,600 are homozygotes) Rare in the rest of the world Why spread so successfully? A selection advantage? Thromboembolism tends to occur after reproduction? Protection from fatal bleeding post partum or traumatic injury

29 Thrombophilia testing is appropriate if it affects clinical management

30 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Baglin et al. JTH April 2012; 10: Thrombophilis testing Does not usefully predict likelihood of recurrent VTE Testing for heritable in selected patients such as those with a strong FH of unprovoked VTE may influence duration of anticoagulation. Not possible to give a validated statement as to how to select the patients as a FH is a poor predictor of likelihood of identifying thrombophilic defects

31 New NICE guidelines for thrombophilia testing after VTE Do not offer thrombophilia testing to patients who are continuing anticoagulation treatment. Consider testing for antiphospholipid antibodies in patients who have unprovoked VTE if it is planned to stop anticoagulation treatment. Consider testing for hereditary thrombophilia in those with unprovoked VTE and have a first degree relative with VTE if it is planned to stop anticoagulation. Do not offer testing to patients with a provoked VTE Do not routinely offer testing to first-degree relatives with a history of VTE & thrombophilia

32 Antiphospholipid antibody testing is appropriate : Unexplained arterial and venous thromboses Unexplained pregnancy loss, pre-eclampsia, small babies Young stroke (40%), young peripheral vascular disease, thrombotic MI

33 Will advice change with the new oral anticoagulants? Predictable anticoagulant effect Fixed dose No need for monitoring O N N O Cl O H S N O O Xarelto rivaroxaban Rapid onset of action Low potential for drug drug interactions Trials have shown similar,better efficacy and safety Rivaroxaban binds directly to the active site of Factor Xa (K i 0.4 nm)

34 Oral rivaroxaban for symptomatic venous thromboembolism Einstein Investigators New Engl J 2010; 363: DVT patients randomised to Rivaroxaban 15mg BD for 3/52 then 20mg daily Versus Enoxaparin then vit K antagonist for 3/12 or 6/12 or 12/12 THEN Randomised for a further 6-12/12 rivaroxaban 20mg v placebo

35 Rivaroxaban in the management of acute DVT EINSTEIN INVESTIGATORS New Engl J 2010; 363: patients Recurrent VTE 1731 rivaroxaban 38 (2.1%) 1718 conventional 51 (3.0%) Rivaroxaban non inferior Hazard ratio 0.68 (CI ) Extended 602 rivaroxaban 8 (1.3%) 594 placebo 42 (7.1%) Rivaroxaban had superior efficacy. Hazard ratio 0.18 ( ) 4 rivaroxaban had non fatal bleeds v 0 with placebo We are awaiting NICE single technology assessment. Scottish Medicines Agency, Europe and North America all ahead of us!

36 EINSTEIN PE New Engl J Med March 26 th 2012; Randomised, open label, event driven, non-inferiority trial Of 4832 patients Rivaroxaban 15mg BD for 3 weeks then 20mg a day v enoxaparin and adjusted dose vitamin K antagonist For 3,6, or 12 months Primary efficacy outcome was symptomatic recurrent VTE Recurrent VTE 50 events in rivarixaban (2.1%) vs 44 in standard RX (1.8%) Rivaroxaban was non-inferior. Major bleeds In 26 (1.1%) of the riva group vs 52 (2.2%) of standard Rx (p=0.003)

37 Development status of novel anticoagulants in Europe 1 Licensed indication Phase III study completed Phase III study in progress No study ongoing Rivaroxaban Dabigatran Apixaban VTE prevention in orthopaedic surgery RECORD 1-4 RE-NOVATE RE-MODEL ADVANCE 1-3 Stroke prevention in AF ROCKET AF RE-LY AVERROES ARISTOTLE VTE treatment EINSTEIN DVT EINSTEIN PE RE-COVER AMPLIFY VTE prevention medically ill MAGELLAN ADOPT ACS ATLAS 51 TIMI APPRAISE-2 stopped 1.

38 Bleeding with dabigatran Case reports of bleeding and difficulty of reversal In mutiple journals Cotton BA,MacCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. New Engl J Med 2011; 365: Eikelboom JW, Weitz JI. More on acutely injured patients receiving dabigatran. New Engl J Med 2012; 366: 9

39 Summary More research required in judging who should continue or stop anticoagulation in the management of VTE Will the new oral anticoagulants alter the risk-beneft balance? Poor reversibility of the new orals may lead to a reappreciation of the old anticoagulants!

40 Thrombosis protocols!

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42 iphone and Android app for patients = iclot