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LONG TERM TREATMENT AFTER VENOUS THROMBOEMBOLISM ERIC WATTS

LONG TERM TREATMENT AFTER VENOUS THROMBOEMBOLISM ERIC WATTS BASILDON + THURROCK UNIVERSITY HOSPITAL. TO TREAT OR NOT TO TREAT? TO STOP OR CONTINUE? TO DECIDE ON CLINICAL GROUNDS OR ON THE BASIS OF INFORMATION WHICH CAN PREDICT RECURRENCE?

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LONG TERM TREATMENT AFTER VENOUS THROMBOEMBOLISM ERIC WATTS

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  1. LONG TERM TREATMENT AFTER VENOUS THROMBOEMBOLISM ERIC WATTS BASILDON + THURROCK UNIVERSITY HOSPITAL

  2. TO TREAT OR NOT TO TREAT? TO STOP OR CONTINUE? TO DECIDE ON CLINICAL GROUNDS OR ON THE BASIS OF INFORMATION WHICH CAN PREDICT RECURRENCE? CAN WE DETERMINE THE RISK OF STOPPING OR CONTINUING IN ORDER TO MAKE AN INFORMED DECISION?

  3. Subsequent management following 1st spontaneous thrombosis Risk of recurrence 20% at 2yrs 1% fatal if no AC Annual mortality approx. 0.2% On warfarin risk of serious Hge 1% 25% fatal Annual mortality approx. 0.25%

  4. How can we quantify the risk of recurrence? Provoked vs unprovoked Past history Family history ? Thrombo screen

  5. G S Aged 14 admitted with abdo pain Found to have ileo femoral DVT Mother – a long term anticoagulant patient with recurrent DVT Thrombo testing: Mother - S deficiency Son – S deficiency & FVL

  6. Thrombophilic families • Recognised for decades • Some associated with other genetic markers eg blood group A&B • In these families the age of onset of 1st thrombosis would often be less than 30 yrs • Antithrombin III deficiency reported in such kindreds in 1965 – a single gene defect

  7. THROMBOPHILIA CONFERENCE 1988 ATIII, S, C, + LAC - defective fibrinolysis ‘Abnormalities are present in situations with thrombotic risk – detailed studies are required to establish the nature of the relationships.’

  8. Thrombosis is Multifactorial • Most patients are elderly bedridden hospitalised post op or other illnesses IV cannulae etc • How relevant are findings from such patients to fit young mobile relatives?

  9. Virchow’s Triad abnormalities in • Vessel wall • Composition of the blood • Stasis • The evidence is emerging through a fog

  10. The Assays • Functional • Antithrombin reliable test with tight normal range & good QC • Prot C results vary with technique & lab overlap between normal & heterozygotes • Prot S more variable than Prot C • APCR differing methods - a screening test

  11. Genetic Tests • Factor V Leiden- reliable test –takes time • Prothrombin G20210A genetic test only – no screening test • Homocysteine- thermolabile tetrahydrofolate reductase variant can be identified but does not correlate with thrombosis

  12. Risk Factor %gp %VTE Ratio • Antithrombin 0.02 1 x50 • Prot C 0.2-0.4 3 x10 • Prot S varies 0.1-0.4 1-2 x5-10 -?co factors • Factor V Leiden 5 20 x4

  13. Risk Factor %gp %VTE Ratio • Prothrombin G20210A 2 6 x3 • FVIII >150% 12 24 x2 • Hyperhomocystein 5 10 x2 • >18.5umol/l • Hyperhomocysteinaemia can be secondary to a wide range of chronic inflammatory & Malignant disease & renal failure poor diet etc

  14. Population based perspective • Worcester DVT Study Anderson FA Arch Intern Med 1991 151(5):933-8 • Population of 380,000 served by 16 hospitals 78-578 beds –all cases of DVT & PE documented for 18/12 & followed up for 4 years

  15. Worcester study • Overall inc of DVT 48/100,000 • Overall inc of PE 23/100,000 • Average age 67 but exponential increase with age

  16. 1yr 19% 2yrs 25% 3yrs 30% Co morbid conditions Cancer 29% CCF 23% COPD 26% Fractures 12% MI 6% Worcester Study long term case fatality post discharge

  17. FH of thrombosis • The potential value value of testing families is in the possibility of preventing a first thrombosis - the EFECTIVENESS & RISKS of this approach have not been formally assessed • If there is a very strong FH prophylaxis may be justified should all tests be normal • Large families with several affected members where the abnormality corresponds with thrombosis may informative

  18. Basildon Experience • 8yrs – 500+ young patients • All advised that they have an increased risk of thrombosis but that the absolute risk is small • The risk of a second thrombosis overall is 20% in 2 yrs • Patients are advised to report early if they have any relevant symptoms- pain & swelling • Very few good FHs • More married couples than parents and children

  19. Fatal VTE 9% 91% Non Fatal VTE 15% Fatal MB Continue R First MB 85% Non Fatal MB No event Cor S defie Fatal VTE 9% 3/12 after 1st VTE 91% Non Fatal VTE Stop R No event A decision analysis based on epidemiological data Risk of recurrent VTE (0-20% first 2-3 years then declines) Risk higher in spontaneous VTE Incidence of major bleeding higher with age Oral anticoagulation 90% successful in preventing recurrences

  20. Baseline estimates and ranges Recurrent VTE (% per 3 months) Time since initial VTE (months) Spontaneous Secondary 4-6 5.60 2.78 7-12 2.70 1.35 13-24 2.30 1.15 25-36 1.50 0.77 >36 1.00 0.48 Case fatality 9% Major bleeding (% per 3 months) Age (years) <40 0.16 40-49 0.25 50-59 0.37 60-69 0.57 >70 0.87 Case fatality 15% Relative risk reduction achieved with treatment with vitamin K antagonists: 90%

  21. ISTH JULY 2003 Risk factors for recurrent VTE De Stefano 2003 205 patients medium age 36 36% had thrombophilia markers Relative risk of recurrence Tphil/Normal = 1.1 CI =00.9-1.4

  22. Risk factors for recurrent VTE Leiden Thrombophilia Study (LETS) S Christiansen 2003 474 consecutive patients with a first episode of VTE Age 18-70 without known malignancy 94% followed up for 7 years 87 recurrences (16%)

  23. Influence of Thrombophilia Efficacy of warfarin for prevention of recurrent VTE a randomised trial Kearon 2003 Objective ‘to determine if the risk of recurrence during anticoagulation is increased by thrombophilia markers’ 661 patients with spontaneous VTE 1600 patient years follow up Overall risk of recurrence 3%

  24. Why? The new genetics and genome scanning ‘Novel family-based approaches to genetic risk in Thrombosis’ J Blangero JT Williams L Almasy Journal of Thrombosis and Haemostasis 2003 1,7 1391-1397 Few diseases are the result of a single gene defect. The field of common complex disease genetics has progressed through a major paradigmatic change focussing on measurable quantitative traits that correlate with disease as against dichotomous disease traits. They identify quantitative trait loci (QTL) – works best on extended families

  25. Trait Score Location Gene FXII/Thrombosis 11.7 5q35 F12 FII/Thrombosis 4.7 11p11 F2 APCR/FVIIIc/ Thrombosis 4.5 18p11 ? The bigger the pedigree, the more information. Biggest is from Jirel, 2000 relatives gerome scanned and being assessed for haemostasis related traits. The story so far

  26. Recommendations Indefinite anticoagulation at a target of 2.0-3.0 is recommended only in these high risk patients Bauer KA The Thrombophilias – well defined risk factors with uncertain therapeutic implications Am.Int.Med. 2001 135 367-73 2 or more spontaneous thromboses One spontaneous thrombosis and LAC One spontaneous life threatening thrombosis One spontaneous thrombosis at an unusual site eg. mesenteric or cerebral One spontaneous thrombosis with multiple thrombophilic abnormalities

  27. CONCLUSION In spite of many years of thrombophilia testing, the usefulness of this approach is unproven. There are still differing approaches in clinical practice. The main purpose of thrombophilia testing is to generate data for epidemiological research. Patient management is determined largely by clinical factors

  28. Oral ximelagatran rapidly absorbed and biotransformed to the active form, melagatran Renal excretion Clinical studies demonstrate efficacywith bid dosing No coagulation monitoring required Low potential for drug/food/alcohol interaction Fixed dosing and predictable response Ximelagatran Overview

  29. Extended secondaryprevention with the oral direct THRombin Inhibitor ximelagatranin patients with VEnous thromboembolism THRIVE III

  30. Study design Initial VTEevent ximelagatran 24 mg bid n=612 ITT R n=611 placebo INR <1.5 Standard AC 2-weekfollow-up 18 months 6±1 months Baseline: UltrasonographyPerfusion lung scan

  31. 14 12 10 8 6 4 2 0 VTE events - DVT and/or PE Estimated cumulative risk (%) 12.6% p<0.0001 HR=0.16 (95% CI 0.09;0.30) RRR=78% 9.8% placebo ximelagatran 2.8% 0 3 6 9 12 15 18 Months

  32. Major and/or minor bleeding events Estimated cumulative risk (%) 30 p=0.1703 HR=1.19 (95% CI 0.93;1.53) 25 23.9% 21.0% 20 15 placebo 10 ximelagatran 5 0 0 3 6 9 12 15 18 Months

  33. Efficacy and safety of the oral direct thrombin inhibitor ximelagatran for acute symptomatic deep vein thrombosis with or without pulmonary embolism THRIVE Treatment Study

  34. DVT  PE (onset ofsymptoms) ximelagatran 36 mg bid R enoxaparin 1 mg/kg sc bid* warfarin INR 2-3 E 6 months 14 daysfollow up 14 days 24 hours Objectiveconfirmationof DVT End oftreatment = study entry; R = randomisation E Study design Double-blind, double-dummy design* enoxaparin 5 - 20 days until INR  2.0 on warfarin

  35. enoxaparin/warfarin (n=1249) Difference x-e/w(95% CI) ximelagatran(n=1240) 2.0%(n=24) 2.1%(n=26) +0.2% (-1.0; 1.3%) Total VTE, ITT 1.5%(n=17) 2.0%(n=23) +0.5% (-0.6; 1.6%) Total VTE, OT Non-inferiority -4 -2 0 2 4 ximelagatranbetter enoxaparin/warfarinbetter Total VTE Estimated treatment differences at 182 dayswith 95% confidence intervals

  36. ximelagatran (26 events) enoxaparin/warfarin (24 events) ximelagatran (23 events) enoxaparin/warfarin (17 events) 2.1% 2.0% 2.0% 1.5% 95% CI: –1.0%; 1.3% 95% CI: –0.6%; 1.6% Total VTE Cumulative risk versus time after randomisation Cumulative risk (%) 5 4 3 2 1 0 0 30 60 90 120 150 180 Days after randomisation

  37. enoxaparin/warfarin (25 events) 5 4 3 2 1 0 Major bleeding Cumulative risk versus time after randomisation Cumulative risk (%) ximelagatran (14 events) 2.2% NS 1.3% 0 30 60 90 120 150 180 Days after randomisation

  38. Stroke Prevention Using theORal Direct Thrombin InhibitorXimelagatran in Patients With Nonvalvular Atrial FibrillationSPORTIFIII

  39. 4 3 2 1 0 Primary events: stroke and SEEIntention-to-treat analysis Cumulativeevent rate (%) 56 events (2.3%/year) warfarin ximelagatran 40 events (1.6%/year) 0 3 6 9 12 15 18 21 Duration (months)

  40. Primary events: stroke and SEEIntention-to-treat analysis ximelagatranbetter warfarinbetter ximelagatran 1.6%/year(40 events) warfarin2.3%/year(56 events) Superiority Non-inferiority -3 -2 -1 0 1 2 3 Event rate difference (%) Difference per year = –0.7% (95% CI: –1.5, 0.1; p=0.10)

  41. Adverse eventsHaemorrhage Event rate(% per year) p=0.007 29.8% 25.8% 1.8% 1.3% 0.4% 0.2% Intracranialhaemorrhage Majorbleeding Major + minorbleeding

  42. Warfarin Decades of experience Vast quantities of data Patients and professionals familiar with the INR Cheap Ximelagatran Appears safe and effective No drug interactions No tests ? cost

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