1. The DASH Study Patrick Leonberger MSIV BGSMC Nov 8, 2013

2. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH) Tosetto et al. Journal of Thrombosis and Haemostasis 2012

3. Goal of study Develop a score to predict the recurrence risk following a first episode of unprovoked VTE after treatment with at least three months of VKA (Vitamin K antagonist)

4. D-Dimer (500 ng/mL) Age >50 Sex Hormones D 2 A 1 S 1 H -2

5. Introduction 25-30% recurrence of VTE at 5 years  current recommendations for at least 3 months AC with option for lifelong AC in patients at low risk for bleeding AC does prevent recurrence, but recurrence risk diminishes with time and the risk of AC associated hemorrhage increases with ongoing AC and increasing age Must consider NET CLINICAL BENEFIT

7. More on Net Clinical Benefit For long-term AC, may vary over long term Recurrent VTE in select patients may be lower in certain patients (female, age < 50, HRT use)

8. AC associated hemorrhage 1-3% overall 5% in elderly

9. Spoiler Alert! DASH score can predict recurrence rate to determine if VKA should be continued indefinitely or stopped after an initial period of at least three months

10. Male vs. Female 3 year cumulative risk Men 22% Women 12% Women at 45% lower risk

11. D-dimer (cutoff < 500 ng/mL) Annual risk, after AC stopped Normal 3.5% Abnormal: 8.9% Normal is 60% lower risk

12. Methods Meta-analysis of studies that included patients with a first VTE from prospective studies who received conventional AC and were followed for 5 years for recurrence

13. Eligibility Criteria

14. No major clinical VTE risk factor (surgery, trauma, active cancer, immobility, pregnancy/puerperium (6 weeks after) Accepted: thrombophilia or HRT/OCP cases HRT is weak risk factor for VTE (all were PO) Thrombophilia increases initial risk but not recurrent risk of VTE HRT and OC were combined; they have similar 2 to 4 fold increase in VTE Only PROXIMAL VTE or PE (+/- VTE association) were considered eligible

15. Hypercoagulability Antiphospholipid antibodies and thrombin deficiency were excluded because they were excluded from source studies D-Dimer = positive if > or equal to 500 ng/mL after stopping AC (3-5 weeks)

16. Follow-up

17. Started when AC discontinued and ended when: Symptomatic recurrent VTE Death from another cause Resumption of AC for another reason Source study ended

18. Statistics and Model Development Cox regression stratified by study to identify variables Full model includes DASH, mode of initial presentation, previous history of cancer (currently inactive) Previous analysis showed timing of post AC d-dimer testing, duration of AC, BMI, and thrombophilia were not associated with increased risk of recurrent VTE

19. Statistics Age: quartiles to control for nonlinear effect on age Initially backward approach is often overly optimistic; corrected with heuristic formula and linear shrinkage with bootstrapping Incidence rates calculated for each score in the whole cohort, aiming to identify a score threshold for low risk patients (meaning below 5% annually)

21. Results Database of 2554 patients, excluded 727 (calf or provoked VTE) or follow up ended before d- dimer was measured (9 patients) totaling 1818 patients Median f/u = 22.4 months 826/1818 (45%) had abnormal d-dimer (median 30 day post AC)

22. Cohort Characteristics

23. AGE Age was significantly higher when age stratified dichotomously with first quartile 14- 48 years having significantly higher risk of recurrence than those >/= 48 years Age < 50 years was retained in the model No significant interaction observed between age and sex or age and hormone use

24. Scoring 2+ for abnormal post AC d-dimer 1+ for age less than or equal to 50 years 1+ for male sex Negative 2 for hormone use at initial time of VTE (females only) D 2 A 1 S 1 H -2

26. Significant factors

27. DASH Annual Recurrence rates DASH SCOREAnnual Recurrence 1 or less3.1% 26.4% 3 or more12.3%

28. Risks of recurrence

29. Risks continued

30. Success! DASH predictive capability significantly higher than that based on d-dimer alone P < 0.0001

32. Case 1 55 year old male with unprovoked VTE on Coumadin for 6 months, AC stopped and d- dimer normal at 1 month What is this patients DASH Score? D 2 A 1 S 1 H -2

33. Case 1 For a patient wish a DASH score of 1 it may be considered acceptable to stop AC after 3-6 months of treatment because the score predicts a 3.9% annual recurrence and 5.1% cumulative recurrence

34. Case 2 65 year old female with MTHFR+ has unprovoked VTE has d-dimer 656 ng/mL 1 month after stopping VKA; not on HRT. DASH score? Recurrence?

35. DASH Annual Recurrence rates DASH SCOREAnnual Recurrence 1 or less3.1% 26.4% 3 or more12.3%

36. Results Annual incidence VTE = 3.1% in those with DASH = 1 or less 9.3% in those with DASH greater than 1 Those with DASH less than 1 have acceptably low risk of recurrence; lifelong AC could be avoided in 51.6% of patients in this cohort

37. Discussion 7 prospective studies 4 easily measured variables Strengths: large sample with few relevant predictors, internal validation by bootstrap, consistency of result in all considered studies

38. Limitations D-dimer assay heterogeneity may reduce discriminatory power (although no significant differences between available assays ability to predict recurrent VTE) Relatively short mean observation period (22 months) could have caused low recurrent VTE rate (13.1%) Retrospective meta-analysis meant researchers were unable to address potential predictors – residual DVT by LE-US or post-thrombotic syndrome – these could further improve prediction

39. Recurrence rates

40. Goals for future studies High PPV for recurrent VTE High NPV for recurrent free survival Balance patient safety (minimize recurrence) while minimizing those on indefinite/lifelong AC

41. Wrap up Patients on AC bleeding risk is 1-3% overall, 4- 5% in the elderly Annual recurrence less than 5% is acceptable by expert consensus Similar to annual risk for patients with provoked VTE in whom indefinite AC is deemed unnecessary

42. Summary DASH </= 1 fulfills requirements with annual risk 3.1%  justify stopping AC in average patient 3-6 months after AC started DASH >/= 2 warrants prolonged AC, assuming significant bleeding risk is not present DASH was less than or equal to one in 51.6% of patients in study suggesting we could stop AC in this amount of patients with unprovoked VTE DASH > D-dimer alone as lifelong AC could be avoided in 51.6% of patients in this cohort