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The DASH Study

The DASH Study. Patrick Leonberger MSIV BGSMC Nov 8, 2013. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH) Tosetto et al. Journal of Thrombosis and Haemostasis 2012. Goal of study.

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The DASH Study

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  1. The DASH Study Patrick Leonberger MSIVBGSMC 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 >50SexHormones D2A1S1H-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

  6. 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)

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

  8. 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

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

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

  11. 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

  12. Eligibility Criteria

  13. Eligibility Criteria • 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

  14. 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)

  15. Follow-up

  16. Follow-up • Started when AC discontinued and ended when: • Symptomatic recurrent VTE • Death from another cause • Resumption of AC for another reason • Source study ended

  17. 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

  18. 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)

  19. 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)

  20. Cohort Characteristics

  21. 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

  22. 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) • D2A1S1H-2

  23. Significant factors

  24. DASH Annual Recurrence rates

  25. Risks of recurrence

  26. Risks continued

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

  28. Had Unprovoked VTE Doctors said I could stop AC after 3 months with < 5% annual risk of recurrence

  29. 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? • D2A1S1H-2

  30. 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

  31. 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?

  32. DASH Annual Recurrence rates

  33. 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

  34. 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

  35. 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

  36. Recurrence rates

  37. 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

  38. 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

  39. 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

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