the dash study
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The DASH Study
Patrick Leonberger MSIVBGSMC 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
• 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)
D-Dimer (500 ng/mL) Age >50
SexHormones
D2A1S1H-2
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
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)
AC associated hemorrhage
• 1-3% overall• 5% in elderly
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
Male vs. Female
• 3 year cumulative risk• Men 22%• Women 12%
• Women at 45% lower risk
D-dimer (cutoff < 500 ng/mL)
• Annual risk, after AC stopped• Normal 3.5%• Abnormal: 8.9%
• Normal is 60% lower risk
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
Eligibility Criteria
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
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)
Follow-up
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
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
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)
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)
Cohort Characteristics
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
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
Significant factors
DASH Annual Recurrence ratesDASH SCORE Annual Recurrence
1 or less 3.1%
2 6.4%
3 or more 12.3%
Risks of recurrence
Risks continued
Success!
• DASH predictive capability significantly higher than that based on d-dimer alone P < 0.0001
Had Unprovoked VTE
Doctors said I could stop AC after 3 months with < 5% annual risk of recurrence
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
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
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?
DASH Annual Recurrence ratesDASH SCORE Annual Recurrence
1 or less 3.1%
2 6.4%
3 or more 12.3%
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
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
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
Recurrence rates
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
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
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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