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