Acute Deep Vein Thrombosis
Conditions
Keywords
Deep vein thrombosis, Post thrombotic syndrome, Thrombus resolution
Brief summary
Despite standard care, 25%-50% of patients with clots in the deep veins of the arms and legs progress to chronic post-clot problems resulting in significant disability, loss of productivity, and healthcare costs. Reverse flow in the veins from an organizing clot is the primary cause of post-clot problems. Veins with early clot breakdown have a lower incidence of reverse flow. The investigators have observed that clot breakdown is enhanced by increased blood flow and that moderate arm and leg exercise result in increased venous blood flow. Hence, the investigators predict that a supervised exercise program in patients with deep vein clots could increase leg vein blood flow, accelerate clot breakdown, and decrease the risk of post clot problems. The primary hypothesis is that increased blood flow across the clot (induced by supervised exercise) will increase clot breakdown and decrease severity of post clot problems. The investigators are conducting a randomized clinical trial of standard therapy compared to progressive exercise training in patients with leg deep vein clots.
Detailed description
Standard anticoagulation therapy for acute deep vein thrombosis (DVT) reflects the current short term focus on preventing pulmonary embolism (PE) and recurrent DVT. Despite standard care, 25% to 50% of patients with DVT progress to the chronic post-thrombotic syndrome (PTS) resulting in significant disability, loss of productivity, and healthcare costs. The investigators postulate that a supervised exercise program in patients with acute DVT could increase lower extremity venous flow, accelerate thrombus resolution, and thereby decrease the risk of PTS. If the patient is unable to perform exercises, neuromuscular electrical stimulation (NMES) will be used to induce contraction of the muscles of the lower extremities. Aim 1 will test whether a 3-month exercise program has long-term clinical benefits in acute DVT. The primary outcome measures will be the 2-year change in Villalta score for PTS and VEINES-QOL score (Venous Insufficiency Epidemiological and Economic Study-QOL). Aim 2 will evaluate whether exercise therapy in patients with acute DVT enhances thrombus resolution. The outcome measure will be 3-month change in thrombus volume. Aim 3 will assess the relationship between PTS, venous hemodynamics and exercise capacity. The outcome measures will be Villalta score, common femoral reflux, and 400-meter walk time.
Interventions
OTHERExercise
Upper and Lower extremity exercise
OTHERStandard Care
anticoagulation, compression, and ad-lib ambulation
Sponsors
University of Maryland
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Acute Lower Extremity DVT * DVT documented by ultrasound, CT/Magnetic Resonance imaging (MR) venogram, or conventional venogram * Enrolled within 4 weeks of onset of symptoms * Age 18 years or older
Exclusion criteria
* Peripheral arterial disease (disabling claudication, rest pain, tissue loss) with ankle brachial index (ABI)<0.5 * Immediate need for thrombolysis/thrombectomy * DVT involving the inferior vena cava (IVC) * Contraindication to anticoagulation * Contraindications to exercise training * Medical illness interfering with evaluation/follow-up * Life expectancy <2 years * Pregnancy * Inability to walk * Hemodynamically significant PE
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2-year Change in Villalta Score | Change from baseline to 2-year follow-up | The Villalta score quantifies severity of symptoms and can be used to diagnose Post-Thrombotic Syndrome (PTS). The Villalta score quantifies severity of symptoms and can be used to diagnose Post-Thrombotic Syndrome (PTS). Higher Villalta scores denote more severe symptoms and greater likelihood of PTS. The outcome measure is not the score itself, but change in scores over time, calculated by subtracting the baseline score from the score at the 2-year follow-up. The range of the Villalta score is 0-33, so the minimum possible change is -33 and the maximum possible change is 33, with 0 indicating no change in Villalta scores (same score at baseline and at 2-year follow-up). An increase (positive change) in Villalta score indicates worsening symptoms, while a decrease (negative change) indicates improving symptoms. |
| 2-year Change in VEINES-QOL Summary Score | Change from baseline to 2-year follow-up | The VEINES-QOL summary score is calculated from the Venous Insufficiency Epidemiological and Economic Study (VEINES) Quality of Life (QOL) questionnaire, and it provides an estimate of the overall impact of deep venous thrombosis (DVT) on the patient's quality of life. A higher VEINES-QOL score indicates better quality of life. The outcome measure is not the score itself, but change in scores over time, calculated by subtracting the baseline score from the score at the 2-year visit. The range of the VEINES-QOL summary score is 25-117, so the minimum possible change is -92 and the maximum possible change is 92, with 0 indicating no change in VEINES-QOL scores (same score at baseline and at 2-year follow-up). An increase (positive change) in VEINES-QOL score indicates an improvement in quality of life, and a decrease (negative change) indicates worsening quality of life. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 2-year Change in SF-36 Domain Scores | Change from baseline to 2-year follow-up | The 36-Item Short Form survey (SF-36) produces 8 domain scores, each quantifying a different aspect of quality of life: * PF = Physical Functioning * RP = Role limitations due to Physical health problems * RE = Role limitations due to mental health or Emotional problems * VT = energy/fatigue/Vitality * MH = Mental Health/emotional well-being * SF = Social Functioning * BP = Bodily Pain * GH = General Health The outcome measure is not the score itself, but change in scores over time, calculated by subtracting the baseline score from the score at the 2-year visit. The range for each domain score is 0-100, so the minimum possible change is -100 and the maximum possible change is +100, with 0 indicating no change in domain scores (same score at baseline and at 2-year follow-up). An increase (positive change) in a domain score indicates improvement in that specific aspect of quality of life, and a decrease (negative change) indicates worsening quality of life in that domain. |
| 3-month Percent-change in Thrombus Volume | Change from baseline to 3-month follow-up | Percent-change in thrombus volume (mL) is calculated by subtracting the baseline volume from the volume at the 3-month visit then dividing the result by the baseline volume and multiplying by 100. A negative change indicates a decrease in thrombus volume; i.e. the thrombus shrank in size and is therefore closer to complete resolution. A percent-change of -100% indicates complete thrombus resolution. |
Countries
United States
Participant flow
Recruitment details
Adult (18+) patients who recently experienced acute lower extremity Deep Vein Thrombosis (DVT) were screened and enrolled within 28 days of the DVT diagnosis, received a 3-month treatment (either standard care alone or standard care + exercise program), followed for 2 years, and evaluated at 1 month, 3 months, 6 months, 1 year, and 2 years. Participants were recruited from a vascular imaging lab based on physician referral. Participants were enrolled September 2014 - June 2019.
Pre-assignment details
Of 107 enrolled participants, 102 were randomized to one of the treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Control Standard care (anticoagulation, compression, and ad-lib ambulation) | 48 |
| Exercise Standard care + 3-month exercise therapy
Exercise: upper and lower extremity exercise
Standard care: anticoagulation, compression, and ad-lib ambulation | 54 |
| Total | 102 |
Baseline characteristics
| Characteristic | Control | Total | Exercise |
|---|---|---|---|
| Age, Continuous | 55 years STANDARD_DEVIATION 15 | 53 years STANDARD_DEVIATION 14 | 52 years STANDARD_DEVIATION 12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 97 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 27 Participants | 53 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 19 Participants | 43 Participants | 24 Participants |
| Sex: Female, Male Female | 21 Participants | 39 Participants | 18 Participants |
| Sex: Female, Male Male | 27 Participants | 63 Participants | 36 Participants |
| SF-36 domain scores BP domain score | 47.9 units on a scale STANDARD_DEVIATION 36.3 | 50.2 units on a scale STANDARD_DEVIATION 32.7 | 52.2 units on a scale STANDARD_DEVIATION 29.4 |
| SF-36 domain scores GH domain score | 55.2 units on a scale STANDARD_DEVIATION 25.3 | 59.1 units on a scale STANDARD_DEVIATION 23.8 | 62.5 units on a scale STANDARD_DEVIATION 22 |
| SF-36 domain scores MH domain score | 68.4 units on a scale STANDARD_DEVIATION 25 | 70.5 units on a scale STANDARD_DEVIATION 22.6 | 72.3 units on a scale STANDARD_DEVIATION 20.3 |
| SF-36 domain scores PF domain score | 44.9 units on a scale STANDARD_DEVIATION 32.5 | 56.5 units on a scale STANDARD_DEVIATION 32.7 | 66.7 units on a scale STANDARD_DEVIATION 29.7 |
| SF-36 domain scores RE domain score | 15.1 units on a scale STANDARD_DEVIATION 11.3 | 15.6 units on a scale STANDARD_DEVIATION 10.9 | 15.6 units on a scale STANDARD_DEVIATION 10.7 |
| SF-36 domain scores RP domain score | 7.4 units on a scale STANDARD_DEVIATION 10.2 | 8.7 units on a scale STANDARD_DEVIATION 10.3 | 9.8 units on a scale STANDARD_DEVIATION 10.4 |
| SF-36 domain scores SF domain score | 58.1 units on a scale STANDARD_DEVIATION 35.7 | 62.1 units on a scale STANDARD_DEVIATION 33.4 | 65.6 units on a scale STANDARD_DEVIATION 31.2 |
| SF-36 domain scores VT domain score | 54.2 units on a scale STANDARD_DEVIATION 27.9 | 57.2 units on a scale STANDARD_DEVIATION 26.5 | 59.9 units on a scale STANDARD_DEVIATION 25.2 |
| Thrombus volume | 3.0 mL STANDARD_DEVIATION 6.7 | 2.7 mL STANDARD_DEVIATION 5.6 | 2.4 mL STANDARD_DEVIATION 4.4 |
| VEINES-QOL summary score | 84.2 units on a scale STANDARD_DEVIATION 15 | 84.8 units on a scale STANDARD_DEVIATION 15.9 | 85.4 units on a scale STANDARD_DEVIATION 16.8 |
| Villalta score | 5.4 units on a scale STANDARD_DEVIATION 4.5 | 4.8 units on a scale STANDARD_DEVIATION 4.1 | 4.2 units on a scale STANDARD_DEVIATION 3.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 48 | 3 / 54 |
| other Total, other adverse events | 0 / 48 | 0 / 54 |
| serious Total, serious adverse events | 14 / 48 | 9 / 54 |
Outcome results
Primary
2-year Change in VEINES-QOL Summary Score
The VEINES-QOL summary score is calculated from the Venous Insufficiency Epidemiological and Economic Study (VEINES) Quality of Life (QOL) questionnaire, and it provides an estimate of the overall impact of deep venous thrombosis (DVT) on the patient's quality of life. A higher VEINES-QOL score indicates better quality of life. The outcome measure is not the score itself, but change in scores over time, calculated by subtracting the baseline score from the score at the 2-year visit. The range of the VEINES-QOL summary score is 25-117, so the minimum possible change is -92 and the maximum possible change is 92, with 0 indicating no change in VEINES-QOL scores (same score at baseline and at 2-year follow-up). An increase (positive change) in VEINES-QOL score indicates an improvement in quality of life, and a decrease (negative change) indicates worsening quality of life.
Time frame: Change from baseline to 2-year follow-up
Population: Patients who completed the VEINES-QOL questionnaire at baseline and at the 2-year visit (some patients refused or were unable to complete the questionnaire, and some patients did not complete a 2-year follow-up visit).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | 2-year Change in VEINES-QOL Summary Score | 6.4 units on a scale | Standard Deviation 8.2 |
| Exercise | 2-year Change in VEINES-QOL Summary Score | 6.9 units on a scale | Standard Deviation 16.5 |
p-value: 0.8995% CI: [-7.1, 8]t-test, 2 sided
Primary
2-year Change in Villalta Score
The Villalta score quantifies severity of symptoms and can be used to diagnose Post-Thrombotic Syndrome (PTS). The Villalta score quantifies severity of symptoms and can be used to diagnose Post-Thrombotic Syndrome (PTS). Higher Villalta scores denote more severe symptoms and greater likelihood of PTS. The outcome measure is not the score itself, but change in scores over time, calculated by subtracting the baseline score from the score at the 2-year follow-up. The range of the Villalta score is 0-33, so the minimum possible change is -33 and the maximum possible change is 33, with 0 indicating no change in Villalta scores (same score at baseline and at 2-year follow-up). An increase (positive change) in Villalta score indicates worsening symptoms, while a decrease (negative change) indicates improving symptoms.
Time frame: Change from baseline to 2-year follow-up
Population: Patients who underwent physical examination at baseline and at the 2-year visit (some patients could not tolerate the physical examination necessary to ascertain Villalta score, and some patients did not complete a 2-year follow-up visit).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | 2-year Change in Villalta Score | -1.5 units on a scale | Standard Deviation 4.3 |
| Exercise | 2-year Change in Villalta Score | -0.5 units on a scale | Standard Deviation 3.7 |
p-value: 0.3495% CI: [-1.1, 3.1]t-test, 2 sided
Secondary
2-year Change in SF-36 Domain Scores
The 36-Item Short Form survey (SF-36) produces 8 domain scores, each quantifying a different aspect of quality of life: * PF = Physical Functioning * RP = Role limitations due to Physical health problems * RE = Role limitations due to mental health or Emotional problems * VT = energy/fatigue/Vitality * MH = Mental Health/emotional well-being * SF = Social Functioning * BP = Bodily Pain * GH = General Health The outcome measure is not the score itself, but change in scores over time, calculated by subtracting the baseline score from the score at the 2-year visit. The range for each domain score is 0-100, so the minimum possible change is -100 and the maximum possible change is +100, with 0 indicating no change in domain scores (same score at baseline and at 2-year follow-up). An increase (positive change) in a domain score indicates improvement in that specific aspect of quality of life, and a decrease (negative change) indicates worsening quality of life in that domain.
Time frame: Change from baseline to 2-year follow-up
Population: Patients who completed the SF-36 questionnaire at baseline and at the 2-year visit (some patients refused or were unable to complete the questionnaire, and some patients did not complete a 2-year follow-up visit).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control | 2-year Change in SF-36 Domain Scores | Change in PF domain score | 20.2 units on a scale | Standard Deviation 30.9 |
| Control | 2-year Change in SF-36 Domain Scores | Change in RP domain score | 5.2 units on a scale | Standard Deviation 13.8 |
| Control | 2-year Change in SF-36 Domain Scores | Change in RE domain score | 3.1 units on a scale | Standard Deviation 11.5 |
| Control | 2-year Change in SF-36 Domain Scores | Change in VT domain score | 3.1 units on a scale | Standard Deviation 26.9 |
| Control | 2-year Change in SF-36 Domain Scores | Change in MH domain score | 1.9 units on a scale | Standard Deviation 22.4 |
| Control | 2-year Change in SF-36 Domain Scores | Change in SF domain score | 21.4 units on a scale | Standard Deviation 28.4 |
| Control | 2-year Change in SF-36 Domain Scores | Change in BP domain score | 12.5 units on a scale | Standard Deviation 34.8 |
| Control | 2-year Change in SF-36 Domain Scores | Change in GH domain score | 1.1 units on a scale | Standard Deviation 22 |
| Exercise | 2-year Change in SF-36 Domain Scores | Change in GH domain score | -2.4 units on a scale | Standard Deviation 16.6 |
| Exercise | 2-year Change in SF-36 Domain Scores | Change in PF domain score | 14.4 units on a scale | Standard Deviation 22.2 |
| Exercise | 2-year Change in SF-36 Domain Scores | Change in MH domain score | -0.7 units on a scale | Standard Deviation 18.6 |
| Exercise | 2-year Change in SF-36 Domain Scores | Change in RP domain score | 10.2 units on a scale | Standard Deviation 10.4 |
| Exercise | 2-year Change in SF-36 Domain Scores | Change in BP domain score | 22.0 units on a scale | Standard Deviation 38.4 |
| Exercise | 2-year Change in SF-36 Domain Scores | Change in RE domain score | 5.8 units on a scale | Standard Deviation 8.8 |
| Exercise | 2-year Change in SF-36 Domain Scores | Change in SF domain score | 17.5 units on a scale | Standard Deviation 31.8 |
| Exercise | 2-year Change in SF-36 Domain Scores | Change in VT domain score | 8.7 units on a scale | Standard Deviation 25.4 |
Comparison: Note that this analysis uses only 1 of the 8 SF-36 domain scores, the Physical Functioning (PF) domain score.p-value: 0.4395% CI: [-20.3, 8.4]t-test, 2 sided
Comparison: Note that this analysis uses only 1 of the 8 SF-36 domain scores, the Role limitations due to Physical health problems (RP) domain score.p-value: 0.1395% CI: [-1.6, 11.6]t-test, 2 sided
Comparison: Note that this analysis uses only 1 of the 8 SF-36 domain scores, the Role limitations due to mental health or Emotional problems (RE) domain score.p-value: 0.3395% CI: [-2.8, 8.2]t-test, 2 sided
Comparison: Note that this analysis uses only 1 of the 8 SF-36 domain scores, the energy/fatigue/Vitality (VT) domain score.p-value: 0.4395% CI: [-8.7, 20]t-test, 2 sided
Comparison: Note that this analysis uses only 1 of the 8 SF-36 domain scores, the Mental Health/emotional well-being (MH) domain score.p-value: 0.6495% CI: [-13.8, 8.6]t-test, 2 sided
Comparison: Note that this analysis uses only 1 of the 8 SF-36 domain scores, the Social Functioning (SF) domain score.p-value: 0.6495% CI: [-20.5, 12.8]t-test, 2 sided
Comparison: Note that this analysis uses only 1 of the 8 SF-36 domain scores, the Bodily Pain (BP) domain score.p-value: 0.3595% CI: [-10.7, 29.7]t-test, 2 sided
Comparison: Note that this analysis uses only 1 of the 8 SF-36 domain scores, the General Health (GH) domain score.p-value: 0.595% CI: [-14.1, 7]t-test, 2 sided
Secondary
3-month Percent-change in Thrombus Volume
Percent-change in thrombus volume (mL) is calculated by subtracting the baseline volume from the volume at the 3-month visit then dividing the result by the baseline volume and multiplying by 100. A negative change indicates a decrease in thrombus volume; i.e. the thrombus shrank in size and is therefore closer to complete resolution. A percent-change of -100% indicates complete thrombus resolution.
Time frame: Change from baseline to 3-month follow-up
Population: Patients for whom thrombus volume could be determined through imaging at baseline and at the 3-month visit (thrombus volume could not be determined for some patients, and some patients did not complete a 3-month follow-up visit).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | 3-month Percent-change in Thrombus Volume | -35.9 Percent of baseline thrombus size | Standard Deviation 138.1 |
| Exercise | 3-month Percent-change in Thrombus Volume | -69.8 Percent of baseline thrombus size | Standard Deviation 63.2 |
p-value: 0.2795% CI: [-95.5, 27.7]t-test, 2 sided
Post Hoc
Time Required to Walk 400 Meters in Patients With vs Without PTS
The 400-meter walk tests exercise capacity. Post-thrombotic syndrome (PTS) is defined as a Villalta score of 5 or higher.
Time frame: Baseline
Population: Patients who underwent physical examination to ascertain Villalta score and completed 400-meter walk at baseline (some patients could not tolerate physical examination and some patients were unable to complete walk).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control | Time Required to Walk 400 Meters in Patients With vs Without PTS | Exercise | 5.9 minutes | Standard Deviation 2 |
| Control | Time Required to Walk 400 Meters in Patients With vs Without PTS | Control | 4.9 minutes | Standard Deviation 1.3 |
| Exercise | Time Required to Walk 400 Meters in Patients With vs Without PTS | Exercise | 5.4 minutes | Standard Deviation 1.1 |
| Exercise | Time Required to Walk 400 Meters in Patients With vs Without PTS | Control | 5.6 minutes | Standard Deviation 1.4 |
p-value: 0.9195% CI: [-0.8, 0.9]t-test, 2 sided
Post Hoc
Villalta Score in People With vs Without Common Femoral Reflux
Common femoral reflux (yes/no) is used as a measure of hemodynamics; determined through lower extremity Ultrasonography. The Villalta score quantifies severity of symptoms and can be used to diagnose Post-Thrombotic Syndrome (PTS). Higher Villalta scores denote more severe symptoms and greater likelihood of PTS. The minimum possible score is 0, and the maximum possible score is 33.
Time frame: Baseline
Population: Patients who underwent physical examination (to ascertain Villalta score) as well as lower extremity Ultrasonography (to assess hemodynamics of the common femoral vein) at baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control | Villalta Score in People With vs Without Common Femoral Reflux | Exercise | 3.9 units on a scale | Standard Deviation 3.8 |
| Control | Villalta Score in People With vs Without Common Femoral Reflux | Control | 4.1 units on a scale | Standard Deviation 3 |
| Exercise | Villalta Score in People With vs Without Common Femoral Reflux | Exercise | 4.4 units on a scale | Standard Deviation 3.9 |
| Exercise | Villalta Score in People With vs Without Common Femoral Reflux | Control | 6.9 units on a scale | Standard Deviation 5.5 |
p-value: 0.0795% CI: [-3.4, 0.1]t-test, 2 sided