Deep Vein Thrombosis, Pulmonary Embolism, Recurrent Thromboembolic Disease, Thromboembolic Disease Recurrent, Venous Thromboembolism
Conditions
Brief summary
Patients with a history of blood clots are at risk of developing additional clots in the future. Doctors use a tool called a clinical decision rule to tell them how likely it is that a patient has a blood clot and if they should have further testing to look for the clot. This tool may cause doctors to over-diagnosis a recurrent clot because the symptoms may be left over from the previous clot. Correctly diagnosing a recurrent blood clot is very important since there are risks associated with both over-diagnosis and under-diagnosis. If a recurrent blood clot is missed (under-diagnosis) the patient is at risk of death from a clot in the lungs. If blood thinners are prescribed when they are not needed (over-diagnosis), the patient may have to take blood thinners for their lifetime and risk having serious bleeding.
Detailed description
Several tools have been developed to standardize the diagnostic management of a suspected first blood clot. One of these tools is the use of a clinical decision rule. Clinical decision rules have been designed to help clinicians make diagnostic and therapeutic decisions at the bedside. A score is computed on the presence of some criteria from the patient's medical history, clinical signs and symptoms. The score provides the probability of a blood clot. The rules can be used in combinations with a simple blood test - called D-dimer - to identify patients at low risk who don't require diagnostic imaging testing. Benefits include reduced costs, length in hospital and radiation exposure. Patients with prior blood clots have been shown to be less likely to benefit from the non-invasive testing. Therefore, they often need to undergo imaging tests, which are frequently difficult to interpret in patients with prior blood clots since residual clots are often present and are difficult to distinguish from a recurrent clot. The objective of this study is to try to prospectively assess the role of existing clinical decision rules in patients with prior blood clots, and to attempt to improve them in order to increase the yield of non-invasive testing and to reduce the risk of over-diagnosis with imaging tests. With respect to this study, clots within the deep veins of the legs are called deep vein thrombosis (DVT), while clots in the lungs are called pulmonary embolism (PE).
Interventions
None listed
Sponsors
Ottawa Hospital Research Institute
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Outpatients with clinically suspected acute recurrent DVT or PE regardless of whether the previous event was a DVT or PE * Age ≥18 years old * Willing and able to give informed consent
Exclusion criteria
* Life expectancy less than 3 months * Suspicion of upper extremity thrombosis or thrombosis at an unusual site (e.g. cerebral or abdominal venous thrombosis) * Previous VTE was distal DVT or subsegmental PE * Suspected recurrent VTE is asymptomatic * Previously enrolled in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Validation of the Wells DVT Clinical Decision Rule | Day 0 (at time of suspected recurrent DVT) | The Wells DVT Clinical Decision Rule (CDR) assigns a score from -2 to +9 based on clinical variables (e.g., active cancer, limb swelling, localized tenderness, prior history of DVT, alternative diagnosis as likely or more likely than DVT). In this study, the 3-level Wells DVT CDR was applied prospectively at presentation (Day 0) to participants with suspected recurrent DVT, using data collected from patient history and physical examination. Scores classify patients into low (≤0), moderate (1-2), or high (≥3) probability of DVT. Higher scores indicate greater probability of recurrent DVT. The outcome measure was the rate of confirmed recurrent DVT events within each Wells category, confirmed by objective imaging and adjudicated by an independent committee. |
| Validation of the Wells PE Clinical Decision Rule | Day 0 (at time of suspected recurrent PE) | The 3-level Wells PE score (range 0-12.5) was calculated from history and exam at the index visit. Scores ≤4 = PE unlikely, \>4 = PE likely. Higher scores indicate greater likelihood of PE. The outcome is the proportion with confirmed recurrent PE at the index diagnostic work-up, adjudicated by blinded review of imaging. |
| Validation of the Geneva PE Clinical Decision Rule | Day 0 (at time of suspected recurrent PE) | The revised Geneva score (range 0-22) was calculated from history and exam at the index visit. Scores 0-3 = low, 4-10 = intermediate, ≥11 = high probability. Higher scores indicate greater likelihood of PE. The outcome is the proportion with confirmed recurrent PE at the index diagnostic work-up, adjudicated by blinded review of imaging. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Accuracy of Current D-dimer Testing Methods | Day 0 (at time of suspected recurrent VTE) | D-dimer testing at the index visit was performed using the institutional cut-off for positivity in place during the study period (2014-2019). Results were classified as positive or negative. The outcome is the proportion with confirmed recurrent VTE in each test category at the index diagnostic work-up, adjudicated by blinded review of imaging. |
| Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Day 0 (at time of suspected recurrent VTE) | The Wells DVT, Wells PE, and Geneva PE scores were calculated at the index visit in participants on anticoagulation. Score ranges and cut-offs as per respective rules. The outcome is the proportion with confirmed recurrent VTE in each risk category at the index diagnostic work-up, adjudicated by blinded review of imaging. |
| All-Cause Mortality Within 90 Days of Index Visit | From enrollment (Day 0) through Day 90 follow-up for those not diagnosed with a confirmed recurrent VTE at enrollment | Number of participants who died from any cause from enrollment (Day 0) through Day 90 follow-up for those without confirmed recurrent VTE at enrollment. |
Countries
Canada, Netherlands, Switzerland
Participant flow
Recruitment details
Between November 2014 to January 2019, eligible patients were recruited from six Canadian teaching hospitals, one academic center in Switzerland and one academic hospital in the Netherlands. All adult outpatients presenting to the Emergency Departments or Thrombosis Clinics of the participating hospitals with signs or symptoms suggestive of recurrent VTE and who were willing and able to give informed consent were eligible for inclusion.
Pre-assignment details
Between Nov 2014 and Jan 2019, 744 participants consented and had baseline data and blood samples collected. Verification of prior VTE history excluded 21 with non-qualifying events, leaving 723 who met eligibility and were included. Those with recurrent VTE diagnosed at enrolment completed participation at the initial visit; those who did not have recurrent VTE diagnosed at enrolment were followed up by phone at Day 90.
Participants by arm
| Arm | Count |
|---|---|
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism Of the 744 participants consented, 723 met all eligibility criteria and were included in the study. | 723 |
| Total | 723 |
Baseline characteristics
| Characteristic | Patients Presenting With Suspicion of Recurrent Venous Thromboembolism |
|---|---|
| Active cancer | 79 participants |
| Age, Continuous | 57.7 years STANDARD_DEVIATION 16.5 |
| Body Mass Index | 29.6 kg/m2 STANDARD_DEVIATION 6.8 |
| Current Medication Anticoagulation | 322 participants |
| Current Medication Aspirin | 104 participants |
| Current Medication Clopidogrel | 11 participants |
| Current Medication Oral estrogen therapy | 16 participants |
| Family History of Venous Thromboembolism (VTE) No | 510 Participants |
| Family History of Venous Thromboembolism (VTE) Yes | 213 Participants |
| Known thrombophilia Anti-Beta 2 glycoprotein 1 | 4 participants |
| Known thrombophilia Anti-cardiolipins | 12 participants |
| Known thrombophilia Antithrombin deficiency | 3 participants |
| Known thrombophilia Factor V Leiden unknown if heterozygote or homozygote | 5 participants |
| Known thrombophilia Heterozygote Factor V Leiden | 46 participants |
| Known thrombophilia Homozygote Factor V Leiden | 1 participants |
| Known thrombophilia Lupus anticoagulant | 8 participants |
| Known thrombophilia Protein C deficiency | 8 participants |
| Known thrombophilia Protein S deficiency | 6 participants |
| Known thrombophilia Prothrombin gene mutation | 16 participants |
| Number of confirmed previous events 1 | 559 Participants |
| Number of confirmed previous events 2 | 130 Participants |
| Number of confirmed previous events 3 | 22 Participants |
| Number of confirmed previous events 4 | 10 Participants |
| Number of confirmed previous events >/= 5 | 2 Participants |
| Race/Ethnicity, Customized Aboriginal | 10 Participants |
| Race/Ethnicity, Customized Asian | 19 Participants |
| Race/Ethnicity, Customized Black | 30 Participants |
| Race/Ethnicity, Customized Caucasian | 657 Participants |
| Race/Ethnicity, Customized Caucasian and Aboriginal | 2 Participants |
| Race/Ethnicity, Customized Caucasian and Asian | 1 Participants |
| Race/Ethnicity, Customized Caucasian and Black | 2 Participants |
| Race/Ethnicity, Customized Hispanic | 2 Participants |
| Sex: Female, Male Female | 367 Participants |
| Sex: Female, Male Male | 356 Participants |
| Smoking status Current smoker | 104 Participants |
| Smoking status No smoking history | 392 Participants |
| Smoking status Previous smoker | 227 Participants |
| Type of Anticoagulation (n) Apixaban | 31 Participants |
| Type of Anticoagulation (n) Blinded study drug | 7 Participants |
| Type of Anticoagulation (n) Dabigatran | 1 Participants |
| Type of Anticoagulation (n) Edoxaban | 1 Participants |
| Type of Anticoagulation (n) Low molecular weight heparin | 66 Participants |
| Type of Anticoagulation (n) Rivaroxaban | 124 Participants |
| Type of Anticoagulation (n) Warfarin | 92 Participants |
| Type of last VTE event Deep vein thrombosis (DVT) | 357 Participants |
| Type of last VTE event PE and DVT | 129 Participants |
| Type of last VTE event Pulmonary embolism (PE) | 237 Participants |
| Weight | 87.6 kilograms STANDARD_DEVIATION 21.5 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 723 |
| other Total, other adverse events | 0 / 723 |
| serious Total, serious adverse events | 0 / 723 |
Outcome results
Primary
Validation of the Geneva PE Clinical Decision Rule
The revised Geneva score (range 0-22) was calculated from history and exam at the index visit. Scores 0-3 = low, 4-10 = intermediate, ≥11 = high probability. Higher scores indicate greater likelihood of PE. The outcome is the proportion with confirmed recurrent PE at the index diagnostic work-up, adjudicated by blinded review of imaging.
Time frame: Day 0 (at time of suspected recurrent PE)
Population: Of the 723 participants included in the study, 268 presented with suspicion of PE, without signs or symptoms of DVT. Of the 268 presenting with suspicion of isolated PE, 79 had a confirmed diagnosis of PE.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Geneva PE Clinical Decision Rule | Suspicion of recurrent PE | Score >/= 11 (high) | 41 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Geneva PE Clinical Decision Rule | Confirmed diagnosis of PU | Score 0-3 (low) | 2 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Geneva PE Clinical Decision Rule | Suspicion of recurrent PE | Score 0-3 (low) | 46 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Geneva PE Clinical Decision Rule | Suspicion of recurrent PE | Score 4-10 (intermediate) | 181 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Geneva PE Clinical Decision Rule | Confirmed diagnosis of PU | Score 4-10 (intermediate) | 56 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Geneva PE Clinical Decision Rule | Confirmed diagnosis of PU | Score >/= 11 (high) | 21 Participants |
Primary
Validation of the Wells DVT Clinical Decision Rule
The Wells DVT Clinical Decision Rule (CDR) assigns a score from -2 to +9 based on clinical variables (e.g., active cancer, limb swelling, localized tenderness, prior history of DVT, alternative diagnosis as likely or more likely than DVT). In this study, the 3-level Wells DVT CDR was applied prospectively at presentation (Day 0) to participants with suspected recurrent DVT, using data collected from patient history and physical examination. Scores classify patients into low (≤0), moderate (1-2), or high (≥3) probability of DVT. Higher scores indicate greater probability of recurrent DVT. The outcome measure was the rate of confirmed recurrent DVT events within each Wells category, confirmed by objective imaging and adjudicated by an independent committee.
Time frame: Day 0 (at time of suspected recurrent DVT)
Population: Of the 723 participants included in the study, 401 presented with suspicion of isolated DVT, without signs or symptoms of PE. Of the 401 presenting with suspicion of isolated DVT, 108 had a confirmed diagnosis of DVT.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells DVT Clinical Decision Rule | Suspicion of Recurrent DVT | Score >/= 1-2 (moderate) | 186 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells DVT Clinical Decision Rule | Suspicion of Recurrent DVT | Score </= 0 (low) | 67 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells DVT Clinical Decision Rule | Suspicion of Recurrent DVT | Score >/= 3 (high) | 148 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells DVT Clinical Decision Rule | Confirmed DVT during follow-up period | Score </= 0 (low) | 4 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells DVT Clinical Decision Rule | Confirmed DVT during follow-up period | Score >/= 1-2 (moderate) | 39 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells DVT Clinical Decision Rule | Confirmed DVT during follow-up period | Score >/= 3 (high) | 65 Participants |
Primary
Validation of the Wells PE Clinical Decision Rule
The 3-level Wells PE score (range 0-12.5) was calculated from history and exam at the index visit. Scores ≤4 = PE unlikely, \>4 = PE likely. Higher scores indicate greater likelihood of PE. The outcome is the proportion with confirmed recurrent PE at the index diagnostic work-up, adjudicated by blinded review of imaging.
Time frame: Day 0 (at time of suspected recurrent PE)
Population: Of the 723 participants enrolled, 268 presented with a suspicion of recurrent PE without concomitant DVT suspicion. Of the 268 presenting with suspicion of isolated PE, 79 had a confirmed diagnosis of PE.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells PE Clinical Decision Rule | Suspicion of PE | Score <2 (low) | 83 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells PE Clinical Decision Rule | Suspicion of PE | Score 2-6 (moderate) | 160 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells PE Clinical Decision Rule | Suspicion of PE | Score >6 (high) | 25 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells PE Clinical Decision Rule | VTE recurrence confirmed during follow-up | Score <2 (low) | 11 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells PE Clinical Decision Rule | VTE recurrence confirmed during follow-up | Score 2-6 (moderate) | 56 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Validation of the Wells PE Clinical Decision Rule | VTE recurrence confirmed during follow-up | Score >6 (high) | 12 Participants |
Secondary
Accuracy of Current D-dimer Testing Methods
D-dimer testing at the index visit was performed using the institutional cut-off for positivity in place during the study period (2014-2019). Results were classified as positive or negative. The outcome is the proportion with confirmed recurrent VTE in each test category at the index diagnostic work-up, adjudicated by blinded review of imaging.
Time frame: Day 0 (at time of suspected recurrent VTE)
Population: Of the 723 participants in the study cohort, the attending physician ordered D-dimer testing in 482 at presentation for suspected recurrent VTE. This outcome measure is based on the 169 participants from that group who had negative D-dimer results and were evaluated for recurrent VTE.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Accuracy of Current D-dimer Testing Methods | Negative D-dimer with recurrent VTE diagnosed | 6 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Accuracy of Current D-dimer Testing Methods | Negative D-dimer with no recurrent VTE diagnosed | 163 Participants |
Secondary
All-Cause Mortality Within 90 Days of Index Visit
Number of participants who died from any cause from enrollment (Day 0) through Day 90 follow-up for those without confirmed recurrent VTE at enrollment.
Time frame: From enrollment (Day 0) through Day 90 follow-up for those not diagnosed with a confirmed recurrent VTE at enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | All-Cause Mortality Within 90 Days of Index Visit | 9 Participants |
Secondary
Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy
The Wells DVT, Wells PE, and Geneva PE scores were calculated at the index visit in participants on anticoagulation. Score ranges and cut-offs as per respective rules. The outcome is the proportion with confirmed recurrent VTE in each risk category at the index diagnostic work-up, adjudicated by blinded review of imaging.
Time frame: Day 0 (at time of suspected recurrent VTE)
Population: Of the 723 participants included, 38 were receiving anticoagulant therapy at the time of study inclusion and had a confirmed recurrent VTE. Of the 38 confirmed recurrent VTE events, 27 were for recurrent DVT and 11 were recurrent PE.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Patients on anticoagulation with confirmed DVT using 3-level Wells Score | Low | 1 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Patients on anticoagulation with confirmed DVT using 3-level Wells Score | Moderate/Intermediate | 9 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Patients on anticoagulation with confirmed DVT using 3-level Wells Score | High | 17 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Patients on anticoagulation with confirmed PE using 3-level Wells Score | Low | 1 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Patients on anticoagulation with confirmed PE using 3-level Wells Score | Moderate/Intermediate | 7 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Patients on anticoagulation with confirmed PE using 3-level Wells Score | High | 3 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Patients on anticoagulation with confirmed PE using revised Geneva Score | Low | 0 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Patients on anticoagulation with confirmed PE using revised Geneva Score | Moderate/Intermediate | 10 Participants |
| Patients Presenting With Suspicion of Recurrent Venous Thromboembolism | Rate of Confirmed Events Using Current Wells DVT/Wells PE/Geneva PE in Participants on Anticoagulant Therapy | Patients on anticoagulation with confirmed PE using revised Geneva Score | High | 1 Participants |