Clinical Predictors for Venous Thromboembolism in Patients With a History of Thrombosis
Conditions: Thromboembolic Disease Recurrent, Deep Vein Thrombosis, Pulmonary Embolism, Venous Thromboembolism, Recurrent Thromboembolic Disease
Sponsor: Ottawa Hospital Research Institute

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Research Protocol: 
 
Clinical Predictors for Venous Thromboembolism in Patients with a History of 
Thrombosis 
 
 
Short Title: PREDICTORS Study 
 
 
Protocol Number: 20140622-01H 
 
 
Funding Source: Heart and Stroke Foundation of Canada 
 
 
Principal Investigator: Dr. Gregoire Le Gal 
 
Coordinating Centre:  Ottawa Hospital Research Institute 
 
 
Study Personnel: Dr. Marc Rodger, Dr. Phil Wells, Dr. David Anderson, Dr. Susan 
Kahn, Dr. Michael Kovacs, Dr. Timothy Ramsay 
 
 
Protocol Date: Version 2, 06-Nov-2014 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SPONSOR SIGNATURE PAGE 
 
Protocol Title 
Clinical Predictors for Venous Thromboembolism in Patients 
with a History of Thrombosis 
Protocol Number 
20140622-01H 
Coordinating Centre 
Ottawa Hospital Research Institute 
Protocol Date 
Version 2, 06-Nov-2014 
 
 
 
 
 

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SITE INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title 
Clinical Predictors for Venous Thromboembolism in Patients 
with a History of Thrombosis 
Protocol Number 
20140622-01H 
Coordinating Centre 
Ottawa Hospital Research Institute 
Protocol Date 
Version 2, 06-Nov-2014 
 
 
 
 
Confidentiality Agreement 
This protocol contains confidential information belonging to Dr. Gregoire Le Gal except 
as may be otherwise agreed to in writing, by accepting or reviewing these materials, you 
agree to hold such information in confidence and not to disclose it to others (except 
where required by applicable law) nor use it for unauthorized purposes. In the event of 
actual or suspected breach of this obligation, Dr. Gregoire Le Gal and The Ottawa 
Hospital should be promptly notified. 
 
Signature:___________________________Date:___________________________  
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
BMI 
Body Mass Index 
CDR 
Clinical Decision Rule 
CIAC 
Central Independent Adjudication Committee 
CRF 
Case report Form 
CUS 
Compression Unltrasound 
DVT 
Deep Vein Thrombosis 
eCRF 
Electronic Case Report Form 
OHRI 
Ottawa Hospital Research Institute 
PE 
Pulmonary Embolism 
VTE 
Venous Thromboembolism 
V/Q 
Ventilation-perfusion 
 
 
 

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Table of Contents 
PROTOCOL SUMMARY ................................................................................................ 7 
Inclusion Criteria .......................................................................................................... 8 
Exclusion Criteria ......................................................................................................... 8 
2. BACKGROUND AND RATIONALE ........................................................................... 9 
2.1 
Background Information .......................................................................... 9 
2.2. 
Available Knowledge of Risk Stratification before Imaging ................... 10 
2.2.2. A survey of thrombosis experts ............................................................................ 11 
2.2.3 Retrospective cohort study in patients with suspected recurrent VTE ............ 12 
1. STUDY OBJECTIVES .............................................................................................. 13 
1.1 
Primary Objective .................................................................................. 13 
1.2 
Secondary Objectives ........................................................................... 13 
3. STUDY DESIGN ....................................................................................................... 13 
3.1 
Patient Safety ........................................................................................ 13 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .......................................... 13 
4.1 
Eligibility ................................................................................................ 14 
4.2 
Inclusion Criteria ................................................................................... 14 
4.3 
Exclusion Criteria .................................................................................. 14 
4.3.1 Rationale for Exclusion Criteria ............................................................................ 14 
6. STUDY PROCEDURES ............................................................................................ 15 
6.1 
Screening and Consenting .................................................................... 15 
6.2 
Baseline Assessments and Diagnostic Management ............................ 16 
6.2.1 Clinical examination and data collection ............................................................ 16 
6.2.2 D-dimer testing ....................................................................................................... 16 
6.2.3 Imaging .................................................................................................................... 16 
6.3 
Follow-up Visits ..................................................................................... 17 
9. STATISTICAL CONSIDERATIONS .......................................................................... 17 
9.2 
Sample Size Calculation ....................................................................... 17 
9.5 
Primary Outcome Analysis .................................................................... 18 
9.6 
Secondary Outcome Analysis ............................................................... 18 
9.5.1 Recalibration / minor adjustment to existing rules ............................................ 18 
9.5.2 Derivation of a new CDR....................................................................................... 18 
9.5.3 D-dimer testing ....................................................................................................... 19 

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9.5.4 Participants treated with anticoagulant therapy ................................................ 19 
9.5.5 Compare indeterminate imaging results in participants with and without 
available information about previous imaging .................................................. 19 
10. DATA COLLECTION AND QUALITY ASSURANCE ............................................. 19 
10.1 
Data Collection Forms ........................................................................... 19 
10.2 
Data Management ................................................................................. 20 
10.3 
Retention of Study Records .................................................................. 20 
10.4 
Quality Assurance ................................................................................. 20 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................ 21 
11.1 
Research Ethics Board ......................................................................... 21 
11.2 
Informed Consent Forms ...................................................................... 21 
11.3 
Participant Confidentiality ...................................................................... 21 
12. STUDY ORGANIZATION ....................................................................................... 21 
12.1 
Study Coordination ................................................................................ 21 
12.2 
Central Independent Adjudication Committee (CIAC) ........................... 21 
12.3 
Steering Committee .............................................................................. 22 
14. REFERENCES ........................................................................................................ 23 
15. APPENDICES ......................................................................................................... 26 
Appendix A: Current Clinical Decision Rule for Suspected DVT ................................ 26 
Appendix B: Current Clinical Decision Rules for Suspected PE ................................ 27 
Appendix C: Flow Chart of Suggested Diagnostic Approach for Assessing Suspected 
Recurrent VTEs ..................................................................................... 28 
Appendix D: Collection of Clinical Predictors for Suspected Recurrent VTE ............. 29 
Appendix E: Adjudication of Suspected Recurrent VTE Events ................................ 32 
 
 
 
 

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PROTOCOL SUMMARY 
Protocol Title 
Clinical Predictors for Venous Thromboembolism in Patients 
with a History of Thrombosis 
Protocol Number 
20140622-01H 
Coordinating 
Centre 
Ottawa Hospital Research Institute 
Protocol Date 
Version 2, 06-Nov-2014 
Population 
Outpatients presenting with suspected acute recurrent VTE.  
Objectives 
Primary Objective: To assess the accuracy and usefulness of 
the Wells DVT, Wells PE and Geneva clinical decision rules in 
patients with a clinically suspected recurrent VTE. 
 
Secondary Objectives: 
 To assess the utility of recalibrating the existing clinical 
decision rules.  
 To derive a new CDR, specific to patients with a 
suspected recurrent VTE, and to assess whether this CDR 
would improve risk stratification as compared with existing 
CDRs. 
 To assess the accuracy of D-dimer testing in patients with 
suspected recurrent VTE both on and off anticoagulation. 
 
To evaluate the accuracy of current CDRs in patients on 
anticoagulant therapy at the time of suspected recurrent 
VTE. 
 
Duration 
 
All consecutive eligible patients will be approached for 
enrolment into this study over 3 years.  
Design 
This is a multicentre, observational cohort study to prospectively 
identify potential predictors of recurrent VTE. The predictive 
value of individual and combined candidate predictors will be 
evaluated in patients with suspected recurrent VTE. All 
suspected recurrences will be blindly and independently 
adjudicated. 
Significance 
If the newly developed clinical decision rule is proven to 
accurately determine the pre-test probability in patients with a 
suspected acute recurrent VTE, it could be integrated in 
diagnostic strategies that might lower cost, avoid radiation 
exposure and potentially decrease over-diagnosis of patients 
with suspected recurrent VTE. 

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Target Sample Size 
A total of 745 participants will be enrolled at Canadian sites. 
Participant 
Population 
Inclusion Criteria 
1. Outpatient with clinically suspected acute recurrent DVT or 
PE regardless of whether the previous event was a DVT or 
PE 
2. Age ≥18 years old 
3. Willing and able to give informed consent 
Exclusion Criteria 
1. Life expectancy less than 3 months 
2. Suspicion of upper extremity thrombosis or thrombosis at 
an unusual site (e.g. cerebral or abdominal venous 
thrombosis) 
3. Previous VTE was distal DVT or subsegmental PE 
4. Suspected recurrent VTE is asymptomatic 
5. Previously enrolled in this study 
 
 
 
 

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2. BACKGROUND AND RATIONALE 
2.1 
Background Information 
The diagnostic management of suspected recurrent venous thromboembolism is 
challenging, since missing the diagnosis exposes the patient to the risk of 
(potentially) fatal PE while a false-positive diagnosis leads to unnecessary lifelong 
anticoagulant treatment and exposes patients to (potentially) fatal bleeding. 
Furthermore, not treating or a delay in treatment of recurrent DVT could worsen the 
symptoms of the post-thrombotic syndrome (PTS) 17;18. 
 
 
A suspected acute recurrent VTE is common: among all patients with a suspected 
VTE, 20% have a history of previous VTE. In the 18 months after the withdrawal of 
anticoagulant therapy, 40% of patients will present with suspected recurrent VTE.  
The mainstays of VTE diagnosis include clinical probability, diagnostic imaging, and 
D-dimer testing.  However, there are important implications for diagnostic 
management when a patient has a history of prior thrombosis. Few research studies 
have focused specifically on patients with suspected recurrent VTE and no study has 
focused on the clinical predictors of VTE in patients with suspected VTE and a 
history of VTE. 
 
Clinical probability assessment is a crucial step in the management of patients with 
clinically suspected VTE. Pretest probability refers to the probability of a target 
disease or disorder being present before a diagnostic test result is known. Current 
diagnostic strategies for VTE rely on the sequential use of diagnostic tests based on 
the pretest probability of disease. Clinical decision rules (CDR) estimate the 
probability of a clinical outcome using simple available clinical data. Several 
predictive factors and CDR have been established to estimate the pretest probability 
of VTE.1-5 The most commonly used CDR for suspected DVT is the Wells rule, and 
for suspected PE the Wells and Geneva rules. The pretest probability can aid in the 
interpretation of imaging test results, and to identify a group of patients at low risk of 
disease in whom a less intensive diagnostic work up is warranted. For example, VTE 
can be safely excluded in a patient deemed to be at low risk according to the CDR in 
combination with a negative D-dimer test result.6;7 
 
Diagnostic Imaging 
Post-hoc analyses of diagnostic studies have been reassuring in terms of the safety 
of ruling out VTE on the basis of a non-high pretest probability using the Wells or 
Geneva rule in combination with a negative D-dimer in patients with a previous 
history of VTE.4;9 However, the proportion of patients in whom the diagnosis could be 
ruled out non-invasively was very low: approximately 10%, as compared with 30% 
among all-comers with suspected VTE.10 
 
Moreover, residual thrombosis is often present after a VTE event (up to 50% of 
patients at one year). Therefore, it is more likely to misdiagnose a recurrent VTE in 
saying it is present, while it‟s absent. As a result of over diagnosis, these patients 
have a long period of exposure to anticoagulants and the associated risk of major 
bleeding.  

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Patients with a high risk according to the CDR and/or a positive D-dimer test result 
require imaging. However, diagnostic imaging of a suspected recurrent VTE is more 
challenging to interpret if a residual thrombus is present, and distinguishing a 
recurrent acute thrombosis from a residual thrombosis is often difficult on imaging. In 
a study in which all patients with a first unprovoked VTE underwent baseline imaging 
before discontinuing anticoagulant therapy, almost one half of patients had a 
suspected VTE during the first 18 months of follow-up. In 20% of patients with 
suspected recurrent VTE, the imaging test was positive for VTE but unchanged as 
compared with baseline, which means that without the results of baseline imaging 
tests, up to 20% of patients could have received a false-positive diagnosis of 
recurrent VTE.11 In another study by Tan et al., 32% of patients with a suspected 
acute ipsilateral recurrent DVT had an inconclusive ultrasound result, yet all patients 
were treated with anticoagulants.13 In patients with no baseline imaging available, 
12;13 this may result in misdiagnoses in patients with previous VTE, with consequent 
unnecessary anticoagulant therapy conveying a risk of major bleeding in those over-
diagnosed or potentially fatal recurrent PE in untreated patients with a true 
recurrence. Therefore improved risk stratification of suspected recurrent events 
before imaging could be of high clinical value to increase the yield of CDR and D-
dimer, and thus decrease the need for imaging in this subgroup of patients. Potential 
benefits include reduction in radiation exposure, misdiagnosis, and costs associated 
with imaging, drug treatment, monitoring and medical follow-up. 
2.2. 
Available Knowledge of Risk Stratification before Imaging 
 
What follow are a review of the literature on predictors of recurrent VTE and the 
results of a retrospective study that we‟ve performed to look at the predictive value 
of individual potential clinical predictors. 
 
Clinical Probability Assessment  
The Wells rule is the most well validated CDR for DVT (Refer to Appendix A: 
Current Clinical Decision Rule for Suspected DVT). In the „original‟ Wells rule the 
item of „deep vein thrombosis in the past‟ was not included21 but this item was 
added to a subsequent version of the rule, adding one point to the rule if it is 
present.7 Hence, by design, the Wells rule will have a lower specificity (less likely to 
be low pre-test) in patients with prior VTE. Furthermore, because the symptoms: 
increase in calf diameter, swelling of the leg and pain on the deep vein tract, are 
also symptoms of PTS and are often present in patients with a history of DVT, the 
performance of these variables in patients with a suspected recurrent DVT might be 
altered.  
 
In patients with clinically suspected recurrent PE, the challenges for accurate 
diagnosis are similar to patients with suspected recurrent DVT. Patients often have 
persistent complaints of dyspnea after a PE.22 In patients with suspected PE the 
Wells rule and Geneva rule are the most validated rules (Refer to Appendix B: 
Current Clinical Decision Rules for Suspected PE).2-5 Both rules include an item 
related to a history of VTE in the past. Similarly to DVT, patients with a previous 
VTE are less likely to be classified as having a low clinical probability of PE: 26%, 
versus 58% in patients with no previous VTE in a post-hoc analysis of a PE 
diagnostic study using the Geneva score.4 Of note, existing CDR use „previous VTE‟ 

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as a single criterion, regardless of the location, characteristics and time elapsed 
since the previous episode, although these criteria could have an important impact 
on the pretest probability. 
 
 
D-dimer Testing 
In patients with a suspected VTE event, D-dimer testing, in combination with a 
CDR, can safely rule out a VTE.7;23 In a study in 300 patients with clinically 
suspected recurrent DVT by Rathbun et al., 45% of the 300 patients had a negative 
D-dimer test and these patients were not treated with anticoagulants on the basis of 
this test alone.20 One patient who had recurrent DVT excluded by a negative D-
dimer test had confirmed VTE during 3 months follow-up (0.75% (95% CI, 0.02-
4.09%). The Wells score in combination with a D-dimer test has been used to 
manage patients with clinically suspected acute recurrent DVT in a study by 
Anderson et al.19 In this study, 16 of 105 patients (15%) had an unlikely clinical 
probability and a normal D-dimer test; during three months follow-up none of these 
patients had a recurrent DVT. This study suggests that an unlikely clinical 
probability in combination with a normal D-dimer test result could potentially be 
used to exclude a DVT, but this strategy should be evaluated in a larger cohort of 
patients. The proportion of confirmed recurrent DVT was 22%. In a third study, 
among 308 patients with suspected acute PE with a VTE in the past, the D-dimer 
test was negative in 49 patients (16%), and none of them had a recurrent VTE 
during the 3-month follow-up: failure rate 0% (95% CI, 0.0-7.9%). The proportion of 
confirmed recurrent PE was 40%.4 
 
In conclusion, D-dimer testing may play a role in excluding a recurrent VTE; 
however the presently available studies show broad confidence intervals for the 3 
month recurrent VTE failure rates after a negative test result. Most importantly, the 
combination of current CDRs and D-dimer testing shows a low proportion (10-16%) 
of patients who could have VTE excluded by a low pretest probability and a 
negative D-dimer test result.  
 
2.2.2. A survey of thrombosis experts 
As a second approach to identify candidate predictors, we performed a survey in 
our own nation-wide collaborative research group to evaluate what the thrombosis 
experts consider potential predictors of recurrent VTE, based on their clinical 
experience in managing these patients. The following items were proposed by 
thrombosis experts as potential clinical predictors and will be collected in this study:  
 
Pulmonary embolism 
• 
Leg symptoms and signs of DVT 
• 
Tachycardia 
• 
Cancer  
• 
Recent surgery or immobilization  
• 
Subtherapeutic INR or recent dose reduction 
• 
Clean X-ray 
• 
No alternative diagnosis 
 
Deep vein thrombosis of the leg 
• 
Tenderness in deep vein distribution 

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• 
New onset of significant leg swelling 
• 
New onset of edema or worsening of chronic state of lower extremity edema 
• 
Cancer  
• 
Subtherapeutic INR or recent dose reduction 
• 
Recent surgical procedure 
• 
No alternative diagnosis 
 
General predictors for DVT and PE 
• 
Age 
• 
Gender 
• 
Whether previous event was provoked/unprovoked 
• 
Active cancer 
• 
D-dimer testing at moment of suspected recurrence and on baseline visit 
• 
Recent (within one year) discontinuation of anticoagulation after previous 
event 
• 
Estrogen therapy  
 
2.2.3 Retrospective cohort study in patients with suspected recurrent VTE 
Finally, we examined potential predictors of recurrence by performing a post-hoc 
analysis of the REVERSE I study26). Each patient in the REVERSE I cohort that had 
a suspected recurrent VTE during follow-up were screened for eligibility in the post-
hoc analysis. Only patients with a first adjudicated suspected recurrent event were 
included. Potential clinical predictors of recurrent VTE consisted of clinical predictors 
collected at the baseline visit, information collected in physicians‟ clinical notes, and 
laboratory or imaging results at the time of the suspected recurrent VTE. The 
predictive value of each predictor was determined by the Chi-square test for nominal 
data and the unpaired 2-tailed T-test for continuous data.  
 
In the REVERSE I cohort, out of the 646 patients who were followed, 402 patients 
had a suspected recurrent VTE within a mean of 20.2 months (range: 0 – 97 months) 
of follow-up. Of these, 376 patients were eligible for our study: 52.7% of patients 
were males, and the mean age was 53.1 years (± 17.5). Among all suspected 
recurrent VTE events, male gender and a positive D-dimer result at the time of 
suspected recurrent VTE (p < 0.01), as well as symptoms occurring for 10 days or 
less at the time of presentation (p < 0.05) were in favor of a recurrent VTE diagnosis. 
In addition, mean age was higher in patients with a confirmed recurrent VTE (p < 
0.05). Patients who had a previous DVT confirmed were at higher risk of having a 
recurrence confirmed at their next suspected event than when the previous event 
was a proven PE (p<0.05).  
 
This is the first study to show that predictors for the diagnosis of a recurrent VTE 
may be different than predictors for the diagnosis of a first VTE. For instance, our 
results show that male gender is not only a risk factor for recurrent VTE27, but is also 
an important predictor for confirmed VTE among patients with suspected recurrent 
VTE. None of the existing CDRs take gender into consideration. The main limitation 
of this analysis is that clinical information at the time of the suspected recurrence 
was extracted from patients‟ charts, and therefore is subject to bias, as the amount of 
clinical data in the case report form was limited. Nevertheless, the findings of this 
post-hoc analysis, along with the survey and literature review, support the need for a 
modified CDR specific to patients with a history of VTE. Improved diagnostic 

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management in this population would lead to more optimal clinical management and 
improved safety for these patients. 
 
1. STUDY OBJECTIVES 
1.1 
Primary Objective 
To assess the accuracy and usefulness of the Wells DVT, Wells PE and Geneva 
clinical decision rules (CDR) in patients with a clinically suspected recurrent Venous 
Thromboembolism (VTE). 
1.2 
Secondary Objectives 
 
To assess the utility of recalibrating the existing clinical decision rules.  
 
To derive a new CDR, specific to patients with a suspected recurrent VTE, and to 
assess whether this CDR would improve risk stratification as compared with 
existing CDRs. 
 
To assess the accuracy of D-dimer testing in patients with suspected recurrent 
VTE both on and off anticoagulation. 
 
To evaluate the accuracy of current CDRs in patients on anticoagulant therapy at 
the time of suspected recurrent VTE. 
3. STUDY DESIGN 
This is a multicentre, observational cohort study to prospectively identify potential 
predictors of recurrent VTE. The cohort consists of outpatients in the Thrombosis 
Clinic that are evaluated for suspected recurrent DVT and/or PE.  Diagnostic 
management of suspected recurrent VTE will be according to usual clinical practice; 
therefore all patients with suspected recurrent VTE will receive a diagnostic work–up 
as per local standards of care. All consecutive eligible patients will be approached for 
enrolment into this study. A total of 745 participants will be enrolled at Canadian 
sites. 
3.1 
Patient Safety 
This observational study poses minimal risk to participants. The study procedure 
consists of some additional questions and one follow-up call if the diagnosis is 
excluded. The risks associated with venipuncture (discomfort or bruising) are 
disclosed in the consent form. As per usual clinical care, all patients will be instructed 
on signs and symptoms of DVT and PE and advised to return to the hospital in case 
of any suspicion of a DVT or PE. As this is an observational study, adverse events 
will not be collected. 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
This study will be conducted at Canadian sites. Consecutive outpatients 
presenting to the Thrombosis Clinics of the participating hospitals with signs or 
symptoms suggestive of recurrent VTE will be screened for eligibility. 

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4.1 
Eligibility 
Eligibility status of all participants must be confirmed by the local investigator or 
designate before enrolment.  It is important that no exceptions be made to the 
eligibility criteria. Questions related to the eligibility requirements or specific criteria 
must be discussed with the coordinating centre before enrolment.  
 
4.2 
Inclusion Criteria 
Participants must meet all of the inclusion criteria to participate in this study. 
1) 
Outpatient with clinically suspected acute recurrent DVT or PE regardless of 
whether the previous event was a DVT or PE 
2) 
Age ≥18 years old 
3) 
Willing and able to give informed consent 
4.3 
Exclusion Criteria 
Participants who meet one or more of the exclusion criteria at baseline screening will 
be excluded from study participation. 
1) 
Life expectancy less than 3 months 
2) 
Suspicion of upper extremity thrombosis or thrombosis at an unusual site 
(e.g. cerebral or abdominal venous thrombosis) 
3) 
Previous VTE was distal DVT or subsegmental PE or at an unusual site 
4) 
Suspected recurrent VTE is asymptomatic 
5) 
Previously enrolled in this study 
 
4.3.1 Rationale for Exclusion Criteria 
 
1) precludes complete follow-up; 2) and 3) there are uncertainties surrounding the 
characteristics, diagnostic management, treatment and prognosis of these entities. 
Inter-observer agreement in imaging interpretation is lower, the risk of recurrent 
VTE appears to be much lower, and patients‟ management remains very 
heterogeneous; 4) uncertainties surrounding the clinical relevance of these 
findings; 5) prevents duplication of study data.  

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6. STUDY PROCEDURES  
Symptomatic presentation 
leads to assessment by 
Thrombosis Staff 
Eligible patients are 
approached for  
Informed Consent 
Baseline Assessment and 
Blood Sample 
VTE Negative  
VTE Positive  
 
Management as per 
treating physician 
 
Telephone follow-up 
90 ± 7 days 
 
Imaging for Suspected PE 
and/or DVT 
Figure 1: Study Flow 
 
6.1 
Screening and Consenting  
Potentially eligible patients will be identified by a healthcare professional according to 
institutional policy on privacy. The investigator or delegate will obtain written 
informed consent from the patient before collecting any data or performing any 
study-related procedures.  
Patients who meet the inclusion criterion, but who are excluded due to an exclusion 
criterion or who do not provide written consent will be recorded on a screening log.

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6.2 
Baseline Assessments and Diagnostic Management 
 
6.2.1 Clinical examination and data collection 
Once a patient has consented to participate, an investigator or attending physician 
will complete an assessment of suspected clinical predictors of recurrent VTE and 
will calculate the participant‟s clinical pretest probability using the existing CDRs. The 
diagnostic work-up of each participant will be handled in line with the current 
standard of care at the discretion of the treating physician. (For reference of the 
current standard practices, refer to Appendix C: Flow Chart of Suggested 
Diagnostic Approach for Assessing Suspected Recurrent VTEs)    
 
Data collection of clinical predictors will be completed by the investigator or delegate, 
by way of participant interview, reviewing medical records, and physical examination.  
(For a complete list of clinical predictors, refer to Appendix D: Collection of Clinical 
Predictors for Suspected Recurrent VTE).  Clinical notes and results of all diagnostic 
tests for suspicion of VTE, as well as the diagnostic conclusion and therapeutic 
management will be recorded for all patients. 
 
6.2.2 D-dimer testing 
All study patients will have a blood sample drawn at the time of suspected 
recurrence and frozen for central D-dimer testing.  Serum samples will also be stored 
for future potential predictor assessment (other D-dimer assays or other biomarkers). 
Samples will be shipped in batches to the coordinating site and D-dimer levels will be 
determined in all patients using a single commercial assay (VIDAS D-dimer 
Exclusion II, bioMérieux Inc, Durham, NC). Please refer to the resource manual for 
details on processing, storage and shipping of D-dimer samples.   
 
6.2.3 Imaging 
All imaging results will be recorded and kept in the patient‟s study folder. Confirmed 
recurrent VTE will be treated according to the standard of care at the local institution 
by the primary physician. 
 
Suspected DVT 
Current practice for patients with suspected recurrent DVT is to receive a 
compression ultrasound (CUS) of the symptomatic leg to confirm or exclude the 
diagnosis. CUS will assess venous compressibility of the proximal veins from the 
common femoral vein down to and including the calf vein trifurcation.   
 
Suspected PE 
Suspected recurrent PE is most commonly investigated by CT pulmonary angiogram 
(CTPA) and confirmed by an intraluminal filling defect in a subsegmental or greater 
pulmonary artery. Alternatively, a ventilation-perfusion (V/Q) lung scan will assess for 
a “high probability” perfusion defect.  
 
 
 

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6.3 
Follow-up Visits 
 
All patients in whom a recurrent VTE is ruled out will receive a follow-up call at 3 
months (90 ± 7 days) after the initial evaluation using a structured interview script.   
Research coordinators will be trained by the investigator or multicenter coordinator 
prior to follow-up to ensure consistency in eliciting new signs and symptoms of DVT 
and PE between sites. Any new leg or chest symptoms reported to study personnel 
during study follow-up will prompt clinical and diagnostic assessment.  Participants 
with suspected VTE will be assessed in the Thrombosis Clinic (or Emergency 
Department) and ordered diagnostic testing as judged necessary by their physician 
or the investigator.  If participants report that they sought medical attention for 
complaints of possible VTE, medical records and imaging results will be collected to 
prepare an adjudication report. Any participant who seeks medical attention during 
their follow-up period and is once again not diagnosed with a recurrent VTE will have 
an additional call at 90 (± 7 days) days after they were last assessed. 
 
All deaths during follow-up will prompt chart review and all available information 
including interviews with next of kin will be documented to permit preparation of an 
adjudication report to determine if the death is PE related. 
 
The follow-up period is relatively short and therefore participant loss to follow-up 
should be minimal. However, for participants that cannot be reached by phone, an 
exhaustive search will determine if outcome events have occurred (including calls to 
next of kin or pre-identified contacts, obituary searches, retrieval of death certificates, 
review local hospital databases) prior to participants being declared lost to follow-up. 
9. STATISTICAL CONSIDERATIONS  
9.2 
Sample Size Calculation 
Beyond our primary objective of validating existing CDRs, we aim at enrolling 
enough participants to allow the derivation of a new CDR specific to patients with 
suspected recurrent VTE, in order to assess whether such a new CDR could improve 
risk stratification in this patient population. As per accepted methodological criteria 
for the development of CDRs, 5-10 patients per predictor studied are required in the 
smallest outcome category.29 At this point, we don‟t know if we will be able to derive 
a single CDR for recurrent VTE or if deriving two separate CDRs for DVT and PE will 
be more useful. Our sample size estimation takes this uncertainty into account. We 
would like to be able to use up to 10 predictors for patients with suspected DVT with 
a history of VTE and separately up to 10 predictors for patients with suspected PE 
with a history of VTE; this means that the required study sample is 100 participants 
with a confirmed recurrent DVT and 100 participants with confirmed recurrent PE.  
 
In a study by Le Gal et al. for the diagnostic management of recurrent VTE, 26.6% of 
participants with suspected VTE had the diagnosis confirmed.11 In another paper 
40.3% of the participants with suspected PE with a history of VTE had their diagnosis 
confirmed.4  In the retrospective study that we performed as preparation for this 
prospective study, 29% of the participants with a suspected recurrent DVT had their 
recurrence confirmed and 25% of the participants with a suspected recurrent PE had 
the diagnosis confirmed.  
 

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For DVT, in order to be conservative, we used the percentage from our retrospective 
study, that is, 29%. That means that we need to enroll 345 participants with 
suspected recurrent DVT to have 100 participants with a confirmed recurrent DVT. 
For PE, using an estimate of a 25% confirmation rate we need 400 participants with 
a suspected recurrence to have 100 participants with confirmed PE.  Total sample 
size for the study is estimated at 745. 
 
If we consider that 15% of the potentially eligible participants approached for this 
study will be found to be ineligible or will not consent for this study, we need to 
screen 397 patients with a suspected recurrent DVT and 460 patients with a 
suspected recurrent PE for this study. Hence, to meet our total sample size of 745 
we will need to screen approximately 857 for eligibility. 
9.5 
Primary Outcome Analysis  
The primary analysis is the validation of existing CDRs. The Wells DVT score will be 
computed in all participants with suspected DVT, and both the Wells‟ PE score and 
revised Geneva score will be computed in participants with suspected PE. 
Calibration will be assessed by comparing predicted and observed rates of confirmed 
VTE (Hosmer-Lemeshow „goodness-of-fit test‟), and discrimination will be assessed 
using the area under the receiver operating characteristics curve (c-statistic). 
Further, the proportion of participants with the combination of a non-high clinical 
probability and negative D-dimer test, and the false-negative rate of this combination 
(ie the proportion of participants with confirmed recurrent VTE among those with a 
non-high clinical probability and negative D-dimer) will be estimated along with their 
95% confidence intervals. 
 
9.6 
Secondary Outcome Analysis 
9.5.1 Recalibration / minor adjustment to existing rules 
Recalibration 
For each existing CDR, a multivariate regression analysis including all predictors 
from the CDR will be conducted. The regression coefficients obtained from this 
model in our sample will be examined to evaluate whether changes in the points 
given to each predictor in the rule need to be modified in patients with a suspected 
recurrent VTE. 
 
Minor adjustments 
For each existing CDR, a multivariate regression analysis including all predictors 
from the CDR will be performed. Candidate predictors will also be included in the 
analysis, but keeping in the model predictors from the CDR. Should one or two 
candidate predictors significantly improve risk stratification, a modified score could 
be proposed for patients with suspected recurrent VTE. Potential improvements in 
classification will be assessed using the Net Reclassification Improvement and the 
Integrated Discrimination Improvement indices. 
 
9.5.2 Derivation of a new CDR 
Univariate Analysis 

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Univariate analysis will be used to assess the association between each variable and 
VTE recurrence. This process will aid selection of the best variables for the 
multivariate analysis. The appropriate univariate technique will be chosen according 
to the type of data. 
 
 
Multivariate Analysis 
Multivariate analysis will derive one model to predict recurrent VTE. Those variables 
found to be strongly associated with the outcome measure (P 0.05), by the 
univariate analysis and have good inter-observer reliability (kappa >0.6), will be 
combined using logistic regression. For continuous and ordinal variables various cut-
points will be examined to determine the optimal cut-point(s). The derived CDR must 
be easy to use by clinicians and therefore should contain as few variables as 
possible. Thus, only the most informative variables will be kept in the final model. 
Points for the score will be attributed according to regression coefficients. The CDR 
will be presented in clear narrative form that does not require computation or use of 
statistical aids. Discrimination and calibration of the new CDR will be estimated and 
compared to those obtained with existed/modified CDRs using the same indices as 
described above. 
 
9.5.3 D-dimer testing 
We will estimate what the proportion of participants will be with a non-high pre-test 
probability (using all the possible stratification tools described above) and negative 
D-dimer test result and in whom imaging could potentially be withheld. We 
furthermore will estimate what the false negative rate will be in this proportion of 
participants. These proportions will be computed along with their 95% confidence 
intervals. 
 
9.5.4 Participants treated with anticoagulant therapy 
Evaluate the accuracy and usefulness of CDR and D-dimer testing in participants 
with a suspected recurrent VTE who are receiving therapeutic anticoagulant therapy. 
 
9.5.5 Compare indeterminate imaging results in participants with and without 
available information about previous imaging 
We will compare the proportion of participants with indeterminate results in 
participants with and without available baseline imaging. We will assess how these 
participants were managed (treated vs. not treated). Of the participants who were not 
treated we will evaluate the 3 months VTE failure rate.  
 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
Data collection is the responsibility of the designated research study staff at the 
clinical centre under the supervision of the local Investigator. During the study, the 
Investigator must maintain complete and accurate documentation for the study. 
Study Case Report Forms (CRFs) are designed to record the disease status, 

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treatment, observations, follow-up and other pertinent data on each enrolled study 
participant. Participants will be identified by a unique study ID number. Data reported 
on the CRF derived from source documents must be consistent with the source 
documents. All source documents and laboratory reports must be reviewed by the 
designated research study staff at the participating clinical centre.  
10.2 Data Management  
Data management will be performed using a web-based system designed by the 
OHRI Data Management Services. Only trained research personnel from each site 
will have authorization with an access password to enter and modify electronic case 
report forms (eCRFs). The web based system functions with a secure server and 
backups will be done regularly. A user tracking system will track the date and time 
that users enter or modify data.  Once eCRFs are completed, data verification may 
result in additional requests to clarify the data.  
10.3 Retention of Study Records  
To enable future evaluations and audits, the local investigator must maintain 
confidential study documentation and ensure the retention of the study documents 
for a minimum of 10 years, as per OHRI, the sponsor. Study documents will include 
the identity of all study participants (sufficient information to link records, e.g., eCRFs 
and hospital records); all original signed Informed Consent Forms, and source 
documents.   
   
After a minimum of 10 years, all study documents will be destroyed (via incineration 
or shredding) at the local site. 
 
10.4 Quality Assurance  
 
Study related procedures must be conducted in compliance with the protocol, 
amendments, regulations and guidelines, in order to ensure data integrity.  Any 
deviations from the protocol will be accurately documented, reported and reconciled. 
 
Protocol deviations refer to incidents involving non-compliance with the protocol that 
are unlikely to have a significant impact on the on data integrity.  
 
If a protocol deviation occurs the following procedures will be followed: 
 
• 
The local investigator or delegate will document and explain any deviation 
from the approved protocol 
• 
Deviations from the protocol must be reported in the study source document 
• 
Deviations will be reviewed during monitoring visits. 
• 
A log of all deviations at the site must be maintained (ideally in an excel 
spreadsheet) 
 
As this is an observational study that does not affect patient safety, there will be no 
protocol violations to collect. 

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11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Research Ethics Board 
This study will be reviewed and approved by the Ottawa Health Science Network 
Research Ethics Board before commencement of the study. Each participating site 
must also obtain Ethics Board approval before study initiation. Annual ongoing 
review will also be performed. Any amendment to the protocol or informed consent 
form must be approved by the local Research Ethics Board before implementation.  
11.2 Informed Consent Forms 
Prior to inclusion in the study, the investigator, or his designee, will provide each 
participant (or the participant‟s acceptable representative), full and adequate verbal 
and written information regarding the objectives and procedures of the study and the 
possible risks involved.  The participants must be informed about their right to 
withdraw from the study at any time.  Written participant information will be given to 
each participant before enrolment.  The investigator or his designee will obtain 
signed informed consent (or witnessed verbal consent according to applicable 
regulations) from all participants prior to inclusion in the study. 
11.3 Participant Confidentiality  
To protect the participant‟s confidentiality, source documents containing personal 
identifiers and informed consent forms will be kept separate from research notes 
and worksheets. Case report forms will not contain any identifying information. The 
identification log which links the identification of the participant to the assigned 
participant code will, according to local policy, be kept in a cabinet under lock and 
key or on a secure electronic drive. 
12. STUDY ORGANIZATION 
12.1 Study Coordination 
The study will be coordinated through the Thrombosis Research Program, Ottawa 
Hospital Research Institute (OHRI), located at The Ottawa Hospital General Campus 
in Ottawa, Ontario. The multicentre coordinator, under the direction of the study 
Principal Investigator, Dr. Gregoire Le Gal, will be responsible for the overall study 
management including implementation of study protocol logistics, data management, 
and quality assurance related to study data. Local coordinators and site investigators 
will work together to screen, recruit, and follow study participants. Each co-
investigator will be responsible for the conduct of the study at their respective sites. 
12.2 Central Independent Adjudication Committee (CIAC) 
All cases of confirmed VTE will be adjudicated by independent adjudicators. The 
results of all imaging tests performed at the time of suspected recurrent VTE will be 
compared with the patient‟s previous imaging, baseline or index, when available, and 
will be performed according to the predefined definitions (Refer to Appendix E: 

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Adjudication of Suspected Recurrent VTE Events). The adjudicators will confirm or 
refute suspected recurrent DVT and PE events. 
 
The adjudication committee will also evaluate secondary outcomes including all 
suspected VTE events and deaths occurring during the 90 (±7) day follow-up period. 
The adjudication results will be the basis for the final analysis. 
12.3 Steering Committee 
A Steering Committee consisting of the study co-investigators will manage the 
overall conduct of the study and will meet regularly via teleconference or face to face 
meetings to monitor study progress, execution, management, analysis and reporting. 
 
 
 

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14. REFERENCES  
 
1) Goodacre S, Sutton AJ, Sampson FC. Meta-analysis: The value of clinical assessment 
in the diagnosis of deep venous thrombosis. Ann Intern Med 2005;143:129-139. 
 
2) Wells PS, Ginsberg JS, Anderson DR et al. Use of a clinical model for safe management 
of patients with suspected pulmonary embolism. Ann Intern Med 1998;129:997-1005. 
 
3) Wicki J, Perneger TV, Junod AF, Bounameaux H, Perrier A. Assessing clinical 
probability of pulmonary embolism in the emergency ward: a simple score. Arch Intern 
Med 2001;161:92-97. 
 
4) Le Gal G, Righini M, Roy PM et al. Value of D-dimer testing for the exclusion of 
pulmonary embolism in patients with previous venous thromboembolism. Arch Intern 
Med 2006;166:176-180. 
 
5) Wells PS, Anderson DR, Rodger M et al. Derivation of a simple clinical model to 
categorize patients probability of pulmonary embolism: increasing the models utility with 
the SimpliRED D-dimer. Thromb Haemost 2000;83:416-420. 
 
6) Kruip MJ, Leclercq MG, van der Heul C, Prins MH, Buller HR. Diagnostic strategies for 
excluding pulmonary embolism in clinical outcome studies. A systematic review. Ann 
Intern Med 2003;138:941-951. 
 
7) Wells PS, Anderson DR, Rodger M et al. Evaluation of D-dimer in the diagnosis of 
suspected deep-vein thrombosis. N Engl J Med 2003;349:1227-1235. 
 
8) van Belle A, Buller HR, Huisman MV et al. Effectiveness of managing suspected 
pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, 
and computed tomography. JAMA 2006;295:172-179. 
 
9) Anderson DR, Wells PS, Kovacs MJ, Rodger M, McCarron B, Robinson S. Management 
of patients with suspected recurrent deep vein thrombosis using clinical probability and 
D-dimer [abstract]Anderson DR, Wells PS, Kovacs MJ, Rodger M, McCarron B, 
Robinson S. Blood 2001;98:1878. 
 
10) Carrier M, Righini M, Djurabi RK et al. VIDAS D-dimer in combination with clinical pre-
test probability to rule out pulmonary embolism. A systematic review of management 
outcome studies. Thromb Haemost 2009;101:886-892. 
 
11) Le Gal G, Kovacs MJ, Carrier M et al. Validation of a diagnostic approach to exclude 
recurrent venous thromboembolism. J Thromb Haemost 2009;7:752-759. 
 
12) Hamadah A, Alwasaidi T, Le Gal G et al. Baseline imaging after therapy for unprovoked 
venous thromboembolism: a randomized controlled comparison of baseline imaging for 
diagnosis of suspected recurrence. J Thromb Haemost 2011;9:2406-2410. 
 
13) Tan M, Velthuis SI, Westerbeek RE, van Rooden CJ, van der Meer FJ, Huisman MV. 
High percentage of non-diagnostic compression ultrasonography results and the 

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diagnosis of ipsilateral recurrent proximal deep vein thrombosis. J Thromb Haemost 
2010;8:848-850. 
 
14) Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral 
anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 
2003;139:893-900. 
 
15) Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of 
recurrent venous thromboembolism and major bleeding events among patients treated 
for venous thromboembolism. Ann Intern Med 2010;152:578-589. 
 
16) Kahn SR. Frequency and determinants of the postthrombotic syndrome after venous 
thromboembolism. Curr Opin Pulm Med 2006;12:299-303. 
 
17) Galanaud JP, Holcroft CA, Rodger MA et al. Comparison of the Villalta post-thrombotic 
syndrome score in the ipsilateral vs. contralateral leg after a first unprovoked deep vein 
thrombosis. J Thromb Haemost 2012;10:1036-1042. 
 
18) Kahn SR, Shrier I, Julian JA et al. Determinants and time course of the postthrombotic 
syndrome after acute deep venous thrombosis. Ann Intern Med 2008;149:698-707. 
 
19) Aguilar C, del Villar, V. Combined D-dimer and clinical probability are useful for 
exclusion of recurrent deep venous thrombosis. Am J Hematol 2007;82:41-44. 
 
20) Rathbun SW, Whitsett TL, Raskob GE. Negative D-dimer result to exclude recurrent 
deep venous thrombosis: a management trial. Ann Intern Med 2004;141:839-845. 
 
21) Wells PS, Anderson DR, Bormanis J et al. Value of assessment of pretest probability of 
deep-vein thrombosis in clinical management. Lancet 1997;350:1795-1798. 
 
22) Klok FA, Tijmensen JE, Haeck ML, van Kralingen KW, Huisman MV. Persistent dyspnea 
complaints at long-term follow-up after an episode of acute pulmonary embolism: results 
of a questionnaire. Eur J Intern Med 2008;19:625-629. 
 
23) Kruip MJ, Leclercq MG, van der Heul C, Prins MH, Buller HR. Diagnostic strategies for 
excluding pulmonary embolism in clinical outcome studies. A systematic review. Ann 
Intern Med 2003;138:941-951. 
24) Douma RA, Le Gal G, Sohne M et al. Potential of an age adjusted D-dimer cut-off value 
to improve the exclusion of pulmonary embolism in older patients: a retrospective 
analysis of three large cohorts. BMJ 2010;340:c1475. 
 
25) Chan WS, Lee A, Spencer FA et al. D-dimer testing in pregnant patients: towards 
determining the next 'level' in the diagnosis of deep vein thrombosis. J Thromb Haemost 
2010;8:1004-1011. 
 
26) Rodger MA, Kahn SR, Wells PS et al. Identifying unprovoked thromboembolism patients 
at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 
2008;179:417-426. 
 
27) McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of patient's sex on risk of 
recurrent venous thromboembolism: a meta-analysis. Lancet 2006;368:371-378. 

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28) Kearon C, Ginsberg JS, Douketis J et al. A randomized trial of diagnostic strategies after 
normal proximal vein ultrasonography for suspected deep venous thrombosis: D-dimer 
testing compared with repeated ultrasonography. Ann Intern Med 2005;142:490-496. 
 
29) Wasson JH, Sox HC, Neff RK, Goldman L. Clinical prediction rules. Applications and 
methodological standards. N Engl J Med 1985;313:793-799. 
 
30) Wells PS, Hirsh J, Anderson DR et al. Accuracy of clinical assessment of deep-vein 
thrombosis. Lancet 1995;345:1326-1330. 
 
31) Anderson DR, Kahn SR, Rodger MA et al. Computed tomographic pulmonary 
angiography vs ventilation-perfusion lung scanning in patients with suspected pulmonary 
embolism: a randomized controlled trial. JAMA 2007;298:2743-2753. 
 
32) Righini M, Le Gal G, Aujesky D et al. Diagnosis of pulmonary embolism by multidetector 
CT alone or combined with venous ultrasonography of the leg: a randomised non-
inferiority trial. Lancet 2008;371:1343-1352. 
 
33) Flack VF, Afifi AA. Sample size determinations for the two rater kappa statistic. 
Psychometrica 1988;53:321-325. 
 
34) Stiell IG, Wells GA. Methodologic standards for the development of clinical decision 
rules in emergency medicine. Ann Emerg Med 1999;33:437-447. 
 
 
 
 

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15. APPENDICES 
 
Appendix A: Current Clinical Decision Rule for Suspected DVT 
 
 
Wells Rule for Suspected DVT 
 
Clinical characteristics 
Points 
Active cancer (patient receiving treatment for cancer within the previous 
6 mo or currently receiving palliative treatment) 
 
+ 1 
Paralysis, paresis, or recent plaster immobilization of the lower 
extremities 
 
+ 1 
Recently bedridden for 3 days or more, or major surgery within the 
previous 12 wk requiring general or regional anaesthesia 
 
+ 1 
Localized tenderness along the distribution of the deep venous system  
+ 1 
 
Entire leg swollen  
 
+ 1 
 
Calf swelling at least 3 cm larger than that on the asymptomatic side 
(measured 10 cm below tibial tuberosity) 
 
+ 1 
 
Pitting edema confined to the symptomatic leg  
 
+ 1 
 
Collateral superficial veins (nonvaricose) 
 
+1 
 
Previously documented deep-vein thrombosis  
 
+1 
 
Alternative diagnosis at least as likely as deep-vein thrombosis 
 
–2 
Total score 
< 2 points 
> 2 points 
Clinical probability 
   DVT unlikely 
   DVT likely 
Prevalence of DVT 
5.5 % (95%CI: 3.8 to 7.6%) 
27.9 % (95%CI: 23.9 to 31.8%) 
 
 
 

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Appendix B: Current Clinical Decision Rules for Suspected PE 
 
Wells Rule for Suspected PE 
 
 
Wells score  
 
Revised Geneva score 
Active cancer 
+ 1 
 Age > 65 years 
+ 1 
Hemoptysis 
+ 1 
 Active cancer 
+ 2 
History of previous DVT or PE 
+ 1,5 
 Hemoptysis 
+ 2 
Heart rate > 100 /min 
+ 1,5 
 History of previous DVT or PE 
+ 3 
Surgery or bedrest > 3 days within 1 
month 
+ 1,5 
 Surgery or lower limb fracture within 
one  month 
+ 2 
Clinical signs or symptoms of DVT 
+ 3 
 Unilateral edema and pain at palpation 
+ 4 
No alternative diagnosis as or more 
likely than PE 
+ 3 
 Spontaneously reported calf pain 
+ 3 
 Heart rate 
 
    75-94 / min 
+ 3 
> 95 / min 
+ 5 
Clinical 
Probability 
Low 
Total 
Score 
< 2 
Prevalence of 
PE 
 
5.7 (3.7-8.2) 
 
Clinical 
Probability 
Low 
Total 
Score 
0-3 
Prevalence of PE 
 
9.0 (7.6-10.6) 
Intermediate 
2-6 
23.2 (18.3-28.4) 
 
Intermediate 
4-10 
26.2 (24.4-28.0) 
High 
> 6 
49.3 (42.6-56.0) 
 
High 
> 11 
75.7 (69.0-81.8) 
Unlikely 
< 4 
8.4 (6.4-10.6) 
 
 
Likely 
> 4 
34.4 (29.4-39.7) 
 
 
 
 
 

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Appendix C: Flow Chart of Suggested Diagnostic Approach for Assessing 
Suspected Recurrent VTEs 
 
 
 
On anticoagulant? 
Yes 
No 
 PTP Assessment 
 D-dimer 
 INR if on  Coumadin 
 PTP Assessment 
 D-dimer 
PTP likely and/or 
positive D-dimer 
PTP unlikely and 
negative D-dimer 
Recurrent VTE 
excluded 
- No imaging 
Suspicion at same 
site as last event? 
No 
Yes 
No 
Yes 
Prior imaging 
available? 
Standard 
diagnostic 
algorithm? 
 Do same test (CUS, 
CT/VQ) 
 Comparison with prior  
New vein segment / 
pulmonary artery involved 
- Recurrent VTE  diagnosed 
Unchanged, improved or 
negative 
- Recurrent VTE  excluded 
- Serial imaging? 
Suspicion of Recurrent VTE 

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Appendix D: Collection of Clinical Predictors for Suspected Recurrent VTE 
 
 
Presenting history  
Age 
Gender 
Duration of symptoms (days) 
Inpatient/outpatient  
Any dyspnea 
Sudden dyspnea 
Any chest pain 
Pleuritic chest pain 
Sudden chest pain 
Hemoptysis 
Affected leg: left/right 
Leg pain 
Cramps in the leg 
Pruritus of the leg 
Heaviness of the leg 
Paraesthesia of the leg 
Symptoms worse after walking and standing 
Symptoms worse at end of the day 
Symptoms best first thing in morning 
Symptoms improve with rest or elevating leg 
Symptoms worse after prolonged standing (>2 h, > 6 h) 
Symptoms relieved after elevating leg 
Symptoms relieved with compression stockings 
Current use of anticoagulant therapy 
Type and dose of anticoagulant therapy (e.g. LMWH, warfarin, NOACs) 
Anxious personality 
 
Risk factors 
Family history of VTE (first and second degree) 
Known thrombophilia 
Pregnancy 
Post-partum (<6 weeks after delivery) 
Recent surgery (< 4 weeks, 8 weeks, 12 weeks) 
Orthopedic surgery (< 4 weeks, 8 weeks, 12 weeks) 
Active malignancy (< 6 months; malignancy required therapy, recurrent or metastatic, 
palliative) 
Recent immobilization (< 10% walking hours for 3 consecutive days < 4 weeks, 8 
weeks, 12 weeks) 
Major trauma (< 4 weeks, 8 weeks, 12 weeks) 
Congestive heart failure 

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Estrogen use 
Paralysis of the leg 
Paresis of the leg 
Recent plaster cast (< 4 weeks, 8 weeks, 12 weeks) 
Long distance flight (< 4 h, < 8 hours, < 12 hours, 12 hours and more), within 4 weeks, 
8 weeks and 12 weeks 
 
Characteristics of previous event and period between current and previous 
event 
Number of previous events 
Previous event: DVT/PE 
Provoked/unprovoked 
Time between previous event and current suspected recurrence 
Location of previous event (in case of PE: central, lobar, segmental, subsegmental) 
Location of previous event (in case of DVT: proximal, distal) 
In case of DVT, affected leg (left/right) 
Duration of anticoagulation  
Type of anticoagulation (e.g. UFH, LMWH, warfarin, NOACs) 
Previous use of compression stockings 
Current use of compression stockings 
Duration of use of compression stockings 
Residual thrombosis present on baseline imaging  
D-dimer test result after stopping anticoagulation  
 
Physical examination 
Height 
Weight 
O2 Saturation 
Heart rate 
Respiratory rate 
Temperature 
Systolic blood pressure 
Diastolic blood pressure 
Crackles 
Swelling of the whole leg 
Redness of the leg 
Warmth of the leg 
Calf pain 
Calf diameter of symptomatic leg 
Calf diameter of asymptomatic leg 
Superficial vein dilatation of the leg 
Localized tenderness along the deep venous system 
Pitting edema 
Telangiectasia 
Erythema 
Varicose veins 

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Pigmentation 
Eczema 
Lipodermatosclerosis 
Pretibial edema 
 
ECG changes 
ST changes 
T wave changes 
 
Chest x- ray 
Parenchymal change 
Band atelectasis 
Elevation of hemidiaphragm 
 
Laboratory test 
D-dimer test 
INR 
INR values over the last 4 weeks 
CRP (C-reactive protein) 
pro – BNP (Brain natriuretic peptide) 
 
Physician impression 
Likelihood of recurrent DVT(%) 
Likelihood of recurrent PE (%) 
Another diagnosis more likely 
 
Patient impression 
Patient recognizes the symptoms from previous event(s) 
 
 

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Appendix E: Adjudication of Suspected Recurrent VTE Events 
 
 
Recurrent VTE  
Recurrent VTE will be excluded if participants have a low/intermediate or unlikely pre-
test clinical probability with the Geneva or Wells rule and a negative D-dimer test result. 
 
Recurrent Deep Vein Thrombosis 
Recurrent DVT will be ruled out if participants have a normal ultrasound (fully 
compressible veins) or an unchanged/improved incompressible segment as 
compared with baseline when available. 
 
The criteria for diagnosis of recurrent DVT will be: 
 
1. 
Compression ultrasound revealing a new (compared to baseline/index 
ultrasound) area of non compressibility of a venous segment above the 
trifurcation of the popliteal vein will be considered diagnostic of a deep vein 
thrombosis. 
-OR- 
2. 
Venography demonstrating a constant intraluminal filling defect in the deep 
veins above the trifurcation of the popliteal vein will be considered diagnostic 
of a deep vein thrombosis.  
 
Recurrent Pulmonary Embolism 
1. If the V/Q scan is normal or unchanged from baseline/index imaging, PE will 
be considered excluded.  
2. If the V/Q scan is non-normal and a new unmatched segmental or greater 
perfusion defect is documented then recurrent PE will be diagnosed.  
3. If a new matched or subsegmental perfusion defect is documented the test 
won‟t be considered positive for PE.  
4. If participants receive a spiral CT scan and an intraluminal filling defect is 
seen in a segmental or greater vessel that was previously free of thrombus, 
pulmonary embolism is diagnosed. If the CT scan is normal or unchanged as 
compared with baseline, PE will be considered excluded. 
5. Pulmonary angiography demonstrating a constant intraluminal filling defect or 
a cutoff of a vessel > 2.5 mm in diameter will be considered diagnostic for PE.  
 
Death 
All deaths during follow-up will be adjudicated as to the likelihood that the death was 
related to PE. The following criteria will be used: Certain: hypotension, hypoxia, cardiac 
arrest with no other explanation than PE, autopsy or radiographic confirmation; Highly 
probable: criteria for certain but another disease could have caused the death; 
Probable: other cause suspected based on clinical evidence but 100% certainty not 
available; Unlikely: all other cases.