Ten-year trends in iliofemoral deep vein thrombosis treatment and referral pathways

Abstract

Objectives

Iliofemoral deep venous thrombosis is associated with an increased risk of developing post-thrombotic syndrome resulting in reduced quality of life. As there is debate about best management practices, this study aimed to examine the referral and treatment pathways for patients presenting with iliofemoral deep venous thrombosis over an 11-year period at our institution.

Methods

We conducted a retrospective review of patients diagnosed with lower limb deep vein thrombosis between 2010 and 2020. Ultrasound report findings were reviewed for the presence of iliofemoral deep venous thrombosis with acute, occlusive, or proximal clot. Multiple factors were extracted, including patient demographics, risk factors, diagnostic methods, interventions, referrals, and details of follow-up. The CaVenT and ATTRACT trials studied the benefit of thrombolysis in the early phase of iliofemoral deep venous thrombosis management as compared to anticoagulation alone. An analysis was conducted of patients requiring thrombolysis to determine whether these trials impacted physician practice patterns for thrombolysis. Data were organized and examined by year for trends in treatment and referral pathways.

Results

The review yielded 2792 patients assessed for lower limb deep venous thrombosis by ultrasound. Four hundred and sixty-seven (16.7%) patients were confirmed to have an occlusive iliofemoral deep venous thrombosis. The average age was 62.7 years (18–101 years). Half (50.4%) of the patients were male. The most common etiology for clot was malignancy-induced hypercoagulable state (39.0%). There was no difference in incidence of iliofemoral deep venous thrombosis diagnosed by ultrasound per year, with an average of 42.5 per year and a peak of 61. There was a trend towards increased rates of computed tomography imaging, ranging between 9.1% and 52.9%. The rate thrombolysis per year ranged between 1.8% and 8.9%, with a range of 4.3% (n = 20) to 8.9% (n = 5) in 2018. The use of pharmacomechanical thrombolysis increased, from 25% (n = 1) in 2010–2012 to 87.5% (n = 7) in 2018–2020. The rate of inferior vena cava filter insertion alone decreased from 18.2% in 2010 (n = 4) to 5.9% (n = 1) in 2020. The length of thrombolysis treatment also decreased, from 100% of patients (n = 4) receiving treatment duration greater than 24 h in 2010–2012 to 0% (n = 0) in 2018–2020. About 45% of patients receiving thrombolysis (n = 9) had venous stenting. No difference in treatment outcomes were observed, with greater than 87.5% of patients reaching intermediate to full resolution of clot burden. No patients experienced intracranial hemorrhage.

Conclusions

The results of this analysis highlight the change in practice in our institution over time. The low rate of intervention likely reflects the current lack of consensus in published guidelines. It is important for future work to elicit the most appropriate management pathways for patients with iliofemoral deep venous thrombosis.

Keywords

Deep vein thrombosis iliofemoral post-thrombotic syndrome thrombolysis management referral

Introduction

Deep vein thrombosis (DVT) is a major global health concern associated with disabling long-term vascular sequelae that are costly to manage. As more than 50% of those affected are of working age, long-term disability poses significant economic burden.¹ Despite appropriate medication, 20–50% of DVT patients subsequently develop post-thrombotic syndrome (PTS) within two years, with 5–10% experiencing moderate–severe symptoms.² PTS is a chronic, debilitating spectrum of disease severity, ranging from mild swelling to disabling leg ulcers, associated with significant morbidity and no curative options.^2,3 The open vein hypothesis posits that early clot elimination with subsequent restoration of venous flow reduces the risk of developing PTS after DVT.⁴

Patients with iliofemoral DVT (IFDVT) are an important subgroup, as proximal location has been found to be the strongest predictor of developing PTS and recurrent DVT, resulting in reduced quality of life (QOL).⁵ There is controversy about best management practices for IFDVT. Conventional management has involved anticoagulation, which effectively reduces the risk for subsequent pulmonary embolism (PE) or thrombus propagation, recurrent venous thromboembolism (VTE), and death; however, as the clot is not removed, venous damage following DVT is not prevented, thus the risk for PTS after six months of anticoagulation remains at 40–60%.¹ Thrombolysis demonstrates advantage over anticoagulation as it involves actively breaking down clot and restoring venous patency. A variety of catheter-based endovascular techniques exist, including catheter-directed thrombolysis (CDT), pharmacomechanical CDT (PCDT), and percutaneous mechanical thrombectomy (PMT). Data from randomized clinical trials are limited and two landmark studies, the CaVenT trial and the more recent ATTRACT trial, have shown conflicting results that thrombolysis in the early phase of IFDVT has an advantage over anticoagulation alone in terms of the development of long-term PTS.^6,7

Management of IFDVT is challenging, as there is a need to balance the risks of more invasive intervention with the benefits of improving QOL and reducing PTS and recurrent DVT. At present, there is limited literature studying rates of thrombolysis or the impact of the landmark CaVenT and ATTRACT trials on physician practice patterns and awareness of thrombolysis in managing patients with IFDVT. This study aims to examine the patterns of treatment and referral pathways for patients who present with IFDVTs over an 11-year period at our institution, and to ascertain the impact of the CaVenT and ATTRACT trials.

Methods

We conducted a retrospective review of a single-center database of patients who were diagnosed with lower limb DVT between January 2010 and May 2020. The majority (97.4%) of patients referred for US had presented with symptoms concerning for VTE and ultrasound (US) was performed in searching for an embolic source. A minority (2.6%) had an incidental finding of lower limb DVT after undergoing radiographic investigation for another indication. USs were performed by registered vascular technologists in an accredited vascular lab and reports signed off by vascular surgeons or interventional radiologists.

US report findings were reviewed for presence of IFDVT, defined as proximal clot in the iliac (external and internal) veins or common femoral vein.⁸ Patients with acute, occlusive, proximal clot were included, and excluded if they had chronic, nonocclusive, distal or superficial clot, inconclusive findings, or upper limb DVT. The study received local ethics board approval.

Of those patients identified, multiple factors were extracted from electronic medical records, including patient demographics (age, gender) and most significant etiology (idiopathic, malignancy, surgery, thrombophilia, anatomic). Referral pathways were examined to ascertain physician practice patterns and awareness of thrombolysis in managing patients with IFDVT. This included data on diagnostic methods used (computed tomography (CT), magnetic resonance imaging (MRI), angiography), their findings, interventions (thrombolysis, inferior vena cava (IVC) filter insertion), referrals (thrombosis clinic, Vascular Service), and details of follow-up (use of elastic compression stockings (ECS), long-term symptoms) to determine whether their rates changed in response to notable trial publications. In our institution, a dedicated thrombosis clinic, staffed by hematologists, fellows, and nurse practitioners is available to investigate and manage patients with newly diagnosed DVT. Patients are reviewed within 72 h of referral and those considered for thrombolysis are referred to the Vascular Service for evaluation. Decision-making regarding thrombolysis suitability involved thrombus acuity, symptom severity, and patient factors, such as age and fitness. Data were organized and examined by year for trends in treatment and referral pathways.

The presence of PTS and symptom severity was gathered from patient subjective report in the follow-up appointment documentation. As the CaVenT and ATTRACT trials studied the benefit of thrombolysis in the early phase of IFDVT management as compared to anticoagulation alone, an analysis was conducted to determine whether these trials impacted physician practice patterns for thrombolysis. Data were organized into three groups: 2010–2012, prior to publication of any randomized trials of CDT for DVT; 2013–2017, after publication of the CaVenT trial; and 2018–2020, after publication of the ATTRACT Trial. This analysis was completed by a retrospective review of records for the type of thrombolysis used (catheter-directed, pharmacomechanical using the Angiojet device, or both), treatment length, whether or not stenting was performed, and treatment outcome.

Results

Baseline demographics and risk factors

US data from 2010 to 2020 yielded 2792 patients that were assessed for lower limb DVT by US. Of these, 556 (19.9%) patients were confirmed to have occlusive IFDVT. Eighty-nine (3.2%) had inaccessible medical records, resulting in 467 patients (16.7%) confirmed to have IFDVT by US comprising the study cohort (Figure 1). The study population had an average age of 62.7 years (R = 18–101 years) and was evenly divided between males and females (236 males (50.4%) and 232 females (49.6%)). The most common etiology for clot was malignancy-induced hypercoagulable state (39.0%), followed by idiopathic (31.0%), thrombophilia (15.4%), surgery (11.6%), and anatomic (3.0%). Of thrombophilic etiologies, acquired (12.4%) were more common than genetic (3.0%). Thirty-three patients (7.1%) had greater than one risk factor. Details can be found in Table 1.

Figure 1.

Consort diagram for patients included in study.

Table 1.

Demographics and risk factors.

Demographics	n = 467
Age (years)	62.7 (18–101)
Gender
Male	236 (50.4%)
Female	232 (49.6%)
Etiology (most significant)	n = 467 (%)
Idiopathic	145 (31.0)
Malignancy	182 (39.0)
Surgery	54 (11.6)
Thrombophilia	72 (15.4)
Genetic	14 (3.0)
Active connective tissue disease/autoimmune	3 (0.6)
Antiphospholipid antibody syndrome	3 (0.6)
Factor V Leiden heterozygosity	4 (0.9)
Protein S deficiency	3 (0.6)
Sickle cell	1 (0.2)
Acquired	58 (12.4)
Flight	3 (0.6)
HIT	1 (0.2)
Immobility d/t hospitalization, medical disorder, trauma	51 (10.9)
Pregnancy/ postpartum	3 (0.6)
Anatomical	14 (3.0)
Congenital abnormality vasculature	1 (0.2)
Fibroids (compressing vasculature)	5 (1.1)
Line (dialysis, femoral)	2 (0.4)
Lymphocele compressing vasculature	1 (0.2)
May–Thurner syndrome	3 (0.6)
Post-operative distortion pelvic vasculature	1 (0.2)
Retroperitoneal fibrosis	1 (0.2)
>1 risk factor	33 (7.1)

Management

Investigations

Over the duration of study, there was no difference in the incidence of IFDVT diagnosed by US per year, with an average of 42.5 per year with a peak of 61 in 2017 (Table 2). There was an increase in usage rates of CT imaging, from a low of 2 (9.1%) in 2010 to a high of 9 (52.9%) in 2020. This constituted a greater than 10% increase in patients receiving CT scans in the 2018–2020 group as compared to the 2010–2012 group (Table 3). However, no patients underwent a CT scan as a primary diagnostic investigation for DVT. There was no difference in the use of MRI. Following CT, 17.8% (n = 83) of patients were diagnosed with a PE over the duration of study. Nearly one quarter (22.9%, n = 19) of CT scans demonstrating PE were performed in conjunction with US for IFDVT as part of a diagnostic workup for VTE; this percentage of CT scans increased over time, with a greater than 5% increase in the 2018–2020 group when compared to the 2010–2012 group. A small number (1.3%, n = 6) of patients were diagnosed with the extension of clot on CT.

Table 2.

Management results by year.

	All	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019	2020
IFDVT diagnosed on US	467 (100%)	22 (4.7%)	45 (9.6%)	44 (9.4%)	48 (10.3%)	44 (9.4%)	56 (12.0%)	33 (7.1%)	61 (13.1%)	56 (12.0%)	41 (8.8%)	17 (3.6%)
Investigations	n = 467 (%)	n = 22 (%)	n = 45 (%)	n = 44 (%)	n = 48 (%)	n = 44 (%)	n = 56 (%)	n = 33 (%)	n = 61 (%)	n = 56 (%)	n = 41 (%)	n = 17 (%)
CT	119 (25.5)	2 (9.1)	11 (24.4)	9 (20.5)	11 (22.9)	11 (25.0)	15 (26.8)	12 (36.4)	13 (21.3)	13 (25.0)	13 (31.7)	9 (52.9)
PE alone	83 (17.8)	1 (4.5)	9 (20)	6 (13.6)	7 (14.6)	8 (18.1)	9 (16.1)	8 (24.2)	11 (18.0)	13 (23.2)	5 (12.2)	6 (35.3)
Extension clot alone	6 (1.3)	0 (0)	1 (2.2)	1 (2.3)	0 (0)	0 (0)	1 (1.8)	0 (0)	1 (1.6)	0 (0)	2 (4.9)	0 (0)
Both	1 (0.2)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (2.4)	0 (0)
No additional findings beyond DVT	29 (6.2)	1 (4.5)	1 (2.2)	2 (4.5)	4 (8.3)	3 (6.8)	5 (8.9)	4 (12.1)	1 (1.6)	0 (0)	5 (12.2)	3 (17.6)
MRI	1 (0.2)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1.8)	0 (0)	0 (0)
PE	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Extension	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Both	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
No findings	1 (0.2)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1.8)	0 (0)	0 (0)
Neither	347 (74.3)	20 (90.9)	34 (75.6)	35 (79.5)	37 (77.1)	33 (75.0)	41 (73.2)	21 (63.6)	48 (78.7)	42 (75.0)	28 (68.3)	8 (47.1)
Angiography	n = 467 (%)	n = 22 (%)	n = 45 (%)	n = 44 (%)	n = 48 (%)	n = 44 (%)	n = 56 (%)	n = 33 (%)	n = 61 (%)	n = 56 (%)	n = 41 (%)	n = 17 (%)
Thrombolysis	20 (4.3)	1 (4.5)	2 (4.4)	1 (2.3)	1 (2.1)	3 (6.8)	1 (1.8)	1 (3.0)	2 (3.3)	5 (8.9)	2 (4.9)	1 (5.9)
tPA alone	16 (3.4)	0 (0)	1 (2.2)	1 (2.3)	1 (2.1)	3 (6.8)	0 (0)	1 (3.0)	2 (3.3)	4 (7.1)	2 (4.9)	1 (5.9)
tPA and IVC filter	4 (0.9)	1 (4.5)	1 (2.2)	0 (0)	0 (0)	0 (0)	1 (1.8)	0 (0)	0 (0)	1 (1.8)	0 (0)	0 (0)
IVC filter insertion alone	37 (7.9)	4 (18.2)	3 (6.7)	4 (9.1)	1 (2.1)	2 (4.5)	6 (10.7)	5 (15.2)	4 (6.6)	4 (7.1)	3 (7.3)	1 (5.9)
Neither	411 (88.0)	17 (77.3)	40 (88.9)	39 (88.6)	46 (95.8)	39 (88.6)	50 (89.3)	27 (81.8)	55 (90.2)	47 (83.9)	36 (87.8)	15 (88.2)
Declined tPA	2 (0.4)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	2 (3.3)	0 (0)	0 (0)	0 (0)
Referred to vascular but not tPA candidate	12 (2.6)	0 (0)	0 (0)	0 (0)	2 (4.2)	0 (0)	0 (0)	0 (0)	1 (1.6)	1 (1.8)	6 (14.6)	2 (11.8)
Thrombolysis	n = 20 (%)	n = 1 (%)	n = 2 (%)	n = 1 (%)	n = 1 (%)	n = 3 (%)	n = 1 (%)	n = 1 (%)	n = 2 (%)	n = 5 (%)	n = 2 (%)	n = 1 (%)
Length Tx
<1 h	4 (20.0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (100)	1 (50.0)	2 (40.0)	0 (0)	0 (0)
12 h	7 (35.0)	0 (0)	0 (0)	0 (0)	0 (0)	2 (66.7)	0 (0)	0 (0)	0 (0)	3 (60.0)	1 (50.0)	1 (100)
24 h	4 (20.0)	0 (0)	2 (100)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (50.0)	0 (0)	1 (50.0)	0 (0)
36 h	1 (5.0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (100)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
48 h	4 (20.0)	1 (100)	0 (0)	1 (100)	1 (100)	1 (33.3)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Stent
Yes	9 (45.0)	1 (100)	0 (0)	0 (0)	0 (0)	1 (33.3)	0 (0)	1 (100)	2 (100)	4 (80.0)	0 (0)	0 (0)
No	11 (55.0)	0 (0)	2 (100)	1 (100)	1 (100)	2 (66.7)	1 (100)	0 (0)	0 (0)	1 (20.0)	2 (100)	1 (100)
Resolution
Full	13 (65.0)	0 (0)	2 (100)	1 (100)	0 (0)	1 (33.3)	0 (0)	1 (100)	2 (100)	4 (80.0)	1 (50.0)	1 (100)
Intermediate	6 (30.0)	1 (100)	0 (0)	0 (0)	1 (100)	1 (33.3)	1 (100)	0 (0)	0 (0)	1 (20.0)	1 (50.0)	0 (0)
Minimal	1 (5.0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (33.3)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Type
Catheter-directed	9 (45.0)	1 (100)	1 (50.0)	1 (100)	1 (100)	3 (100)	1 (100)	0 (0)	0 (0)	0 (0)	1 (50.0)	0 (0)
Mechanical	1 (5.0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (50.0)	0 (0)	0 (0)	0 (0)
Both	10 (50.0)	0 (0)	1 (50.0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (100)	1 (50.0)	5 (100)	1 (50.0)	1 (100)

Table 3.

Management results by grouped years.

	All	2010–2012	2013–2017	2018–2020
IFDVT diagnosed on US	467 (100%)	111 (23.8%)	242 (51.8)	114 (24.4%)
Investigations	n = 467 (%)	n = 111 (%)	n = 242 (%)	n = 114 (%)
CT	119 (25.5)	22 (19.8)	62 (25.6)	35 (30.7)
PE alone	83 (17.8)	16 (14.4)	43 (17.8)	24 (21.1)
Extension clot alone	6 (1.3)	2 (1.8)	2 (0.8)	2 (1.8)
Both	1 (0.2)	0 (0)	0 (0)	1 (0.9)
No additional findings beyond DVT	29 (6.2)	4 (3.6)	17 (7.0)	8 (7.0)
MRI	1 (0.2)	0 (0)	0 (0)	1 (0.9)
PE	0 (0)	0 (0)	0 (0)	0 (0)
Extension	0 (0)	0 (0)	0 (0)	0 (0)
Both	0 (0)	0 (0)	0 (0)	0 (0)
No findings	1 (0.2)	0 (0)	0 (0)	1 (0.9)
Neither	347 (74.3)	89 (80.2)	180 (74.4)	78 (68.4)
Angiography	n = 467 (%)	n = 111 (%)	n = 242 (%)	n = 114 (%)
Thrombolysis	20 (4.3)	4 (3.6)	8 (3.3)	8 (7.0)
tPA alone	16 (3.4)	2 (1.8)	7 (2.9)	7 (6.1)
tPA and IVC filter	4 (0.9)	2 (1.8)	1 (0.4)	1 (0.9)
IVC filter insertion alone	37 (7.9)	11 (9.9)	18 (7.4)	8 (7.0)
Neither	411 (88.0)	96 (86.5)	217 (89.7)	98 (86.0)
Declined tPA	2 (0.4)	0 (0)	2 (0.8)	0 (0)
Referred to vascular but not tPA candidate	12 (2.6)	0 (0)	3 (1.2)	9 (7.9)
Thrombolysis	n = 20 (%)	n = 4 (%)	n = 8 (%)	n = 8 (%)
Length Tx
<1 h	4 (20.0)	0 (0)	2 (25.0)	2 (25.0)
12 h	7 (35.0)	0 (0)	2 (25.0)	5 (62.5)
24 h	4 (20.0)	2 (50.0)	1 (12.5)	1 (12.5)
36 h	1 (5.0)	0 (0)	1 (12.5)	0 (0)
48 h	4 (20.0)	2 (50.0)	2 (25.0)	0 (0)
Stent
Yes	9 (45.0)	1 (25.0)	4 (50.0)	4 (50.0)
No	11 (55.0)	3 (75.0)	4 (50.0)	4 (50.0)
Resolution
Full	13 (65.0)	3 (75.0)	4 (50.0)	6 (75.0)
Intermediate	6 (30.0)	1 (25.0)	3 (37.5)	2 (25.0)
Minimal	1 (5.0)	0 (0)	1 (12.5)	0 (0)
Type
Catheter-directed	9 (45.0)	3 (75.0)	5 (62.5)	1 (12.5)
Mechanical	1 (5.0)	0 (0)	1 (12.5)	0 (0)
Both	10 (50.0)	1 (25.0)	2 (25.0)	7 (87.5)

IFDVT: iliofemoral deep vein thrombosis; US: ultrasound; CT: computed tomography; PE: pulmonary embolism; DVT: deep vein thrombosis; MRI: magnetic resonance imaging; tPA: tissue plasminogen activator; IVC: inferior vena cava.

Referral patterns

Referral rates to the Thrombosis Clinic remained stable, with 60.1% of patients with IFDVT referred to either the Thrombosis Clinic alone, or in conjunction with a referral to the Vascular Service (see Table 4). There was an increase in the percentage of patients referred to both the Thrombosis Clinic and Vascular Service with an average of 7.1% (n = 33) and a maximum of 19.5% (n = 8) in 2019 (see Table 4). The number of patients increased from 1.8% (n = 2) in 2010–2012, to 5.4% (n = 13) in 2013–2017, to 15.8% (n = 18) in 2018–2020 (see Table 5). There was a corresponding decrease in the percentage of patients referred to the Thrombosis Clinic alone. Very few (0.9%, n = 4) patients were only referred the Vascular Service. A total of 7.9% (n = 37) of patients were referred to the Vascular Service, either alone or with referral to the Thrombosis Clinic, during the study period. The number of noneligible candidates for thrombolysis increased from 0% (n = 0) in 2010–2012, to 1.2% (n = 3) in 2013–2017, to 7.9% (n = 9) in 2018–2020.

Table 4

. Follow-up results by year.

	All	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019	2020
Referral	n = 467 (%)	n = 22 (%)	n = 45 (%)	n = 44 (%)	n = 48 (%)	n = 44 (%)	n = 56 (%)	n = 33 (%)	n = 61 (%)	n = 56 (%)	n = 41 (%)	n = 17 (%)
Thrombosis only	250 (53.5)	12 (54.5)	25 (55.6)	24 (54.5)	31 (64.6)	17 (38.6)	26 (46.4)	19 (57.6)	37 (60.7)	30 (53.6)	20 (48.8)	9 (52.9)
Vascular only	4 (0.9)	0 (0)	1 (2.2)	0 (0)	1 (2.1)	0 (0)	0 (0)	0 (0)	2 (3.3)	0 (0)	0 (0)	0 (0)
Both	33 (7.1)	1 (4.5)	1 (2.2)	0 (0)	2 (4.2)	3 (6.8)	1 (1.8)	1 (3.0)	6 (9.8)	7 (12.5)	8 (19.5)	3 (17.6)
Referred but not attend thrombosis	13 (2.8)	0 (0)	0 (0)	0 (0)	1 (2.1)	4 (9.1)	0 (0)	1 (3.0)	0 (0)	5 (8.9)	2 (4.9)	0 (0)
Neither	167 (35.8)	9 (40.9)	18 (40.0)	20 (45.5)	13 (27.1)	20 (45.5)	29 (51.2)	12 (36.4)	16 (26.2)	14 (25.0)	11 (26.8)	5 (29.4)
Died during admission	29 (6.2)	0 (0)	4 (8.9)	2 (4.5)	5 (10.4)	3 (6.8)	7 (12.5)	0 (0)	1 (1.6)	4 (7.1)	1 (2.4)	2 (11.8)
Palliative	24 (5.1)	1 (4.5)	4 (4.4)	2 (4.5)	0 (0)	2 (4.5)	9 (16.1)	5 (15.2)	2 (3.3)	0 (0)	1 (2.4)	0 (0)
Compression	n = 467 (%)	n = 22 (%)	n = 45 (%)	n = 44 (%)	n = 48 (%)	n = 44 (%)	n = 56 (%)	n = 33 (%)	n = 61 (%)	n = 56 (%)	n = 41 (%)	n = 17 (%)
Treatment	56 (12.0)	3 (13.6)	6 (13.3)	4 (9.1)	6 (12.5)	6 (13.6)	3 (5.4)	1 (3.0)	10 (16.4)	6 (10.7)	10 (24.4)	1 (5.9)
Prevention	27 (5.8)	2 (9.1)	3 (6.7)	4 (9.1)	2 (4.2)	4 (9.1)	0 (0)	4 (12.1)	2 (3.3)	3 (5.4)	2 (4.9)	1 (5.9)
No	383 (82)	17 (77.3)	36 (80.0)	36 (81.8)	40 (83.3)	34 (77.3)	53 (94.6)	28 (84.8)	48 (78.7)	47 (83.9)	29 (70.7)	15 (88.2)
Declined	1 (0.2)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1.6)	0 (0)	0 (0)	0 (0)
Long-term symptoms	n = 467 (%)	n = 22 (%)	n = 45 (%)	n = 44 (%)	n = 48 (%)	n = 44 (%)	n = 56 (%)	n = 33 (%)	n = 61 (%)	n = 56 (%)	n = 41 (%)	n = 17 (%)
No documentation	346 (74.1)	14 (63.6)	33 (73.3)	32 (72.7)	42 (87.5)	35 (79.5)	42 (75.0)	30 (90.9)	41 (67.2)	41 (73.2)	21 (51.2)	15 (88.2)
Documentation	121 (25.9)	8 (36.4)	12 (26.7)	12 (27.3)	6 (12.6)	9 (20.5)	14 (25.0)	3 (9.1)	20 (32.8)	15 (26.8)	20 (48.8)	2 (11.8)
No symptoms	40 (8.6)	3 (13.6)	7 (15.6)	4 (9.1)	2 (4.2)	0 (0)	8 (14.3)	2 (6.1)	5 (8.2)	2 (3.6)	6 (14.6)	1 (5.9)
Mild-moderate PTS	79 (16.9)	4 (18.2)	5 (11.1)	8 (18.2)	4 (8.3)	9 (20.5)	6 (10.7)	1 (3.0)	14 (23.0)	13 (23.2)	14 (34.1)	1 (5.9)
Severe PTS	2 (0.4)	1 (4.5)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (16.4)	0 (0)	0 (0)	(0)

PTS: post-thrombotic syndrome.

Table 5.

Follow-up results by grouped years.

	All	2010–2012	2013–2017	2018–2020
Referral	n = 467 (%)	n = 111 (%)	n = 242 (%)	n = 114 (%)
Thrombosis only	250 (53.5)	61 (55.0)	130 (53.7)	59 (51.8)
Vascular only	4 (0.9)	1 (0.9)	3 (1.2)	0 (0)
Both	33 (7.1)	2 (1.8)	13 (5.4)	18 (15.8)
Referred but not attend thrombosis	13 (2.8)	0 (0)	6 (2.5)	7 (6.1)
Neither	167 (35.8)	47 (42.3)	90 (37.2)	30 (26.3)
Died during admission	29 (6.2)	6 (5.4)	16 (6.6)	7 (6.1)
Palliative	24 (5.1)	7 (6.3)	18 (7.4)	1 (0.9)
Compression	n = 467 (%)	n = 111 (%)	n = 242 (%)	n = 114 (%)
Treatment	56 (12.0)	13 (11.7)	26 (10.7)	17 (14.9)
Prevention	27 (5.8)	9 (8.1)	12 (5.0)	6 (5.3)
No	383 (82)	89 (80.2)	203 (83.9)	91 (79.8)
Declined	1 (0.2)	0 (0)	1 (0.4)	0 (0)
Long-term symptoms	n = 467 (%)	n = 111 (%)	n = 242 (%)	n = 114 (%)
No documentation	346 (74.1)	79 (71.2)	190 (78.5)	77 (67.5)
Documentation	121 (25.9)	32 (28.8)	52 (21.5)	37 (32.5)
No symptoms	40 (8.6)	14 (12.6)	17 (7.0)	9 (7.9)
Mild-moderate PTS	79 (16.9)	17 (15.3)	34 (14.0)	28 (24.6)
Severe PTS	2 (0.4)	1 (0.9)	1 (0.4)	0 (0)

PTS: post-thrombotic syndrome.

Angiography

The rate thrombolysis per year demonstrated a range between 1.8% and 8.9% over the 11-year study period, resulting in an average rate per year of 4.3% (n = 20) and a maximum of 8.9% (n = 5) in 2018 (Table 2). When looking at the potential impact of published trials, the rate of thrombolysis alone increased from an average of 1.8% (n = 2) in 2010–2012, to 2.9% (n = 7) in 2013–2017, to 6.1% (n = 7) in 2018–2020. Conversely, the rate of IVC filter insertion alone decreased, from 18.2% in 2010 (n = 4) to 5.9% (n = 1) in 2020 (Table 3). A small number of patients (n = 2) declined thrombolysis, there was no trend towards an increase or decrease in the rate over the years.

Thrombolysis

The length of thrombolysis treatment decreased, with all patients (n = 4) receiving treatment duration greater than 24 h in 2010–2012, 50% (n = 4) in 2013–2017, and 0% (n = 0) in 2018–2020. Forty-five percent of patients receiving thrombolysis (n = 9) had venous stenting; there was no trend towards an increase or decrease in the rate of stenting. No difference in treatment outcomes were observed, with greater than 87.5% of patients reaching intermediate to full resolution of clot burden across the years. No patients experienced intracranial hemorrhage. There was an increased use of PCDT, especially as adjunctive therapy to CDT, with the use of both treatment modalities reaching a maximum of 87.5% (n = 7) in 2018–2020.

Follow-up

Overall, there was no difference in the rate of prescription for ECSs during the study period (see Table 5). Similarly, there was no difference in patients experiencing no symptoms, mild–moderate symptoms, or severe PTS symptoms over the years (see Table 5).

Discussion

PTS is a long-term adverse outcome of DVT associated with significant medical, social, and economical burden. A study by Kahn et al.⁸ found the development of PTS to be the principal determinant of QOL after lower limb DVT, with its impact on QOL to be as debilitating as angina, congestive heart failure, and cancer.⁹ Patients with IFDVT are at a greater risk of developing PTS, as well as more severe PTS. Management is, however, complicated by the lack of consensus for best practice.

Thrombolysis

Thrombolysis demonstrates an advantage over anticoagulation as it involves actively breaking down clot. CDT is a minimally invasive endovascular intervention used as an adjunct to anticoagulation and involves the delivery of a thrombolytic agent directly into the clot. Compared to systemic thrombolysis, there is a reduction in the dose of thrombolytic needed and systemic drug exposure, resulting in a reduced risk of bleeding, as well as optimization of the delivery of thrombolytic directly to the clot.¹ Studies have shown that thrombolysis restores venous patency faster than anticoagulation, resulting in a faster relief of acute symptoms. Many observational and retrospective studies have demonstrated benefit of CDT plus anticoagulation over anticoagulation alone in the prevention of PTS. Patients with IFDVT have been found to derive the greatest benefit, thus both the American Heart Association (AHA) and Society of Interventional Radiology (SIR) recommend CDT as first line adjunctive therapy for acute IFDVT.

PCDT involves CDT combined with adjunctive PMT at the time of catheter placement and is increasingly popular with greater availability of new technology. Studies have shown similar efficacy rates as CDT with potential for reduced total thrombolytic dose, treatment time, and length of hospital stay; however, randomized trials are lacking.^10–12 PMT can be used without thrombolytic, and is useful in the cases of contraindication to thrombolysis.

Data from randomized clinical trials are limited and the two landmark studies provide seemingly conflicting evidence. The 2012 CaVenT trial was the first large randomized prospective trial that assessed long-term outcomes after CDT with PTS as a primary outcome. Investigators demonstrated a clinically significant reduction in PTS after additional CDT compared with conventional treatment alone. It also demonstrated that proximal thrombus was associated with increased risk for developing PTS, as well as increased severity in PTS symptoms.⁶ The 2017 ATTRACT trial was a multicenter randomized controlled trial comparing PCDT with standard anticoagulation in patients with acute above-knee DVT, with PTS incidence at two-year follow-up as a primary outcome. Investigators found that the addition of PCDT to anticoagulation did not result in decreased risk of PTS.⁷ However, subgroup analysis of patients with IFDVT showed fewer patients developed moderate–severe PTS with PCDT than anticoagulation alone and those with severe symptoms had faster resolution of symptoms in the first 30 days after PCDT, suggesting PCDT may benefit more proximal DVT. It also demonstrated that PCDT reduced severity of PTS and resulted in improved relief of DVT-related pain and swelling.¹³ Thus, the ATTRACT trial provided high-quality evidence that most patients with acute DVT do not benefit from PCDT, especially those with distal clot, allowing physicians frequently using PCDT to re-evaluate their approach and target the use of PCDT for select patients and allow most to avoid an unnecessary procedure. The results of the recently published CAVA trial compound these findings, in which no significant difference in the development of PTS was found between patients receiving standard treatment with US-accelerated CDT versus standard treatment alone.¹⁴

Numerous societal guidelines have given recommendations on this topic. The NICE guidelines from the UK recommend considering CDT for patients with symptomatic IFDVT who have symptoms less than 14 days, good functional status, life expectancy greater than one year, and low risk of bleeding.¹⁵ The Society for Vascular Surgery propose thrombolysis is recommended in patients who meet the following criteria: first episode IFDVT, symptoms less than 14 days, low risk of bleeding, and the patient being ambulatory with good functional capacity. Thrombolysis is strongly recommended in patients with limb-threatening ischemia due to IFDVT (Grade 1 A). In patients with femoropopliteal DVT, anticoagulation alone is recommended over thrombolysis (Grade 1 C).¹⁶ However, the CHEST guidelines advise anticoagulant therapy alone for patients with acute proximal DVT over CDT (Grade 2 C). The basis for this recommendation is that evidence for thrombolysis is low quality, while the risks and benefits are uncertain. These guidelines nonetheless comment that patients most likely to benefit from thrombolysis have IFDVT, good functional status, and low risk of bleeding.¹⁷

This study aimed to examine the patterns of treatment and referral pathways for patients who presented with IFDVTs over an 11-year period, and whether they were impacted by the publication of the aforementioned landmark trials.

The stable rate of referral of patients presenting with IFDVT to the Thrombosis Clinic likely reflects the traditional belief in the need to investigate etiology and optimize medical management with anticoagulation. There was a simultaneous increase in referrals to the Vascular Service for the consideration of thrombolytic therapy, which may reflect an increase in the awareness of this treatment modality in the literature; this was the most significant in 2018–2020, potentially following the 2017 ATTRACT trial publication, which demonstrated improvements in symptoms and QOL. Despite reporting lower rates of PTS in patients treated with CDT, the CaVenT trial did not appear to significantly impact referral rates at our institution. In 2010–2012, prior to any robust randomized trials, the rate of thrombolysis per year was 1.8%. After the 2012 CaVenT and 2017 ATTRACT trials were published, the rate increased to 2.9% in 2013–2017 and 6.1% in 2018–2020. The reason that our institutional rates were not higher may reflect that major guidelines currently offer little to advocate for thrombolysis above anticoagulation alone for IFDVT. However, the number of patients referred to the Vascular Service and found to be unsuitable candidates for thrombolysis also increased. As the initial results of the ATTRACT trial demonstrated fewer than anticipated benefits for PCDT, the increase in patients found to be unsuitable candidates may reflect the judicious use of PCDT to a target patient population with acceptable risk–benefit ratios. The subgroup analysis of patients with IFDVT pointed towards positive effects on immediate symptom relief, reduction in the severity of PTS symptoms, and an increase in QOL.¹³ The increased benefit of PCDT for patients with IFDVT, in combination with greater provider awareness and confidence in utilization, may have contributed to its overall increased use.

During the study period, thrombolysis treatment time decreased in length, with 100% of patients receiving treatment duration greater than or equal to 24 h in 2010–2012, to 50% in 2013–2017, to 0% in 2018–2020. Despite this, no difference in treatment outcomes were observed, with more than 87.5% of patients reaching intermediate to full resolution of clot burden across the years. No patient experienced any serious bleeding complications. This is in keeping with the literature, which describes adverse outcomes as rare, with the risk of intracranial hemorrhage less than 1%.¹ Unfortunately, inconsistent documentation of thrombolytic dosage in the medical records precludes comment on changes in dose impacting treatment duration. The reduction in treatment duration with concurrent increase in the use of PMT is consistent with a meta-analysis¹² that found the treatment duration was significantly shorter in the group receiving PMT as compared to CDT (P < 0.00001, I² = 0%).¹² The increase in the use of PMT, especially as adjunctive CDT, likely reflects increasingly available technology both on the market and in our institution. Furthermore, the increase in PMT use combined with reduced treatment time and preservation of treatment efficacy may reflect increases in physician skill and confidence with time.

Stenting rates performed for patients in whom there is residual thrombus after CDT and/or PMT or those with anatomical risk factors appeared to vary widely in the literature, ranging from 16% to 79%.^18–20 Stenting was performed selectively at our institution with 45.0% of patients receiving thrombolysis also receiving venous stenting. However, the rate of stenting over the years has remained largely unchanged. Given the young age of some patients, some practitioners are reluctant to perform primary stenting and as such, a trial of anticoagulation without stenting may initially be preferred to stenting.

IVC filters and elastic compression stockings

Due to limited evidence and unclear long-term advantages, the role of IVC filters and ECS remains controversial and likely of little benefit in routine practice for the prevention of PTS.^1,21 The results of our study are in keeping with the literature, as rates of IVC filter insertion decreased while rates of ECS prescriptions remained unchanged.²² While ECS are unlikely to cause harm, they are costly, cumbersome, and uncomfortable to patients. Thus, a trial of ECS should be reserved for patients presenting swelling secondary to DVT for symptomatic benefit.

Imaging

Over the study period, there was an increased use of CT imaging, consistent with the increased use of CT and other imaging modalities in the clinical environment. Similarly, there was an increase in the ratio of CT scans performed as part of the initial diagnostic work-up for VTE compared to scans performed within the two weeks following the diagnosis of IFDVT by US. This more liberal use of CT scanning patients may explain the increase in the diagnosis of PE. As this was a retrospective study, inconsistent clinical documentation in the medical records prevented the analysis of how many PEs were clinically relevant. It may be hypothesized that scanning patients presenting solely with IFDVT symptoms led to an increase in the incidental diagnosis of clinically asymptomatic PE.

Limitations

This analysis is subject to several limitations. Firstly, it is a retrospective analysis of patient data, which inherently introduces bias to the methodology. PTS is primarily a clinical diagnosis in the context of a DVT at least three months prior, as there is no objective diagnostic test. In the literature, at least six different scoring systems exist to assess PTS.²³ While the total number of patients in our study (n = 467) provided a fairly large sample, the retrospective nature of our review limited analysis to data gathered from clinical and radiographic reports. As such, incomplete medical records constituted a limitation. Notably, 74.1% (n = 346) of patient charts had no documentation on long-term symptoms. Assessment of PTS symptoms was limited to subjective reports by patients gathered from follow-up appointment records. We also observed a relatively low incidence of May–Thurner syndrome (MTS) in our cohort (0.6%), as compared to a study by Heller et al. of patients with left-sided and bilateral iliac vein and/or thigh DTS where MTS was diagnosed on US in 31% of patients.²⁴ However, as ultrasounds were performed to rule out DVT and not to evaluate for the presence of MTS, it is likely radiologists were not evaluating for this diagnosis and thus our review missed capturing additional patients with MTS. Low rates of thrombolysis resulted in a smaller thrombolysis sub-group (n = 20). Greater statistical significance may be reached in future studies by evaluating a larger cohort.

Conclusion

The CaVenT trial and recent subgroup analysis of the ATTRACT trial have shown that thrombolysis in the early phase of IFDVT has an advantage over anticoagulation alone in terms of the development of severe PTS afterward. The results of this analysis highlight changes in treatment and referral pathways in keeping with the literature, as well as the large discrepancy in management, with the vast majority of patients with IFDVT not receiving thrombolysis. Increases in referrals to the Vascular Service and rates of thrombolysis, in conjunction with an increase in patients found to be unsuitable candidates, reflect judicious use to a targeted patient population. It is important for future work to continue to elicit the most appropriate management pathways for patients with IFDVTs.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Graham Roche-Nagle

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