The Anticoagulation of Calf Thrombosis (ACT) Project

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Original Research Pulmonary Vascular Disease

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The Anticoagulation of Calf Thrombosis (ACT) Project Results From the Randomized Controlled External Pilot Trial Daniel Horner, MD; Kerstin Hogg, PhD; Richard Body, PhD; Michael J. Nash, MD; Trevor Baglin, PhD; and Kevin Mackway-Jones, MA

There is currently little evidence defining the clinical importance of detecting and treating isolated distal DVT (IDDVT). International guidelines vary regarding diagnostic and therapeutic advice. The potential benefits of anticoagulation are unquantified. We sought to evaluate the feasibility of a randomized controlled study within a modern framework and provide a primary outcome point estimate.

BACKGROUND:

In this open-label, external pilot randomized controlled trial, consecutive, symptomatic, ambulatory patients with IDDVT were approached for inclusion. Participants were allocated to receive either therapeutic anticoagulation or conservative management. Patients underwent blinded color-duplex imaging at 7 and 21 days and follow-up at 3 months. Principal feasibility outcomes included recruitment rate and attrition. The principal clinical outcome was a composite including proximal propagation, pulmonary embolism, death attributable to VTE disease, or major bleeding. Analysis was by intention to treat.

METHODS:

In total, 93 patients with IDDVT were screened, and 70 of those eligible (88.6%) were recruited. All patients but one were followed-up by direct contact after 90 days. Allocation crossover occurred in 15 patients (21.4%). The principal clinical outcome occurred in four of 35 of those conservatively treated (11.4%) and zero of 35 in the anticoagulated group (absolute risk reduction, 11.4%; 95% CI, 21.5 to 26.7, P 5 .11, number needed to treat of nine). There were no major bleeding episodes.

RESULTS:

We have established the feasibility of definitive study regarding the value of therapeutic anticoagulation in IDDVT and provide an approximate point estimate for serious complications with a contemporary conservative strategy.

CONCLUSIONS:

TRIAL REGISTRY:

Current Controlled Trials; No.: ISRCTN75175695; URL: www.controlledCHEST 2014; 146(6):1468-1477

trials.com.

Manuscript received January 29, 2014; revision accepted June 2, 2014; originally published Online First July 10, 2014. ABBREVIATIONS: AE 5 adverse event; ARR 5 absolute risk reduction; IDDVT 5 isolated distal DVT; INR 5 international normalized ratio; RCT 5 randomized controlled trial; TTR 5 time in therapeutic range AFFILIATIONS: From the Emergency Department (Drs Horner and Body and Mr Mackway-Jones), Manchester Royal Infirmary, and Department of Haematology (Dr Nash), Central Manchester University Hospitals, NHS Foundation Trust, Manchester, England; The University of Manchester (Drs Horner and Body and Mr Mackway-Jones), Manchester, England; Thrombosis Group (Dr Hogg), The Ottawa Hospital, Ottawa, ON, Canada; and Department of Haematology (Dr Baglin), Cambridge University Hospitals, NHS Foundation Trust, Cambridge, England. 1468 Original Research

Parts of this article were presented at the Annual Scientific Conference for the College of Emergency Medicine (United Kingdom and Ireland), September 2013, London, England, and at the XXIV Congress for the International Society on Thrombosis and Haemostasis, July 2013, Amsterdam, The Netherlands, and published in abstract form (Horner D, Hogg K, Body R, Nash MJ, Baglin T, Mackway-Jones K. Emerg Med J. 2013;30:869-870; winner of the Roderick Little Prize as highest scoring trainee abstract and subsequently published in the Emergency Medicine Journal and Horner D, Hogg K, Body R, Nash MJ, Baglin T, MackwayJones K. J Thromb Haemost. 2013;11(S2):845-846; winner of a Young Investigator award and subsequently published in the Journal of Thrombosis and Haemostasis). FUNDING/SUPPORT: This work was funded by the College of Emergency Medicine and supported by the National Institute for Health Research through the comprehensive local research network.

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VTE disease is a topical and costly health-care burden. Diagnosis is associated with significant morbidity and mortality despite modern advances in care.1,2 Unfortunately, standard therapeutic dose anticoagulation also carries a quantifiable and significant risk.3,4 There are many gray areas where the benefits of aggressive treatment are counterbalanced by potential harm. Isolated distal DVT (IDDVT) is one such area. A composite of calf muscle and axial calf vein thrombosis, isolated disease restricted below the popliteal trifurcation, continues to divide clinical opinion.5 This is demonstrated clearly by the ongoing international variation in practice and recent vernacular debate.6-12 Only one prospective randomized controlled trial (RCT) has compared phased oral anticoagulation against conservative management in IDDVT, reporting an absolute risk reduction (ARR) of 29% with anticoagulation for recurrence.13 This article was followed by multiple additional case series highlighting the dangers of conservative management.14-18 Subsequent international guidance

Materials and Methods Design, Setting, and Participants The trial protocol has previously been published and gives a detailed account of the background, methods, and oversight.32 Briefly, we undertook a pilot RCT set in the ED at a university-affiliated teaching hospital with approximately 100,000 ED attendances per annum. Recruitment occurred over a consecutive 16-month period in 2011 and 2012. Patients presenting with symptoms compatible with DVT underwent standardized investigation in line with current international guidance. Patients aged . 16 years who were diagnosed with acute IDDVT following whole-leg compression ultrasound were eligible for inclusion. Exclusion criteria have been recorded within the trial protocol. We retrospectively defined provocation using the recent criteria proposed by the National Institute for Health and Clinical Excellence (NICE) within the United Kingdom.33 The trial was approved by the Greater Manchester Central Research Ethics Committee (reference, 10/H1008/97) and the Medicines and Healthcare Products Regulatory Agency (reference, 2010-021813-22). The study was sponsored by Central Manchester University Hospitals, NHS Foundation Trust. All patients provided full written informed consent. Randomization and Masking Randomization occurred via a web-based platform (www.sealedenvelope. com) with an externally generated randomization sequence in variable permuted block sizes. Recruiting clinicians randomized patients in the ED to receive either therapeutic anticoagulation (intervention group) or conservative treatment (control group) in a 1:1 allocation ratio.

CORRESPONDENCE TO:

Daniel Horner, MD, Emergency Department, Central Manchester University Hospitals, NHS Foundation Trust, Oxford Rd, Manchester, M13 9WL, England; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0235

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was produced supporting therapeutic anticoagulation for IDDVT.19-21 Further trials have recently suggested a lower risk in more conservatively managed IDDVT.22-24 The American College of Chest Physicians (CHEST) has consequently adjusted recommendations in current guidance to principally support surveillance rather than anticoagulation treatment in low-risk patients.25 No systematic review or meta-analysis has been able to provide clear recommendations due to the paucity of publication and heterogeneity of available results.12,26,27 There is a current widespread call for prospective randomized trial data on the treatment of IDDVT.7-10,12,22,26-31 We sought to establish the feasibility of a definitive trial. Specific objectives of this project were to define the incidence of IDDVT in ambulatory patients and to evaluate recruitment and compliance to trial protocol. We also sought to assess clinically relevant complication rates in patients treated with or without anticoagulation.

Randomization occurred following written informed consent, such that allocation concealment was maintained until the absolute point of inclusion. Intervention and Follow-up Patients in the intervention group were initially given a subcutaneous therapeutic dose of dalteparin with phased transition to an oral vitamin K antagonist for a total of 3 months. All patients were followed-up in a dedicated anticoagulant clinic for international normalized ratio (INR) monitoring. The target INR was 2.5 (range, 2.0-3.0), with overall quality of anticoagulation assessed by proportional time in therapeutic range (TTR). Patients in the control group were provided with a supply antiinflammatory medication and paracetamol for symptomatic relief, but received no anticoagulation. All patients regardless of treatment allocation were referred for fitted grade 2 compression stockings. All patients, regardless of allocation, underwent sequential repeat wholeleg compression ultrasound imaging on days 7 and 21, performed by an accredited vascular sonographer blinded to treatment allocation. Each scan was immediately followed by a clinical review to assess the extent of radiologic and/or clinical progression. Any patient in the control arm propagating to the level of the popliteal fossa, or who developed symptomatic pulmonary embolism at any stage during follow-up, was immediately commenced on therapeutic anticoagulation as per the trial protocol. In addition to repeat imaging and clinical assessment, a standardized data collection template was completed by the research team for each attendance episode. Patients were finally followed-up by telephone on day 90 using the same standardized data collection template. Imaging and Laboratory Protocols Patients were scanned using a 9-4 MHz linear and 5-2 MHz curvilinear transducer to a standard proforma. This includes documented assessment of all proximal, muscular calf, and deep calf veins using B mode, color Doppler, and spectral Doppler including compression, augmentation, and Valsalva maneuver. Clot burden at recruitment was assessed and recorded using the Marder scoring system.34 All D-dimer measurements were conducted using a rapid and quantitative

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immunoturbidometric assay (STA Liatest; Stago) and reported in nanograms per milliliter. Outcomes Feasibility outcomes were defined a priori by consensus decision as (1) . 5% incidence of the target condition within the ambulatory population of interest, (2) . 70% recruitment rate, and (3) attrition (, 5% loss to follow-up, . 50% protocol completion rate, and , 25% allocation crossover). The key clinical outcome was the proposed primary outcome for the full future trial: that of serious thromboembolic complications. This composite outcome was defined as the occurrence of either proximal propagation to the level of the popliteal trifurcation or above (recorded objectively at blinded ultrasound) with or without symptoms, development of symptomatic pulmonary embolism, VTErelated sudden death, or major bleeding. Additional outcomes included minor and nuisance bleeding episodes and pharmacovigilance. Bleed-

Results During the recruitment phase (January 2010 to February 2011), 951 patients underwent ambulatory assessment for suspected DVT. Proximal disease was confirmed in 104 cases. A total of 93 patients were diagnosed with IDDVT, of whom 79 were deemed eligible for the trial. Seventy patients provided consent and were included in the study (Fig 1). Baseline characteristics of recruited and missed participants are shown in Table 1. Clinical features at presentation are described in Table 2. One participant (1.4%) was unable to be contacted by telephone at 90 days. Accurate follow-up data were obtained by review of electronic medical records and telephone discussion with the primary care practitioner. Feasibility and Clinical Outcomes

The incidence of IDDVT within the screening cohort was 93 of 951 patients at 9.8% (95% CI, 8.1%-11.8%). Seventy-nine of these patients (84.9%) with confirmed IDDVT were eligible for participation. Therefore, 75.3% of all patients with IDDVT (95% CI, 65.5%-82.9%) and 88.6% of eligible patients (95% CI, 79.7%-93.9%) during the study period were successfully recruited. Sixty-five of 70 patients (92.9%) and 60 of 70 patients (85.7%) attended for follow-up at days 7 and 21, respectively. All patients were alive at day 90, and only one could not be contacted directly. Therefore, 59 of 70 patients (84.3%; 95% CI, 74.0%-91.0%) completed the full protocol. Nine of the 10 patients who did not attend follow-up at day 21 had been allocated to the intervention group. Allocation crossover occurred in 15 patients (21.4%; 95% CI, 13.4%-32.4%) by day 90, including 13 of 35 (37.1%) in the control group and two of 35 (5.7%) in the

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ing events were defined and categorized as per the harmonized definition produced by the standardization committee of the International Society on Thrombosis and Haemostasis (ISTH).35 Diagnosis of pulmonary embolism was objectively confirmed by Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED)-reported ventilation/ perfusion scan or CT pulmonary angiogram imaging. Statistical Analysis Categorical data are described as percentages and compared using the Fisher exact test. Parametric data were summarized by the mean (SD). Nonparametric data were summarized by the median (interquartile range) and compared using the Mann-Whitney U test. We calculated 95% CIs with the Wilson method. All P values reported are two-tailed, with a value of , .05 considered statistically significant. Analysis of clinical outcomes was by intention to treat. All analyses were performed using SPSS, version 20.0 (IBM).

intervention group. Crossover was significantly more likely to occur in the patients allocated to conservative management (P 5 .003). In this cohort, four patients achieved the primary outcome (thus mandating anticoagulation), one requested anticoagulation therapy at day 7, six patients were admitted to hospital for other reasons and commenced on anticoagulation treatment, and the remaining two patients received anticoagulation therapy in the community. Table 3 shows the proportion of patients with each predefined clinical outcome, stratified by treatment allocation. Four patients (11.4%) in the control group and zero in the anticoagulated group reached the composite clinical outcome of serious thromboembolic complications. The ARR can, therefore, be estimated at 11.4% (95% CI, 21.5%-26.7%) (P 5 .11). The rate of adverse events (AEs) and serious AEs are reported in Table 3. Serious AEs were most often related to unplanned hospital admission in both groups, for reasons unrelated to VTE. AEs were chiefly characterized by repeat attendance to the ED or complaints of increased pain and/or swelling in the control group. Regarding time to events, clot propagation to the popliteal vein occurred in three patients (two patients at day 7; one patient at day 21) and a single patient developed symptomatic pulmonary embolism (on day 3; confirmed by both high-probability ventilation/perfusion scan and diagnostic CT pulmonary angiogram). Specific patient details, progression, and provocation are provided in Figure 2. No patient in either group developed major bleeding. Minor bleeding episodes occurred in seven of 35 patients (20%) receiving anticoagulation therapy and three of 35 conservatively treated patients (8.6%; P 5 .31). The

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Figure 1 – Flow diagram of patient assessment, recruitment, and follow-up. D 5 day.

incidence of nuisance bleeding was equal in both groups (nine of 35; 25.7%). Quality of Anticoagulation

The median time from diagnosis to formal anticoagulant clinic review was 6 days (4 days to 11 days). Patients requiring five or more doses of interim low-molecular-weight heparin were instructed to attend the ED for platelet monitoring and clinical review. Following registration with the anticoagulant clinic, an average of nine visits (seven to 10 visits) were needed per patient for INR testing during the treatment period. Patients were treated for a median of 14 weeks (12 to 14 weeks). The average proportion of TTR for patients in the intervention group was 56.0% (41.7%-73.5%). The

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proportion of time in or above the target INR range was 68% (48.2%-87.7%).

Discussion Although these are pilot data, to our knowledge this trial is the largest to date comparing phased oral anticoagulation with conservative therapy in the management of IDDVT. There are two key findings from this work. First, we have established feasibility for conduct of a definitive RCT. Our findings will enable design modifications, including revision of the proposed sample size, to maximize the scientific value of that work. Second, we have established an approximate point estimate of clinically relevant complication rates in conservatively 1471

TABLE 1

] Demographic and Provocation Data for All Randomized Patients and Excluded Cases

Demographics Age

Therapeutic Anticoagulation (n 5 35)

Conservative Management (n 5 35)

Excluded IDDVT Cases (n 5 23)

60.9 (17.8)

59.8 (17.9)

53.8 (18.3)

Female sex

26 (74.3)

20 (57.1)

12 (57.1)

Left-sided DVT

14 (40)

19 (54.3)

10 (47.6)

White

29 (82.9)

27 (77.1)

17 (81.0)

Black

4 (11.4)

5 (14.3)

1 (4.8)

Asian

2 (5.8)

1 (2.9)

0 (0)

Ethnicity

Hispanic

0

Other

0

Provoked

24/35 (68.6)

Plaster application

6 (17.1)

0

1 (4.8)

2 (5.7) 19/35 (54.3) 3 (8.6)

2 (9.5) 13/23 (56.5) 1 (4.8)

Recent hospital admission

11 (31.4)

8 (22.9)

6 (28.6)

Recent surgery

12 (34.3)

5 (14.3)

2 (9.5)

Recent air travel

4 (11.4)

4 (11.4)

3 (14.3)

Immobilization

9 (25.7)

9 (26)

7 (33.3)

Estrogen intake

2 (5.7)

3 (8.6)

4 (19.0)

Pregnancy/puerperium

0 (0)

0 (0)

0 (0)

Unprovoked Lower limb trauma

11/35 (31.4) 7 (20)

16/35 (45.7)

10/23 (43.5)

6 (17.1)

3 (14.3)

Acute infection

2 (5.7)

1 (2.9)

4 (19.0)

Family history VTE

5 (14.3)

7 (20)

5 (23.8)

Past history VTE

5 (14.3)

6 (17.1)

9 (42.9)

Thrombophilia

2 (5.7)

0 (0)

1 (4.8) 0 (0)

Previous cancer

4 (11.4)

1 (2.9)

Varicosities

9 (25.7)

13 (37.1)

4 (19.0)

Obesity

11 (31.4)

8 (22.9)

4 (19.0)

Smoker

11 (31.4)

13 (37.1)

10 (47.6)

IV drug use

0 (0)

0 (0)

1 (4.8)

Age is presented as mean (SD). All other data are presented as numerator with proportion (n/N). IDDVT 5 isolated distal DVT.

managed ambulatory patients with IDDVT (11.4%). These data can help to inform clinical decision-making and discussions of perceived risk and benefit with therapeutic anticoagulation, pending further evidence. Strengths

The key strengths of this study are reproducible methodology and robust internal validity. We were able to approach a consecutive sample of patients for participation and manage them to a strict, standardized protocol. This trial was designed to be replicated by other centers after publication of pilot results; we have seen no reason why this could not be the case. Our chosen follow-up method and secondary end points were also clinically relevant. Serial sonography is widely considered the gold standard for patients with IDDVT treated conser1472 Original Research

vatively throughout the developed world.25,29 Assessor blinding within our protocol limited potential bias and ensured objective interpretation of results. The inclusion of symptomatic PE within the composite outcome also specified that only patients returning with symptoms would be assessed and diagnosed with complications. The potential of silent proximal propagation and new symptomatic pulmonary embolism are the key issues upon which clinicians are likely to make treatment decisions. An additional strength of this study is that of pragmatism. Our open-label design purposefully allowed clinicians encountering recruited patients to manage any complications as they saw fit. Thus, many patients in the conservative group received additional investigations

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TABLE 2

] Baseline Clinical Data Therapeutic Anticoagulation (n 5 35)

Clinical Data Duration of symptoms Days of treatment prior to allocation

7 (4-14)

Conservative Management (n 5 35) 7 (3-10)

Excluded IDDVT Cases (n 5 23) 6 (3.25-13)

1 (1-1)

1 (1-2)

1 (1-1)

Verbal analog pain score

4.34 (2.1)

4.6 (1.9)

3.84 (1.6)

Pulse rate

79.9 (9.8)

82.9 (18.2)

Early warning score, total High-risk Wells score Marder score Active cancer Calf swelling Varicosities Pitting edema Swelling of entire leg

85.9 (14.8)

0 (0-1)

0 (0-1)

0 (0-1)

17 (48.6)

13 (37.1)

10 (47.6)

2 (2-3)

2 (2-3)

3 (2-5)

0 (0)

0 (0)

1 (4.8)

12 (34.3)

6 (17.1)

6 (28.6)

4 (11.4)

13 (37.1)

2 (9.5)

19 (54.3)

17 (48.6)

5 (23.8)

5 (14.3)

4 (11.4)

3 (14.3)

Local pain

24 (68.6)

25 (71.4)

16 (76.2)

Immobilization

10 (28.6)

6 (17.1)

3 (14.3)

7 (20.0)

5 (14.3)

4 (19.0)

Bedridden Previous DVT

3 (8.6)

4 (11.4)

6 (28.6)

Alternative diagnosis

1 (2.9)

6 (17.1)

0 (0)

D-dimer, ng/mL

690 (405-1,290)

C-reactive protein, mg/L WBC count, 3 109/L Platelet count, 3 10 /L 9

Estimated glomerular filtration rate Isolated calf muscle vein thrombi Deep calf vein thrombi Combined calf muscle and deep calf vein thrombi

6 (3-13)

650 (325-1,260) 9 (3-19)

6.9 (5.3-10.3) 266.4 (79.4)

7.5 (5.6-9.5) 275.0 (79.6)

81 (65.75-90)

80 (67.75-87.75)

6 (17.1)

5 (14.3)

25 (71.4)

28 (80.0)

4 (11.4)

2 (5.7)

612.5 (471-813) 13 (5-37) 7.9 (6.1-10.9) 303.2 (123.5) 85 (70-90) 2 (8.7) 5 (21.7) 16 (69.6)

Baseline clinical data, presenting features, and laboratory values for patients randomized to therapeutic anticoagulation, conservative therapy, and excluded cases. Patients with previous proximal VTE were ineligible for the study. Patients with previous IDDVT were eligible. All other data are presented as proportions by n (n/N). See Table 1 legend for expansion of abbreviation.

and reviews and over one-third received anticoagulation therapy at some stage during the 3-month follow-up. Despite this, we were still able to show a sizeable ARR between treatment groups. Limitations

There are limitations. We chose to use an open-label methodology a priori. This perhaps contributed to the high rate of allocation crossover. We attempted to minimize limitations by assessor blinding and objective standardization whenever possible with regard to outcomes and adverse events. With the introduction of safe and effective novel oral anticoagulant agents not requiring monitoring, a blinded trial design may be optimal. The median TTR in these patients taking warfarin was notably lower than in other previous exploratory journal.publications.chestnet.org

studies. Indeed, this has already been a criticism of several novel oral anticoagulant trials.36 However, this is reflective of our pragmatic trial design and makes the results more generalizable. In addition, no patient achieved the composite end point in the intervention group despite the proportion of subtherapeutic TTR. It may well be the case that any degree of anticoagulation is beneficial in preventing propagation and complication from calf thrombosis. Several studies have already suggested this.23,31 This is pilot data. As such, CIs surrounding the composite outcome and ARR are broad. In addition, we saw an uneven distribution of potential confounding variables (such as provocation) between the control and intervention subjects at baseline. Such issues are unavoidable with an open-label pilot study. Our main subject of 1473

TABLE 3

] Incidence of the Primary Composite and All Clinical Secondary End Points, Strati¿ed by Intervention

Incidences

Therapeutic Anticoagulation (n 5 35)

Conservative Management (n 5 35)

Absolute Risk Reduction, % (95% CI) 11.4 (21.5 to 26.7)

P Value

Composite outcome

0 (0)

4 (11.4)

Symptomatic popliteal propagation

0 (0)

3 (8.6)

8.6 (23.5 to 23.1)

.24

Symptomatic pulmonary embolism

0 (0)

1 (2.9)

2.9 (27.5 to 15.0)

1.00

VTE-related death

0 (0)

0 (0)

…

…

Major bleeding

0 (0)

0 (0)

…

…

Minor bleeding

7 (20.0)

3 (8.6)

Nuisance bleeding

9 (25.7)

9 (25.7)

Investigated for suspected pulmonary embolism

0 (0)

4 (11.4)

11.4 (21.5 to 26.7) 22.9 (218.12 to 23.69)

Serious adverse event rate

8 (22.9)

7 (20.0)

Adverse event rate

9 (25.7)

17 (48.6)

211.4 (229.7 to 7.1) 0 (211.9 to 11.9)

22.9 (21.66 to 44.78)

.11

.31 1.00 .11 1.00 .08

All P values are calculated using the Fisher exact test. All numerical values are listed as n (n/N). Serious adverse events were recorded as predefined within clinical trial literature. Adverse events were recorded in the event of any new or acute deterioration in symptoms, regardless of causation.

investigation was feasibility; all other outcomes should be considered as hypothesis-generating prior to formal assessment in future robustly designed scientific research. We also chose to use a composite outcome. There are multiple issues with the use of composite outcomes that will be applicable to a definitive study and must be acknowledged when interpreting the results. We have

explored these issues in more detail within the study protocol.32 Our pilot results suggest principal findings within a larger trial will be based primarily on the frequency of popliteal propagation within each group. We consider this to be a clinically relevant marker for failure of conservative management. However, there are additional relevant outcomes as reflected in the composite; it remains vital that each aspect of the composite

Figure 2 – Individual patients achieving the composite primary outcome and associated relevant clinical details at baseline and review. Propagation/PE development was followed by immediate therapeutic anticoagulation. COCP 5 combined oral contraceptive pill; F&W 5 fit and well at d 90 follow-up; IDDVT 5 isolated distal DVT; PE 5 pulmonary embolism confirmed by CT pulmonary angiogram; POP 5 plaster of Paris immobilization.

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is reported in isolation, such that clinicians can view further research in the context they deem to be most appropriate, whether this is the ability of therapeutic anticoagulation to reduce mortality, pulmonary embolism, popliteal extension, or symptoms. Comparison and Meaning

Our data have several notable strengths in comparison with other studies. First, we chose to compare conservative management to current international recommendations of phased oral anticoagulation. Many studies on IDDVT have compared serial follow-up with short, intermediate, and prophylactic dose courses of low-molecularweight heparin.23,24,31 Our results are, therefore, potentially more generalizable.

managed group, a further 13 patients in this cohort showed evidence of either local propagation (below the level of the popliteal vein) on sequential compression ultrasound or increasing severity of symptoms at review. Adherence to latest guidelines in our cohort (suggesting therapeutic anticoagulation with any evidence of local propagation, popliteal propagation, complications, or severe symptoms25) would have resulted in consequent treatment of 17 of 35 conservatively managed patients, 48.6% (95% CI, 33.0%-64.4%) within the 3-month study period. This raises questions regarding the potential cost-effectiveness of surveillance ultrasonography. The Direction of Future Research

Second, we chose to investigate only an ambulatory cohort specifically, with extensive exclusion criteria. This reflects the patient cohort of interest; previous studies including hospitalized patients and those with previous disease can be criticized for including high-risk participants.13,14 Our methodology attempted to include only patients for whom there is genuine equipoise about the need for anticoagulation.

First and foremost, our pilot results need to be validated in an adequately powered large prospective multicenter cohort. Several interventional trials are already under way or at funding application stage and will no doubt provide further data on risk and characteristics associated with propagation in the interim.37,38 Even if a statistically significant and definitive benefit can be eventually shown from therapeutic anticoagulation, discussions will follow regarding cost-effectiveness. Future research should be designed with this in mind.

The results of our trial carry several key messages. Most importantly, further research is clearly achievable in this population and may offer definitive answers. Second, conservatively managed IDDVT in the symptomatic ambulatory population appears to carry a reasonable level of associated risk. In addition to the four patients achieving the composite outcome in the conservatively

In conclusion, our pilot data suggest that a definitive trial to assess the benefits of therapeutic anticoagulation in the management of IDDVT is both acceptable to patients and feasible in a modern health-care environment. This definitive trial is urgently needed, to provide a concise and generalizable estimate of the clinical benefit and cost-effectiveness seen with therapeutic anticoagulation.

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Acknowledgments Author contributions: D. H. is the guarantor for the paper. D. H., K. H., and K. M.-J. contributed to identification of the research question, obtained funding, and drafted of the initial protocol; R. B. and M. J. N. contributed to the development of the protocol and oversaw implementation of the study; T. B. contributed to protocol advisement and participated in the steering committee; D. H. and R. B. contributed actively to patient recruitment; D. H. drafted the initial manuscript; and D. H., K. H., R. B., M. J. N., T. B., and K. M,-J. provided comments on the drafts, critically revised the manuscript, and read and approved the final version prior to submission. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Baglin has received honoraria and consultancy fees as a member of advisory boards for Bayer AG, Boehringer Ingelheim GmbH, Daiichi Sankyo Company Limited, and Pfizer Inc. He is a founder member and shareholder of XO1 Ltd developing novel anticoagulant drugs. Drs Horner, Hogg, Body, and Nash and Mr MackwayJones have reported that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Role of sponsors: This study was sponsored by Central Manchester University Teaching Hospitals NHS Foundation Trust. The role of the sponsor included assistance with study set-up and site initiation, research governance and oversight, pharmacovigiliance and adverse event reporting, statistical support, steering committee oversight, annual reporting to both the Medicines and Healthcare Products Regulatory Agency and National Research Ethics Service, and study closure. Other contributions: The ACT research team thanks all members of Manchester Royal Infirmary Vascular Ultrasound Laboratory for their invaluable contribution to the management of the study patients. We are also indebted to the clerical and clinical staff of the Emergency Department for assistance with identification of eligible patients and their ensuing treatment. The ACT research team also acknowledges the support of the National Institute for Health Research, through the comprehensive clinical research network. In particular, we thank the new Greater Manchester Comprehensive Local Research Network Emergency Medicine/Critical Care theme for assistance and guidance with research support staff.

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