Table 2

BET 2 relevant papers

Author, year and country Patient group Study type (level of evidence) Outcomes Key results Study weaknesses
Schwarz et al, 2010,8 Germany107 patients with symptomatic isolated calf muscle thrombosis confirmed by sonogrophy. 54 received low molecular weight heparin for 10 days then 3 months compression therapy. 53 received compression therapy alone.Open-label randomised controlled trial (2b)Composite endpoint: extension into the deep veins and/or clinical PE confirmed by objective testing.No cases of PE occurred during follow-up. No significant difference was reported in primary outcome rate between intervention and control groups (2 patients in each).Low risk cohort (only 10.72% hospitalised). Atypical drug regimen.
Preselected lower risk thrombi (calf muscle only).
Unblinded selection and assessor bias introduced.
Long-term anticoagulation not tested.
Palareti et al, 2010,9 Italy431 symptomatic patients without proximal DVT and with high pre-test clinical probability or altered D-dimer.Prospective cohort study with patients and clinicians initially blinded to below-knee ultrasound results (2a)Rate of venous thromboembolism at 3 monthsA significantly higher rate of outcomes was recorded in subjects with than without isolated calf DVT (5/64; 7.8%; 95% CI 3 to 17 vs 3/351; 0.8%; 95% CI 0 to 2; p=0.003).Relatively small number of patients studied. Patients were non-consecutive—selection bias cannot be excluded.
No exploration of anterior tibial veins. Small numbers of VTEs, thus large confidence intervals.
No randomisation—as such, treatment of patients may not have reduced outcomes.
De Martino et al, 2012,5 USA2 randomised control trials and 6 prospective cohorts studying patients with calf DVT confirmed by ultrasound scanning (126 patients treated with anticoagulation and 328 controls).Meta-analysis (2a)Rate of pulmonary embolism and thrombus propagation in anticoagulated patients versus controlsSignificantly increased rates of PE (OR 0.12; 95% CI 0.02 to 0.77; p=0.03) and thrombus propagation (OR 0.29; 95% CI 0.14 to 0.62; p=0.04) in those who received anticoagulation.Small number of studies included. Overall methodological quality of included studies was low.
No standardised criteria for control status of patients with a range of ‘control’ therapies across different studies.
Heterogeneity across inclusion criteria and therapeutic regimes.
Olson et al, 2014,11 USA251 trauma inpatients with DVT±PE on surveillance lower extremity duplex ultrasound.Retrospective cohort study (2b)Time of DVT onset and progression or regressionBelow-knee DVT progressed to above-knee DVT and/or PE in 12.9% of patients. PE rates were 6.1% in below-knee DVT compared with 1.1% in above-knee DVT (p=0.1).Retrospective: only trauma patients evaluated.
Small numbers of VTEs. Conservative use of pharmacological prophylaxis during time of study.
High PE rates in below-knee DVT probably represent undertreatment.
Focused high-risk cohort (hospitalised trauma patients).
Use of anticoagulation between below-knee DVT and above-knee DVT groups86% of AKDVT received anticoagulation compared with 24% of BKDVT (p≤0.0001).
Horner et al, 2014,6 UK70 consecutive patients with symptomatic isolated distal DVT. Equal allocation to receive either conservative management or therapeutic anticoagulation for 3-month study period.Prospective, open-label randomised controlled feasibility trial.Composite clinical outcome including (1) proximal propagation of thrombus, (2) PE, (3) death related to VTE, (4) major bleedingComposite clinical outcome in 4/35 patients treated conservatively (11.4%) and 0/35 patients anticoagulated. Absolute risk reduction 11.4% (95% CI −1.5 to 26.7)Small number of patients studied.
Not powered for detection of clinical outcomes (feasibility trial).
High rate of allocation crossover as open label methodology.
Low median time in therapeutic range for those anticoagulated compared with other international standards.
Composite outcome used potentially overestimates clinical benefit.
Utter et al, 2016,10 USA384 patients with isolated distal DVT confirmed by ultrasound. Therapeutic anticoagulation given in 243 patients, 141 control patients (of whom >50% received prophylactic dose low molecular weight heparin).Retrospective cohort studyProximal DVT or PE within 180 days of diagnosisProximal DVT in 5% of controls and 1.6% of anticoagulation recipients. PE in 4.3% of controls and 1.6% of anticoagulation recipients. Anticoagulation is associated with decreased risk for VTE-related complication at 180 days (OR 0.34; 95% CI 0.14 to 0.83) but increased bleeding risk (OR 4.35; 95% CI 1.27 to 14.9).Retrospective chart review in single centre.
Testing for proximal DVT and PE not standardised and not performed in all patients.
57.4% of controls received prophylactic anticoagulation; therefore, not true controls.
Unable to differentiate anticoagulation for calf DVT from concomitant conditions in some patients. Bleeding episodes far higher than other reported studies (8.6%) probably because not standardised and recorded as ‘clinically relevant’ in a subjective manner.
Righini et al, 2016,7 SwitzerlandLow-risk (without active cancer or prior venous thromboembolic disease) outpatients with a symptomatic isolated calf DVT.International multi-centre, prospective double-blind randomised controlled trial comparing therapeutic nadroparin with placebo over a 6-week treatment period.The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT and symptomatic pulmonary embolism by day 42 in the modified intention-to-treat population.There was no significant difference between the groups in the composite primary outcome, which occurred in four patients (3%) in the nadroparin group and in seven (5%) in the placebo group (risk difference −2·1%; 95% CI −7·8 to 3.5; p=0.54)Only enrolled <50% of predicted sample size; terminated early due to slow recruitment and expiration of study drug. Atypical drug regimen. Nadroparin not used in the UK. Pre-selected low-risk cohort—patients with active risk factors for extension excluded from recruitment. Limited duration of treatment and follow-up compared with comparable trials.
The primary safety outcome was major or clinically relevant non-major bleeding at day 42Bleeding occurred in five patients (4%) in the nadroparin group and no patients in the placebo group (risk difference 4.1; 95% CI 0.4 to 9.2; p=0.0255)
  • DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolic event.