The Clots in Legs Or sTockings after Stroke (CLOTS) 3 trial: a randomised controlled trial to determine whether or not intermittent pneumatic compression reduces the risk of post-stroke deep vein thrombosis and to estimate its cost-effectiveness

Abstract

BackgroundVenous thromboembolism (VTE) is a common cause of death and morbidity in stroke patients. There are few data concerning the effectiveness of intermittent pneumatic compression (IPC) in treating patients with stroke.ObjectivesTo establish whether or not the application of IPC to the legs of immobile stroke patients reduced their risk of deep vein thrombosis (DVT).DesignClots in Legs Or sTockings after Stroke (CLOTS) 3 was a multicentre, parallel-group, randomised controlled trial which allocated patients via a central randomisation system to IPC or no IPC. A technician blinded to treatment allocation performed compression duplex ultrasound (CDU) of both legs at 7–10 days and 25–30 days after enrolment. We followed up patients for 6 months to determine survival and later symptomatic VTE. Patients were analysed according to their treatment allocation.SettingWe enrolled 2876 patients in 94 UK hospitals between 8 December 2008 and 6 September 2012.ParticipantsInclusion criteria: patients admitted to hospital within 3 days of acute stroke and who were immobile on the day of admission (day 0) to day 3. Exclusion criteria: age < 16 years; subarachnoid haemorrhage; and contra-indications to IPC including dermatitis, leg ulcers, severe oedema, severe peripheral vascular disease and congestive cardiac failure.InterventionsParticipants were allocated to routine care or routine care plus IPC for 30 days, or until earlier discharge or walking independently.Main outcome measuresThe primary outcome was DVT in popliteal or femoral veins, detected on a screening CDU, or any symptomatic DVT in the proximal veins, confirmed by imaging, within 30 days of randomisation. The secondary outcomes included death, any DVTs, symptomatic DVTs, pulmonary emboli, skin breaks on the legs, falls with injury or fractures and duration of IPC use occurring within 30 days of randomisation and survival, symptomatic VTE, disability (as measured by the Oxford Handicap Scale), quality of life (as measured by the European Quality of Life-5 Dimensions 3 Level questionnaire) and length of initial hospital stay measured 6 months after randomisation.ResultsWe allocated 1438 patients to IPC and 1438 to no IPC. The primary outcome occurred in 122 (8.5%) of 1438 patients allocated to IPC and 174 (12.1%) of 1438 patients allocated to no IPC, giving an absolute reduction in risk of 3.6% [95% confidence interval (CI) 1.4% to 5.8%] and a relative risk reduction of 0.69 (95% CI 0.55 to 0.86). After excluding 323 patients who died prior to any primary outcome and 41 who had no screening CDU, the primary outcome occurred in 122 of 1267 IPC participants compared with 174 of 1245 no-IPC participants, giving an adjusted odds ratio of 0.65 (95% CI 0.51 to 0.84;p = 0.001). Secondary outcomes in IPC compared with no-IPC participants were death in the treatment period in 156 (10.8%) versus 189 (13.1%) (p = 0.058); skin breaks in 44 (3.1%) versus 20 (1.4%) (p = 0.002); and falls with injury in 33 (2.3%) versus 24 (1.7%) (p = 0.221). Among patients treated with IPC, there was a statistically significant improvement in survival to 6 months (hazard ratio 0.86, 95% CI 0.73 to 0.99;p = 0.042), but no improvement in disability. The direct cost of preventing a DVT was £1282 per event (95% CI £785 to £3077).ConclusionsIPC is an effective and inexpensive method of reducing the risk of DVT and improving survival in immobile stroke patients.Future researchFurther research should test whether or not IPC improves survival in other groups of high-risk hospitalised medical patients. In addition, research into methods to improve adherence to IPC might increase the benefits of IPC in stroke patients.Trial registrationCurrent Controlled Trials ISRCTN93529999.FundingThe start-up phase of the trial (December 2008–March 2010) was funded by the Chief Scientist Office of the Scottish Government (reference number CZH/4/417). The main phase of the trial was funded by the National Institute for Health Research Health Technology Assessment programme (reference number 08/14/03). Covidien Ltd (Mansfield, MA, USA) lent its Kendall SCD™ Express sequential compression system controllers to the 105 centres involved in the trial and donated supplies of its sleeves. It also provided logistical help in keeping our centres supplied with sleeves and training materials relevant to the use of their devices. Recruitment and follow-up were supported by the National Institute for Health Research-funded UK Stroke Research Network and by the Scottish Stroke Research Network, which was supported by NHS Research Scotland.

Early thrombosis prophylaxis with enoxaparin is not associated with hematoma expansion in patients with spontaneous intracerebral hemorrhage

“…Despite recent recommendations for using intermittent pneumatic compression devices, pharmacological prophylaxis with LMWH remains important due to higher costs, low adherence rates and improved efficacy using devices together with LMWH .…”

“…Patient selection for early DVT prophylaxis seems important as shown in two previous trials excluding patients with hemorrhagic diathesis and secondary causes of ICH [24,25]. Despite recent recommendations for using intermittent pneumatic compression devices, pharmacological prophylaxis with LMWH remains important due to higher costs, low adherence rates and improved efficacy using devices together with LMWH [26,27].…”

Effect of Intermittent Pneumatic Compression on Preventing Deep Vein Thrombosis Among Stroke Patients: A Systematic Review and Meta‐Analysis

“…Overall, there was a significant excess of IPC‐related adverse event among patients allocated to IPC (RR = 2.22, 95% CI [1.32, 3.72]; I 2 = 0%; Figure S4). At the 6‐month follow‐up, 388 of the 1,098 (35.3%) stroke patients allocated to IPC and 396 of the 1,058 (37.4%) allocated to the control group reported swelling of the leg since the stroke (Dennis, Sandercock, Graham, Forbes, & Stroke, ). In addition, 24 of the 1,098 (2.2%) stroke patients allocated to IPC and 19 of the 1,058 (1.8%) allocated to the control group reported having a leg ulcer since the stroke (Dennis et al., ).…”

“…Most adverse events occurred when IPC had been removed, or skin breaks affected the heels (which are not covered by the IPC sleeves) and thus were unlikely to be due to the IPC (Dennis, ). Due to the lack of blinding of the nursing staff, these adverse event data are therefore prone to ascertainment bias (Dennis et al., ). The authors of CLOTS 3 attempted to detect post‐phlebitic leg syndrome including leg swelling and ulcers at the 6‐month follow‐up.…”

“…The authors of CLOTS 3 attempted to detect post‐phlebitic leg syndrome including leg swelling and ulcers at the 6‐month follow‐up. In the 6‐month follow‐up, it is not clear whether these symptoms indicate the development of post‐phlebitis leg syndrome, or if they simply reflect comorbidities such as heart failure or ulcers due to other causes (Dennis et al., ). These questions were unlikely to be specific due to the high frequency of swelling in stroke affected limbs and leg ulcers of other types.…”