By GA Wardle
Reviewed by Alan S. Weinstein, MD, FACP, Senior Physician Advisor, Virtua Fox Chase
Cancer Program, Marlton, NJ
Physical methods for prevention of deep vein thrombosis (DVT)—including intermittent
pneumatic compression (IPC)—have documented efficacy in surgical patients. As recently as
2010, however, a Cochrane review found insufficient evidence to recommend IPC in stroke
patients, calling for larger randomized trials to assess potential risks and benefits in this
population.1 One such study is CLOTS 3, the results from which were presented at the European
Stroke Conference (ESC) in May 2013 and published simultaneously in The Lancet.2
Although venous thromboembolism (VTE) is a common complication of hospitalized medical
and surgical patients, VTE prevention measures are persistently underutilized, especially in
medical patients, in whom the risk-benefit ratio is less certain.2,3 In the UK alone, there are an
estimated 80,000 stroke patients at risk for DVT because they are immobilized. Among these,
10% will experience DVT and 1.5% will have a pulmonary embolus within the first month after
a stroke.4 Hence, the clinical and economic costs of not treating VTE in at-risk patients are
Here’s a brief review of the history of the Clots in Legs Or sTockings after Stroke study: CLOTS
1 failed to show a benefit for thigh-length graduated compression stockings (GCS) in stroke
patients.5 CLOTS 2, which compared thigh-length to calf-length GCS, also failed to find any
benefit for GCS and was halted before enrollment was completed to avoid exposing study
subjects to the discomfort and risk of thigh-length GCS.6 IPC, which includes sleeves that are
inflated one leg at a time to compress the legs at intervals and stimulate venous flow, is thought
to lessen the risk of DVT both by reducing stasis and stimulating release of fibrinolytic factors.2
CLOTS 3 was a large randomized, controlled, multicenter trial that enrolled immobile patients
(N=2876) admitted following stroke.2 Within 3 days of hospitalization, patients were randomly
assigned not to receive IPC or to receive open-label IPC for a minimum of 30 days, or until
restoration of mobility, discharge, or death. The primary outcome was asymptomatic DVT
discovered in the proximal veins by compression duplex ultrasound at 7 to 10 days and 25 to 30
days, or symptomatic DVT in the proximal veins confirmed on imaging within 30 days of
IPC resulted in an absolute risk reduction of 3.6% (95% confidence interval [CI] 1.4 to 4.8). A
somewhat unexpected finding was a nonsignificant reduction in mortality in the IPC group (11%
versus 13%; P=.057). Benefit was found across all patient subgroups, including both
hemorrhagic and ischemic stroke patients. On the negative side, the IPC-treated group had an
increased risk of skin breaks (3% versus 1%, P=.002) and there was a minimal nonsignificant
increase in the risk of falls with injury (33 versus 24, 2% in each group, P=.221).2
“At last we have a simple, safe, and affordable treatment that reduces the risk of DVT and even
appears to reduce the risk of dying after a stroke,” commented Professor Martin Dennis of the
University of Edinburgh, who presented the study at ESC on behalf of the CLOTS Trials
This favorable risk-benefit profile is especially encouraging since issues surrounding the use of
anticoagulant prophylaxis include bleeding risk and uncertain benefit in medical patients.2
Despite a long list of potential study limitations—from the nonblinded nature of the trial to the
method of detecting symptomatic DVT to the lack of IPC adherence—the results of CLOTS 3
appear both valid and generalizable to stroke populations and perhaps to other medical patients
“Finding a way of preventing blood clots from developing in the legs after stroke has been a huge
challenge, with all the research up until now failing to identify a safe and effective treatment to
this common and dangerous complication,” said Professor Tony Rudd, chair of the
Intercollegiate Stroke Working Party at the UK Royal College of Physicians in London. “This
study is a major breakthrough, showing how a simple and safe treatment can save lives. It is one
of the most important research studies to emerge from the field of stroke in recent years.”7
Naccarato M, Chiodo Grandi F, Dennis M, et al. Physical methods for preventing deep vein
thrombosis in stroke. Cochrane Database Syst Rev. 2010 Aug 4;(8):CD001922.
CLOTS (Clots in Legs Or sTockings after Stroke) Trials Collaboration. Effectiveness of
intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who
have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet.
Stevens SM, Woller SC. Intermittent pneumatic compression in patients with stroke. Lancet.
Dennis M, Sandercock P, Reid J, et al; CLOTS Trials Collaboration. Does intermittent
pneumatic compression reduce the risk of post stroke deep vein thrombosis? The CLOTS 3 trial:
study protocol for a randomized controlled trial. Trials. 2012;13:26.
CLOTS Trials Collaboration. Effectiveness of thigh-length graduated compression stockings to
reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised
controlled trial. Lancet. 2009;373:1958-1965.
CLOTS Trials Collaboration. Thigh-length versus below-knee stockings for deep venous
thrombosis prophylaxis after stroke: a randomized trial. Ann Intern Med. 2010;153:553-562.
Hope for stroke patients [press release]. The University of Edinburgh College of Medicine and
Veterinary Medicine. June 3, 2013.
trokepatients310513. Accessed September 3, 2013.