Intermittent pneumatic compression after stroke
Authors: Graeme J Hankey
Journal: The Lancet Neurology (2014)

Acute stroke often causes immobility, which predisposes to deep vein thrombosis and pulmonary embolism and these can be fatal or disabling. Low-dose subcutaneous anticoagulation with heparins and heparinoids reduces the risk of venous thromboembolism, but the benefit is offset by haemorrhagic complications.1Geeganage CM Sprigg N Bath MW Bath PMW Balance of symptomatic pulmonary embolism and symptomatic intracerebral hemorrhage with low-dose anticoagulation in recent ischemic stroke: a systematic review and meta-analysis of randomized controlled trials.J Stroke Cerebrovasc Dis. 2013; 22: 1018-1027Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar Even targeting anticoagulation to patients at high risk of venous thromboembolism and low risk of bleeding does not add value because patients at high risk of venous thromboembolism (eg, increased severity of stroke) are also at high risk of bleeding.2Whiteley WN Adams Jr, HP Bath PMW et al.Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials.Lancet Neurol. 2013; 12: 539-545Summary Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 3Dennis M Sandercock P Reid J et al.CLOTS Trials CollaborationCan clinical features distinguish between immobile patients with stroke at high and low risk of deep vein thrombosis? Statistical modelling based on the CLOTS trials cohorts.J Neurol Neurosurg Psychiatry. 2011; 82: 1067-1073Crossref PubMed Scopus (22) Google Scholar Application of graduated compression stockings to the legs is a physical method for the prevention of deep vein thrombosis in patients undergoing surgery, but it was ineffective in immobile patients with acute stroke in the CLOTS (Clots in Legs Or sTockings after Stroke) trials 1 and 2.4The CLOTS Trials CollaborationEffectiveness 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: 1958-1965Summary Full Text Full Text PDF PubMed Scopus (330) Google Scholar, 5The CLOTS Trials CollaborationThigh-length versus below-knee stockings for DVT prophylaxis after stroke: a randomized trial.Ann Int Med. 2010; 153: 553-562Crossref PubMed Scopus (129) Google ScholarIntermittent pneumatic compression (IPC) is another physical method for the prevention of deep vein thrombosis in patients undergoing surgery. In 2013, according to the results of the CLOTS 3 trial, IPC, through thigh-length sleeves worn on both legs for 30 days and nights, was also effective in immobile patients with acute stroke.6Dennis M Sandercock P Reid J Graham C Forbes J Murray G CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffectiveness 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. 2013; 382: 516-524Summary Full Text Full Text PDF PubMed Scopus (219) Google Scholar In The Lancet Neurology, the CLOTS Trials Collaboration now reports the results of a prespecified follow-up analysis of important secondary outcomes of CLOTS 3.7CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffect of intermittent pneumatic compression on disability, living circumstances, quality of life, and hospital costs after stroke: secondary analyses from CLOTS 3, a randomised trial.Lancet Neurology. 2014; (published online Oct 31.)http://dx.doi.org/10.1016/S1474-4422(14)70258-3Google ScholarIn CLOTS 3, allocation to IPC was associated with a reduction in the primary outcome of proximal deep vein thrombosis within 30 days of randomisation by a third compared with no IPC (8·5% vs 12·1%; risk ratio [RR] 0·68, 95% CI 0·54–0·85) and a reduction in the important secondary outcome of symptomatic deep vein thrombosis by a quarter (4·6% vs 6·3%; 0·73, 0·53–0·99).6Dennis M Sandercock P Reid J Graham C Forbes J Murray G CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffectiveness 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. 2013; 382: 516-524Summary Full Text Full Text PDF PubMed Scopus (219) Google Scholar Also, mortality was significantly lower at 6 months after randomisation in patients in the IPC group than in the no IPC group. Although the proportion of patients who had died at the 6 month follow-up was not significantly different between the treatment groups (IPC 23·2% vs no IPC 25·8%; p=0·12), the probability of death up to 6 months after randomisation was significantly lower in the IPC group according to the results of the Cox model survival analysis (hazard ratio 0·86, 95% CI 0·74–0·99; p=0·042).6Dennis M Sandercock P Reid J Graham C Forbes J Murray G CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffectiveness 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. 2013; 382: 516-524Summary Full Text Full Text PDF PubMed Scopus (219) Google Scholar This apparent discrepancy in the mortality has confused some readers. However, the survival analysis is the key analysis because it is more sensitive to a small, yet real, treatment effect of IPC. For example, if all patients in CLOTS 3 are followed up for the next 50 years, the proportion of patients in each group who will have died will be 100%, suggesting that there is no difference in mortality between the treatment groups. Yet, according to the results of a survival analysis there will be a difference in the time to death.After the publication of the primary results of CLOTS 3, IPC has been widely implemented in stroke units because clinicians, for the first time, have felt confident that they now have a safe strategy for the prevention of deep vein thrombosis after stroke. But does a reduction in deep vein thrombosis by a third and in death by a seventh with IPC translate into an improvement in other outcomes that arguably matter more to immobile patients with stroke and their families (ie, long-term disability, living circumstances, and quality of life) and more to hospital managers (ie, hospital costs)?Although the CLOTS 3 was not powered to reliably identify or exclude differences in these secondary outcomes, the main clinical findings from the new secondary analyses are that IPC use reduces the risk of deep vein thrombosis and improves survival, but does not improve disability, likelihood of living at home, quality of life, or quality-adjusted life days over the first 6 months compared with no IPC use. A caveat to these results is that the utility values used to estimate quality of life and quality-adjusted life days were based on the preferences of stroke-free individuals in the UK and might, or might not, reflect the views of patients with stroke or their carers. The main economic results are that IPC use is not expensive (£64·10 per patient or £5·48 per day of treatment), but that it increases overall hospital costs by improving survival and thus increasing the duration of hospital stay.In the IPC group, case fatality was reduced by 3% at 6 months compared with no IPC (23% vs 26%; p=0·12).7CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffect of intermittent pneumatic compression on disability, living circumstances, quality of life, and hospital costs after stroke: secondary analyses from CLOTS 3, a randomised trial.Lancet Neurology. 2014; (published online Oct 31.)http://dx.doi.org/10.1016/S1474-4422(14)70258-3Google Scholar It is presumed, but not reported, that the reduction in case fatality with IPC was due to a reduction in the risk of fatal pulmonary embolism. The survival advantage with IPC was offset, however, by a 4% absolute increase in patients severely disabled (Oxford Handicap Score 5) at 6 months compared with no IPC (22% vs 18%; p=0·013). This finding might be due to chance because it is the result of a post-hoc exploratory analysis. However, it could also be real because the patients who are likely to develop a deep vein thrombosis, and have their life saved by IPC, are also likely to be disabled should they survive; stroke severity is a predictor of both deep vein thrombosis and severe disability.3Dennis M Sandercock P Reid J et al.CLOTS Trials CollaborationCan clinical features distinguish between immobile patients with stroke at high and low risk of deep vein thrombosis? Statistical modelling based on the CLOTS trials cohorts.J Neurol Neurosurg Psychiatry. 2011; 82: 1067-1073Crossref PubMed Scopus (22) Google Scholar, 8Luengo-Fernandez R Paul NL et al.Oxford Vascular StudyPopulation-based study of disability and institutionalization after transient ischemic attack and stroke: 10-year results of the Oxford Vascular Study.Stroke. 2013; 44: 2854-2861Crossref PubMed Scopus (139) Google Scholar If so, the situation is similar to that of decompressive hemicraniectomy for malignant middle-cerebral-artery infarction in patients older than 60 years, whereby early hemicraniectomy significantly increases the probability of survival but most survivors have substantial disability.9Jüttler E Unterberg A Woitzik J et al.DESTINY II InvestigatorsHemicraniectomy in older patients with extensive middle-cerebral-artery stroke.N Engl J Med. 2014; 370: 1091-1100Crossref PubMed Scopus (384) Google Scholar Survival with substantial disability instead of death is an outcome that might be acceptable to some patients and carers whereas it might not be acceptable to others.The CLOTS Trials Collaboration is to be congratulated for completing the long-term follow-up of enrolled patients beyond that required for the primary outcome. The results of this secondary analysis provide important contextual information that tempers the enthusiastic conclusions drawn from the results of the primary efficacy analysis and enrich the evidence base for deciding whether to use or not use IPC. On the one hand, IPC use is an affordable intervention that prevents deep vein thrombosis and saves lives in some immobile patients with stroke who are hospitalised in the UK. On the other hand, IPC use does not improve overall functional outcome or quality-adjusted survival. Whether these findings are generalisable to immobile patients with acute stroke who are managed with IPC outside the UK is uncertain and awaits further study.I declare no competing interests. Acute stroke often causes immobility, which predisposes to deep vein thrombosis and pulmonary embolism and these can be fatal or disabling. Low-dose subcutaneous anticoagulation with heparins and heparinoids reduces the risk of venous thromboembolism, but the benefit is offset by haemorrhagic complications.1Geeganage CM Sprigg N Bath MW Bath PMW Balance of symptomatic pulmonary embolism and symptomatic intracerebral hemorrhage with low-dose anticoagulation in recent ischemic stroke: a systematic review and meta-analysis of randomized controlled trials.J Stroke Cerebrovasc Dis. 2013; 22: 1018-1027Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar Even targeting anticoagulation to patients at high risk of venous thromboembolism and low risk of bleeding does not add value because patients at high risk of venous thromboembolism (eg, increased severity of stroke) are also at high risk of bleeding.2Whiteley WN Adams Jr, HP Bath PMW et al.Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials.Lancet Neurol. 2013; 12: 539-545Summary Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 3Dennis M Sandercock P Reid J et al.CLOTS Trials CollaborationCan clinical features distinguish between immobile patients with stroke at high and low risk of deep vein thrombosis? Statistical modelling based on the CLOTS trials cohorts.J Neurol Neurosurg Psychiatry. 2011; 82: 1067-1073Crossref PubMed Scopus (22) Google Scholar Application of graduated compression stockings to the legs is a physical method for the prevention of deep vein thrombosis in patients undergoing surgery, but it was ineffective in immobile patients with acute stroke in the CLOTS (Clots in Legs Or sTockings after Stroke) trials 1 and 2.4The CLOTS Trials CollaborationEffectiveness 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: 1958-1965Summary Full Text Full Text PDF PubMed Scopus (330) Google Scholar, 5The CLOTS Trials CollaborationThigh-length versus below-knee stockings for DVT prophylaxis after stroke: a randomized trial.Ann Int Med. 2010; 153: 553-562Crossref PubMed Scopus (129) Google Scholar Intermittent pneumatic compression (IPC) is another physical method for the prevention of deep vein thrombosis in patients undergoing surgery. In 2013, according to the results of the CLOTS 3 trial, IPC, through thigh-length sleeves worn on both legs for 30 days and nights, was also effective in immobile patients with acute stroke.6Dennis M Sandercock P Reid J Graham C Forbes J Murray G CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffectiveness 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. 2013; 382: 516-524Summary Full Text Full Text PDF PubMed Scopus (219) Google Scholar In The Lancet Neurology, the CLOTS Trials Collaboration now reports the results of a prespecified follow-up analysis of important secondary outcomes of CLOTS 3.7CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffect of intermittent pneumatic compression on disability, living circumstances, quality of life, and hospital costs after stroke: secondary analyses from CLOTS 3, a randomised trial.Lancet Neurology. 2014; (published online Oct 31.)http://dx.doi.org/10.1016/S1474-4422(14)70258-3Google Scholar In CLOTS 3, allocation to IPC was associated with a reduction in the primary outcome of proximal deep vein thrombosis within 30 days of randomisation by a third compared with no IPC (8·5% vs 12·1%; risk ratio [RR] 0·68, 95% CI 0·54–0·85) and a reduction in the important secondary outcome of symptomatic deep vein thrombosis by a quarter (4·6% vs 6·3%; 0·73, 0·53–0·99).6Dennis M Sandercock P Reid J Graham C Forbes J Murray G CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffectiveness 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. 2013; 382: 516-524Summary Full Text Full Text PDF PubMed Scopus (219) Google Scholar Also, mortality was significantly lower at 6 months after randomisation in patients in the IPC group than in the no IPC group. Although the proportion of patients who had died at the 6 month follow-up was not significantly different between the treatment groups (IPC 23·2% vs no IPC 25·8%; p=0·12), the probability of death up to 6 months after randomisation was significantly lower in the IPC group according to the results of the Cox model survival analysis (hazard ratio 0·86, 95% CI 0·74–0·99; p=0·042).6Dennis M Sandercock P Reid J Graham C Forbes J Murray G CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffectiveness 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. 2013; 382: 516-524Summary Full Text Full Text PDF PubMed Scopus (219) Google Scholar This apparent discrepancy in the mortality has confused some readers. However, the survival analysis is the key analysis because it is more sensitive to a small, yet real, treatment effect of IPC. For example, if all patients in CLOTS 3 are followed up for the next 50 years, the proportion of patients in each group who will have died will be 100%, suggesting that there is no difference in mortality between the treatment groups. Yet, according to the results of a survival analysis there will be a difference in the time to death. After the publication of the primary results of CLOTS 3, IPC has been widely implemented in stroke units because clinicians, for the first time, have felt confident that they now have a safe strategy for the prevention of deep vein thrombosis after stroke. But does a reduction in deep vein thrombosis by a third and in death by a seventh with IPC translate into an improvement in other outcomes that arguably matter more to immobile patients with stroke and their families (ie, long-term disability, living circumstances, and quality of life) and more to hospital managers (ie, hospital costs)? Although the CLOTS 3 was not powered to reliably identify or exclude differences in these secondary outcomes, the main clinical findings from the new secondary analyses are that IPC use reduces the risk of deep vein thrombosis and improves survival, but does not improve disability, likelihood of living at home, quality of life, or quality-adjusted life days over the first 6 months compared with no IPC use. A caveat to these results is that the utility values used to estimate quality of life and quality-adjusted life days were based on the preferences of stroke-free individuals in the UK and might, or might not, reflect the views of patients with stroke or their carers. The main economic results are that IPC use is not expensive (£64·10 per patient or £5·48 per day of treatment), but that it increases overall hospital costs by improving survival and thus increasing the duration of hospital stay. In the IPC group, case fatality was reduced by 3% at 6 months compared with no IPC (23% vs 26%; p=0·12).7CLOTS (Clots in Legs Or sTockings after Stroke) Trials CollaborationEffect of intermittent pneumatic compression on disability, living circumstances, quality of life, and hospital costs after stroke: secondary analyses from CLOTS 3, a randomised trial.Lancet Neurology. 2014; (published online Oct 31.)http://dx.doi.org/10.1016/S1474-4422(14)70258-3Google Scholar It is presumed, but not reported, that the reduction in case fatality with IPC was due to a reduction in the risk of fatal pulmonary embolism. The survival advantage with IPC was offset, however, by a 4% absolute increase in patients severely disabled (Oxford Handicap Score 5) at 6 months compared with no IPC (22% vs 18%; p=0·013). This finding might be due to chance because it is the result of a post-hoc exploratory analysis. However, it could also be real because the patients who are likely to develop a deep vein thrombosis, and have their life saved by IPC, are also likely to be disabled should they survive; stroke severity is a predictor of both deep vein thrombosis and severe disability.3Dennis M Sandercock P Reid J et al.CLOTS Trials CollaborationCan clinical features distinguish between immobile patients with stroke at high and low risk of deep vein thrombosis? Statistical modelling based on the CLOTS trials cohorts.J Neurol Neurosurg Psychiatry. 2011; 82: 1067-1073Crossref PubMed Scopus (22) Google Scholar, 8Luengo-Fernandez R Paul NL et al.Oxford Vascular StudyPopulation-based study of disability and institutionalization after transient ischemic attack and stroke: 10-year results of the Oxford Vascular Study.Stroke. 2013; 44: 2854-2861Crossref PubMed Scopus (139) Google Scholar If so, the situation is similar to that of decompressive hemicraniectomy for malignant middle-cerebral-artery infarction in patients older than 60 years, whereby early hemicraniectomy significantly increases the probability of survival but most survivors have substantial disability.9Jüttler E Unterberg A Woitzik J et al.DESTINY II InvestigatorsHemicraniectomy in older patients with extensive middle-cerebral-artery stroke.N Engl J Med. 2014; 370: 1091-1100Crossref PubMed Scopus (384) Google Scholar Survival with substantial disability instead of death is an outcome that might be acceptable to some patients and carers whereas it might not be acceptable to others. The CLOTS Trials Collaboration is to be congratulated for completing the long-term follow-up of enrolled patients beyond that required for the primary outcome. The results of this secondary analysis provide important contextual information that tempers the enthusiastic conclusions drawn from the results of the primary efficacy analysis and enrich the evidence base for deciding whether to use or not use IPC. On the one hand, IPC use is an affordable intervention that prevents deep vein thrombosis and saves lives in some immobile patients with stroke who are hospitalised in the UK. On the other hand, IPC use does not improve overall functional outcome or quality-adjusted survival. Whether these findings are generalisable to immobile patients with acute stroke who are managed with IPC outside the UK is uncertain and awaits further study. I declare no competing interests. Effect of intermittent pneumatic compression on disability, living circumstances, quality of life, and hospital costs after stroke: secondary analyses from CLOTS 3, a randomised trialIPC is inexpensive, prevents deep vein thrombosis, improves survival but not functional outcomes, and does not lead to a significant gain in quality-adjusted survival. When deciding whether to treat patients with IPC, clinicians need to take into account all these potential effects. Full-Text PDF Open Access