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survived 2 weeks or more after subcortical lacunar ischaemic stroke. Systolic blood pressure should be lowered gradually and cautiously, in view of the potential for serious complications related to hypotension. Researchers should assess further the safety and effectiveness of this target in survivors of other ischaemic stroke subtypes and of haemorrhagic stroke, and continue to explore the effects of blood-pressure lowering in patients with acute ischaemic or haemorrhagic stroke.14,15
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Graeme J Hankey
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School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia
[email protected]
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I declare that I have no conflicts of interest. 1
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Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338: b1665. Rothwell PM, Algra A, Amarenco P. Medical treatment in acute and longterm secondary prevention after transient ischaemic attack and ischaemic stroke. Lancet 2011; 377: 1681–92. Chapman N, Huxley R, Anderson C, et al, for the Writing Committee for the PROGRESS Collaborative Group. Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial. Stroke 2004; 35: 116–21. Hankey GJ, Gubbay SS. Focal cerebral ischaemia and infarction due to antihypertensive therapy. Med J Aust 1987; 46: 412–14. Rothwell PM, Howard SC, Spence JD, for the Carotid Endarterectomy Trialists’ Collaboration. Relationship between blood pressure and stroke risk in patients with symptomatic carotid occlusive disease. Stroke 2003; 34: 2583–90.
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Aries MJ, Elting JW, De Keyser J, Kremer BP, Vroomen PC. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. Stroke 2010; 41: 2697–704. Furie KL, Kasner SE, Adams RJ, et al, for the American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42: 227–76. European Stroke Organisation (ESO) Executive Committee, ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25: 457–507. The SPS3 Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; published online May 29. http://dx.doi.org/10.1016/S0140-6736(13)60852-1. Arima H, Anderson C, Omae T, et al, for the PROGRESS Collaborative Group. Perindopril-based blood pressure lowering reduces major vascular events in Asian and Western participants with cerebrovascular disease: the PROGRESS trial. J Hypertens 2010; 28: 395–400. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010; 375: 895–905. Webb AJS, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010; 375: 906–15. Hackshaw A, Kirkwood A. Interpreting and reporting clinical trials with results of borderline significance. BMJ 2011; 343: d3340. ENOS Trial Investigators. Glyceryl trinitrate vs. control, and continuing vs stopping temporarily prior antihypertensive therapy, in acute stroke: rationale and design of the Efficacy of Nitric Oxide in Stroke (ENOS) trial (ISRCTN99414122). Int J Stroke 2006; 1: 245–49. Delcourt C, Huang Y, Wang J, et al, for the INTERACT2 Investigators. The second (main) phase of an open, randomised, multicentre study to investigate the effectiveness of an intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT2). Int J Stroke 2010; 5: 110–16.
Biophoto Associates/Science Photo Library
Intermittent pneumatic compression in patients with stroke
Published Online May 31, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)61099-5 See Articles page 516 Copyright © S M Stevens and S C Woller. Open Access article distributed under the terms of CC BY-NC-ND
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A patient with acute stroke has just been admitted who is immobile, and cannot walk to the bathroom without help. Looking at the patient’s unmoving legs the risk of thrombosis is clear, but a low molecular weight heparin (LMWH) might lead to bleeding, and elastic compression stockings cause skin problems. So you settle on intermittent pneumatic compression devices (IPCs)—but do they actually prevent blood clots? Decades after IPCs were first reported to prevent venous thromboembolism (VTE) in surgical patients, Martin Dennis and colleagues1 present the results of the randomised CLOTS 3 trial in The Lancet, showing that IPCs reduce the risk of VTE in immobilised medical inpatients who have had a stroke. VTE is among the most significant complications associated with hospital stay.2 Several entities recommend strategies to prevent hospital-acquired VTE;3,4
indeed, the US Center for Medicare Services does not compensate hospitals for treating VTEs acquired in hospital or diagnosed in the month after discharge. Yet VTE prevention measures are persistently underused, and their use is substantially lower in medical inpatients than in surgical inpatients.5 Is it surprising that three-quarters of hospital-acquired VTEs occur in medical patients?6 There are several reasons doctors fail to provide prophylaxis. One could simply forget; or hesitate to use an anticoagulant because of a fear of excessive bleeding. Medical patients often have disorders that place them at high risk of bleeding and can require invasive procedures, sometimes at short notice. Although regulatory bodies dictate use of pharmacological prophylaxis in ever-larger populations of medical inpatients, recent trials have shown a very tight balance www.thelancet.com Vol 382 August 10, 2013
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between preventing VTE and causing bleeding.7 In patients who have had a stroke, anticoagulant prophylaxis causes a 0·6% absolute increase in major bleeding, whereas the degree of protection against VTE is debated.7,8 IPCs, which do not increase bleeding risk, are therefore attractive. IPCs are often used in non-surgical patients, on the basis of indirect evidence from surgical populations. However, the benefits seen in surgical patients cannot be assumed to translate to medical patients. Elastic compression stockings were reported to cause net harm in patients who have had a stroke,9,10 despite studies showing net benefit in surgical patients. Direct evidence has been needed. To our knowledge, CLOTS 3 is the highest quality, and by far the largest, study to date of IPC use for VTE prophylaxis in non-surgical patients. It enrolled immobile (ie, unable to walk to the toilet without assistance) patients admitted with stroke. Patients were randomly assigned to either not receive IPC or to receive open-label IPCs (given the impracticality of masking this intervention), which were continued for a minimum of 30 days, until the patient regained mobility or was discharged. Background prophylaxis with additional methods was allowed, and anticoagulant prophylaxis or therapeutic anticoagulation was given to about a third of patients in both intervention groups. 118 (8%) of 1438 patients allocated IPCs and 42 (3%) of 1438 control patients also used elastic stockings. Thrombotic outcomes were assessed by mandatory screening ultrasound on days 7–10 and 25–30 and by objective assessment if VTE symptoms arose. Masked assessors did the ultrasounds. The investigators paid careful attention to the randomisation scheme, and patients’ characteristics were well balanced between study groups. IPC use resulted in an absolute risk reduction of 3·6% (95% CI 1·4–5·8) of the primary outcome of all proximal deep vein thrombosis (DVT) by day 30 compared with no IPC use. Most other thrombotic outcomes were also significantly reduced with IPC use. Although the trial was not powered to show a significant reduction in either pulmonary embolism or death, the IPC group appeared to be favoured compared with the no IPC group. Skin breaks occurred more frequently in the IPC group than in the no IPC group, and a non-significant increase in falls with injury was noted in the IPC group. www.thelancet.com Vol 382 August 10, 2013
The trial has several limitations. The prospective, randomised, open, blinded endpoint (PROBE) design is subject to bias, but a double-blind design for an IPC study would be impractical. Both the size of the study and the design of the IPC device were changed during trial execution; but neither change is likely to have materially affected the results. The rate of symptomatic (vs asymptomatic) DVT was unexpectedly high, which could be attributed to the method of ascertainment (clinicians were asked to indicate if DVT symptoms were present after completion of the scheduled screening ultrasound tests). Had more traditional methodology been used, more DVTs would have been classified as asymptomatic, and a smaller reduction in symptomatic DVT would probably have been reported. How well asymptomatic DVT predicts the risk of symptomatic VTE is debated, but asymptomatic DVT is a common trial endpoint.11 IPCs are hard to keep on patients;12 and adherence issues were noted in the trial. Perfect adherence (IPC use for the entire intended duration) occurred in less than a third of patients. Moreover, adherence was monitored by nurses who were asked to assess IPC use three times a day; yet adherence was counted in whole days. This method probably yielded an incomplete picture of actual device use. Outside a trial, IPC adherence might be even worse, leading to less benefit. Future studies should explore methods to improve device compliance, and could use technology that continually monitors IPC use.13 Nonetheless, CLOTS 3 has convinced us, and we will prescribe IPCs to patients who have had a stroke and are immobile in hospital. The benefit of IPCs in reducing VTE outweighs the risk of skin complications. More studies of IPCs in other medical inpatients are needed, but it could be years until similar high-quality evidence is available. Until then, CLOTS 3 provides reassurance to clinicians who choose to prescribe IPCs to immobilised medical inpatients without stroke. *Scott M Stevens, Scott C Woller Thrombosis Clinic, Intermountain Medical Center, Murray, UT 84107, USA; and Department of Medicine, University of Utah, Salt Lake City, UT, USA
[email protected] We declare that we have no conflicts of interest. 1
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 2013; published online May 31. http://dx.doi.org/10.1016/S0140-6736(13)61050-8.
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Zhan C, Miller MR. Excess length of stay, charges, and mortality attributable to medical injuries during hospitalization. JAMA 2003; 290: 1868–74. Wakefield TW, McLafferty RB, Lohr JM, Caprini JA, Gillespie DL, Passman MA. Call to action to prevent venous thromboembolism. J Vasc Surg 2009; 49: 1620–23. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients. Chest 2012; 141 (2 suppl): e195S–226S. Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371: 387–94. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809–15. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med 2011; 155: 602–15. Bath PM, Iddenden R, Bath FJ. Low-molecular-weight heparins and heparinoids in acute ischemic stroke : a meta-analysis of randomized controlled trials. Stroke 2000; 31: 1770–78.
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Dennis M, Sandercock PA, Reid J, et al. 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: 1958–65. The CLOTS (Clots in Legs Or sTockings after Stroke) Trial Collaboration. Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: a randomized trial. Ann Intern Med 2010; 153: 553–62. Bounameaux H, Agnelli G. Symptoms and clinical relevance: a dilemma for clinical trials on prevention of venous thromboembolism. Thromb Haemost 2013; 109: 585–88. Bockheim HM, McAllen KJ, Baker R, Barletta JF. Mechanical prophylaxis to prevent venous thromboembolism in surgical patients: a prospective trial evaluating compliance. J Crit Care 2009; 24: 192–96. Colwell CW Jr, Froimson MI, Mont MA, et al. Thrombosis prevention after total hip arthroplasty: a prospective, randomized trial comparing a mobile compression device with low-molecular-weight heparin. J Bone Joint Surg Am 2010; 92: 527–35.
Andrew Aitchison/In Pictures/Corbis
Early nutrition and adult outcomes: pieces of the puzzle
Published Online March 28, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)60716-3 See Articles page 525
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The association between nutrition in early life and long-term health has been of interest for decades. Since the articulation of the fetal origins hypothesis by David Barker and colleagues,1 there has been debate about the implications of fetal undernutrition and early childhood growth on outcomes of importance in adult health and risks of chronic diseases. Both epidemiological and animal studies have shown that the risk of metabolic syndrome is significantly increased after exposure to suboptimum nutrition during crucial periods of development.1 The importance of these findings greatly increased after reports about the global burden of non-communicable diseases and risk factors were published in December, 2012.2 Evidence for the importance of early nutrition for adult outcomes was derived initially from observational cohort studies3 and was reaffirmed by analysis of outcome data from several cohort studies in 2008.4 This analysis4 was focused on a meta-analysis of coefficients from different sites: birthweight, weight and length Z scores, and stunting at age 2 years. In The Lancet, Linda Adair and colleagues5 report findings from a study in which they pooled data from five birth cohorts and investigated how linear growth and relative weight gain in several age ranges affected adult outcomes. They report that higher birthweight was associated with an adult body-mass index of greater than 25 kg/m² (odds ratio 1·28, 95% CI 1·21–1·35) and a reduced likelihood of short
stature (0·49, 0·44–0·54) and of not completing secondary school (0·82, 0·78–0·87). Faster linear growth was also strongly associated with reduced likelihood of short adult stature (age 2 years: 0·23, 0·20–0·52; mid-childhood 0·39, 0·36–0·43) and of not completing secondary school (age 2 years: 0·74, 0·67–0·78; mid-childhood 0·87, 0·83–0·92). Faster relative weight gain was associated with an increased risk of adult overweight (age 2 years: 1·51, 1·43–1·60; mid-childhood 1·76, 1·69–1·91) and elevated blood pressure (age 2 years: 1·07, 1·01–1·13; mid-childhood: 1·22, 1·15–1·30). Notwithstanding the key findings, several limitations of this pooled analysis should be recognised. The authors had to make do with disparate information about socioeconomic status and income, and impute some information that was missing. Although they adjusted for maternal education and socioeconomic status (largely assets rather than income), other potential confounding factors (eg, household and learning environment) could not be assessed in relation to attained schooling. Several additional limitations preclude firm conclusions. Little or no information was available about maternal nutrition and micronutrient status. Additionally, Adair and colleagues do not report any outcomes related to intrauterine growth retardation or gestational age at birth, and merely report association with birthweight, which might be oversimplified. Being small for www.thelancet.com Vol 382 August 10, 2013
