Comment
3 4 5
6 7
8
Langendorff O. Untersuchungen am überlebenden säugethierherzen. Pflügers Arch 1895; 61: 291–332. Zimmer HG. The isolated perfused heart and its pioneers. News Physiol Sci 1998; 13: 203–10. Ardehali A, Esmailian F, Deng M, et al, for the PROCEED II trial investigators. Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial. Lancet 2015; published online April 15. http://dx.doi.org/10.1016/S0140-6736(15)60261-6. Quader MA, Wolfe LG, Kasirajan V. Heart transplantation outcomes from cardiac arrest-resuscitated donors. J Heart Lung Transplant 2013; 32: 1090–95. Hamed A, Tsui S, Huber J, Lin R, Poggio EC, Ardehali A. Serum lactate is a highly sensitive and specific predictor of post cardiac transplant outcomes using the Organ Care System. J Heart Lung Transplant 2009; 28: S71. Stamp NL, Shah A, Vincent V, et al. Successful heart transplant after ten hours out-of-body time using the TransMedics Organ Care System. Heart Lung Circ 2015; published online Feb 5. DOI:10.1016/j.hlc.2015.01.005.
9
10 11
12
13
Messer S, Ardehali A, Tsui S. Normothermic donor heart perfusion: current clinical experience and the future. Transpl Int 2014; published online May 23. DOI:10.1111/tri.12361. Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab 2009; 297: E578–91. Iyer A, Gao L, Doyle A, et al. Increasing the tolerance of DCD hearts to warm ischemia by pharmacological postconditioning. Am J Transplant 2014; 14: 1744–52. Iyer A, Gao L, Doyle A, et al. Normothermic ex vivo perfusion provides superior organ preservation and enables viability assessment of hearts from DCD donors. Am J Transplant 2015; 15: 371–80. Gallagher J. Surgeons transplant heart that had stopped beating. Oct 24, 2014. http://www.bbc.co.uk/news/health-29751880 (accessed March 9, 2015).
Cardiac donation after circulatory death: a time to reflect Published Online April 15, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60683-3 This online publication has been corrected. The corrected version first appeared at thelancet.com on April 27, 2015 See Articles page 2585
Heart transplantation is a cost-effective method of enhancing quality of life and survival.1 However, this procedure depends on the generosity and support of the community in making organs available for donation. Unfortunately, the availability of organs is a major challenge, resulting in unnecessary death and suffering. Progress in finding new solutions has been patchy, Latvia UK Netherlands Belgium Australia Spain Canada France Russia Switzerland Ireland Austria Japan Czech Republic Romania Italy Mexico 0
2
4
6
8
10
12
14
Donors (per million people)
Figure: Number of donors after cardiac death per million people Data from International Registry in Organ Donation and Transplantation report, October 2013; data provided from each national organisation to www.Irodat.org.6
2554
episodic, and very slow—the number of cardiac and multiorgan donations has remained almost constant during the past 20 years and varies widely between countries.2 Solving this problem will need a collective integrated effort to address some difficult issues surrounding transplantation.1 In The Lancet, Kumud Dhital and colleagues3 report the early results of three successful transplantations of hearts donated after circulatory death. Four donors, all aged younger than 40 years, were initially considered, and three, with controlled donation after cardiac death (Maastricht category III),4 were then used for the operations. The fourth donor, a trauma victim, was excluded owing to the time from withdrawal of ventilation to cessation of circulation, and because the warm ischaemic time exceeded the limits for enrolment. After periods of warm ischaemia ranging from 22 to 28 min, ex-vivo perfusion was done with commercially available technology (ie, the TransMedics device) to resuscitate, assess, and transport the donor hearts. Postoperative recovery was moderately prolonged, with one patient needing extracorporeal membrane oxygenation for 3 days. Complete recovery of both right and left ventricular function was reported for all three patients by the end of the study. I congratulate the investigators for their meticulous application of novel techniques after a lengthy experimental programme to refine organ preservation. The use of a novel cardioplegic solution developed during earlier studies was probably instrumental to enhancing recovery in these patients. The adoption of donation after circulatory death has been widely credited with increasing the number www.thelancet.com Vol 385 June 27, 2015
Comment
of available organs for kidney, lung, and liver transplantations by up to 10%.5 As Dhital and colleagues mention, the hope is that it could have a similar effect on heart availability for cardiac transplantation. However, the use of organs donated after circulatory death has varied greatly between different countries (figure),6 and concern is mounting about the increased incidence of ischaemic cholangiopathy after transplantation of livers donated after circulatory death.7 A meta-analysis has shown that the risk of developing ischaemic cholangiopathy is increased in such livers by a factor of 2·4 compared with livers from brain-dead donors.8 The heart is especially vulnerable to ischaemic damage. Dhital and colleagues’ findings3 provide an opportunity to consider some fundamental aspects of cardiac donation, particularly relating to controlled donation after cardiac death following withdrawal of treatment (ie, Maastricht type III). The first issue relates to the definition of death. While adhering to the rule that organ donation should not of itself constitute the cause for donor death, a balance must be found between sensitivity to the needs and feelings of donors and their families, and the need to maintain and maximise the viability of organs for successful transplantation to recipients.9 A potentially worrying observation is the temporary development of a Takotsubo-like cardiomyopathy in one patient.3 This cardiomyopathy is associated with extreme emotional stress,10 and, to my knowledge, has not been previously described in heart donors. It should therefore be further investigated. At present, definitions of circulatory death as an irreversible cessation of mechanical or electrical activity of the heart involve a variable period of deteriorating circulatory state, followed by 3–5 min (depending on the guidelines) of total circulatory arrest.11 This definition results in varying degrees of ischaemic damage to the myocardium, which might be irreversible or which can require prolonged resuscitation of the donor heart without guaranteed adequate organ recovery. A re-examination of the definition of death might be beneficial not only for improving organ viability for cardiac transplantation, but also for considering organ donation in relation to other ethically fraught areas of medicine, such as donors with anencephaly12 or those in a permanent vegetative state.13 A second issue raised by Dhital and colleagues’ study3 is the use of ex-vivo perfusion for resuscitating so-called www.thelancet.com Vol 385 June 27, 2015
marginal donors. Roughly 60% of hearts offered for transplantation are not used because of dysfunction.14 Therefore, at least in theory, refinement of this technology, coupled with advances in cell biology and regeneration,15 could substantially increase the number and quality of available organs. The report by Dhital and colleagues3 once again shows the need for both a continued frank discussion and an integrated effort by opinion leaders, professionals, patient representatives, and society as a whole to confront the dilemma: balancing protection and sensitivity to donors with the need to increase the availability of viable donor hearts for transplantation. This discussion should revisit a consensus position on the definition of death itself. Furthermore, the latest advances in scientific knowledge need to be adopted to prevent and reverse organ damage, and to modify donor organ function, in order to maximise the availability and benefits of heart transplantation worldwide. Magdi Yacoub Magdi Yacoub Institute, Imperial College London, London UB9 6JH, UK [email protected] I declare no competing interests. 1 2 3
4 5 6
7
8
9 10
11
12
Yacoub M. Heart transplantation: the end of the beginning. Am J Transplant 2008; 8: 1767–68. Rodsenblum AM, Li AHT, Garg AX. Worldwide variability in deceased organ donation registries. Transpl Int 2012; 25: 801–11. Dhital KK, Iyer A, Connellan M, et al. Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series. Lancet 2015; published online April 15. http://dx.doi.org/10.1016/S0140-6736(15)60038-1. Dunne K, Doherty P. Donation after circulatory death. Contin Educ Anaesth Crit Care Pain 2011; 11: 82–86. Immer FF. Organ donation after circulatory death in Switzerland: slow but constant progress. Swiss Med Wkly 2015; 145: w14062. International Registry in Organ Donation and Transplantation. Final numbers 2012. October, 2013. http://www.irodat.org/img/database/grafics/ newsletter/IRODaT%20Newsletter%202012.pdf (accessed March 31, 2015). Chan EY, Olson LC, Kisthard JA, et al. Ischemic cholangiopathy following liver transplantation from donation after cardiac death. Liver Transpl 2008; 14: 604–10. Jay CL, Lyuksemburg V, Ladner DP, et al. Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation: a meta-analysis. Ann Surg 2011; 253: 259–64. Truog RD, Miller FG, Halpern SD. The dead donor rule and the future of organ donation. N Engl J Med 2013; 369: 1287–89. Spadotto V, Elmaghawry M, Zorzi A, Migliore F, Marra MP. Apical ballooning with mid-ventricular obstruction: the many faces of Takotsubo cardiomyopathy. Glob Cardiol Sci Pract 2013; 2013: 163–68. Working Party of the British Transplantation Society. United Kingdom guidelines: transplantation from donors after deceased circulatory death. June, 2013. http://www.bts.org.uk/Documents/FINAL%20July%20 2013%20DCD%20guidelines.pdf (accessed March 25, 2015). Gilman SJ. The use of anencephalic infants as an organ source: an on-going question. Elon L Rev 2012; 4: 71–92.
2555
Comment
13
14
Hoffenberg R, Lock M, Tiney N, et al. Should organs from patients in permanent vegetative state be used for transplantation? Lancet 1997; 350: 1320–21. Zaroff JG, Rosengard BR, Armstrong WF, et al. Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations: March 28–29, 2001, Crystal City, Va. Circulation 2002; 106: 836–41.
15
Raynaud CM, Ahmad FS, Allouba M, Abou-Saleh H, Liu KO, Yacoub M. Reprogramming for cardiac regeneration. Glob Cardiol Sci Pract 2014; 44: 309–29.
ASTIER/BSIP/BSIP/Corbis
The case for stepped-wedge studies: a trial of falls prevention
Published Online April 10, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)62288-1 See Articles page 2592
2556
To do no harm is a fundamental tenet of clinical practice. Falls are harmful, especially for elderly people, because they can result in loss of confidence and permanent restriction of mobility. This is particularly the case in hospital settings, where hard flooring, sharp-edged furniture, and moveable bed furniture all increase the potential for serious injury. Patients are, by being in hospital, in a state of vulnerability. Disorientation, delirium, and weakness can increase the risk of falls. In The Lancet, Anne-Marie Hill and colleagues1 show the effectiveness of a physiotherapy-led intervention that decreases the probability of falling and injury in the rehabilitation hospital setting. The intervention overcomes the difficulties of generalisation that are commonly noted in fall prevention strategies that have been developed in community-dwelling populations and translated into hospital settings.2 The approach of the intervention is one of individualised education, promotion of risk-reduction strategies through supervised activity, and recognition of the risk of falls for each individual. It involves both staff and patients in a heightened state of vigilance. Patients were followed up to the point of hospital discharge, but not beyond. The targeting of knowledge of risky situations and behaviours in such an explicit manner could have either short-term or lasting effects on activity levels and fear of falling. Studies of levels of physical activity in subacute and hospital rehabilitation settings3,4 have underlined the low levels of activity that patients engage in, and that activity levels could be an important mediator or indicator of successful rehabilitation.3 Fear of falling substantially limits physical activity in older people.4 However, Hill and colleagues1 provide no details on the extent of discharge instructions or postdischarge rehabilitation, or whether the intervention specifically addressed how to regain confidence in mobility and physical activity. After joint replacement, well meant restrictions on specific movements and education
about how to avoid the risk of joint dislocation were found to restrict physical activity to such an extent that recovery of basic function for activities of daily living was impaired.5 Hill and colleagues’ experimental design was a steppedwedge cluster-randomisation. Readers might be unfamiliar with judging the integrity of stepped-wedge designs, and this is only the third instance that such a design has been reported in Lancet journals. The stepped-wedge design is often used in implementation trials and in situations where equipoise is tipped in favour of the intervention.6 It is a difficult design to use, and often bias cannot be controlled by experimental procedure, but rather is estimated through parallel and post-hoc analyses.7 In Hill and colleagues’ study,1 eight separate hospital units were initially randomly assigned to intervention or control groups and, as the study progressed, all units were gradually assigned to the intervention. The substantial disadvantage of this situation is that clusters were not assembled before random assignment; however, the groups seemed well matched, and eight hospitals provide for sufficient study power.7 The ascertainment of falls data might have been affected by the open-label nature of the design. Even with robust masking of the people involved in collecting data from hospital records relevant to the trial, the focus on patient falls might have changed vigilance or behaviour of those involved in the trial, which in turn might have affected the source data, leading to over-reporting rather than under-reporting of falls, hence a tendency for the bias to run toward the null. Secular trends are a particular problem in the analysis of stepped-wedge designs.7 Successive cross-sectional analyses are the most robust method of analysis for these studies,7 but these were not used by Hill and colleagues,1 who instead adjusted data for the baseline rate of falls. Additionally, data showing the stability of fall rates in the control group across time were provided to lend support to the interpretation of the results. Any www.thelancet.com Vol 385 June 27, 2015
3 4 5
6 7
8
Langendorff O. Untersuchungen am überlebenden säugethierherzen. Pflügers Arch 1895; 61: 291–332. Zimmer HG. The isolated perfused heart and its pioneers. News Physiol Sci 1998; 13: 203–10. Ardehali A, Esmailian F, Deng M, et al, for the PROCEED II trial investigators. Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial. Lancet 2015; published online April 15. http://dx.doi.org/10.1016/S0140-6736(15)60261-6. Quader MA, Wolfe LG, Kasirajan V. Heart transplantation outcomes from cardiac arrest-resuscitated donors. J Heart Lung Transplant 2013; 32: 1090–95. Hamed A, Tsui S, Huber J, Lin R, Poggio EC, Ardehali A. Serum lactate is a highly sensitive and specific predictor of post cardiac transplant outcomes using the Organ Care System. J Heart Lung Transplant 2009; 28: S71. Stamp NL, Shah A, Vincent V, et al. Successful heart transplant after ten hours out-of-body time using the TransMedics Organ Care System. Heart Lung Circ 2015; published online Feb 5. DOI:10.1016/j.hlc.2015.01.005.
9
10 11
12
13
Messer S, Ardehali A, Tsui S. Normothermic donor heart perfusion: current clinical experience and the future. Transpl Int 2014; published online May 23. DOI:10.1111/tri.12361. Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab 2009; 297: E578–91. Iyer A, Gao L, Doyle A, et al. Increasing the tolerance of DCD hearts to warm ischemia by pharmacological postconditioning. Am J Transplant 2014; 14: 1744–52. Iyer A, Gao L, Doyle A, et al. Normothermic ex vivo perfusion provides superior organ preservation and enables viability assessment of hearts from DCD donors. Am J Transplant 2015; 15: 371–80. Gallagher J. Surgeons transplant heart that had stopped beating. Oct 24, 2014. http://www.bbc.co.uk/news/health-29751880 (accessed March 9, 2015).
Cardiac donation after circulatory death: a time to reflect Published Online April 15, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60683-3 This online publication has been corrected. The corrected version first appeared at thelancet.com on April 27, 2015 See Articles page 2585
Heart transplantation is a cost-effective method of enhancing quality of life and survival.1 However, this procedure depends on the generosity and support of the community in making organs available for donation. Unfortunately, the availability of organs is a major challenge, resulting in unnecessary death and suffering. Progress in finding new solutions has been patchy, Latvia UK Netherlands Belgium Australia Spain Canada France Russia Switzerland Ireland Austria Japan Czech Republic Romania Italy Mexico 0
2
4
6
8
10
12
14
Donors (per million people)
Figure: Number of donors after cardiac death per million people Data from International Registry in Organ Donation and Transplantation report, October 2013; data provided from each national organisation to www.Irodat.org.6
2554
episodic, and very slow—the number of cardiac and multiorgan donations has remained almost constant during the past 20 years and varies widely between countries.2 Solving this problem will need a collective integrated effort to address some difficult issues surrounding transplantation.1 In The Lancet, Kumud Dhital and colleagues3 report the early results of three successful transplantations of hearts donated after circulatory death. Four donors, all aged younger than 40 years, were initially considered, and three, with controlled donation after cardiac death (Maastricht category III),4 were then used for the operations. The fourth donor, a trauma victim, was excluded owing to the time from withdrawal of ventilation to cessation of circulation, and because the warm ischaemic time exceeded the limits for enrolment. After periods of warm ischaemia ranging from 22 to 28 min, ex-vivo perfusion was done with commercially available technology (ie, the TransMedics device) to resuscitate, assess, and transport the donor hearts. Postoperative recovery was moderately prolonged, with one patient needing extracorporeal membrane oxygenation for 3 days. Complete recovery of both right and left ventricular function was reported for all three patients by the end of the study. I congratulate the investigators for their meticulous application of novel techniques after a lengthy experimental programme to refine organ preservation. The use of a novel cardioplegic solution developed during earlier studies was probably instrumental to enhancing recovery in these patients. The adoption of donation after circulatory death has been widely credited with increasing the number www.thelancet.com Vol 385 June 27, 2015
Comment
of available organs for kidney, lung, and liver transplantations by up to 10%.5 As Dhital and colleagues mention, the hope is that it could have a similar effect on heart availability for cardiac transplantation. However, the use of organs donated after circulatory death has varied greatly between different countries (figure),6 and concern is mounting about the increased incidence of ischaemic cholangiopathy after transplantation of livers donated after circulatory death.7 A meta-analysis has shown that the risk of developing ischaemic cholangiopathy is increased in such livers by a factor of 2·4 compared with livers from brain-dead donors.8 The heart is especially vulnerable to ischaemic damage. Dhital and colleagues’ findings3 provide an opportunity to consider some fundamental aspects of cardiac donation, particularly relating to controlled donation after cardiac death following withdrawal of treatment (ie, Maastricht type III). The first issue relates to the definition of death. While adhering to the rule that organ donation should not of itself constitute the cause for donor death, a balance must be found between sensitivity to the needs and feelings of donors and their families, and the need to maintain and maximise the viability of organs for successful transplantation to recipients.9 A potentially worrying observation is the temporary development of a Takotsubo-like cardiomyopathy in one patient.3 This cardiomyopathy is associated with extreme emotional stress,10 and, to my knowledge, has not been previously described in heart donors. It should therefore be further investigated. At present, definitions of circulatory death as an irreversible cessation of mechanical or electrical activity of the heart involve a variable period of deteriorating circulatory state, followed by 3–5 min (depending on the guidelines) of total circulatory arrest.11 This definition results in varying degrees of ischaemic damage to the myocardium, which might be irreversible or which can require prolonged resuscitation of the donor heart without guaranteed adequate organ recovery. A re-examination of the definition of death might be beneficial not only for improving organ viability for cardiac transplantation, but also for considering organ donation in relation to other ethically fraught areas of medicine, such as donors with anencephaly12 or those in a permanent vegetative state.13 A second issue raised by Dhital and colleagues’ study3 is the use of ex-vivo perfusion for resuscitating so-called www.thelancet.com Vol 385 June 27, 2015
marginal donors. Roughly 60% of hearts offered for transplantation are not used because of dysfunction.14 Therefore, at least in theory, refinement of this technology, coupled with advances in cell biology and regeneration,15 could substantially increase the number and quality of available organs. The report by Dhital and colleagues3 once again shows the need for both a continued frank discussion and an integrated effort by opinion leaders, professionals, patient representatives, and society as a whole to confront the dilemma: balancing protection and sensitivity to donors with the need to increase the availability of viable donor hearts for transplantation. This discussion should revisit a consensus position on the definition of death itself. Furthermore, the latest advances in scientific knowledge need to be adopted to prevent and reverse organ damage, and to modify donor organ function, in order to maximise the availability and benefits of heart transplantation worldwide. Magdi Yacoub Magdi Yacoub Institute, Imperial College London, London UB9 6JH, UK [email protected] I declare no competing interests. 1 2 3
4 5 6
7
8
9 10
11
12
Yacoub M. Heart transplantation: the end of the beginning. Am J Transplant 2008; 8: 1767–68. Rodsenblum AM, Li AHT, Garg AX. Worldwide variability in deceased organ donation registries. Transpl Int 2012; 25: 801–11. Dhital KK, Iyer A, Connellan M, et al. Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series. Lancet 2015; published online April 15. http://dx.doi.org/10.1016/S0140-6736(15)60038-1. Dunne K, Doherty P. Donation after circulatory death. Contin Educ Anaesth Crit Care Pain 2011; 11: 82–86. Immer FF. Organ donation after circulatory death in Switzerland: slow but constant progress. Swiss Med Wkly 2015; 145: w14062. International Registry in Organ Donation and Transplantation. Final numbers 2012. October, 2013. http://www.irodat.org/img/database/grafics/ newsletter/IRODaT%20Newsletter%202012.pdf (accessed March 31, 2015). Chan EY, Olson LC, Kisthard JA, et al. Ischemic cholangiopathy following liver transplantation from donation after cardiac death. Liver Transpl 2008; 14: 604–10. Jay CL, Lyuksemburg V, Ladner DP, et al. Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation: a meta-analysis. Ann Surg 2011; 253: 259–64. Truog RD, Miller FG, Halpern SD. The dead donor rule and the future of organ donation. N Engl J Med 2013; 369: 1287–89. Spadotto V, Elmaghawry M, Zorzi A, Migliore F, Marra MP. Apical ballooning with mid-ventricular obstruction: the many faces of Takotsubo cardiomyopathy. Glob Cardiol Sci Pract 2013; 2013: 163–68. Working Party of the British Transplantation Society. United Kingdom guidelines: transplantation from donors after deceased circulatory death. June, 2013. http://www.bts.org.uk/Documents/FINAL%20July%20 2013%20DCD%20guidelines.pdf (accessed March 25, 2015). Gilman SJ. The use of anencephalic infants as an organ source: an on-going question. Elon L Rev 2012; 4: 71–92.
2555
Comment
13
14
Hoffenberg R, Lock M, Tiney N, et al. Should organs from patients in permanent vegetative state be used for transplantation? Lancet 1997; 350: 1320–21. Zaroff JG, Rosengard BR, Armstrong WF, et al. Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations: March 28–29, 2001, Crystal City, Va. Circulation 2002; 106: 836–41.
15
Raynaud CM, Ahmad FS, Allouba M, Abou-Saleh H, Liu KO, Yacoub M. Reprogramming for cardiac regeneration. Glob Cardiol Sci Pract 2014; 44: 309–29.
ASTIER/BSIP/BSIP/Corbis
The case for stepped-wedge studies: a trial of falls prevention
Published Online April 10, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)62288-1 See Articles page 2592
2556
To do no harm is a fundamental tenet of clinical practice. Falls are harmful, especially for elderly people, because they can result in loss of confidence and permanent restriction of mobility. This is particularly the case in hospital settings, where hard flooring, sharp-edged furniture, and moveable bed furniture all increase the potential for serious injury. Patients are, by being in hospital, in a state of vulnerability. Disorientation, delirium, and weakness can increase the risk of falls. In The Lancet, Anne-Marie Hill and colleagues1 show the effectiveness of a physiotherapy-led intervention that decreases the probability of falling and injury in the rehabilitation hospital setting. The intervention overcomes the difficulties of generalisation that are commonly noted in fall prevention strategies that have been developed in community-dwelling populations and translated into hospital settings.2 The approach of the intervention is one of individualised education, promotion of risk-reduction strategies through supervised activity, and recognition of the risk of falls for each individual. It involves both staff and patients in a heightened state of vigilance. Patients were followed up to the point of hospital discharge, but not beyond. The targeting of knowledge of risky situations and behaviours in such an explicit manner could have either short-term or lasting effects on activity levels and fear of falling. Studies of levels of physical activity in subacute and hospital rehabilitation settings3,4 have underlined the low levels of activity that patients engage in, and that activity levels could be an important mediator or indicator of successful rehabilitation.3 Fear of falling substantially limits physical activity in older people.4 However, Hill and colleagues1 provide no details on the extent of discharge instructions or postdischarge rehabilitation, or whether the intervention specifically addressed how to regain confidence in mobility and physical activity. After joint replacement, well meant restrictions on specific movements and education
about how to avoid the risk of joint dislocation were found to restrict physical activity to such an extent that recovery of basic function for activities of daily living was impaired.5 Hill and colleagues’ experimental design was a steppedwedge cluster-randomisation. Readers might be unfamiliar with judging the integrity of stepped-wedge designs, and this is only the third instance that such a design has been reported in Lancet journals. The stepped-wedge design is often used in implementation trials and in situations where equipoise is tipped in favour of the intervention.6 It is a difficult design to use, and often bias cannot be controlled by experimental procedure, but rather is estimated through parallel and post-hoc analyses.7 In Hill and colleagues’ study,1 eight separate hospital units were initially randomly assigned to intervention or control groups and, as the study progressed, all units were gradually assigned to the intervention. The substantial disadvantage of this situation is that clusters were not assembled before random assignment; however, the groups seemed well matched, and eight hospitals provide for sufficient study power.7 The ascertainment of falls data might have been affected by the open-label nature of the design. Even with robust masking of the people involved in collecting data from hospital records relevant to the trial, the focus on patient falls might have changed vigilance or behaviour of those involved in the trial, which in turn might have affected the source data, leading to over-reporting rather than under-reporting of falls, hence a tendency for the bias to run toward the null. Secular trends are a particular problem in the analysis of stepped-wedge designs.7 Successive cross-sectional analyses are the most robust method of analysis for these studies,7 but these were not used by Hill and colleagues,1 who instead adjusted data for the baseline rate of falls. Additionally, data showing the stability of fall rates in the control group across time were provided to lend support to the interpretation of the results. Any www.thelancet.com Vol 385 June 27, 2015
