- Email: [email protected]
Donepezil for severe Alzheimer's disease
Comment
Donepezil for severe Alzheimer’s disease
www.thelancet.com Vol 367 April 1, 2006
are based on finding an absolute difference between the treatment arms of 3·5 on the ADCS-ADL-severe and 7 on the SIB. The authors later state that these treatment differences are of “clinical significance”. Even though I doubt these values truly represent minimum important differences, the results obtained do not meet the modest thresholds set by the authors. Winblad and colleagues state that: “if treatment can help patients in the late phase of dementia, without necessarily increasing the length of time they have severe Alzheimer’s disease, then this is a treatment option that should be available.” They are addressing the concern that cholinesterase inhibitors for patients already in a nursing home might increase overall costs, especially if use prolongs survival. They go on to assert, however, that the benefits seen are “not associated with any survival advantage”. This statement is contentious. To buttress their claim, a relatively small community-based observational study is referenced.7 Yet even in this report, those on active treatment tended to live longer than controls (relative risk 0·38, 95% CI 0·14–1·04). A larger retrospective matched-cohort study8 of residents in nursing homes also showed a significantly lower mortality rate in users of donepezil compared with non-users (hazard ratio 0·89, 95% CI 0·83–0·95). Irrespective of whether treated patients live longer, decisions on treatment should be based on a comprehensive assessment of the balance between benefit and risk for an individual and not solely on cost.
Published Online March 23, 2006 DOI:10.1016/S0140-6736(06) 68395-5 See Articles page 1057
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Science Photo Library
In today’s Lancet, Bengt Winblad and colleagues1 report a randomised placebo-controlled trial of donepezil for patients with severe Alzheimer’s disease. At entry, participants had Mini-Mental State Examination (MMSE) scores of between 1 and 10, functional assessment stages 5–7c, and lived in nursing homes run by skilled staff. After 6 months’ treatment, those assigned donepezil did significantly better on the primary cognitive and functional measures than those assigned placebo. Two of the secondary outcome measures also favoured donepezil, but there were no significant benefits noted for the behavioural measure. We congratulate Winblad and colleagues for completing this study in a challenging group of patients. Their conclusion is that, when started in individuals with severe Alzheimer’s disease, donepezil benefits patients. So should we be prescribing cholinesterase inhibitors to patients with severe Alzheimer’s disease residing in long-term care facilities? For various reasons, I believe such treatment might be a case of too little, too late. The primary analyses of efficacy were done on a modified intent-to-treat population with the last observation carried forward to account for missing data. Of the 128 patients assigned donepezil, 95 (74%) completed the study, compared with 99 of 120 (83%) assigned placebo. The limitations of using last observation carried forward in trials of progressively deteriorating diseases, especially when the proportion and timing of withdrawals between the treatment groups might not be equivalent, are well known.2 Furthermore, when drop-out rates are 20% or higher, the interpretation of a study becomes problematic.3 The primary outcome measures were the severe impairment battery (SIB) and the modified Alzheimer’s Disease Cooperative Study activities of daily living inventory for severe Alzheimer’s disease (ADCS-ADLsevere).4,5 At 6 months, mean differences between groups were 5·7 on the SIB and 1·7 on the ADCS-ADL-severe. Although statistically significant, are these differences clinically important? To most doctors, these outcome measures are numbers without meaning. A minimum important difference is the smallest effect size that would lead a physician to recommend therapy in the absence of unacceptable side-effects, inconvenience, or costs.6 The sample size calculations for Winblad and colleagues’ study
Coloured MRI of brain affected by Alzheimer’s disease
1031
Comment
Opportunity cost refers to the value of the opportunities lost by allocating disposable resources in a particular way.9 Is paying for cholinesterase inhibitors, even if deemed worthwhile for severe Alzheimer’s disease, the best use of scarce resources? Without knowing more of the opportunities forgone, we cannot decide. This issue is outside the scope of the trial as reported, but faces policymakers, administrators, clinicians, and families daily. More meaningful outcomes are needed in dementia trials. Before a trial starts, we should define what will be a clinically important outcome for an individual patient and explore the use of outcome measures such as goalattainment scaling.10 If not, we are doomed to neverending debates about the meaning of the tea leaves at the bottom of the cup.
I have participated as a principal investigator in studies sponsored by JanssenOrtho, Neurochem, Novartis, and Pfizer, and I have received speakers’ fees from Merck, Novartis, and Pfizer within the past 3 years. 1
2 3
4
5
6
7
8
David B Hogan Division of Geriatric Medicine, University of Calgary Health Sciences Centre, Calgary, Alberta T2N 4N1, Canada [email protected]
9 10
Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006; 367: 1057–65. Streiner DL. The case of the missing data: methods of dealing with dropouts and other research vagaries. Can J Psychiatry 2002; 47: 68–75. Unnebrink K, Windeler J. Intention-to-treat: methods for dealing with missing values in clinical trials of progressively deteriorating diseases. Stat Med 2001; 20: 3931–46. Panisset M, Roudlier M, Saxton J, Boller F. Severe impairment battery: a neuropsychological test for severely demented patients. Arch Neurol 1994; 51: 41–45. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. Alzheimer Dis Assoc Disord 1997; 11 (suppl 2): S33–39. Van Walraven C, Mahin JL, Moher D, Bohm C, Laupacis A. Surveying physicians to determine minimal important difference: implications for sample size calculation. J Clin Epidemiol 1999; 52: 717–23. Lopez OL, Becker JT, Wisniewski S, Saxton J, Kaufer DI, DeKosky ST. Cholinesterase inhibitor treatment alters the natural history of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002; 72: 310–14. Gasper MC, Ott BR, Lapane KL. Is donepezil therapy associated with reduced mortality in nursing home residents with dementia? Am J Geriatr Pharmacother 2005; 3: 1–7. Last JM, ed. A dictionary of epidemiology, 4th edn. Oxford: Oxford University Press, 2001: 129. Rockwood K, Graham JE, Fay S. Goal setting and attainment in Alzheimer’s disease patients treated with donepezil. J Neurol Neurosurg Psychiatry 2002; 73: 500–07.
Are any of the criticisms of the CNEP trial true? See Editorial page 1030; Comment pages 1033, 1035, and 1037; and Articles page 1080
“Parents were misled over hospital trials that killed premature babies”
Those who saw this banner headline on the front page of
The Independent on Monday, May 8, 2000,1 could be forgiven for thinking that something had gone seriously wrong with clinical research in the UK, and with the oversight of neonatal research in particular. The story was triggered by a Government inquiry into clinical research done in Stoke-on-Trent.2 Richard Smith, Editor of the BMJ, was in no doubt at the time that “yet another NHS [UK National Health Service] scandal” had been uncovered.3 “At best”, he wrote, “the episode will lead to an overdue improvement in research practice throughout the NHS. At worst, it will further undermine public confidence in the NHS and doctors, and lead to a proliferation of bureaucracy that will increase the difficulties of doing research.” Even though doubts about the reliability of the Government inquiry4 subsequently prompted Smith to call for an “inquiry into inquiries”,5 many people, including influential experts in research ethics and governance,6,7 continue to believe that a scandal was uncovered in Stoke. So had hospital trials killed 1032
premature babies? No. The two-centre trial8 compared two ways of nursing babies with lungs so immature that most would have died without respiratory support at birth, yet four-fifths survived. Has The Independent ever acknowledged its error? No. The paper’s Editor, Simon Kelner, was still refusing to apologise for its misleading headline when questioned by a Parliamentary Select Committee 3 years later.9 The article in today’s Lancet by Katherine Telford and colleagues10 shows that, compared with babies assigned standard treatment with a tube through the larynx, marginally more of the babies whose lungs were kept open by continuous negative extrathoracic pressure (CNEP) died, and marginally fewer of the survivors were disabled. Both differences are so small as to be well within what might be expected by chance. Unfortunately this finding does not bring the affair to a close, because some parents have been saying for 9 years now that they never gave consent for inclusion of their children in the study. Whether their allegations are true remains unclear,11 but, like The Independent, some people made up their minds long ago. The Editor of the Bulletin of Medical Ethics, for example, has stated that: “The core of www.thelancet.com Vol 367 April 1, 2006
Donepezil for severe Alzheimer’s disease
www.thelancet.com Vol 367 April 1, 2006
are based on finding an absolute difference between the treatment arms of 3·5 on the ADCS-ADL-severe and 7 on the SIB. The authors later state that these treatment differences are of “clinical significance”. Even though I doubt these values truly represent minimum important differences, the results obtained do not meet the modest thresholds set by the authors. Winblad and colleagues state that: “if treatment can help patients in the late phase of dementia, without necessarily increasing the length of time they have severe Alzheimer’s disease, then this is a treatment option that should be available.” They are addressing the concern that cholinesterase inhibitors for patients already in a nursing home might increase overall costs, especially if use prolongs survival. They go on to assert, however, that the benefits seen are “not associated with any survival advantage”. This statement is contentious. To buttress their claim, a relatively small community-based observational study is referenced.7 Yet even in this report, those on active treatment tended to live longer than controls (relative risk 0·38, 95% CI 0·14–1·04). A larger retrospective matched-cohort study8 of residents in nursing homes also showed a significantly lower mortality rate in users of donepezil compared with non-users (hazard ratio 0·89, 95% CI 0·83–0·95). Irrespective of whether treated patients live longer, decisions on treatment should be based on a comprehensive assessment of the balance between benefit and risk for an individual and not solely on cost.
Published Online March 23, 2006 DOI:10.1016/S0140-6736(06) 68395-5 See Articles page 1057
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Science Photo Library
In today’s Lancet, Bengt Winblad and colleagues1 report a randomised placebo-controlled trial of donepezil for patients with severe Alzheimer’s disease. At entry, participants had Mini-Mental State Examination (MMSE) scores of between 1 and 10, functional assessment stages 5–7c, and lived in nursing homes run by skilled staff. After 6 months’ treatment, those assigned donepezil did significantly better on the primary cognitive and functional measures than those assigned placebo. Two of the secondary outcome measures also favoured donepezil, but there were no significant benefits noted for the behavioural measure. We congratulate Winblad and colleagues for completing this study in a challenging group of patients. Their conclusion is that, when started in individuals with severe Alzheimer’s disease, donepezil benefits patients. So should we be prescribing cholinesterase inhibitors to patients with severe Alzheimer’s disease residing in long-term care facilities? For various reasons, I believe such treatment might be a case of too little, too late. The primary analyses of efficacy were done on a modified intent-to-treat population with the last observation carried forward to account for missing data. Of the 128 patients assigned donepezil, 95 (74%) completed the study, compared with 99 of 120 (83%) assigned placebo. The limitations of using last observation carried forward in trials of progressively deteriorating diseases, especially when the proportion and timing of withdrawals between the treatment groups might not be equivalent, are well known.2 Furthermore, when drop-out rates are 20% or higher, the interpretation of a study becomes problematic.3 The primary outcome measures were the severe impairment battery (SIB) and the modified Alzheimer’s Disease Cooperative Study activities of daily living inventory for severe Alzheimer’s disease (ADCS-ADLsevere).4,5 At 6 months, mean differences between groups were 5·7 on the SIB and 1·7 on the ADCS-ADL-severe. Although statistically significant, are these differences clinically important? To most doctors, these outcome measures are numbers without meaning. A minimum important difference is the smallest effect size that would lead a physician to recommend therapy in the absence of unacceptable side-effects, inconvenience, or costs.6 The sample size calculations for Winblad and colleagues’ study
Coloured MRI of brain affected by Alzheimer’s disease
1031
Comment
Opportunity cost refers to the value of the opportunities lost by allocating disposable resources in a particular way.9 Is paying for cholinesterase inhibitors, even if deemed worthwhile for severe Alzheimer’s disease, the best use of scarce resources? Without knowing more of the opportunities forgone, we cannot decide. This issue is outside the scope of the trial as reported, but faces policymakers, administrators, clinicians, and families daily. More meaningful outcomes are needed in dementia trials. Before a trial starts, we should define what will be a clinically important outcome for an individual patient and explore the use of outcome measures such as goalattainment scaling.10 If not, we are doomed to neverending debates about the meaning of the tea leaves at the bottom of the cup.
I have participated as a principal investigator in studies sponsored by JanssenOrtho, Neurochem, Novartis, and Pfizer, and I have received speakers’ fees from Merck, Novartis, and Pfizer within the past 3 years. 1
2 3
4
5
6
7
8
David B Hogan Division of Geriatric Medicine, University of Calgary Health Sciences Centre, Calgary, Alberta T2N 4N1, Canada [email protected]
9 10
Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006; 367: 1057–65. Streiner DL. The case of the missing data: methods of dealing with dropouts and other research vagaries. Can J Psychiatry 2002; 47: 68–75. Unnebrink K, Windeler J. Intention-to-treat: methods for dealing with missing values in clinical trials of progressively deteriorating diseases. Stat Med 2001; 20: 3931–46. Panisset M, Roudlier M, Saxton J, Boller F. Severe impairment battery: a neuropsychological test for severely demented patients. Arch Neurol 1994; 51: 41–45. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. Alzheimer Dis Assoc Disord 1997; 11 (suppl 2): S33–39. Van Walraven C, Mahin JL, Moher D, Bohm C, Laupacis A. Surveying physicians to determine minimal important difference: implications for sample size calculation. J Clin Epidemiol 1999; 52: 717–23. Lopez OL, Becker JT, Wisniewski S, Saxton J, Kaufer DI, DeKosky ST. Cholinesterase inhibitor treatment alters the natural history of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002; 72: 310–14. Gasper MC, Ott BR, Lapane KL. Is donepezil therapy associated with reduced mortality in nursing home residents with dementia? Am J Geriatr Pharmacother 2005; 3: 1–7. Last JM, ed. A dictionary of epidemiology, 4th edn. Oxford: Oxford University Press, 2001: 129. Rockwood K, Graham JE, Fay S. Goal setting and attainment in Alzheimer’s disease patients treated with donepezil. J Neurol Neurosurg Psychiatry 2002; 73: 500–07.
Are any of the criticisms of the CNEP trial true? See Editorial page 1030; Comment pages 1033, 1035, and 1037; and Articles page 1080
“Parents were misled over hospital trials that killed premature babies”
Those who saw this banner headline on the front page of
The Independent on Monday, May 8, 2000,1 could be forgiven for thinking that something had gone seriously wrong with clinical research in the UK, and with the oversight of neonatal research in particular. The story was triggered by a Government inquiry into clinical research done in Stoke-on-Trent.2 Richard Smith, Editor of the BMJ, was in no doubt at the time that “yet another NHS [UK National Health Service] scandal” had been uncovered.3 “At best”, he wrote, “the episode will lead to an overdue improvement in research practice throughout the NHS. At worst, it will further undermine public confidence in the NHS and doctors, and lead to a proliferation of bureaucracy that will increase the difficulties of doing research.” Even though doubts about the reliability of the Government inquiry4 subsequently prompted Smith to call for an “inquiry into inquiries”,5 many people, including influential experts in research ethics and governance,6,7 continue to believe that a scandal was uncovered in Stoke. So had hospital trials killed 1032
premature babies? No. The two-centre trial8 compared two ways of nursing babies with lungs so immature that most would have died without respiratory support at birth, yet four-fifths survived. Has The Independent ever acknowledged its error? No. The paper’s Editor, Simon Kelner, was still refusing to apologise for its misleading headline when questioned by a Parliamentary Select Committee 3 years later.9 The article in today’s Lancet by Katherine Telford and colleagues10 shows that, compared with babies assigned standard treatment with a tube through the larynx, marginally more of the babies whose lungs were kept open by continuous negative extrathoracic pressure (CNEP) died, and marginally fewer of the survivors were disabled. Both differences are so small as to be well within what might be expected by chance. Unfortunately this finding does not bring the affair to a close, because some parents have been saying for 9 years now that they never gave consent for inclusion of their children in the study. Whether their allegations are true remains unclear,11 but, like The Independent, some people made up their minds long ago. The Editor of the Bulletin of Medical Ethics, for example, has stated that: “The core of www.thelancet.com Vol 367 April 1, 2006