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Effects of Blood Pressure Lowering With Perindopril
and Indapamide Therapy on Dementia
and Cognitive Decline in Patients
With Cerebrovascular Disease
Background: High blood pressure and stroke are as-
(7.1%) of the 3054 randomized participants in the pla- sociated with increased risks of dementia and cognitive cebo group (relative risk reduction, 12% [95% confi- impairment. This study aimed to determine whether blood dence interval, −8% to 28%]; P = .2). Cognitive decline pressure lowering would reduce the risks of dementia and occurred in 9.1% of the actively treated group and 11.0% cognitive decline among individuals with cerebrovascu- of the placebo group (risk reduction, 19% [95% confi- dence interval, 4% to 32%]; P=.01). The risks of the com-posite outcomes of dementia with recurrent stroke and Methods: The Perindopril Protection Against Recur-
of cognitive decline with recurrent stroke were reduced rent Stroke Study (PROGRESS) was a randomized, by 34% (95% confidence interval, 3% to 55%) (P = .03) double-blind, placebo-controlled trial conducted among and 45% (95% confidence interval, 21% to 61%) 6105 people with prior stroke or transient ischemic at- (PϽ.001), respectively, with no clear effect on either de- tack. Participants were assigned to either active treat- mentia or cognitive decline in the absence of recurrent ment (perindopril for all participants and indapamide for those with neither an indication for nor a contraindica-tion to a diuretic) or matching placebo(s). The primary Conclusions: Active treatment was associated with re-
outcomes for these analyses were dementia (using DSM-IV duced risks of dementia and cognitive decline associ- criteria) and cognitive decline (a decline of 3 or more ated with recurrent stroke. These findings further sup- points in the Mini-Mental State Examination score).
port the recommendation that blood pressure loweringwith perindopril and indapamide therapy be considered Results: During a mean follow-up of 3.9 years, demen-
for all patients with cerebrovascular disease.
tia was documented in 193 (6.3%) of the 3051 random-ized participants in the actively treated group and 217 Arch Intern Med. 2003;163:1069-1075 IN1990,dementiawastheeighth sure–loweringagentshavereportedthe
effects of treatment on the risk of demen- tia or measures of cognitive function.14-16 While the first identified no clear effect of study treatment on dementia14 and the sec- is projected to increase by one half.1 The ond no effect on cognitive function,15 the identification of safe and effective inter- third reported a significant beneficial effect ventions for the prevention of dementia is of treatment on the risk of dementia.16 In therefore a clinical and public health pri- that study, however, only 32 cases of de- Tzourio, MD, PhD; CraigAnderson, MD, PhD; Neil strated that elevated blood pressure lev- dence intervals about the estimate of treat- ment effect were very wide. There remains, disease6-8 are each strongly associated with tainty about the effects of blood pressure lowering interventions may reduce the risk of cognitive impairment by direct effects on the prevention of cerebrovascular dis- Protection Against Recurrent Stroke Study ease or by indirect effects on the clinical pressure–lowering regimen, involving an Collaborative Group waspublished previously (Lancet. cesses.9-13 Three completed large-scale ran- hibitor and a diuretic, reduced the risks (REPRINTED) ARCH INTERN MED/ VOL 163, MAY 12, 2003 2003 American Medical Association. All rights reserved.
of stroke and of other major vascular events among in- does this patient have dementia?” Participants who screened dividuals with a history of cerebrovascular disease.18 The positive were referred for a formal diagnostic clinical assess- effects of the study treatment regimen on the prespeci- ment by a local specialist with experience in the diagnosis of fied end points of dementia and cognitive function17 are The clinical assessment included, whenever possible, an interview with both the patient and a close friend or relative.
If study participants were not available for assessment or had died, data were sought from all other available sources, includ-ing medical records, interviews with family members, and con- STUDY DESIGN AND PARTICIPANTS
sultations with other medical practitioners. Information wasgathered with the aid of a checklist based on the criteria for The design of PROGRESS has been described in detail else- the diagnosis of dementia as defined in the Diagnostic and where.17,18 Briefly, 6105 participants were recruited from 172 Statistical Manual of Mental Disorders, Fourth Edition (DSM- collaborating centers in 10 countries between May 1995 and IV).22 For all screen-positive cases, the collected information November 1997. The institutional ethics committee of each col- and the diagnosis made by the local specialist were reviewed laborating center approved the trial, and all participants pro- and either confirmed or refuted by consensus agreement of a vided written informed consent. Participants were eligible if they 2-person central Dementia Adjudication Committee. Based on had a history of cerebrovascular disease (stroke or transient is- the DSM-IV criteria, each screen-positive case was finally cat- chemic attack [but not subarachnoid hemorrhage]) within the egorized by the Dementia Adjudication Committee as (1) cer- previous 5 years. In addition, participants were required to have tain dementia, (2) fairly certain (probable) dementia, (3) un- no clear indication for, nor a contraindication to, treatment with certain (possible) dementia, or (4) no dementia. Since all patients an ACE inhibitor. There were no blood pressure criteria for en- had a history of cerebrovascular disease and other vascular risk try. Blood samples were collected at baseline for later DNA ex- factors were frequently present, no attempt was made to fur- traction and identification of apolipoprotein E gene polymor- ther classify cases into subtypes of dementia. All screen- negative participants were categorized as “no dementia” and Participants who tolerated and adhered to at least 4 weeks all assessments were made without knowledge of study treat- of run-in therapy with perindopril were randomly assigned, in a double-blind manner, to continued active treatment or match-ing placebo. Randomized treatment allocation was provided by OUTCOMES
a central computer-based randomization service with stratifi-cation by study center, age, sex, entry systolic blood pressure, The main outcomes for these analyses were (1) dementia, de- inclusion diagnosis, and the intention to begin combination fined as “certain dementia” or “fairly certain dementia” accord- therapy (with perindopril plus indapamide or double pla- ing to the criteria of DSM-IV, and (2) cognitive decline, de- cebo) or single drug therapy (with perindopril alone or single fined as a drop of 3 points or more between the baseline and placebo). Active treatment comprised a flexible treatment regi- last recorded MMSE scores.23,24 Both dementia and cognitive men based on perindopril (4 mg/d) for all participants, with function were prespecified secondary outcomes of the addition of indapamide (2.5 mg/d or 2 mg/d in Japan) in PROGRESS.17,21 Since, in observational studies, the risk of cog- those participants for whom the responsible study physician nitive impairment is strongly associated with the occurrence believed that there was no specific indication for, nor contra- of stroke,6-8 the effects of treatment on the following 4 addi- indication to, the use of a diuretic. Those participants as- tional composite outcomes were studied: (1) “dementia with signed to placebo received tablets identical in appearance to recurrent stroke” (the diagnosis of dementia after a stroke dur- the active agents. The rationale for the use, whenever pos- ing follow-up); (2) “other dementia” (all other cases of demen- sible, of “combination therapy” (perindopril and indapamide tia diagnosed); (3) “cognitive decline with recurrent stroke” or double placebo) rather than “single drug therapy” (perin- (the diagnosis of cognitive decline after a stroke during follow- dopril or single placebo) was to maximize the fall in blood up); and (4) “other cognitive decline” (all other cases of cog- nitive decline). Quantitative changes in MMSE score betweenthe baseline and final assessment were also compared be- ASSESSMENT OF COGNITIVE FUNCTION
AND DEMENTIA
STATISTICAL ANALYSIS
Cognitive function was assessed in all patients at baseline, atthe 6- and 12-month visits, and annually thereafter until the We calculated the planned study sample size (6000 partici- end of follow-up, using the Mini-Mental State Examination pants) and follow-up (4 years) to provide 90% power, using a (MMSE).20 For each successfully completed item on the MMSE, 2-sided 5% significance test to detect a 30% or greater differ- a score of 1 point (to a maximum of 30) was awarded, with ence in the relative risk of dementia between the randomized missing items receiving a score of zero. Contextually appro- groups. This estimate assumed that the incidence of dementia priate translations of the questionnaire were made for Chi- among individuals with a history of cerebrovascular disease nese and Japanese participants, since the questionnaire was not would be about twice that observed among elderly individuals available in these languages at the time the study began.
with uncomplicated hypertension (7-10 per 1000 person- During the study follow-up period, a 2-phase screening and assessment process was used for the diagnosis of demen- All analyses were conducted according to the intention- tia.21 Participants screened positive for possible dementia if they to-treat principle, and all randomized participants were in- satisfied any of the following criteria during the study fol- cluded in all analyses. Missing baseline MMSE values (n = 32) low-up period: (1) an MMSE score of 25 or less at any fol- were imputed as the values recorded at the 6-month visit when low-up visit, (2) a decline in the MMSE score of 3 or more points possible (n = 7). The remaining 25 participants and those oth- between any 2 follow-up visits, (3) an MMSE score missing for ers for whom there was only a single MMSE assessment (n=192) 2 or more scheduled follow-up visits, or (4) a positive re- were assumed not to have met the criteria for cognitive de- sponse by the investigator to the question, “In your opinion, cline. Logistic regression models were used to estimate odds (REPRINTED) ARCH INTERN MED/ VOL 163, MAY 12, 2003 2003 American Medical Association. All rights reserved.
Baseline Characteristics of Randomized Participants*
Treatment
(n = 3051)
(n = 3054)
Figure 1. Screening and assessment for dementia in the Perindopril
Protection Against Recurrent Stroke Study (PROGRESS).
Abbreviations: ApoE4, apolipoprotein E ⑀4; HMG-CoA, such as age, sex, educational level, MMSE score, and fre- 3-hydroxy-3-methylglutaryl coenzyme A; MMSE, Mini-Mental State quency of the ⑀4 allele of the apolipoprotein E polymor- Examination; TIA, transient ischemic attack.
*Data are percentage of participants unless otherwise specified.
†Participants recruited from People’s Republic of China or Japan.
‡Systolic blood pressure 160 mm Hg or higher or diastolic blood pressure ADHERENCE TO RANDOMIZED TREATMENT
AND EFFECTS OF TREATMENT
§Consumes at least 1 alcoholic drink per week.
࿣Carrier of at least 1 ApoE4 allele.
ON BLOOD PRESSURE
During a mean follow-up period of 3.9 years, 22% of ratios for the effects of study treatment on the dichotomous out- participants permanently discontinued the use of all comes of dementia and cognitive decline. Percentage of risk re- study tablets prior to death or the final scheduled visit ductions were estimated as (1 − odds ratio) ϫ100, and all P val- (active, 23%; placebo, 21% [P=.02]). The main reasons ues were calculated from 2-sided tests of statistical significance.
for permanent discontinuation of treatment were par- The effects of study treatment on mean MMSE scores between ticipant decision (active, 7.6%; placebo, 8.2%), cough baseline and follow-up were determined using general linear (active, 2.2%; placebo, 0.4%) hypotension (active, 2.1%; placebo, 0.9%), and heart failure requiring treatment Analyses of major subgroups were conducted according to study drug regimen (combination drug therapy or single drug with an ACE inhibitor or diuretic (active, 1.5%; pla- therapy); the presence or absence of hypertension (systolic blood pressure Ն160 mm Hg and/or diastolic blood pressure Ն90 The mean difference in blood pressure between mm Hg) at baseline; and evidence or no evidence of cognitive participants assigned active treatment and those impairment (MMSE score Յ25 and/or a positive response to assigned placebo was 9/4 mm Hg (SE, 0.3/0.2 mm the question, “In your opinion, does this patient have demen- Hg).18 Among the 58% of participants treated with com- tia?”) at baseline (2 participants without any baseline assess- bination therapy, the mean difference in blood pressure ment of cognitive impairment were classified as unimpaired at between active and placebo was 12/5 mm Hg (SE, 0.5/ baseline). Standardized estimates of treatment effects in sub- 0.3 mm Hg), whereas among those treated with single groups were calculated by combining subgroup-specific esti- drug therapy it was 5/3 mm Hg (SE, 0.6/0.3 mm Hg) mates of the effects of combination therapy and of single drugtherapy.18 Tests of homogeneity of the effects in the above sub- (P for homogeneity Ͻ.001 for both systolic and dias- groups were performed by adding an interaction term to the appropriate statistical model. All analyses were conducted us-ing SAS Version 8.02 (SAS Institute Inc, Cary, NC).
EFFECTS OF TREATMENT
ON THE RISK OF DEMENTIA
All randomized participants were screened for demen- BASELINE CHARACTERISTICS
tia on at least 1 occasion, and 1580 participants (768 ac-
tive; 812 placebo) screened positive (Figure 1). Clini-
The characteristics of participants in PROGRESS are de- cal assessments for dementia were performed in 1552 scribed in detail elsewhere18,27 and are summarized in the (98.2%) of screen-positive participants; 1049 were as- Table. There was good balance between active treat-
sessed “face to face” and the remaining 503 were as- ment and placebo groups for those baseline participant sessed “in absentia.” The 28 screen-positive partici- characteristics that might influence the risk of dementia pants who did not undergo a clinical assessment were (REPRINTED) ARCH INTERN MED/ VOL 163, MAY 12, 2003 2003 American Medical Association. All rights reserved.
Figure 2. Effects of treatment on the risks of
dementia. Odds ratios and 95% confidence intervals 193/3051 217/3054
(CIs) are provided for all dementia, “dementia withrecurrent stroke,” “other dementia,” and for all dementia in major subgroups of participants. The centers of the boxes are placed at the point estimates of effect and the areas of the boxes areproportional to the number of events. The horizontal lines represent 95% CIs. Diamond represents point estimate and 95% CI of the overall estimate ofeffect.
“Cognitive Decline With Recurrent Stroke” 276/3051 334/3054
Figure 3. Effects of treatment on the risks of
cognitive decline. See Figure 2 for conventions.
assumed not to have dementia. The local specialists di- tered when analyses were restricted to those cases diag- agnosed dementia in 358 individuals and no dementia in 1194 individuals (including 8 for whom there was in-sufficient information to make a diagnosis). The Demen- EFFECTS OF TREATMENT
tia Adjudication Committee reclassified 116 (7.4%) lo- ON THE RISK OF COGNITIVE DECLINE
cal specialists’ diagnoses (32 “dementia” to “no dementia”and 84 “no dementia” to “dementia”) after comparison Assessments of cognitive decline were available for 5888 of the diagnostic details provided with the DSM-IV cri- study participants (96.4%). The 217 participants not as- teria. Therefore, a diagnosis of dementia was made in 410 sessed (active 117; placebo 100) had either no baseline participants, 295 of whom had been assessed face to face MMSE score (n=25) or only 1 measure of MMSE (n=192) and 115 in absentia. Of these 410 participants, 108 and for the purpose of these analyses were assumed not to (26.3%) also had a stroke during follow-up prior to the have cognitive decline. Overall, cognitive decline oc- diagnosis of dementia and were classified as “dementia curred in 610 participants (276 [9.1%] in the active group with recurrent stroke,” leaving the remaining 302 cases and 334 [11.0%] in the placebo group), with incidence rates of 23 and 28 per 1000 person-years, respectively. Of the Of the participants in the active treatment and pla- 610 subjects with cognitive decline, 134 (21.9%) had a cebo groups, 193 (6.4%) and 217 (7.1%), respectively, stroke during follow-up prior to the diagnosis of cogni- were diagnosed with dementia (16 and 19 per 1000 per- tive decline and were classified as “cognitive decline with son-years, respectively). Active treatment was associ- recurrent stroke,” leaving the remaining 476 cases of cog- ated with a nonsignificant, 12% lower risk of dementia nitive decline classified as “other cognitive decline.” (95% confidence interval [CI], −8% to 28%) (P = .2) and Active treatment reduced the risk of cognitive de- a 34% (95% CI, 3% to 55%) (P = .03) lower risk of “de- cline by 19% (95% CI, 4% to 32%) (P = .01) and the com- mentia with recurrent stroke,” but no reduction in the posite outcome of “cognitive decline with recurrent risk of “other dementia” (relative risk reduction, 1% [95% stroke” by 45% (95% CI, 21% to 61%) (P = .001) CI, −24% to 22%]; P = .9) (Figure 2). Estimates of the
(Figure 3). There was no discernible effect of treat-
effects of treatment on dementia were not materially al- ment on “other cognitive decline” (risk reduction, 9% (REPRINTED) ARCH INTERN MED/ VOL 163, MAY 12, 2003 2003 American Medical Association. All rights reserved.
[95% CI, −10% to 24%]; P = .35). Estimates of the effects ment on the overall risk of dementia, the risk of the com- of treatment were not materially altered when analyses posite outcome of “dementia with recurrent stroke” was were made with cognitive decline defined as either a reduced by one third. There were also clear beneficial ef- 2-point fall in MMSE scores (overall risk reduction, 17% fects of treatment on other indicators of cognitive im- [95% CI, 5% to 28%]; P = .009) or a 4-point fall in MMSE pairment—the overall risk of cognitive decline was re- scores (17% [95% CI, −1% to 31%]; P = .07), or by the duced by about one fifth, the risk of the composite exclusion from the calculations of the 217 study partici- outcome of “cognitive decline with recurrent stroke” was reduced by about one half, and the entire decline in meanMMSE scores observed in the placebo group appeared EFFECTS OF TREATMENT
to be averted by active treatment. These benefits were in- IN PARTICIPANT SUBGROUPS
dependent of the effects of study treatment on mortalityand appeared to be similar in both hypertensive and non- There was borderline significant heterogeneity (P = .05) between the effects of treatment on dementia in partici- The observed effects of study treatment on these vari- pant subgroups defined on the basis of cognitive impair- ous indexes of cognitive impairment in PROGRESS ap- ment at entry into the study: there was no apparent effect pear largely to reflect reductions in the risks of demen- of treatment among the 964 (16.4%) participants with tia and cognitive decline associated with the occurrence evidence of baseline impairment (relative risk reduc- of recurrent stroke during follow-up. This suggests that tion, −5% [95% CI, −42% to 22%]; P = .7) but a signifi- the benefits of treatment are primarily the consequence cant relative risk reduction (31% [95% CI, 6% to 49%]; of stroke prevention rather than a direct effect on de- P=.02) among the 5141 participants (84.2%) without evi- mentia or cognitive decline. This finding is consistent with dence of baseline cognitive impairment (Figure 2). There the results of observational studies, which have demon- was also a trend toward greater effects of treatment on strated that the risk of dementia after stroke is high,6-8 dementia among participants treated with combination and with the results of previous randomized trials, which therapy (relative risk reduction, 23% [95% CI, 0% to 41%]; have shown that blood pressure lowering reduces the risk P = .05) than among participants treated with single drug therapy (relative risk reduction, −8% [95% CI, −48% to These results from PROGRESS add substantially to 21%]; P = .6) (Figure 2), although these results did not the available evidence about the effects of blood pressure– differ significantly (P for homogeneity, .1). However, for lowering regimens on dementia and cognitive impair- neither of these pairs of subgroups, defined by baseline ment. Prior to the completion of PROGRESS, there were cognitive impairment or study treatment regimen, were only 113 cases of dementia recorded in large-scale trials there corresponding trends for the outcome of cogni- of blood pressure–lowering agents14,16 in which the con- tive decline (P for homogeneity, both Ն.5) (Figure 3).
fidence intervals about the estimated effects of treat- There was no evidence of any difference in the effects of ment were wide and the overall effects on measures of treatment on either outcome for participant subgroups cognitive function were unclear.14-16 In addition, a re- defined by baseline hypertension status (P for homoge- cent analysis of data from one of these studies suggested neity, both Ն.1) (Figures 2 and 3).
that differential dropout rates between treatment groupsmay have introduced a bias in the estimate of the treat- EFFECTS OF TREATMENT
ment effect obtained.29 The randomized design and the ON MEAN MMSE SCORES
completeness of follow-up achieved in PROGRESS makeit very unlikely that the observed effects of treatment are Measures of baseline to follow-up change in MMSE were biased. However, while the study was much larger than made for 5888 participants (96.4%), but were not avail- preceding trials, there were still relatively few events re- able for the 217 participants who had either no baseline corded and there is moderate imprecision about the effect MMSE score or only 1 measure of MMSE. For these 5888 estimates calculated. Therefore, whether the absence of participants, the fall in MMSE scores between baseline a clear overall effect of study treatment on dementia re- and final evaluations was smaller among participants as- flects a true absence of benefit for this outcome or whether signed active treatment (mean ± SE, 0.05 ± 0.05) than the limited power of the trial fails to reliably detect a more among those assigned placebo (mean ± SE, 0.24 ± 0.05).
modest effect of treatment remains uncertain. For ex- The mean±SE difference between randomized groups in ample, the 95% confidence intervals for the estimated the decline in MMSE scores was 0.19±0.07 (P=.01), with effect of treatment on dementia in PROGRESS do not ex- no clear evidence of differences in the effects of treat- clude a reduction in the relative risk of dementia of 15% ment between any of the subgroups studied (P for ho- to 20%, a treatment effect that would be quite consis- tent with the result observed for cognitive decline.
Premature discontinuation of study treatment by a proportion of study participants18 is likely to have re-sulted in underestimation of the real effects of study treat- This large-scale randomized trial among individuals with ment on each outcome. Otherwise, there were few sources a previous stroke or transient ischemic attack provides of systematic error likely to have had substantive influ- the most reliable evidence to date about the effects of blood ence on the estimates of treatment effect obtained. The pressure lowering on the risks of dementia and cogni- comprehensive screening process, the use of specialists tive decline. While there was no clear effect of treat- in the diagnosis of dementia, and the review of all as- (REPRINTED) ARCH INTERN MED/ VOL 163, MAY 12, 2003 2003 American Medical Association. All rights reserved.
tence of heterogeneity of effects on dementia is reduced by the apparent absence of any such differences in theeffects of treatment on cognitive decline.
A complete listing of the members of the PROGRESS Col- In summary, as the proportion of elderly individu- laborative Group was published previously (Lancet.
als increases, the worldwide burden of disease attribut- able to stroke, dementia, and cognitive impairment is pro- Writing Committee: C. Tzourio, C. Anderson, jected to rise substantially.1 Observational studies have N. Chapman, M. Woodward, B. Neal, S. MacMahon, identified high blood pressure and cerebrovascular dis- J. Chalmers; Management Committee: J. Chalmers ease as important determinants of dementia and cogni- (co–principal investigator), S. MacMahon (co–principal investigator), C. Anderson, M. G. Bousser, tive impairment, and this study has confirmed the ben- J. Cutler, S. Davis, G. Donnan, L. Hansson (deceased), eficial effects of a preventive strategy based on blood S. Harrap, K. R. Lees, L. Liu, G. Mancia, B. Neal, T. Omae, pressure lowering. These benefits, when added to those J. Reid, A. Rodgers, R. Sega, A. Terent, C. Tzourio, previously reported, provide further support for the rec- C. Warlow, M. Woodward; Dementia Adjudication Com- ommendation that blood pressure lowering with perin- mittee: C. Anderson, Y. Ratnasabapathy; Statistical Analy- dopril and indapamide be considered for all patients with sis: S. Colman, C. Dufouil, L. Francis, A. Lee, M. Wood- a history of stroke or transient ischemic attack.
ward; Apolipoprotein E analyses: F. Cambien. Manymembers of the management committee have receivedhonoraria for presenting PROGRESS results.
Accepted for publication August 29, 2002. PROGRESS was funded by grants from Servier (Paris, France), the Health Research Council of New Zealand (Auck-land, New Zealand), and the National Health and Medical sessments by a central Dementia Adjudication Commit- Research Council of Australia (Canberra, Australia). The tee should have ensured that the diagnosis of dementia study was designed, conducted, analyzed and interpreted by was both sensitive and specific and should have mini- the investigators independent of all sponsors. mized the effects of other features of cerebrovascular dis- This article is dedicated to the memory of Lennart ease, which may mimic or mask dementia (eg, aphasia Hansson, MD, who died unexpectedly in November 2002. or depression). However, while misclassification of de- Corresponding author and reprints: John Chalmers, mentia should have been largely avoided, use of the MD, PhD, PROGRESS Collaborative Group c/o Institute for DSM-IV criteria, which require memory impairment for International Health, University of Sydney, PO Box 576, the diagnosis, may have resulted in a slight underesti- Newtown, Sydney, NSW 2042, Australia (e-mail: progress mation of the true incidence of dementia, since memory impairment may be absent in patients who experiencedementia following stroke.30 Although missed cases should have been few, it is possible that more cases were missedin the placebo group, since that group experienced morerecurrent strokes, and this too could have resulted in a 1. Murray CJL, Lopez AD, eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability From Diseases, Injuries and Risk Factors slight underestimation of any true effects of study treat- in 1990 and Projected to 2020. Cambridge, Mass: Harvard University Press; 1996.
2. Skoog I, Lernfelt B, Landahl S, et al. 15-Year longitudinal study of blood pres- For stroke, the primary outcome of the main analy- sure and dementia. Lancet. 1996;347:1141-1145.
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