Annotation 4

Works Cited

Milne, Anne C., Alison Avenell, and Jan Potter. “Meta-Analysis: Protein and Energy Supplementation in Older People.” Annals of Internal Medicine 144.1 (2006): 37-48. ProQuest. Web. 1 Oct. 2014.

Meta-Analysis:  Protein  and  Energy  Supplementation   in  Older  People Anne C. Milne, MSc; Alison Avenell, MD; and Jan Potter, MBChB Background: Protein and energy undernutrition is common in older people, and further deterioration may occur during illness. Purpose: To assess whether oral protein and energy supplementa­ tion improves clinical and
nutritional outcomes for older people in the hospital, in an institution, or in the community. Data Sources: Cochrane Central Register of Controlled Trials (CEN­ TRAL), MEDLINE,  EMBASE, 
HealthStar, CINAHL, BIOSIS, and CAB abstracts. The authors included English- and non-English-language studies and hand-searched journals, contacted manufacturers, and sought information from trialists. The date of the most recent search of CENTRAL and MEDLINE is June 2005. Study Selection: Randomized and quasi-randomized controlled tri­ als of oral protein and energy
supplementation compared with placebo or control treatment in older  people. Data Extraction: Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality.  Differences were resolved by consensus. Data Synthesis: Fifty-five trials were included (n = 9187 randomly tions (Peto odds ratio, 0.72 [95% Cl, 0.53 to 0.97]) and reduced mortality (Peto odds ratio, 0.66 [CI, 0.49 to 0.90]) for those un­ dernourished at baseline. Few studies reported evidence that sug­gested any change in mortality, morbidity, or function for  those given supplements at home. Ten trials reported gastrointestinal disturbances, such as nausea, vomiting, and diarrhea, with oral supplements. Limitations: The quality of most studies, as reported, was poor, particularly for concealment of allocation and blinding of outcome assessors. Many studies were too small or the follow-up time was too short to detect a statistically significant change in clinical out­ come. The clinical results are dominated by 1 very large recent trial in patients with stroke. Although this was a high-quality trial, few participants were undernourished at baseline. Conclusions: Oral nutritional supplements can improve nutritional status and seem to reduce mortality and complications for under­ nourished elderly patients in the hospital. Current evidence does not support routine supplementation for older people at home or for well-nourished  older patients in any setting. assigned participants). For patients in short-term care hospitals who were given oral supplements, evidence suggested fewer complica-Ann Intern Med. 2006:144:37-48. For author affiliations, see end of text.www.annals.OIJ ndernutrition  among  older  people  is  a  continuing source of concern (1, 2). Older people have longer periods of illness and longer hospital stays (3), and data show that up to 55% of elderly
hospitalized patients are undernourished at admission (4, 5). Malnutrition is asso­ ciated with
poorer recovery in a broad range of patients and  conditions  (6- 8). However,  poor  nutritional 
status may be a marker for severity of existing medical conditions, and whether improving
nutritional status with oral protein and energy supplementation can improve acute or chronic
medical conditions is not clear. Recent systematic reviews examining the potential benefits of nutritional supplementation in older
people in­ clude Stratton and colleagues’ review (9) of randomized and nonrandomized trials (166
trials; 7630 patients) across all disease groups and settings, which concluded that nu­ tritional
supplementation had positive effects on nutri­ tional outcomes and mortality in elderly people and,
in some cases, clinical and functional benefits. Potter’s meta­ analysis (10) of 18 trials that
included older patients both in the hospital and in the community suggested a statisti­ cally
significantly lower mortality for the supplemented group (odds ratio, 0.61 [95% CI, 0.45 to 0.82]).
A recent update of a Cochrane review by Avenell and Handoll (11) of nutritional supplementation for
hip fracture care in older people found some evidence that oral protein and energy feeds (evaluated
by 8 trials) reduced unfavorable outcome (death or complications) but did not observe a
demonstrable effect on deaths alone. Overall, the evidence was weak because of methodologic defects in the reviewed studies. Oral nutritional supplements are
widely prescribed for older people both in the hospital and  in the commu­ nity. We undertook a
systematic review of randomized tri­ als of oral protein and energy supplementation to assess
clinical and nutritional outcomes for older people who are offered supplements in different

We identified  studies and performed the analyses ac­ cording to the Cochrane method (12). The
search included the following databases: Cochrane Central Register of Controlled     Trials    
(CENTRAL)      (Issue     2,     2005),
MEDLINE  (1966  to  June  2005),  EMBASE  (1980  to
March  2004),  HealthStar  (1975  to  March  2001),  CI-


See also:

Editors’ Notes ………………………… 38
Editorial comment. …………………….. 59

Web-Only Appendix  Tables Appendix  Figures CME quiz
Conversion of figures and table into slides

© 2006 American College of Physicians 137


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REVIEW   Protein and Energy Supplementation in Older People


Physicians sometimes recommend nutritional supplementa­ tion for sick, older persons.

This review summarizes 55 trials of protein and energy supplementation in people older than 65
years of age. Compared with placebo or no supplementation,  nutritional supplements did not affect
morbidity or mortality in peo­ ple living in the community. Among older and undernour­ ished
hospitalized patients, supplements sometimes re­ duced mortality and complications, such as
poor wound  healing, and pressure sores.  Oral supplements also sometimes caused nausea, vomiting,
and diarrhea.

Many trials  were  small  or  had short follow-up  times  and used outcome assessors  who  knew
which  patients took supplements.

-The Editors

NAHL (1982 to March 2004), BIOSIS  (1985 to March 2004), and CAB abstracts (1973 to March 2004). We
in­ cluded English- and non-English-language studies. We also hand-searched nutrition journals and
reference lists and contacted oral nutritional supplement manufacturers.
We included randomized or quasi-randomized  trials
with an minimum intervention of 1 week. Groups of study participants had to have a minimum average
age of 65 years. We included all patient groups, with the exception of people in critical care or
those who were recovering from cancer treatment. We included commercial supplements, other
milk-based supplements, and fortification of normal food sources. We excluded studies of specially
designed immunomodulatory supplements or supplements of spe­ cific amino acids. The full
description of the search strategy is available elsewhere (13). We contacted trialists for fur­
ther information on ambiguous numerical data and to al­ low trial quality to be more accurately
We examined the following outcomes as prespecified in our protocol: all-cause mortality, number of
people with morbidity or complications, length of hospital stay, func­ tional status, participants’
perceived quality of life, percent­ age change in weight, percentage change in mid-arm mus­ cle
circumference, acceptance of the supplement, and adverse effects. We included trials that reported
at least 1 relevant clinical outcome measure. Two reviewers indepen­ dently extracted outcome data
from the included trials and performed quality assessment of trials. We used a 10-item quality
assessment checklist, which is based on the quality assessment tool of the Cochrane Bone, Joint and
Muscle Trauma Group (14), to rate studies between 0 and 2 points for each item, including
assessment of allocation conceal­ ment, intention-to-treat analysis, and blinding of outcome
assessors. We resolved all differences by discussion.

3813 January 20061 Annals of internal Medi6nel Volume  144 • Number  1



Statistical Analysis
We combined data for the meta-analysis for the di­ chotomous variables of mortality and
complications and adverse effects by using RevMan 4.2 software (Cochrane Collaboration, Oxford,
United Kingdom). Low event rates pose particular problems for summarizing data in a system­ atic
review. Default use of a correction for  continuity or simply adding 0.05 to each cell when  counts
are less than
5.00 tends to produce  biased estimates. Many methods are
recommended in the literature (15). The widely available Peto method (16) produces estimates
without the need for 0-cell corrections, and it produces unbiased estimates when equal numbers of
patients are in each group (17). For each study, we calculated Peto odds ratios and combined the
results by using fixed-effects models with 95% confidence limits. We calculated weighted mean
difference  and 95% Cis for length of hospital stay, percentage weight change, and percentage
mid-arm muscle circumference change by using a fixed-effects model. We explored heterogeneity be­
tween comparable trials with the  test  (18)  by  using greater than 50% as the cutoff value for
statistically signif­ icant heterogeneity. When evidence suggested heterogene­ ity, we applied a
random-effects  model.
The trials reported body weight and anthropometric
measures in several ways. For meta-analyses of weight change and mid-arm muscle circumference
change, we se­ lected the mean and SD of the percentage weight change during the trial period
because of their clinical relevance (19). When the percentage weight change was not avail­ able, we
calculated the difference between the initial and final body weight, expressed as a percentage of 
baseline weight and an SD of 1Oo/o inferred. This SD was conser­ vative and was at the upper limit
of any observed result. If baseline weight was not reported, we assumed a standard value of 60 kg.
As in Potter and colleagues’ study (19), we chose mid-arm muscle circumference  as the
anthropometry measure because it is a measure of muscle. When this was not described in the trial,
we derived it from the mid-arm circumference or mid- upper arm circumference and  tri­ ceps
skinfold by using a standard formula  (20).
We performed prespecified subgroup analyses of the mortality  data  by  comparing  1)  baseline  
nutritional   status as defined by the investigators (nourished or undernour­ ished), 2) mean  age 
(<75 years  or  :=:::75 years),  3) amount of  kilojoules  provided  in  the  supplement   (< 1674 
 kJ [<400 kcal]  or  :=:::1674  kJ  [:=:::400  kcal]),  4)  duration  of
intervention  (<35  days  or  :=:::35  days),  and  5)  patient health  (well  or  unwell).
We performed an exploratory subgroup analysis for mortality on the basis of diagnostic group  (hip 
fracture, chest conditions, stroke, and congestive heart failure), ge­ riatric conditions (trials
that included frail patients with a variety of conditions), and perioperative surgical  patients.
We also stratified the trials by setting (short-term care hospital, long-term care institutions
[including nursing homes],  and  home  in  the  community)  because  we  sus-


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Protein and Energy Supplementation in Older People    REVIEW

peered differences in the nature and duration of the inter­ vention in different settings.
Prespecified sensitivity analy­ sis included only trials that reported clearly concealed
randomization. We evaluated the potential  for publication bias by using a funnel plot. In
addition, we performed a sensitivity analysis to address possible heterogeneity be­ tween findings
of small and large trials, the latter having more than  100 participants  in each group.
Role of the Funding Sources
The Medical Research Council,  United  Kingdom; Chief Scientist Office of the Scottish Executive
Health De­ partment, United Kingdom; and the  Student  Awards Agency for Scotland, United Kingdom,
funded the study. The funding sources had no role in the design, conduct, or reponing of the study
or in the decision  to  submit  the paper  for publication.


Figure 1. Flow chart for study selection.


Potentially relevant publications  Identified through electronic searching. bibliographies, and
(n = 34 870)


Papers retrieved for more detailed evaluation
(n = 242)

Papers exduded on the basis of title and abstract (generally because of lack of suitability of
study design, age group, or intervention)
(n = 34 628)

Description of Studies
From more than 34 000 titles or abstracts screened, we included 55 studies in our review (Figure
1). The 55 stud­ ies  (21-75)  recruited  9187 participants  (Appendix  Tables 1 and 2, available
at Nearly half of the participants were from the recent Feed Or Ordinary Diet
(FOOD) trial (37) of oral nutritional supplements  for pa­ tients with stroke. Most trial
participants (74%; 25 trials) were hospitalized  inpatients.  Fewer patients were at home


I Papers included  I
(n= 83)

I Awaiting  further   infonmatton   I
1                                     (n = 14)

I  Excluded after evaluation
I           (n = 145)”

Studies reporting particular outcomes


in the community (16%; 21 trials) or in long-stay, elderly care, or continuing care wards or
nursing homes ( 1Oo/o; 9 trials). Overall, most participants were patients with stroke (45%; 2
trials) or were mixed groups with various geriatric conditions (42%; 33 trials). We also included
trials of pa­ tients with hip fracture (7%; 10 trials), patients  with chronic obstructive
pulmonary disease (5%; 7 trials), sur­ gical patients (1o/o; 2 trials), and patients with
heart failure (<1o/o; 1 trial).
The source of funding was unclear for most studies. Eleven trials were coauthored by an employee of
the man­ ufacturer of the oral supplement or were fully funded by the manufacturer  (Appendix Table
 1, available at www The interventions in the trials aimed to pro­ vide between 175 kcal (732 kJ) and 1000
kcal (4.2 MJ) and between 10 g and 36 g of protein daily. Fifteen trials provided less than 1674 kJ
(400 kcal) per day, 30 trials provided 1674 kJ or more ( 400 kcal) per day, and 10 trials did not
specify the supplemented energy value. Most supplements included vitamins and minerals. The inter­
vention period ranged from 10 days to 18 months and was 35 days or more in 33 trials, was less than
35 days in 12 trials, and was unspecified in 10 trials. Eight studies, in­ cluding the FOOD trial
(37), provided supplements until hospital discharge (estimated mean ranging from 12 days to 38
days). The duration of follow-up was usually the same as that of the intervention.
Seventeen trials, including the FOOD trial (37), re-



I Primary studies                  Mortality (n = 25)
(n= 55)                         Morbidity and complication (n = 20)
Length of stay (n = 11) Adverse effects (n = 18) Weight change (n = 38)
Anm muscle circumference (n = 15)

*Main reasons were study not randomized, intervention did not meet inclusion criteria (nasogastric
feeding, high-protein vs. low-protein , early vs. late introduction of feeding, and
immunomodulatory supplements) , or participants did not fit the inclusion criteria (too young and
patients with cancer) .


ported that supplements were well-accepted by most pa­ tients, although this was often not defined
or was variously defined. Other studies, particularly those offering supple­ ments over longer
periods of time, reported major prob­ lems with adherence for 24% to 45% of participants (24, 41,
62, 71, 59). Total energy and protein intake were, however, substantially greater than
nonsupplemented in­ take in nearly all studies, although Fiatarone and colleagues
(36) highlighted that the increase in intake from the sup­ plements may be partially offset by a
reduction in normal food intake. When reported, completeness of follow-up varied between 100% and
27% of those randomly as­ signed. Participant withdrawal or dropout was 25% or higher in  12 of the
55 trials.
3 January  20061 Annals of Internal Medicine IVolume  144 • Number  1139


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REVIEW   Protein and Energy Supplementation in Older People

Methodologic Quality of Included Studies
Full details of the quality assessment are available in the Cochrane review (13). Appendix Table 2
(available at www  presents  total  scores.  The trials  had  low scores,
with only 27 of 55 trials achieving 50% or more of the max­ imum quality score. Sixteen studies
confirmed adequate con­ cealment of allocation, and 22 studies reported intention-to­ treat
analysis or we could perform intention-to-treat analysis. The quality was poorest with regard to
blinding. Only 9 stud­ ies dearly reported the blinding of outcome assessors.

We suspected heterogeneity because of the differences in the nature and duration of the
intervention in different set­ tings. We therefore grouped trials post hoc for analysis by setting
(that is, short-term care hospital, long-term care insti­ tutions [including nursing homes], and
community-dwelling elders). The duration of the intervention was 8 weeks or more in 20%, 55%, and
81% of trials set in the hospital, in long­ term care, and in the community, respectively. Three
hospital­ based interventions continued at home after discharge.

At the time of last follow-up, which was usually when supplementation was discontinued, nutritional
supplemen­ tation was associated with reduced mortality from a global analysis of25 trials (6852
randomly assigned participants), which was borderline statistically significant (Peto odds ra­ tio,
0.86 [CI, 0.74 to 1.00]) (Figure 2). For patients in short-term care hospitals, mortality was not
statistically sig­ nificantly reduced (Peto odds ratio, 0.88 [CI, 0.74 to 1.04]), unless only
undernourished patients were included (Peto odds ratio, 0.66 [CI, 0.49 to 0.90]) (Figure 3). A
reduction in mortality from the analysis of patients in long-term care was also not statistically
significant (Peto odds ratio, 0.65 [CI, 0.41 to 1.02]). For participants in long-term care, trials
were too small and were too few in number to examine the effect of supplementation in nour­ ished
and undernourished older people. Evidence did not suggest a reduction in mortality for people
living at home regardless of nutritional status (Peto odds ratio, 1.05 [CI,
0.57 to 1.95]). We found no statistically significant heter­ ogeneity within any setting (I2  = 0%
to 12.6%).
Results of the subgroup analysis suggested improved survival with supplementation in undernourished
people (17 trials; 2093 participants; 3 trials providing separate results for nourished and
undernourished patients) (Peto odds ratio, 0.73 [CI, 0.56 to 0.94]), when people were 75 years of
age or older (18 trials; 1611 participants) (Peto odds ratio, 0.64 [CI, 0.49 to 0.85]), when people
were offered 1674 kJ or more per day in the supplement (15 trials; 6157 participants) (Peto odds
ratio, 0.85 [CI, 0.73 to 0.99]), and when participants were not well (22 trials; 6630 participants)
(Peto odds ratio, 0.86 [CI, 0.74 to 1.00]). The   test for heterogeneity was less than 2% for all

4013  January   20061 Ann.ll, of  I  nrc·rna I     :’vkdicincl Volume    144 • Number    1

The results for mortality were statistically significant when we included only trials with dearly
concealed random­ ization (12 trials; 5991 participants) (Peto  odds  ratio,  0.84 [CI,  0.72  to 
0.98]).  Appendix  Figure   1 (available  at  www  and  our  sensitivity  analysis  do  not  suggest  that
small, positive trials were over-represented (21 trials; 1464 participants) (Peto odds ratio, 0.87
[CI, 0.59 to 1.29]) com­ pared with larger trials (4 trials; 5388 participants) (Peto odds ratio,
0.86 [CI, 0.73 to 1.01]). Our post hoc subgroup  anal­ yses for mortality based on diagnostic group
found statistically significant results for trials that included patients with various geriatric
conditions (15 trials; 2313 participants) (Peto odds ratio, 0.69 [CI, 0.52 to 0.92]). No evidence
suggested  a change in survival with oral supplements from trials  of pa­ tients with stroke (2
trials; 4063 participants)  (Peto odds ratio,
0.92 [CI, 0.76 to 1.11]) or hip fracture (5 trials; 269 partici­ pants) (Peto odds ratio, 0.88 [CI,
0.41 to  1.89]). The  data were too limited to undertake meta-analyses for other diag­ nostic 

Morbidity and Complications
Twenty trials provided data on morbidity and complica­ tions (Appendix Table 2,  available  at Global meta-analysis of 19 trials (5508 participants) reporting participants  with
 infective complications  (38, 61, 62); incom­
plete wound  healing  (30,  35);  total  pressure  sores  (37,  50);
total complications,  excluding deaths (26, 33, 44,  53, 68);
illness that led to discontinuation (42, 54, 63, 74); exacerba­ tion of chronic obstructive
pulmonary disease (67, 69); and hospitalization (52)  suggested fewer complications, although this
was not statistically significant  (Peto odds ratio, 0.82 [CI,
0.65 to 1.03]). Hospitalized patients who were given supple­ ments had a statistically significant
decrease in complications (Peto odds ratio, 0.72 [CI, 0.53 to 0.97]). Supplementation did not have
a statistically significant effect on morbidity or complications in people in long-term care (Peto
odds ratio,
0.92 [CI, 0.56 to 1.52]) or at home (Peto odds ratio, 1.01 [CI, 0.63 to 1.64]) (Figure 4). Subgroup
analyses based on diagnostic group suggested a reduced risk for complications with supplementation
only for patients with hip fracture (4 trials; 147 participants) (Peto odds ratio, 0.48 [CI, 0.24
to 0.96]). In most cases, including the FOOD trial (37), out­ come assessors for complications were
not blinded to treat­ ment allocation.

Adverse  Effects
Most trials did not report adequate methods for assessing potential adverse effects. In most trials
that discussed adverse effects with supplements (18 trials), no comparison with the control group
was performed. Of these trials, 10 reported some problems with tolerance and side effects and 8
reported no adverse effects (Appendix Table 2, available at www.annals
.org). Meta-analysis of 6 trials (477 participants) that reported participants with adverse effects
in both groups suggested a statistically significant  effect on gastrointestinal  disturbances,


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Protein and Energy Supplementation in Older People   REVIEW


Figure 2. Meta-analysis of mortality.

Study, Year (Reference)

Treatment Group,

Control Group,

Peto OR



nIn                           nIn

(95’Yc Cl)


(95’Yc0  Cl

Short-term care hospital

Delmi et al., 1990 (33)                                          6/27                              
    0.64 (0.2Q-2.00)

Madigan, 1994 (54)                                            4/18                             
6.42 (0.78-53.07)
Hankins, 1996 (44)                                             2/17                              
0.35 (0.06-2.05)
Volkert et al., 1996 (71)                                      4/35                             
8/37                                                                               &


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