A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions

ARTICLE IN PRESS

G Model ARR 470 1–14

Ageing Research Reviews xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr

Review

1

A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions

2

3

4 5 6

Q1

Rebecca J. Stratton a,∗ , X. Hebuterne b , M. Elia a a b

Institute of Human Nutrition, University of Southampton, Southampton, UK CHU Nice and University-Nice-Sophia-Antipolis, Nice, France

7

8

a r t i c l e

i n f o

a b s t r a c t

9 10 11 12 13

Q2 Article history: Received 30 January 2013 Received in revised form 3 July 2013 Accepted 15 July 2013 Available online xxx

14

20

Keywords: Oral nutritional supplements Malnutrition Readmissions Meta-analysis Nutritional support

21

Contents

15 16 17 18 19

22 23

1. 2.

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

3.

The adverse effects of disease-related malnutrition (DRM) on health care use and costs are well substantiated. However, the impact of managing DRM with nutritional support on health care use, including hospital (re)admissions requires exploration. This systematic review (9 RCT, N = 1190) examined the effects of oral nutritional supplements (ONS) on hospital (re)admissions. Meta-analysis of 6 RCT (N = 852) with data on the proportion of patients (re)admitted to hospital showed significant reductions with ONS vs. routine care (OR 0.59, 95% CI 0.43–0.80, P = 0.001), including 5 RCT (N = 826) that recorded readmissions (OR 0.59, 95% CI 0.43–0.80, P = 0.001). The significant reduction in (re)admissions was found in metaanalyses of ONS trials in various settings and in patients with DRM or of varied nutritional status. A larger meta-analysis (8 RCT, N = 999) that combined other (re)admissions data using standardised differences also showed a significant reduction with ONS (effect size −0.23, 95% CI −0.36 to −0.10, P = 0.001). Most of these trials (75%) were in older people aged ≥65 years (6 RCT, N = 834, effect size −0.18, 95% CI −0.31 to −0.04, P = 0.011). This systematic review shows that ONS significantly reduce hospital (re)admissions, particularly in older patient groups, with economic implications for health care. © 2013 Published by Elsevier B.V.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subjects and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Synthesis of data and statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. RCT reporting number of patients (re)admitted to hospital (N = 6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Intervention, study design and primary outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Patients and setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Quality of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. RCT reporting hospital (re)admissions data in other ways (3 RCT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Intervention, study design and primary outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Patients and setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Quality of the studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. Outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Series 1: RCT (N = 6) reporting number of patients (re)admitted to hospital during the study period. . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Series 2: All RCT reporting (re)admissions to hospital . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

∗ Corresponding author at: Institute of Human Nutrition, MP 113 Southampton General Hospital, University of Southampton, Southampton SO16 6YD, UK. Tel.: +44 07738 501702. E-mail addresses: [email protected], [email protected] (R.J. Stratton), [email protected] (X. Hebuterne), [email protected] (M. Elia). 1568-1637/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.arr.2013.07.002

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

G Model ARR 470 1–14

4.

42

ARTICLE IN PRESS R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

2

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

There is increasing interest in the influence of interventions used 44 in clinical practice on health care use, and especially the effects 45 on costly hospital admission and readmission rates. The adverse 46 effects of disease-related malnutrition on health care use are well 47 substantiated, and these include increased hospital admissions as 48 well as increased GP visits and longer hospital stays (Elia, 2006; Elia 49 and Stratton, 2005; Stratton et al., 2003). Consequently the financial 50 public expenditure on malnutrition is considerable, most recently 51 estimated to be ∼£13 billion (D 16.24 billion; 02.10.12) annually 52 (population ∼60 million, 2007 data) for the UK (Elia and Stratton, 53 2009). However, these estimates are based on observational studies 54 without specific interventions. The effect of nutritional interven55 tions on resource use, specifically hospital readmissions, is unclear 56 and requires exploration. One of the commonly used treatments for 57 malnutrition is oral nutritional supplements. These supplements 58 are typically ready-made liquids and contain energy, protein and a 59 range of vitamins, minerals and trace elements. There is already 60 a synthesis of the evidence from systematic reviews and meta61 analyses (Koretz et al., 2007; Milne et al., 2006; National Institute 62 for Health and Clinical Excellence (NICE), 2006; Stratton et al., 2005; 63 Stratton and Elia, 2007; Stratton et al., 2003) (including that of 64 the National Institute for Health and Clinical Excellence, NICE) of 65 the effects of all types of oral nutritional supplements on nutri66 tional intake and status (e.g. body weight) and some functional (e.g. 67 muscle strength) and clinical outcomes (e.g. complications such as 68 infections and pressure ulcers) in various patient groups. However, 69 a critical review and synthesis of the impact of the use of liquid 70 multi-nutrient ONS on hospital (re)admissions is lacking. A prelim71 inary communication of the effects of ONS on hospital readmissions 72 (Stratton et al., 2011) and two subsequent systematic reviews of 73Q4 nutritional support dietary approaches and/or ONS (4 RCT) (Beck 74 et al., 2012); ONS high in protein (>20% energy from protein) (2 RCT) 75 (Cawood et al., 2012), which included hospital (re)admissions as an 76 outcome measure, were not designed to comprehensively address 77 the effects of all types of liquid multi-nutrient ONS on this outcome 78 across all patient groups in the community setting. 79 Therefore, this systematic review aimed to critically review 80 and synthesise the literature to assess the impact of oral nutri81 tional supplements used in the community setting across all patient 82 groups on hospital admissions and readmissions (indicated as 83 (re)admissions). 43Q3

00 00 00 00

nursing, rehabilitation/community hospitals, other long term care/institutions. Studies in healthy individuals were excluded. For intervention, all studies using oral nutritional supplements (including those simultaneously using or comparing with dietary counselling and/or standard diet) could be included. All types and doses of ONS were permitted with the exception of supplements that contained only one macronutrient (fat, carbohydrate, protein) or were elemental formulations. Studies of micronutrient (vitamin and mineral) supplements were excluded. Studies of enteral tube feeding, dietary counselling or parenteral nutrition or studies comparing one ONS with another ONS were excluded. Only studies with outcome data relating to hospital admissions and readmissions (referred to as (re)admissions) were included. 2.2. Search strategy The search strategy was developed in MEDLINE using relevant free text and MeSH terms. The search strategy was then modified for searches in EMBASE and The Cochrane Library. Searches were undertaken up until November 26th 2012. The databases searched were the Cochrane Library (incorporating the Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database, NHS Economic Evaluation Database (NHS EED)), OVID Medline (from 1950), OVID EMBASE (from 1980). Additional studies were identified by hand searching reference lists of previous systematic reviews, relevant websites (e.g. Clinicaltrials.gov, ISRCTN Register, Current Controlled Trials (Controlled-trials.com), metaRegister of Controlled Trials, Trial Trove). In addition the conference proceedings from BAPEN and ESPEN were searched for relevant abstracts. On first pass, the results of the searches were reviewed independently by two reviewers on the basis of title or abstract. In the event that a decision could not be made on the title and/or the abstract was missing, the full publication was retrieved for checking. On second pass, two reviewers independently assessed all retrieved articles for their suitability for inclusion. The reviewers discussed any differences of opinion before deciding on the final list of included/excluded articles at each pass. Disagreement between the reviewers at any stage was referred to a third party. A pre-determined data extraction table was designed to capture all key study characteristics and outcome data. 2.3. Quality assessment

84

2. Subjects and methods

85

2.1. Eligibility criteria

86 87 88 89 90 91 92 93 94 95 96

Studies were deemed eligible for inclusion in the review if they conformed to the pre-determined inclusion and exclusion criteria (Table 1). Clinical studies were restricted to randomised controlled trials (RCT) published in English, and there was no exclusion on the basis of study size or duration of follow up. Participants were adults (mean age ≥18 years) of any nutritional status (within the spectrum of malnourished to well nourished, and irrespective of whether the population involved only malnourished patients or a mixture of subjects deemed to be well nourished and malnourished), randomised to receive the intervention in a community setting, such as care homes, own home, outpatients, GP surgeries, district

Quality assessment was undertaken by two independent reviewers according to methods recommended in section six of the Cochrane Reviewer’s handbook version 5.1.0 (Cochrane Collaboration, 2006). The likelihood of bias was judged according to three components: adequacy of randomisation and allocation concealment procedures, adequacy of blinding procedures and completeness of follow-up. Any differences of opinion were resolved by discussion and consensus. 2.4. Synthesis of data and statistics Following extraction of admission data from the included trials, where appropriate and feasible, data was combined and meta-analysis performed. Comprehensive Meta-analysis (version

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

97 98 99 100 101 102 103 104 105 106 107 108 109

110

111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136

137

138 139 140 141 142 143 144 145

146

147 148 149

G Model ARR 470 1–14

ARTICLE IN PRESS R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

3

Table 1 Summary of inclusion and exclusion criteria applied during evaluation of studies for systematic review. Selection criterion

Inclusion criteria

Exclusion criteria

Population

Adults with a mean age ≥18 years Any nutritional status In the community (including all studies that have a community period of supplementation, with or without other settings e.g. hospital)

Animal studies Developing world Pregnancy and lactation Individuals in sports studies Studies in healthy adults Individuals in metabolic studies

Intervention

All studies using ONS (including those simultaneously using or comparing with dietary counselling and/or simultaneous standard diet) All ONS types, ready-made and powders (two or more macronutrients, with and without micronutrients)

Dietary counselling only Parenteral nutrition only Enteral tube feeding Supplements containing only one macronutrient Micronutrient-only supplements ONS vs. ONS studies ONS with elemental formulations

Study type

Randomised controlled trials

Outcome measures

Hospital admissions, including readmissions

164

2, Biostat Inc., NJ, USA) was used to undertake planned metaanalysis on the proportion of patients (re)admitted to hospital. A random effects model was used, unless otherwise stated. The odds ratio (OR) and 95% confidence interval (CI) were calculated. Standardised differences were also calculated for results reported in different units of measurement. Meta-regression was undertaken to explore the effects of the quantity (kcal) of supplementation provided and the duration of supplementation on (re)admissions. The standard deviation of the proportion of patients (re)admitted to hospital was calculated using the traditional binomial method and that for the number of admissions per patient was calculated assuming the Poisson distribution (SD = square route of the mean) (Altman and Gardner, 2000). The number needed to treat was given by the reciprocal of the absolute risk reduction (Cook and Sackett, 1995).

165

3. Results

150 151 152 153 154 155 156 157 158 159 160 161 162 163

166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190

A total of 18,125 potentially relevant publications were identified from electronic database searches (Embase = 5767, Medline = 5858, Cochrane = 6500), of which 660 duplicates were excluded. On the basis of title and abstract, 17,271 studies were excluded at first pass (Fig. 1). On re-application of the review inclusion criteria to the 197 full-text papers, and to 3 additional studies identified via hand searching, a further 188 were excluded at second pass. Therefore, 9 publications meeting the inclusion criteria were included in the systematic review (Table 2 ) (Chapman et al., 2009; Edington et al., 2004; Gariballa et al., 2006; Gazzotti et al., 2003; Hirsch et al., 1993; McMurdo et al., 2009; Miller et al., 2006; Norman et al., 2011; Price et al., 2005). (An earlier report (Norman et al., 2008) of one of the RCT (Norman et al., 2011) was not included, since a more recent publication presented an updated, extended set of data compared to the original older publication). Of the nine RCT of ONS that had data on hospital admissions or readmissions (Chapman et al., 2009; Edington et al., 2004; Gariballa et al., 2006; Gazzotti et al., 2003; Hirsch et al., 1993; McMurdo et al., 2009; Miller et al., 2006; Norman et al., 2011; Price et al., 2005), six reported (re)admission results in a comparable way (Table 3) (Chapman et al., 2009; Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005) (confirmed by personal communication for (Norman et al., 2011)). These six studies (Chapman et al., 2009; Gariballa et al., 2006; Gazzotti et al.,

All non-RCT study designs

2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005) were reviewed together and examined in meta-analysis (series 1). Another 3 trials (Edington et al., 2004; Hirsch et al., 1993; McMurdo et al., 2009) reported (re)admissions to hospitals in different ways, for example the number of admissions per patient (Edington et al., 2004; Hirsch et al., 1993) or per group (McMurdo et al., 2009) and therefore the results of these trials were reviewed together. After standardising all of the results, additional meta-analyses of the comparable studies were undertaken (series 2). Details of these two series of studies are provided separately below so they can be related to the meta-analyses that follow. 3.1. RCT reporting number of patients (re)admitted to hospital (N = 6) Six RCT (Chapman et al., 2009; Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005) reported the number of patients (re)admitted to hospital. These were undertaken in the UK (Gariballa et al., 2006; Price et al., 2005), Australia (Chapman et al., 2009; Miller et al., 2006), Belgium (Gazzotti et al., 2003) and Germany (Norman et al., 2011) and were all published in 2003 or later. 3.1.1. Intervention, study design and primary outcomes The duration of the intervention varied from 6 weeks to 3 months in all but one study in which the intervention continued for 12 months (Chapman et al., 2009) (Table 2). (Re)admissions were assessed either at the end of the intervention period (after 2 months (Gazzotti et al., 2003), 3 months (Norman et al., 2011) or 12 months (Chapman et al., 2009)) of supplementation or some time (4 (Price et al., 2005), 6 (Miller et al., 2006), and 18 (Gariballa et al., 2006) weeks later) after the intervention had finished (Table 3). One study (Chapman et al., 2009) involved a factorial design, but for the purposes of this analysis only the ONS and control groups were used in the meta-analysis. The supplements used were ready-made, multi-nutrient drinks. Energy density ranged from 1.00–2.48 kcal/ml, and prescribed quantities ranged from ∼475 to 1200 kcal (∼21–60 g protein) per day (ONS intakes ranged from 372 to 804 kcal/day (14.9–48 g protein) where reported (Gazzotti et al., 2003) or calculated (Miller et al., 2006; Norman et al., 2011; Price et al., 2005)). The control group received standard care (2 RCT (Gazzotti et al., 2003; Price et al., 2005)), visits where general advice on diet and exercise

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

191 192 193 194 195 196 197 198 199 200 201

202 203

204 205 206 207 208 209 210

211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230

Miller et al. (2006) Primary outcome: Weight? (power calculation used weight)

Norman et al. (2011) (Update from Norman et al., 2008) (Norman et al., 2008, 2011) Primary outcome:? quality of life, intake, non-elective readmissions for cost-effectiveness analysis (Power calculation on hand grip strength in 2008 paper)

Number patients randomised

Setting

ONS

Prescribed ONS (kcal, g protein) and ONS intake

ONS energy density (kcal/ml)

Duration of intervention

Control group

Elderly (men and women aged ≥65 years)

Malnourished (MNA < 24 and BMI < 22 kg/m2 or weight loss ≥5% in 3 months)

13 ONS 13 Control

Community: Own home – free living independent

475 kcal, 21.4 g (Intake?)

2

12 months

No treatment group (standard care + placebo testosterone + dietary advice)

Elderly, hospitalised, acutely ill patients (65–92 years) Mean chronic illness per patient = 1.9 in ONS group and 1.7 in control group (ischaemic heart disease, COPD, chest infections, CVA, falls, elective surgery) Elderly patients 75 years or older hospitalised for acute conditions (not described) Patients (≥70 years) with a fall-related lower limb fracture (86% fractured neck of femur)

?

223 ONS 222 Controla

In hospital and after discharge in the community (various settings)

Nova source liquid (Novartis) + dietary advice (ONS given several hours after meals in divided doses) Liquid ONS

995 kcal, 49.75 g (calculated) (Intake?)

2.48

6 weeks

Placebo 60 kcal (0.15 kcal/ml) but no micronutrients/protein

At risk (MNA 17–23.5) Mean BMI 25.9 ± 5.1 kg/m2

39 ONS 41 Placebo

In hospital and after discharge in the community

500 kcal, 21 g (Intake 407 kcal, 16.9 g)

1.25

60 days

Standard care – no supplementation

At risk (mid arm circumference < 25th percentile)

25 ONS 26 Control

870–1200 kcal, 34.8–48 g (Intake 583–804 kcal, 23.3–32.2 g, calculated from 67% reported compliance)

1.5

6 weeks

Control: (equal number of visits as ONS group when given general advice on nutrition and exercise)

Benign gastrointestinal disease (including IBD, liver disease, biliary disease, pancreatic disease, gastritis) discharged from hospital (Mean age 51 years)

Malnourished (SGA B or C) Mean BMI 21 kg/m2

60 ONS 54 Control (80 in each group at start)

Started 7d after fracture in hospital and some continued after discharge (various community settings) Community – after discharge from hospital

Clinutren Soup and Clinutren 1.5 (2 supplements/day) (Nestle) Fortisip (Nutricia) Administered as 4 doses of equal volume

Fresubin Protein energy drink, (Fresenius) plus dietary counselling (Advised to take ONS slowly and in between meals)

Up to 900 kcal 60 g (Intake = 2.4 ± 0.8 ONS, calculated as 720 kcal, 48 g)

1.5

3 months after hospital discharge

Dietary counselling onlyb

R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

Gazzotti et al. (2003) Primary outcome: weight

Nutrition status

ARTICLE IN PRESS

Series 1 (6 RCT) Chapman et al. (2009) (N.B. There are 2 other groups in this study not included in analysis) Primary outcome: hospital admissions and quality of life Gariballa et al. (2006) Primary outcome: Barthel’s score and hospital readmissions (non-elective) but power calculation for albumin and Barthel’s score

Population

G Model

Study

ARR 470 1–14

4

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

Table 2

Q13 Characteristics of studies in the systematic review with (re)admission data. Q12

Hirsch et al. (1992), Hirsch et al. (1993) Primary outcome:? (no power calculation)

Patients with alcoholism and alcoholic liver disease (mean age 48 years)

66 ONS 70 Control

After discharge in the community

Fortisip and Fortifresh (Nutricia)

600 kcal, 24 g (Intake 372 kcal, 14.9 g calculated from 62% reported compliance)

1.5

8 weeks

Receiving usual care

Malnourished (BMI <20 kg/m2 , or >20 kg/m2 but <25 kg/m2 and with weight loss of ≥10% in the 6 months prior to the study period or ≥5% in the 3 months prior to the study Well nourished and malnourished

51 ONS 49 Control (45 for control group readmissions data)

Community (various settings)–recently discharged

600–1000 kcal, g protein? (Intake 342 kcal, 15.8 g)

NR

Up to 24 weeks (Mean intervention = 99.4 d, 8 weeks minimum and could continue until 24 weeks)

Standard care

32 ONS 33 Control (data on 26 ONS and 26 Control)

Community – outpatients (and in hospital if necessary)

Ensure Plus, Enlive, Formance pudding or Ensure bar (Abbott) (Telephone calls from Dietitian to improve compliance) Commercial casein-based enteral nutrition formula (ADN) (liquid) plus regular diet

1000 kcal, 34 g (Intake?)

1

1 year

Placebo capsule (unknown composition) plus regular diet

126 ONS 127 ‘Control supplement’ (Analysed 93 and 98, respectively)

After discharge in the community

Fresubin Protein energy (Fresenius)

600 kcal, 40 g (Intake?)

1.5

16 weeks

Control supplement: based on skimmed milk 200 kcal, 12.4 g protein (0.5 kcal/ml)

Additional study (only included in sensitivity analysis) Elderly admitted to McMurdo et al. (2009) Undernourished Primary outcome: hospital with an (BMI <24 kg/m2 , Activities of daily acute illness (no MAMC <10th living – Barthel’s details). Care home percentile or index residents excluded weight loss of 5% or more during (readmissions not a primary or secondary hospital stay) outcome)

R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

Additional studies for Series 2 (2 RCT) Edington et al. (2004) Elderly aged ≥ 65 Primary outcome:? years, with a (power calculations variety of on weight change) diagnoses (COPD, MI, chest infections), recently discharged from hospital

Malnourished (BMI ≤ 24 kg/m2 , TSF/MAMC < 10th percentile and/or weight loss ≥5% during hospital stay)

a

Numbers of patients in ONS and control group taken from published text and not table. Undertaken prior to discharge from hospital. ? indicates missing or unclear in paper. b

ARTICLE IN PRESS

Elderly (≥75 years) discharged from general medical and geriatric hospital wards acutely ill (No details)

G Model

ARR 470 1–14

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

Price et al. 2005 (Price et al., 2005) Primary outcome: weight (patients withdrawn from study on readmission)

5

G Model

ARR 470 1–14

6

Setting of intervention

Time period over which (re)admissions recorded

ONS

CON

Type of data

Admission type

Series 1 (6 RCT) Chapman et al. (2009) (Elderly) – Australia

Free living

12 moc

Hospital and discharge Hospital and discharge

6 mod 2 moc

5/13 9/13 89/222 3/41

Number patients admitteda Number admissions per groupb Number patients admitted Number patients admitted

Admissions (all types)

Gariballa et al. (2006) (Elderly) – UK Gazzotti et al. (2003) (Elderly) – Belguim

4/13 5/13 65/223 4/39

Miller et al. (2006) (Lower limb fracture) – Australia Norman et al. (2011) (benign GI disease) – Germany Price et al. (2005) (Elderly) – UK

Hospital and discharge

3 moe

2/25

4/26

Number patients admitted

Readmissions (non-elective) Readmissions (type not described – includes non-elective in at least two cases) Readmissions (type not defined)

After discharge

3 moc

17/60 (n 80 start)

26/54 (n 80 start)

Number patients admitted

Readmissions (acute)

After discharge

3 mof

10/66

17/70

Number patients admitted

Unplanned readmission

Additional studies for Series 2 (2 RCT) Edington et al. (2004) (Elderly) – UK

After discharge

6 mog

1.02 (1.46) (n 51)

1.04 (1.33) (n 45)

Number admissions per person (mean (SD))

Hirsch et al. (1993) (Liver disease) Chile

Outpatients

12 moc

0.85 (0.88) (n26)

1.6 (1.18) (n25)

Number admissions per person (mean (SD))

Readmissions (described as ‘admissions’ but all patients had been discharged from hospital) Admissions (all types)

4 moc

77/93 (n 126 start)

65/98 (n 127)

No. admissions per group

Additional study (only included in sensitivity analysis) McMurdo et al. (2009) (Elderly) – UK After discharge a

Data used in series 1 meta-analysis. Data used in series 2 meta-analysis. c Coincided with the end of the intervention period. d 18 weeks after intervention finished. e 6 weeks after intervention finished. f 4 weeks after intervention finished. g Varying period after intervention (given for 8–24 weeks) had finished. All types of (re)admissions = elective and non-elective (re)admissions (all reasons). b

Unplanned readmissions

R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

Study

ARTICLE IN PRESS

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

Table 3 (Re)admission data.

ARTICLE IN PRESS

G Model ARR 470 1–14

R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

Duplicate studies: 660

Database searches Potential studies 18125

1 pass exclusion: 17271

Included: 17465

st

2

nd

7

pass exclusion: 188

Excluded reasons: Hospital setting: 22 Study design: 14 ONS vs ONS: 30 ONS does not meet criteria/ no ONS: 23 Combined interventions: 12 Earlier publication of study with same outcome: 2 Ineligible population: 1 No admissions data: 84

Included: 197

Hand searching: 3

Included: 9 RCTs (All full text papers)

Fig. 1. Flowchart of inclusions/exclusions.

231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250

251 252 253 254 255 256 257 258 259 260 261 262

was given (1 RCT (Miller et al., 2006)), a placebo drink (minimal energy of 60 kcal (0.15 kcal/ml), corresponding to 6% of the energy content of the intervention ONS, no protein or micronutrients) (1 RCT) (Gariballa et al., 2006), or dietary advice (2 RCT (Chapman et al., 2009; Norman et al., 2011)) (plus a placebo capsule in 1 RCT (Chapman et al., 2009)), which in both trials was also given to the intervention group (see Table 2) The aims of the studies and the primary outcome measures varied. Hospital admissions formed the primary outcome measure in only one study (Chapman et al., 2009). This study provided information on the number of patients admitted to hospital as well as the total number of admissions, which sometimes involved the same patient on two occasions over the 12 month period of study. In one RCT, readmissions were described as one of the main outcomes (Gariballa et al., 2006), together with other clinical outcomes (including mortality, quality of life, infective complications, muscle function). One RCT assessed quality of life for a cost-effectiveness analysis (Norman et al., 2011). In three other studies the primary outcome measure was weight change (Gazzotti et al., 2003; Miller et al., 2006; Price et al., 2005). For more information, see Table 2. 3.1.2. Patients and setting • Recruitment: Five studies recruited patients during or after an admission to hospital (Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005), either a non-elective admission (Gazzotti et al., 2003; Miller et al., 2006; Price et al., 2005), or both elective and non-elective admissions (Gariballa et al., 2006) and in one RCT the types of admission(s) were not specified (Norman et al., 2011) (Table 3). Only one study used an advertisement to recruit independently living subjects from the community where the study was carried out (Chapman et al., 2009), and the only one in this series to assess admissions rather than readmissions as an outcome measure.

• Setting of intervention: In three of the studies, ONS were initiated in hospital and continued in the community after hospital discharge (Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006) while in the other three, supplementation was carried out entirely in the community (Chapman et al., 2009; Norman et al., 2011; Price et al., 2005) (Table 2). • Disease or condition: Four studies involved older people with a mixture of diseases or conditions (Chapman et al., 2009; Gariballa et al., 2006; Gazzotti et al., 2003; Price et al., 2005) and two involved specific disease categories, older people with lower limb fractures following falls (Miller et al., 2006), and younger adults with benign gastrointestinal conditions (Norman et al., 2011) (Table 2). • Nutritional status: In five of the studies (Chapman et al., 2009; Gazzotti et al., 2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005) patients were described as malnourished or at risk of malnutrition (defined using a wide variety of criteria, see Table 2) and in the other (Gariballa et al., 2006) nutritional status was not specified. • Age: Five of the studies (Chapman et al., 2009; Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006; Price et al., 2005) involved only older subjects (≥65 years (17, 19), with a mean age of 78 years (Chapman et al., 2009) and 77 years (Chapman et al., 2009; Gariballa et al., 2006); ≥70 years with a mean age of 84 years (Miller et al., 2006); and ≥75 years with a mean age 85 years (Price et al., 2005)). In the remaining study (Norman et al., 2011), the mean age was 52 years. 3.1.3. Quality of studies The quality of RCT is summarised in Table 4. One of the RCT fulfilled all the criteria (Gariballa et al., 2006), and the remaining studies fulfilled most of the criteria, with the exception of blinding.

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289

290 291 292 293

G Model

ARR 470 1–14

8

Randomisation

Method of randomisation

Blinding

Method of blinding

Fate of withdrawals described

Study groups comparable at baseline

ITT analysis

Series 1 (6 RCT) Chapman et al. (2009)

Adequate

No

NA

Yes

Yes

Yes

Gariballa et al. (2006)

Adequate

Randomly assigned to 1 of 4 groups by using a stratification system to ensure equal ratio across malnutrition risk categories Randomisation sequence generated by statistician, concealed in sealed envelopes, kept in a different city

Yes and adequate

NAa

Yes

Yes

Gazzotti et al. (2003) Miller et al. (2006)

Adequate Adequate

No No

Yes Yes

Yes Yes

Norman et al. (2011)

Adequate

No

NA

Yes

Yes

Yesb For most but not all outcomes Yesc

Price et al. (2005)

Adequate

Sealed envelopes Stratified (for setting), block randomisation, computer generated allocation sequence in sealed opaque envelopes Computer generated randomisation list kept by a co-worker not involved in the study Sealed envelopes from computer-generated random number tables

Placebo was indistinguishable from the supplement NA NA

No

NA

Yes

Nod

No

Using envelopes prepared by the statistician Not described

No No

NA Capsule given to control group

Yes Yes

Yes Yesf

Yese No

Yes and adequate

ONS and ‘control supplement’ packaged identically

Yes

Nog

Yes

Additional studies for Series 2 (2 RCT) Edington et al. (2004) Adequate Hirsch et al. (1993) Unclear

Additional study (only included in sensitivity analysis) Adequate Randomisation stratified according to site in randomly McMurdo et al. (2009) permuted blocks of four. Computer generated random number tables by an individual not involved in study a b c d e f g

Reported some patient outcomes for all patients at 6 months (? No drop outs). Reported intention to treat analysis but results reported for completers only. Reported as intention to treat analysis but indicated that analysis undertaken of completers only (and not according to the originally designated group). Significant difference in male:female ratios (more females in control group), and body fat significantly higher in the control group. Reported as ITT analysis but some outcomes reported for smaller number. Present data on completers, of which no significant differences at baseline. Significantly more women in ONS group.

R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

Study

ARTICLE IN PRESS

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

Table 4 Quality assessment of randomised controlled trials.

G Model ARR 470 1–14

ARTICLE IN PRESS R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325

326 327

328 329 330 331 332 333 334 335

3.1.4. Outcome measures • (Re)admissions: Two of the RCT reported a significantly lower proportion of patients readmitted to hospital with ONS (Gariballa et al., 2006; Norman et al., 2011). In the other four RCT (Chapman et al., 2009; Gazzotti et al., 2003; Miller et al., 2006; Price et al., 2005), there were no significant differences, although (re)admissions were fewer in the ONS arms in 3 of these trials. Chapman et al. (2009) listed separately the reasons for admission to hospital for the two arms of the study. These included lethargy/weakness, exacerbation of chronic obstructive airways disease, and pulmonary aspergillosis. Gazzotti et al. (2003) reported that two out of the total of 7 readmissions were due to falls with fracture (at enrolment into the study 47% of patients had been admitted to hospital with falls).The other studies provided no information on the reasons for readmission. • Other: Studies also assessed a number of other outcome measures. Length of hospital stay on (re)admission to hospital was reported in only one study (Chapman et al., 2009), with no significant differences between the ONS and control groups. A number of other outcome measures were reported in these RCT with variable results. Quality of life was significantly improved in favour of ONS in some ((Norman et al., 2011) and (Gariballa and Forster, 2007), a related publication to (Gariballa et al., 2006)) but not all RCT (Chapman et al., 2009; Miller et al., 2006). Individual studies reported no significant differences in outcomes, such as frailty score (Chapman et al., 2009), mortality and infections (Gariballa et al., 2006) and gait speed (Miller et al., 2006). Muscle strength was improved in favour of the ONS group in several (Chapman et al., 2009; Price et al., 2005) but not all (Miller et al., 2006) studies. In the small study of Chapman et al. the number of falls was lower in the ONS group than the control group (4 vs. 8) but not significantly so (Chapman et al., 2009). 3.2. RCT reporting hospital (re)admissions data in other ways (3 RCT) In addition to the above six RCT, three others carried out in the UK (Edington et al., 2004; McMurdo et al., 2009) and Chile (Hirsch et al., 1993) provided information about the number of readmissions (see Table 3): two reported the mean and sd of the number of (re)admissions per patient in each group (Edington et al., 2004; Hirsch et al., 1993), and the other the total number of (re)admissions per group, from which the mean number of readmissions per patient was calculated (McMurdo et al., 2009).

3.2.1. Intervention, study design and primary outcomes The duration of intervention in the three additional studies var337 ied (16 weeks after hospital discharge (McMurdo et al., 2009), up 338 to 24 weeks after hospital discharge with a minimum of 8 weeks 339 supplementation (mean 99 days)(Edington et al., 2004) and for 1 340 year (Hirsch et al., 1993)) (Table 2). (Re)admissions were assessed 341 either at the end of the intervention (after 16 weeks (McMurdo 342 et al., 2009) or 1 year (Hirsch et al., 1993)) or about 10 weeks after 343 the intervention had finished (Edington et al., 2004). The supple344 ments used in these trials were ready-made, multi-nutrient drinks, 345 with one RCT (Edington et al., 2004) also providing ONS in the 346 form of puddings and bars (Table 2). Where reported, energy den347 sity ranged from 1.00 to 1.5 kcal/ml (Hirsch et al., 1993; McMurdo 348 et al., 2009), and prescribed quantities ranged from 600 to 1000 kcal 349 (Edington et al., 2004; Hirsch et al., 1993; McMurdo et al., 2009) 350 (∼34–40 g protein) (Hirsch et al., 1993; McMurdo et al., 2009) per 351 Q5 day (ONS intakes were reported in only one trial (342 kcal and 15.8 g 352 protein/day (Edington et al., 2004))). 353 The control group received standard care (Edington et al., 2004), 354 a ‘placebo capsule’ (Hirsch et al., 1993) or a ‘control supplement 355 336

9

based on skimmed milk’, with a third of the energy content (200 kcal, 12.4 g protein, 0.5 kcal/ml) of the intervention feed, but packaged in the same way (McMurdo et al., 2009). In none of these three studies was hospital (re)admission the primary outcome measure (Table 2). In McMurdo et al’s study (McMurdo et al., 2009) the primary outcome was activities of daily living (Barthel Index), and in the other two studies no single primary outcome was defined, although both studies assessed muscle strength, mortality and length of hospital stay. 3.2.2. Patients and setting • Recruitment: Two of these additional studies (Edington et al., 2004; McMurdo et al., 2009) recruited patients after admission to hospital (following non-elective admissions only (McMurdo et al., 2009); non-elective and possibly elective admissions (Edington et al., 2004)). These two studies recorded the number of readmissions to hospital as an outcome measure. The other study recruited from an outpatient clinic for patients with alcoholic liver disease (Hirsch et al., 1993) and recorded the number of admissions to hospital as an outcome measure. • Setting: All three of these studies were conducted in the community. None started in the hospital setting (Table 2). • Disease or conditions: Two of the additional RCT involved older people with a mixture of conditions (Edington et al., 2004; McMurdo et al., 2009) and the other younger people suffering from alcoholic liver disease (Hirsch et al., 1993) (Table 2). • Age: Of the additional studies, two recruited only older subjects (≥65 years (mean age 78 years (Edington et al., 2004)) and ≥70 years (mean age 82 years) (McMurdo et al., 2009)). In the third study involving patients with alcoholic liver disease, the mean age was 48 years (Hirsch et al., 1993). 3.2.3. Quality of the studies Table 4 shows that the additional three studies fulfilled most but not all of the quality criteria. Only one trial was double-blinded (McMurdo et al., 2009). 3.2.4. Outcome measures • (Re)admissions: Of the three additional studies only one (Hirsch et al., 1993) reported a significant difference in admissions in favour of the ONS group (23 vs. 35 admissions, ONS vs. control group), with a significantly lower frequency of hospitalisations respectively (0.85 ± 0.88 vs. 1.60 ± 1.18). This RCT also reported the reasons for hospital admission for the separate arms of their study, which included decompensated liver disease (e.g. ascites, encephalopathy, GIT bleeding) and infections (Hirsch et al., 1993). The significant difference between the ONS and control group was for the number of hospital admissions caused by infections (2 in ONS group and 9 in the control group). There were no significant differences in readmissions in the other two RCT (Edington et al., 2004; McMurdo et al., 2009) and they did not report the reasons for (re)admission (Edington et al., 2004; McMurdo et al., 2009). • Other outcome measures: Two studies provided information on the length of hospital stay when patients were (re)admitted, without significant differences between groups (Edington et al., 2004; Hirsch et al., 1993) but it is not entirely clear if the length of stay was per admission or per patient for the whole group. A number of other outcome measures were reported in these RCT with variable results. Edington reported a transient, significant improvement in handgrip strength at 8 weeks and no significant difference in healthcare use or overall expenditure (Edington et al., 2004). McMurdo et al. (2009) reported a significant advantage in favour of the intervention ONS (vs. the control lower energy ONS) in handgrip strength and in spontaneous vector

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

356 357 358 359 360 361 362 363 364

365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385

386 387 388 389

390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417

ARTICLE IN PRESS

G Model ARR 470 1–14

R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

10 Study name

Statistics for each study

Odds ratio and 95% CI

Odds Lower Upper ratio limit limit p-Value Chapman et al 2009 Gariballa et al 2006 Gazzotti et al 2003 Miller et al 2006 Norman et al 2011 Price et al 2005

0.711 0.615 1.448 0.478 0.426 0.557 0.591

0.140 0.414 0.302 0.079 0.196 0.234 0.434

3.606 0.912 6.929 2.879 0.924 1.324 0.804

0.681 0.016 0.643 0.421 0.031 0.185 0.001 0.01

0.1

1

10

100

Favours ONS Favours Control

Fig. 2. Random effects meta-analysis of RCT reporting number of patients (re)admitted to hospital with ONS (6 RCT, n 852, Series 1).

418 419 420 421 422 423 424 425 426

427

428 429 430 431 432

433 434 435 436 437 438 439 440 441 442 443

444 445 446 447 448 449 450 451

452 453 454 455 456 457 458 459 460 461

movements assessed by accelerometry but no significant advantage with respect to activities of daily living, mortality, number of falls, or some other functional measures. Despite some of the benefits recorded in this trial, the failure of the ‘intervention’ ONS to reduce overall disability (compared with the group receiving the ‘control’ ONS) was reported to be due to poor adherence. Mortality was not significantly affected in any of the three studies. Handgrip strength did not differ between the groups in the study of patients with cirrhosis (Hirsch et al., 1993). 3.3. Meta-analyses Two data-sets were used for meta-analysis. The first dataset for meta-analysis was of the 6 RCT that reported the number of patients readmitted to hospital (series 1). After standardising all of the results, additional meta-analyses of the comparable studies were undertaken (series 2). 3.3.1. Series 1: RCT (N = 6) reporting number of patients (re)admitted to hospital during the study period 3.3.1.1. Overall. A meta-analysis of all six RCT (total N = 852) showed that the proportion of patients (re)admitted to hospital was significantly less in the ONS group (23.9%, 102/426) than in the control group (33.8%, 144/426) (odds ratio (OR) 0.591, 95% CI 0.434–0.804, P = 0.001, Fig. 2, number needed to treat = 10).The relative weight of the studies varied from 3.6% for the smallest trial (Chapman et al., 2009) to 61.1% for the largest trial (Gariballa et al., 2006). The results favouring the ONS group were confirmed in the various subgroups indicated below. 3.3.1.2. Type of (re)admission (admissions or readmissions). In the five studies (total N = 826) that recorded (re)admissions after discharge from hospital (Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005), (re)admissions were significantly lower with ONS (OR 0.587, 95% CI 0.429–0.803, P = 0.001). In the only study that involved admissions of patients recruited from the community (Chapman et al., 2009), the OR also favoured the ONS group (0.711) but was not significant; 3.3.1.3. Setting (community alone or hospital plus community). A meta-analysis of three trials (N = 576) (Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006), in which the intervention was started in hospital and continued in the community, showed a significantly lower proportion of patients (re)admitted in the ONS group than the control group (OR 0.639, 95% CI 0.439–0.928, P = 0.019). In the remaining studies which were carried out in the community only (N = 276) there was also a significant reduction in (re)admissions in favour of the ONS group (OR 0.501, 95% CI 0.291–0.864, P = 0.013) (Chapman et al., 2009; Norman et al., 2011; Price et al., 2005).

3.3.1.4. Nutritional status. A meta-analysis of five trials (total N = 410) (Chapman et al., 2009; Gazzotti et al., 2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005) involving only patients with malnutrition or at risk of malnutrition (Table 2) showed a significantly lower proportion of patients (re)admitted to hospital with ONS (OR 0.555, 95% CI 0.339–0.910, P = 0.020).The study of Gariballa et al. (2006), involving an unspecified proportion of malnourished and non-malnourished patients, also showed significantly lower readmissions in the ONS group compared to the control group. (29% vs. 40% respectively; OR 0.615, 95% CI 0.414–0.912, P = 0.016, shown in Fig. 2). (The original paper reported a comparable significance value (P = 0.02) after analysing the results using Cox regression). 3.3.1.5. Age. In the five studies (total N = 738) involving patients with a mean age ≥65 years (Chapman et al., 2009; Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006; Price et al., 2005), hospital (re)admissions were significantly lower with ONS (OR 0.628, 95% CI 0.449–0.879, P = 0.007). In the remaining study involving patients with benign gastrointestinal disease (Norman et al., 2011), in which the mean age was 51 years, there was also significantly fewer hospital readmissions in the ONS group (OR 0.426, 95% CI, 0.196–0.924, P = 0.031). 3.3.1.6. Quality of studies. The study of Gariballa et al. which fulfilled all the graded quality criteria (Table 4), showed a significant reduction in patients readmitted to hospital (OR 0.615, 95% CI 0.414–0.912, P = 0.016) and a meta-analysis of the remaining five studies (total N = 410) showed the same (OR 0.555, 95% CI 0.339–0.910, P = 0.020) (Chapman et al., 2009; Gazzotti et al., 2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005). 3.3.1.7. Disease or condition. A meta-analysis of the four studies (total N = 687) (Chapman et al., 2009; Gariballa et al., 2006; Gazzotti et al., 2003; Price et al., 2005) involving patients with a variety of conditions showed a significant reduction in (re)admissions in favour of the ONS group (OR 0.635, 95% CI 0.451, 0.893, P = 0.009). A similar result was found in a meta-analysis of the two RCT (total N = 165) involving only patients with specific conditions (benign GI disease (Norman et al., 2011); orthopaedic patients who had sustained leg fractures (Miller et al., 2006) (OR 0.434, 95% CI 0.213–0.883, P = 0.021). 3.3.1.8. Amount of supplement prescribed and duration of supplementation. Meta-regression showed no significant effect of either the amount of supplement prescribed, which varied from 475 to 1200 kcal, or the duration of supplementation which varied from 6 Q6 weeks to 1 year. In all the subgroup analyses the random effects model yielded the same results as the fixed effect model because of the lack of statistical heterogeneity between studies (I2 = 0.0%). 3.3.2. Series 2: All RCT reporting (re)admissions to hospital In the immediate section that follows, meta-analyses were carried out using 8 of the 9 RCT identified in the systematic review (Chapman et al., 2009; Edington et al., 2004; Gariballa et al., 2006; Gazzotti et al., 2003; Hirsch et al., 1993; Miller et al., 2006; Norman et al., 2011; Price et al., 2005). The study of McMurdo et al. (one of the three additional studies described above (McMurdo et al., 2009)) was excluded as it potentially used an ONS in the control arm (which was an exclusion criteria). This RCT used two identically packaged feeds, one containing 600 kcal and 40 g protein per day (1.5 kcal/ml) in the intervention group, and a ‘control supplement’ based on skimmed milk containing 200 kcal and 12.4 g protein per day (0.5 kcal/ml) in the

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

462 463 464 465 466 467 468 469 470 471 472 473 474

475 476 477 478 479 480 481 482 483

484 485 486 487 488 489 490 491

492 493 494 495 496 497 498 499 500 501

502 503 504 505 506 507 508 509

510 511 512 513 514 515 516 517 518 519 520 521 522

G Model ARR 470 1–14

ARTICLE IN PRESS R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

523 524 525 526 527 528 529 530 531 532 533 534 535 536 537

538 539 540 541 542 543 544 545 546 547 548 549 550

551 552 553 554 555 556 557 558 559

560 561 562 563 564 565 566 567 568 569 570 571

572 573 574 575 576 577 578 579 580 581 582 583

control group. However, since there might be some controversy about whether the ‘control supplement’ constituted an ONS, a sensitivity meta-analysis with and without this study was carried out. Whenever possible, the number of (re)admissions per patient was used in preference to the proportion of patients (re)admitted to hospital since the former provides more information about healthcare use. This particularly applied to the study of Chapman et al. (in which data on both number of (re)admissions and proportion of patients (re)admitted were provided) (Chapman et al., 2009). However, a sensitivity analysis was undertaken using different measures for admissions, which were either reported or calculated from the published data. In the meta-analyses that follow, a negative standardised difference indicates a reduction in (re)admissions in favour of the ONS group. 3.3.2.1. Overall. A meta-analysis of the 8 RCT (total N = 999) (Chapman et al., 2009; Edington et al., 2004; Gariballa et al., 2006; Gazzotti et al., 2003; Hirsch et al., 1993; Miller et al., 2006; Norman et al., 2011; Price et al., 2005) that met the inclusion criteria revealed that the proportion of patients (re)admitted to hospital was significantly less in the ONS group than the control group. The forest plot with the summary data (standardised difference −0.230, 95% CI −0.363 to −0.097, P = 0.001) is shown in Fig. 3. The weighting of the studies in the meta-analysis varied from 2.9% for the smallest study sample size (Chapman et al., 2009) to 41% for the largest study (Gariballa et al., 2006). A series of subgroup meta-analyses confirmed the reduction in hospital (re)admissions in favour of the ONS group, as indicated below: 3.3.2.2. Type of (re)admission (admissions or readmissions). There was a significant reduction in (re)admissions with ONS in the six studies that examined only readmissions (total N = 922) (Edington et al., 2004; Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005) (overall effect size −0.199, 95% CI −0.328 to −0.069, P = 0.003), as well as the two studies (N = 77) that examined only admissions (overall effect size −0.612, 95% CI −1.070 to −0.155, P = 0.009) (Chapman et al., 2009; Hirsch et al., 1993). 3.3.2.3. Setting (Community alone or hospital plus community). A meta-analysis of three trials (total N = 576) in which the intervention was started in hospital and continued in the community (Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006) revealed a significant reduction in the number of patients (re)admitted with ONS (overall effect size −0.180, 95% CI −0.343 to −0.016, P = 0.032). The remaining five studies, in which the intervention was carried out in the community only (N = 423) (Chapman et al., 2009; Edington et al., 2004; Hirsch et al., 1993; Norman et al., 2011; Price et al., 2005), also revealed a significant reduction in (re)admissions in favour of the ONS group (overall effect size −0.305, 95% CI −0.518 to −0.092, P = 0.005). 3.3.2.4. Nutritional status. There was a significant reduction in (re)admissions with ONS among the six studies (Chapman et al., 2009; Edington et al., 2004; Gazzotti et al., 2003; Miller et al., 2006; Norman et al., 2011; Price et al., 2005) that involved only malnourished patients (N = 503) (overall effect size −0.186, 95% CI −0.362 to −0.010, P = 0.038). Although the other two studies (including both malnourished and well nourished patients) (Hirsch et al., 1993; Gariballa et al., 2006) individually demonstrated a significant reduction in readmissions, the meta-analysis of these two studies (total N = 496) was not significant due to the heterogeneity between them (random effects model: effect size −0.399, 95% CI −0.864–0.066, P = 0.093). Using the fixed effect model,

11

the overall effect size was significant (−0.274, 95% CI −0.451 to −0.096, P = 0.002) but the heterogeneity was large (I2 = 63). 3.3.2.5. Age. There was a significant reduction in (re)admissions in the six studies (Chapman et al., 2009; Edington et al., 2004; Gariballa et al., 2006; Gazzotti et al., 2003; Miller et al., 2006; Price et al., 2005) involving only older people aged 65 years (total N = 834) (overall effect size −0.176, 95% CI −0.312 to −0.040, P = 0.011) as well as in the remaining two studies (N = 165) involving people with a mean age of 51 years (Norman et al., 2011) and 48 years (Hirsch et al., 1993) (overall effect size −0.509, 95% CI −0.820 to −0.199, P = 0.001). 3.3.2.6. Quality of studies. The study of Gariballa et al. (N = 445) (Gariballa et al., 2006), which fulfilled all of the quality criteria listed in Table 4, showed a significant reduction in readmissions in favour of the ONS group (effect size −0.225, 95% CI −0.411 to −0.039, P = 0.018). The remaining seven studies (N = 554) (Chapman et al., 2009; Edington et al., 2004; Gazzotti et al., 2003; Hirsch et al., 1993; Miller et al., 2006; Norman et al., 2011; Price et al., 2005), which fulfilled most but not all of the quality criteria also demonstrated a significant reduction in hospital (re)admissions in favour of ONS (overall effect size −0.237, 95% CI −0.428 to −0.047, P = 0.015). 3.3.2.7. Disease or condition. There was a significant reduction in (re)admissions in favour of the ONS group among the five studies (N = 783) (Chapman et al., 2009; Edington et al., 2004; Gariballa et al., 2006; Gazzotti et al., 2003; Price et al., 2005) involving patients with a variety of diseases (overall effect size −0.172, 95% CI −0.313 to −0.032, P = 0.016), as well as the three studies (N = 216) (Hirsch et al., 1993; Miller et al., 2006; Norman et al., 2011) that involved groups of patients with specific conditions (overall effect size −0.442, 95% CI −0.713 to −0.171, P = 0.001). 3.3.2.8. Amount of supplement prescribed and duration of supplementation. Meta-regression showed no significant effect of either Q7 the amount of supplement prescribed, which varied from 475 to 1200 kcal, or the duration of supplementation which varied from 6 weeks to 1 year. In the subgroup analyses the random effects model yielded the same results as the fixed effect model because there was no statistical heterogeneity between studies (I2 = 0.0%), with the exception of two subgroup analyses in which there was a small amount of heterogeneity between studies: (i) In the subgroup of 5 RCT (Chapman et al., 2009; Edington et al., 2004; Hirsch et al., 1993; Norman et al., 2011; Price et al., 2005) undertaken in the community, the overall effect size was significant using the fixed effect model (−0.298, P = 0.002) with an I2 = 15.0% (P = 0.319); (ii) In the subgroup of 7 RCT (Chapman et al., 2009; Edington et al., 2004; Gazzotti et al., 2003; Hirsch et al., 1993; Miller et al., 2006; Norman et al., 2011; Price et al., 2005) that did not meet all the quality criteria listed in Table 4, the overall effect size using the fixed effect model was also significant (−0.233, P = 0.006) with an I2 = 19.1% (P = 0.284). 3.3.2.9. Sensitivity analyses. Two types of sensitivity analyses were carried out: First, the study of Chapman et al. (Chapman et al., 2009) provided data on readmission rates that could be expressed in different ways (total number of readmissions per group, number of emergency (non-elective) admissions, proportion of patients admitted, the number of hospital days per patient). None of these demonstrated significant differences between ONS and control group and when the different measures of (re)admissions were entered separately into the meta-analysis (total N = 852) the overall results were

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

584 585

586 587 588 589 590 591 592 593 594

595 596 597 598 599 600 601 602 603 604 605

606 607 608 609 610 611 612 613 614

615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634

635 636 637 638 639 640 641 642 643 644

ARTICLE IN PRESS

G Model ARR 470 1–14

R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

12

Study name

Statistics for each study

Std diff in means and 95% CI

Std diff Standard Lower Upper in means error Variance limit limit Z-Value p-Value Chapman et al 2009

-0.405

0.396

0.157 -1.182 0.371

-1.022

0.307

Edington et al 2004

-0.014

0.205

0.042 -0.415 0.387

-0.070

0.944

Gariballa et al 2006

-0.225

0.095

0.009 -0.411 -0.039

-2.365

0.018

Gazzotti et al 2003

0.104

0.224

0.050 -0.335 0.543

0.466

0.642

Hirsch et al 1992

-0.723

0.289

0.084 -1.289 -0.156

-2.500

0.012

Miller et al 2006

-0.231

0.281

0.079 -0.781 0.320

-0.820

0.412

Norman et al 2011

-0.418

0.190

0.036 -0.789 -0.046

-2.203

0.028

Price et al 2005

-0.231

0.172

0.030 -0.568 0.107

-1.340

0.180

-0.230

0.068

0.005 -0.363 -0.097

-3.396

0.001 -2.00

-1.00

0.00

1.00

2.00

Favours ONS Favours Control Fig. 3. Random effects meta-analysis of all RCT reporting (re)admissions to hospital with ONS (8 RCT, n 999, Series 2).

changed very little: with total number of admissions per patient the overall effect size was −0.230 (P = 0.001); with number of emergency (non-elective admissions) it was −0.225 (P = 0.001); with the 647 proportion of patients admitted it was −0.223 (P = 0.001); and with 648 the number of hospital days per patient it was −0.215 (P = 0.003). 649 Second, a sensitivity analysis was carried out by including the 650 study of McMurdo et al. (2009), which was originally excluded from 651 the main meta-analysis because strictly speaking it did not fulfil 652 the entry criteria. Whilst this study by itself showed no signifi653 Q8 cant difference in the number of admissions per patient between 654 the groups that received the intervention supplement and the con655 trol supplement, its inclusion in the meta-analysis (total N = 1190) 656 had a substantial effect in attenuating the overall effect of ONS in 657 reducing hospital admissions (the overall effect size was reduced to 658 −0.171, 95% CI −0.341 to 0.000, P = 0.050). When the same results 659 were analysed using the fixed effect model, the effect size became 660 much more significant in favour of the intervention group (−0.162, 661 95% CI −0.276 to −0.047, P = 0.006) but there was a substantial 662 increase in the study heterogeneity (I2 = 44.8%, P = 0.070). 663 645 646

664

665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690

4. Discussion This is the first systematic review and meta-analysis to comprehensively examine the impact of ONS on hospital (re)admissions. The findings that use of ONS can lead to a subsequent reduction in (re)admissions to hospital appear to be robust in that they are observed in various subgroups of patients (according to reported nutritional status (malnourished or a mixture of malnourished and well nourished), age category (<65 years or ≥65 years), setting (community or hospital initiated), type of (re)admission (admission or readmission)), and across different quality studies. Lack of information in the primary studies did not allow us to examine whether the benefit in mixed groups of patients was greater among those deemed to be malnourished than the well nourished patients. Nevertheless, the reduction in hospital (re)admissions in favour of ONS observed in this systematic review is consistent with improvements in other clinical outcomes reported in previous systematic reviews (Cawood et al., 2012; Collins et al., 2012; Stratton and Elia, 2007). These findings emphasise the need for nutritional screening to identify malnourished patients or those at risk of malnutrition so that they can be appropriately treated. Previously, studies have reported a failure to recognise and treat malnutrition in various care settings (Cawood et al., 2008; Leistra et al., 2009; Meijers et al., 2009; Volkert et al., 2010; Waitzberg et al., 2001). The findings of this review strongly suggest that leaving malnutrition untreated increases the workload for hospitals from which patients have originated from, whilst appropriate treatment with ONS can reduce this workload.

A reduction in (re)admissions is certainly attractive from a societal viewpoint, with benefits for patients, for health insurance companies (where relevant) and for the total health economy. However, a related issue, which emerges from a subgroup analysis in this review, is that the treatment of malnutrition in the community setting alone can influence the burden of care in the hospital setting. Where there are separate funding streams between health care settings, so that the cost of ONS in the community comes from one budget and the hospital costs from another budget, there may be increased expenditure in one setting, for example as a result of having to pay for the supplement, and decreased expenditure in another setting, for example due to reduced (re)admissions. This may cause financial difficulties and varying attitudes towards the benefits of using nutritional supplementation in different health care settings, which could be avoided if there was a single budget for integrated care spanning across care settings. In other health care systems, it may be health insurance companies as opposed to hospitals that financially benefit from fewer hospital (re)admissions. In this review, although economic data were provided in two of the reviewed studies(Edington et al., 2004; Norman et al., 2011), most of the RCT did not provide detailed information about the number of contacts with healthcare professionals, or the costs of various treatments, making it difficult to undertake a full economic meta-analysis using the present dataset. However, (re)admission data from randomised, controlled trials (such as the ones in this review), in conjunction with data on other types of resource use, have been incorporated into budget impact models of oral nutritional supplements in the elderly. These health economic analyses indicate that the extra investment in ONS, is more than offset by a reduction in other health care costs, such as (re)admissions, with a net cost saving in favour of ONS. A recent RCT, which was excluded from this systematic review because it involved multiple nutritional interventions (ONS, enriched diet, dietary advice, micronutrient supplementation), also explored the wider health economic impact of this combination of nutritional support in the elderly, showing a cost effective improvement in functional limitations only (Neelemaat et al., 2012). Most studies in the systematic review involved recruitment of patients who had been hospitalised, mainly for acute illness, often with pre-existing chronic conditions. It is possible that the impact of ONS is different when used in chronic conditions without recent acute illness and without the catabolic effects of elective surgery. It is possible that the impact of ONS administered following acute medical problems, such as infections, acute exacerbations of disease or decompensation of specific chronic diseases, differs from the impact associated with their use in chronic conditions without recent acute medical problems or the catabolic effects of elective surgical procedures. To obtain a wider view of the impact on

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738

G Model ARR 470 1–14

ARTICLE IN PRESS R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804

hospital admissions of nutritional interventions used in the community, where most malnutrition exists (Elia and Russell, 2009), additional clinical trials that recruit from community populations are needed. Such trials are likely to be more demanding because both the prevalence of malnutrition and hospital admission rates among free living people are much lower than in recently hospitalised patients or those with severe clinical conditions attending hospital outpatient clinics. Until such studies are undertaken our knowledge base of the effect of ONS on hospital utilisation will be skewed towards those patients who have been recently hospitalised. The only reviewed study that recruited free living subjects from the community involved a group of malnourished Australians who responded to advertisement about the trial (Chapman et al., 2009). However, the subjects were not randomly selected from the community, and given the small sample size (N = 13 per group) it is not surprising that this study had the least overall weighting in our meta-analyses. The reasons for the effect of ONS in reducing hospital (re)admissions are not entirely clear. Only the small study of free living elderly people (Chapman et al., 2009), which was specifically undertaken to examine hospital admissions as a primary outcome measure, provided detailed information about the accompanying reasons for the hospital admissions. One other study reported reasons for admissions in the control and intervention groups separately (Hirsch et al., 1993) and a further study provided very limited data for both groups combined (Gazzotti et al., 2003). Nevertheless, some insights into the possible reasons for the effects of ONS in reducing hospital (re)admission rates can be obtained by examining the available clinical information. Among the many reasons for (re)admissions were gastrointestinal and cardiovascular problems, lethargy, infections, such as pneumonia and exacerbations of COPD, and falls. Hirsch et al. (Hirsch et al., 1993) reported that infections such as pneumonia and spontaneous peritonitis in their patients with liver disease were significantly lower in the ONS group than the control group. Since malnutrition has detrimental effects on immune function, this could help explain the beneficial effects of supplements given to the malnourished patients. Falls were also a reason for readmission (Chapman et al., 2009; Gazzotti et al., 2003). The small study of Chapman et al. reported the number of falls in each group, which were two times less frequent in ONS than the control group (8 control group vs. 4 ONS group), but given the small sample size of the study the differences were not significant (Chapman et al., 2009). Muscle strength can influence the frequency and damage caused by falls since it can compensate for minor accidental movements that predispose to falls. ONS were shown to improve muscle strength in several of the included studies (Chapman et al., 2009; Edington et al., 2004; McMurdo et al., 2009; Price et al., 2005) and in an earlier report of the same study by Norman et al. (Norman et al., 2008, 2011). Respiratory muscle strength can also influence cough pressure and clearance of infected material from the chest and potentially avert admissions to hospitals, such as for those with COPD, which featured among the reasons for (re)admission to hospital (Chapman et al., 2009). Lethargy and weakness were also reasons for (re)admissions. Alleviation of these symptoms through nutritional supplementation could also help avert hospitalisations. Since malnutrition detrimentally effects both physical and psychological well-being (Elia, 1993), it is likely that treatment of malnutrition will produce beneficial effects by more than one mechanism. The beneficial effects of ONS are not necessarily due to the provision of supplemental energy alone. In the three individual trials that showed significant reductions in hospital (re)admissions (Gariballa et al., 2006; Hirsch et al., 1993; Norman et al., 2011), 900–1000 kcal per day of ONS were prescribed but across all of the studies, meta-regression did not suggest any relationship between prescribed ONS energy intake (475–1200 kcal) and outcome. In all

13

studies, multi-nutrient ONS were used. Therefore, it could be that the breadth of nutrients (including protein, trace elements and vitamins) provided in addition to energy in ONS, is key to influencing outcome. The duration of supplementation may also be important. Although ONS were prescribed for varying periods of time depending on the patient group (from 6 weeks to one year), meta-regression showed no relationship to the duration of supplementation. The need to supplement individual patients for different periods of time is known to be influenced by disease related factors and nutritional status. However, the duration of supplementation was generally fixed within individuals studies, and an evaluation of targeted periods of supplementation in individual patients is not possible from the available dataset. The extent to which oral intake is increased as a result of supplementation is also relevant because a failure to increase total energy and nutrient intake with ONS would not be expected to improve outcome. There was little evidence of suppression of voluntary food intake with ONS, which was reported to be either similar (in an earlier report of Norman et al., 2008 and Edington et al., 2004) or significantly greater (Gazzotti et al., 2003) than in the control groups when this was assessed. Consequently, on the basis of the available information, ONS significantly improved total energy and/or protein intakes (Edington et al., 2004; Gazzotti et al., 2003; Hirsch et al., 1993; Norman et al., 2008; Price et al., 2005) (as indicated by previous reviews (Stratton and Elia, 2007; Stratton et al., 2003)), providing evidence of exposure to the intended nutritional intervention in these studies. Compliance (% of prescribed ONS intake consumed) was good in most of those studies where reported (range 62–88%, mean 75.4%) (Chapman et al., 2009; Gazzotti et al., 2003; Miller et al., 2006; Price et al., 2005), and comparable with those summarised in a recent systematic review on ONS compliance (Hubbard et al., 2012). The study of McMurdo et al. (2009) was not included in the main analyses because both groups within this study received additional intake from a supplement (although one had a lower energy and protein content than the other). This could have attenuated the observed differences between the two groups and it was the reason why the predetermined criteria excluded studies that compared two types of supplements. Apart from these physiological considerations, a substantial increase in statistical heterogeneity between studies developed when a sensitivity meta-analysis was included this study with the other 8 studies. The other sensitivity analysis concerning different methods of expressing results made little difference to the overall effect size and heterogeneity between studies. An issue of specific interest concerns the age of the populations studied. All the trials involving patients with a mixed group of conditions or diseases recruited only older people, so that the mean age was almost 80 years or more (the entry criteria in these studies were ≥65 years, ≥70 years or ≥75 years). One of the advantages of selecting older people is that (re)admission rates in such populations are higher than in younger populations. This means that any differences between intervention and control groups can become apparent with a smaller sample size or over a shorter period of time. However, the studies may have selected older people because such populations are responsible for a disproportionate burden on healthcare resources. Whatever the reason, there is a gap in the knowledge base for an effect of ONS on (re)admissions in younger people. They are also an important population to consider as they account for about 40% of the malnourished adult population admitted to hospitals in the UK (NSW), probably a similar if not greater proportion of free-living malnourished subjects attending hospital outpatient clinics and GP clinics, and in the community as a whole, those aged <65 years typically outnumber those aged >65 years and over by 5–7 times in developed countries and by an even greater amount in developing countries. The only two studies of patients

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870

G Model ARR 470 1–14

ARTICLE IN PRESS R.J. Stratton et al. / Ageing Research Reviews xxx (2013) xxx–xxx

14

890

with a mean age of <65 years included those with specific conditions (benign gastrointestinal diseases, and liver diseases) (Hirsch et al., 1993; Norman et al., 2011) and it is encouraging that in a meta-analysis of these studies there was a significant reduction in hospital (re)admissions. The effect of taking ONS in the community on the (re)admission rates of patients with other specific conditions remains to be investigated. This systematic review and meta-analysis focussed on the ability of ONS to influence hospital (re)admissions, however the effects of other oral nutritional support strategies on such an outcome remains to be established. In conclusion, this systematic review and meta-analysis has shown a significant reduction in hospital (re)admissions over a 2–12 month period with the consumption of ready-made, multinutrient supplements (475–1200 kcal/d (mean ∼767 kcal/d) for 6 weeks to 1 year (mean duration ∼5½ months)), with the benefits mostly observed in older individuals with a variety of conditions post hospitalisation. Although there is also some evidence in specific patient groups (e.g. post hip fracture, benign GI disease, alcoholic cirrhosis) and in younger malnourished individuals, further research in these patient groups is recommended.

891

Disclosure statement

871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889

892

893 Q9

894

895

896 897

898 899 Q10

R.S. is also an employee of Nutricia Ltd. Uncited references Cawood et al. (2010) and Freijer et al. (2012). Acknowledgements Personal communication from S. Gariballa and K. Norman. Abacus International for assistance with systematic searches. References

Altman, D.G., Gardner, M.J., 2000. Statistics with Confidence: Confidence Intervals 900 and Statistical Guidelines. BMJ Books. 901 Beck, A.M., Holst, M., Rasmussen, H.H., 2012. Oral nutritional support of older (65 902 years+) medical and surgical patients after discharge from hospital: systematic 903 review and meta-analysis of randomized controlled trials. Clinical Rehabilita904 tion, 1–9 (May 29 epub). 905 Cawood, A.L., Elia, M., Stratton, R.J., 2012. Systematic review and meta-analysis of the 906 effects of high protein oral nutritional supplements. Ageing Research Reviews 907 11, 278–296. 908 Cawood, A.L., Green, C.J., Stratton, R.J., 2010. The budget impact of using oral nutri909 tional supplements in older community patients at high risk of malnutrition in 910 England. Proceedings of the Nutrition Society 69, 544. 911 Cawood, A.L., Smith, A., Dalrymple-Smith, J., Bolch, R., Pickles, S., Church, S., Strat912 ton, R.J., 2008. Prevalence of malnutrition and use of nutritional support in 913 Peterborough Primary Care Trust. Journal of Human Nutrition and Dietetics 21, 914 384. 915 Chapman, I.M., Visvanathan, R., Hammond, A.J., Morley, J.E., Field, J.B., Tai, K., Belobra916 jdic, D.P., Chen, R.Y., Horowitz, M., 2009. Effect of testosterone and a nutritional 917 supplement, alone and in combination, on hospital admissions in under918 nourished older men and women. American Journal of Clinical Nutrition 89, 919 880–889. 920 Q11 Cochrane Collaboration, 2006. Cochrane Handbook for Systematic Reviews of Inter921 ventions, www.cochrane.org/resources/handbook/ 922 Collins, P.F., Stratton, R.J., Elia, M., 2012. Nutritional support in chronic obstructive 923 pulmonary disease. American Journal of Clinical Nutrition 95, 1385–1395. 924 Cook, R.J., Sackett, D.L., 1995. The number needed to treat: a clinically useful measure 925 of treatment effect. British Medical Journal 310, 452–454. 926 Edington, J., Barnes, R., Bryan, F., Dupress, E., Frost, G., Hickson, M., Lancaster, J., 927 Mongia, S., Smith, J., Torrance, A., West, R., Pant, F., Coles, S.J., 2004. A prospec928 tive randomised controlled trial of nutritional supplementation in malnourished 929 elderly in the community: clinical and health economic outcomes. Clinical Nutri930 tion 23, 195–204. 931 Elia, M., 1993. Artificial nutritional support in clinical practice in Britain. Journal of 932 the Royal College of Physicians London 27, 8–15. Elia, M., 2006. Nutrition and health economics. Nutrition 22, 576–578.

Elia, M., Russell, C.A., 2009. Combating Malnutrition: Recommendations for Action. BAPEN, Redditch. Elia, M., Stratton, R.J., 2005. Geographical inequalities in nutrient status and risk of malnutrition among English people aged 65 years and over. Nutrition 21, 1100–1106. Elia, M., Stratton, R.J., 2009. Calculating the cost of disease-related malnutrition in the UK. In: Elia, M., Russell, C.A. (Eds.), Combating Malnutrition: Recommendations for Action. BAPEN, Redditch. Freijer, K., Nuijten, M.J.C., Schols, J.M.G.A., 2012. The budget impact of oral nutritional supplements for disease related malnutrition in elderly in the community setting. Frontiers in Pharmacology 3, 1–8. Gariballa, S., Forster, S., 2007. Dietary supplementation and quality of life of older patients: a randomized, double-blind, placebo-controlled trial. Journal of the American Geriatrics Society 55, 2030–2034. Gariballa, S., Forster, S., Walters, S., Powers, H., 2006. A randomized, double-blind, placebo-controlled trial of nutritional supplementation during acute illness. American Journal of Medicine 119, 693–699. Gazzotti, C., Arnaud-Battandier, F., Parello, M., Farine, S., Seidel, L., Albert, A., Petermans, J., 2003. Prevention of malnutrition in older people during and after hospitalisation: results from a randomised controlled clinical trial. Age and Ageing 32, 321–325. Hirsch, S., Bunout, D., De La Maza, P., Iturriaga, H., Petermann, M., Icazar, G., Gattas, V., Ugarte, G., 1993. Controlled trial on nutrition supplementation in outpatients with symptomatic alcoholic cirrhosis. Journal of Parenteral and Enteral Nutrition 17, 119–124. Hubbard, G.P., Elia, M., Holdoway, A., Stratton, R.J., 2012. A systematic review of compliance to oral nutritional supplements. Clinical Nutrition 31, 293–312. Koretz, R.L., Avenell, A., Lipman, T.O., Braunschweig, C.L., Milne, A.C., 2007. Does enteral nutrition affect clinical outcome? A systematic review of the randomized trials. The American Journal of Gastroenterology 102, 412–429, quiz 468. Leistra, E., Neelemaat, F., Evers, A.M., van Zandvoort, M.H., Weijs, P.J., van Bokhorstde van der Schueren, M.A., Visser, M., Kruizenga, H.M., 2009. Prevalence of undernutrition in Dutch hospital outpatients. European Journal of Internal Medicine 20, 509–513. McMurdo, M.E., Price, R.J., Shields, M., Potter, J., Stott, D.J., 2009. Should oral nutritional supplementation be given to undernourished older people upon hospital discharge? A controlled trial. Journal of the American Geriatrics Society 57, 2239–2245. Meijers, J.M., Halfens, R.J., van Bokhorst-de van der Schueren, M.A., Dassen, T., Schols, J.M., 2009. Malnutrition in Dutch health care: prevalence, prevention, treatment, and quality indicators. Nutrition 25, 512–519. Miller, M.D., Crotty, M., Whitehead, C., Bannerman, E., Daniels, L.A., 2006. Nutritional supplementation and resistance training in nutritionally at risk older adults following lower limb fracture: a randomized controlled trial. Clinical Rehabilitation 20, 311–323. Milne, A.C., Avenell, A., Potter, J., 2006. Meta-analysis: protein and energy supplementation in older people. Annals of Internal Medicine 144, 37–48. National Institute for Health and Clinical Excellence (NICE), 2006. Nutrition Support in Adults: Oral Nutrition Support, Enteral Tube Feeding and Parenteral Nutrition (Clinical Guideline 32). National Institute for Health and Clinical Excellence (NICE), London. Neelemaat, F., Bosmans, J.E., Thijs, A., Seidell, J.C., Van Bokhorst-de van der Schueren, M.A., 2012. Oral nutritional support in malnourished elderly decreases functional limitations with no extra costs. Clinical Nutrition 31, 183–190. Norman, K., Kirchner, H., Freudenreich, M., Ockenga, J., Lochs, H., Pirlich, M., 2008. Three month intervention with protein and energy rich supplements improve muscle function and quality of life in malnourished patients with non-neoplastic gastrointestinal disease – a randomized controlled trial. Clinical Nutrition 27, 48–56. Norman, K., Pirlich, M., Smoliner, C., Kilbert, A., Schulzke, J.D., Ockenga, J., Lochs, H., Reinhold, T., 2011. Cost-effectiveness of a 3-month intervention with oral nutritional supplements in disease-related malnutrition: a randomised controlled pilot study. European Journal of Clinical Nutrition 65, 735–742. Price, R., Daly, F., Pennington, C.R., McMurdo, M.E., 2005. Nutritional supplementation of very old people at hospital discharge increases muscle strength: a randomised controlled trial. Gerontology 51, 179–185. Stratton, R.J., Ek, A.-C., Engfer, M., Moore, Z., Rigby, P., Wolfe, R., Elia, M., 2005. Enteral nutritional support in prevention and treatment of pressure ulcers: a systematic review and meta-analysis. Ageing Research Reviews 4, 422–450. Stratton, R.J., Elia, M., 2007. A review of reviews: a new look at the evidence for oral nutritional supplements in clinical practice. Clinical Nutrition 26, 5–23. Stratton, R.J., Green, C.J., Elia, M., 2003. Disease-Related Malnutrition: An Evidence Based Approach to Treatment. CABI Publishing, Oxford. Stratton, R.J., van Binsbergen, J., Volkert, D., Hebuterne, X., Elia, M., 2011. Systematic review and meta-analysis of the effects of oral nutritional supplements on hospital admissions. Clinical Nutrition 6, 16. Volkert, D., Saeglitz, C., Gueldenzoph, H., Sieber, C.C., Stehle, P., 2010. Undiagnosed malnutrition and nutrition-related problems in geriatric patients. Journal of Nutrition, Health and Aging 14, 387–392. Waitzberg, D.L., Caiaffa, W.T., Correia, I.T.D., 2001. Hospital malnutrition: the Brazilian national survey (IBRANUTRI): a study of 4000 patients. Nutrition 17, 573–580.

Please cite this article in press as: Stratton, R.J., et al., A systematic review and meta-analysis of the impact of oral nutritional supplements on hospital readmissions. Ageing Res. Rev. (2013), http://dx.doi.org/10.1016/j.arr.2013.07.002

933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014