Review Article SUMMARY. Journal of Clinical Pharmacy and Therapeutics, 2016, 41, doi: /jcpt.12372

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1 Journal of Clinical Pharmacy and Therapeutics, 2016, 41, doi: /jcpt Review Article Effectiveness of the STOPP/START (Screening Tool of Older Persons potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment) criteria: systematic review and meta-analysis of randomized controlled studies B. Hill-Taylor* BSP, BFA, MLIS, K. A. Walsh, BPharm, MPharm, MPSI, S. Stewart BSc, MMath, PhD, J. Hayden BSc, DC, PhD, S. Byrne BSc Pharm, PhD, MPSI and I. S. Sketris* BScPhm, PharmD, MPA(HSA) *College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax, NS, Canada, Pharmaceutical Care Research Group, School of Pharmacy, University College Cork, Cork, Ireland, Department of Epidemiology and Public Health, University College Cork, Cork, Ireland and Faculty of Medicine, Dalhousie University, Halifax, NS, Canada Received 23 October 2015, Accepted 8 February 2016 Keywords: potentially inappropriate medications, potentially prescribing omissions, prescribing practice, STOPP, STOPP and START SUMMARY What is known and objective: STOPP/START are explicit screening tools that identify potentially inappropriate prescribing in older adults. Our objective was to update our 2013 systematic review that showed limited evidence of impact, using new evidence from randomized controlled trials (RCTs) assessing clinical, humanistic and economic outcomes in older adults. Methods: We performed a search of PubMed, EMBASE, CINAHL, Web of Science and grey literature for RCTs published in English since the previous review through June. The Cochrane Risk of Bias Tool was used. We performed a meta-analysis on the effect of STOPP on potentially inappropriate medication (PIM) rates and a narrative synthesis on other outcomes. Results and discussion: Four RCTs (n = 1925 adults) from four countries were included, reporting both acute (n = 2) and longterm care (n = 2) patients. Studies differed in implementation. Two studies were judged to have low risk, and two to have moderate-to-high risk of bias in key domains. Meta-analysis found that the STOPP criteria reduced PIM rates in all four studies, but study heterogeneity (I 2 = 867%) prevented the calculation of a meaningful statistical summary. We found evidence that use of the criteria reduces falls, delirium episodes, hospital length-of-stay, care visits (primary and emergency) and medication costs, but no evidence of improvements in quality of life or mortality. What is new and conclusion: STOPP/START may be effective in improving prescribing quality, clinical, humanistic and economic outcomes. Additional research investigating these tools is needed, especially in frail elderly and community-living patients receiving primary care. WHAT IS KNOWN AND OBJECTIVE Medication use in older adults occurs in a complex environment. Appropriate prescribing involves an understanding of the effect of Correspondence: B. Hill-Taylor, 5968 College Street, P.O.Box 15000, Halifax, Nova Scotia, B3H 4R2 Canada. Tel.: ; fax: ; pharmacy@dal.ca ageing on physiology and pharmacokinetics, a knowledge of pharmacology, the ability to balance risks versus benefits, and a willingness to listen to patient and caregiver concerns. 1,2 Practitioners experience an ongoing challenge in finding age- and disease-appropriate evidence as many clinical trials continue to exclude the very frail, or older patients with multiple morbidities. 3 Moreover, life expectancy and cost efficiency must also be considered in best prescribing practices. Potentially inappropriate prescribing (PIP) is a term that encompasses the prescribing of potentially inappropriate medication (PIM) where risks and costs outweigh potential benefits, as well as potential prescribing omission (PPO), where clinically beneficial medications may not be prescribed for a number of reasons. 1,4 There is agreement that PIP is prevalent in older patients. 1,5 Studies that determine the incidence or prevalence of PIP in older adults report a range of rates dependent on the healthcare setting and the characteristics of population studied. The rates reported also vary depending on the instrument used to measure PIP. A recent study in Sweden used five explicit screening tools and found 38% of older persons had PIP identified by at least one tool. 6 However, the rates of PIP detected by individual tools varied from 16% to 24%. By identifying PIP, adverse drug events and/or cost-inefficient practices may be prevented, providing an opportunity for quality improvement in geriatric medicine. 1 Inappropriate prescribing may increase the risk of adverse drug events, which may lead to serious negative clinical outcomes such as falls, delirium, cardiac distress and other morbidity or mortality. A systematic review of adverse drug reactions in older adults reported a mean prevalence rate of 11%, concluding that this represents a significant healthcare issue in this population. 7 Explicit screening tools such as the STOPP/START (Screening Tool of Older Persons potentially inappropriate Prescriptions/ Screening Tool to Alert doctors to the Right Treatment) criteria assist in the systematic identification of PIP. The first version of the STOPP criteria consisted of 65 indicators of PIM, whereas the START criteria were made up of 22 indicators of PPO. 8,9 Both START and STOPP have been validated and show good inter-rater reliability with both pharmacists and physicians John Wiley & Sons Ltd 158

2 In 2013, we published a systematic review of clinical studies using the STOPP/START criteria. 12 At that time, we retrieved 12 observational studies and a single randomized controlled trial (RCT). The incidence or prevalence of patients exposed to PIP varied across studies and depended on the healthcare setting, patient characteristics and details of the criteria s application. The STOPP criteria were found to be more sensitive than BEERS, but less sensitive than an Australian set of explicit criteria. 13,14 Patients with PIP, as identified by STOPP, had an increased risk of adverse drug events (OR = 185, 95% CI: ; P < 0001) 15. However, we found limited evidence that the criteria optimized prescribing, or clinical and economic outcomes. Since the publication of the 2013 review, the research on the STOPP/START criteria has continued to expand. In addition to evaluating prescribing practices using the STOPP/START criteria to measure PIP prevalence or incidence, and determining predictors of PIP, researchers have studied the incidence of related adverse drug events and other clinical outcomes, the costeffectiveness of medication usage with the application of the criteria, and the use of the criteria as an intervention in several additional RCTs. Our objective was to update the 2013 systematic review using new evidence from RCTs that assess the effectiveness of STOPP/ START criteria on prescribing quality and clinical, humanistic and economic outcomes in adults aged 65 years and older. Table 1. Outcome Measures Prescribing Adverse Drug Events Intervention Outcomes Patient Outcomes Economic Outcomes Number of prescription and over-the-counter drugs used per patient Prevalence of potentially inappropriate medication omissions Prevalence of potentially inappropriate medication use Prevalence of potentially inappropriate prescribing Acute care visit physician soffice Acute care visit emergency care Acute care visit hospitalization Other: for example, falls Number of potential interventions recognized Number of recommendations made Number of recommendations accepted Disease-specific symptoms Quality-adjusted life years Quality-of-life profile European quality of life Self-reported impacts on quality of life Cost of impact on daily activities (from adverse drug events) Cost related to changes in medication use Cost related to changes in health care use Other METHODS This systematic review is an update of a previous review conducted by the authors 12 and was undertaken in accordance with the statement of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) ( Research protocol A research protocol was established to guide the study and is available on request. with authors to determine whether eligible papers were available from conference proceedings and other grey literature records. Search strategy The search terms STOPP criteria, START AND STOPP or START criteria with the date limits January 2012 to June were used. No limits on the publication type were used in the initial search. Eligibility criteria All RCTs involving the prospective application of the STOPP and/ or START criteria on the medication profiles of persons 65 years of age or older were included. Studies that measured robust indicators of the clinical, humanistic and economic impact of the application of the criteria were considered valuable in assessing the effectiveness of the screening tool. Data demonstrating the impact on PIP were also considered primary outcomes. See Table 1 for a list of primary outcomes. Information sources The following databases were searched (BHT): MEDLINE, EMBASE, CINAHL and ISI Web of Science. A grey literature search was carried out using the TRIP database ( the first 100 returns on Google Scholar for each search term, English-language geriatric care and pharmacy care conference proceedings from major national and international meetings, reference lists of relevant studies and reviews. ClinicalTrials.gov was used to discover research in progress that met inclusion criteria. An author (KW) contributed potential records from his contacts, and communicated directly Study selection Two review authors independently appraised the search results for eligibility (KW, BHT). This process was not blinded; author, research institute, journals or results or other publication details were available. Reasons for recommending the exclusion of studies were noted in a spreadsheet. Review authors resolved any discrepancies through consensus. Two authors (IS, SB) were available for consultation to establish consensus on any disagreements; however, they were not required for this purpose. Fig. 1 presents a flow diagram of the study selection process. Data collection procedure Two reviewers (KW, BHT) developed a data abstraction tool, which was used to collect information such as the study citation and design, intervention description, participant demographics and settings, outcomes, fidelity assessment and funding information (Online Appendix 1). Three authors (IS, JH, SB) reviewed the development of the data abstraction tool. It was pilot-tested on five randomly selected studies by one author (BHT). Both review authors independently abstracted data from selected studies (KW, BHT). Consensus was used to resolve discrepancies. 159

3 Included Eligibility Screening Identification Records identified through database searching (n = 354) Records after duplicates removed (n =230) Records screened (n = 230) Full-text articles assessed for eligibility (n = 51) Studies included in synthesis (n = 3 + 1) Studies included in quantitative synthesis (meta-analysis) (n = 4) Additional records identified through other sources (n =126) Records excluded (n =179) Full-text articles excluded, with reasons (n = 48) 46 were not RCTs 2 involved the retrospective application of STOPP/START to a previously conducted Studies included from previous review (n = 1) Fig. 1. Study flow diagram of literature selection. Fidelity assessment A fidelity assessment data abstraction tool was based on the work of Carroll and colleagues. 16 We documented published information on: (i) the use of a conceptual framework to inform the study intervention, (ii) the use of policy and procedure statement(s) intended for research personnel, (iii) any records of training of researchers and outcome assessors, (iv) the method of criteria application, (v) any tools used in outcome assessment (e.g. the Medication Appropriateness Index) and (vi) any documentation of intervention evaluation. Assessment of risk of bias The Cochrane Risk of Bias Tool uses six key domains (with subcategories) and was employed to assess internal validity of included studies. 17 Risk of bias assessments was conducted independently by two review authors (KW, BHT) with discrepancies reconciled by a third review author (SS). The assessments were then reviewed and approved by the remaining authors (IS, JH, SB). One author summarized the risk of bias assessments (BHT). Synthesis of results We conducted a random-effects meta-analysis to synthesize evidence on the effectiveness of the STOPP criteria on reducing the PIM rate in patients due to anticipated clinical heterogeneity. 18 The primary interest was the odds ratios (ORs) for a patient having at least one PIM after intervention. A narrative synthesis was performed for all other outcomes. RESULTS AND DISCUSSION A total of 480 records were retrieved by electronic searching. The database search retrieved 354 records, and 126 records were identified from all other searching methods (e.g. Google Scholar, local experts and contact with authors of conference proceedings). A review author (KW) communicated directly with authors of conference proceedings and other grey literature records to determine whether eligible papers were available. Out of a total of 64 authors, 57 online addresses were found and 34 responses received. From this method of searching, two records were retrieved. When duplicate citations and non-english publications were removed, 230 records remained and their abstracts were screened. At this stage, 179 records were excluded for the following reasons: ineligible design (n = 78), not related to STOPP or START criteria (n = 35), research not published in peer-reviewed journal (n = 43), ongoing research (n = 6), further duplicates found (n = 6), ineligible participant age (n = 5), ineligible criteria use (e.g. modified criteria, truncated criteria) (n = 3) or published in English (n = 3). Full texts were retrieved for 51 studies, of which 46 were excluded because they were not RCTs, and two were excluded because they involved a retrospective application of the STOPP/START criteria to previously conducted randomized trials. An RCT included in our original systematic review was included in this systematic review

4 Table 2. Summary of characteristics of included studies Methods Participants Study Study Design Time Period Setting, Country Setting, Health Care Number at Baseline Age Sex (% Female) Number of Medications at Baseline Gallagher 2011 Randomized controlled trial Dalleur Randomized controlled trial Frankenthal Randomized controlled trial Randomized controlled trial Republic of Ireland Community dwelling in Hospital (patient in transition) Belgium Community dwelling in Hospital (patient in transition) Not reported Spain LTC (patient in stable care) Israel LTC (patient in stable care) Total: 400 Control: 200, 200 Total: 158 Control 81, 77 Total: 1018 Control: 502, 516 Total: 359 Control: 176, 183 Control: Median 77 (IQR ), Median 74.5 (IQR 71 80) Total: Median 85 (IQR 81 88) Control: Median 86 (IQR 81 89), Median 84 (IQR 81 87) Total: Mean SD Control: , Total: Mean SD Control: 102 (53.1%) 101 (53.2%) Control: 49 (68.1%) 43 (58.1%) Total: 744 (73%) Control: 362 (72.1%), 382 (74%) Control: 110 (62.5%), 129 (70.5%), Control: Median 8 (IQR 5 10), Median 7 (IQR 5 10) Control: Median 7 (IQR 5 9), Median 7 (IQR 5 9) Control: Mean SD (range 1-18) (range 1-19) Control: Mean SD Mean Intervention Study Inclusion Criteria Exclusion Criteria Data Sources START/STOPP Criteria Applied Gallagher , admitted via ED under the care of a general medical physician. Dalleur 75, risk of frailty defined by an Identification of Seniors at Risk (ISAR) score of 2/6, admitted to medical ward, availability of a comprehensive geriatric assessment. Frankenthal >65, living in nursing home for at least 3 months, expected to stay for the length of study, clinically stable (no change in prescriptions in the last 2 months), agreement to participate. 65, prescribed at least one medication. Admission under or having been assessed in the year preceding admission by a geriatrician, psychiatrist specializing in the care of the elderly, or clinical pharmacologist; critical or terminal illness; unwillingness of the patient or hospital physician to participate Surgical admission, incomplete medication data in discharge letter Patients on palliative care or cared for by primary care providers outside the nursing home Terminally ill, stay in the facility was shorter than 3 months Paper or electronic medical records (not specified), interviews patient/patient advocate, other Full STOPP/START Electronic medical records, other 64 STOPP criteria applied Paper or electronic medical records (not specified), other Paper or electronic medical records (not specified), other Full STOPP/START Full STOPP/START (continued) 161

5 Table 2 (continued) Outcomes Study Description of Intervention Outcome Measures Reported Gallagher 2011 On admission to hospital, patients received usual pharmaceutical care or screening with STOPP/START to identify prescribing appropriateness. Oral and written recommendations were made within 24 hours of admission. Attending physician decided to accept recommendations. MAI and AOU index used to assess prescribing appropriateness at baseline (admission) and at 2, 4, 6 months following discharge Dalleur On admission, patients received usual IGCT care or geriatrician-based screening with 64/ Frankenthal 65 STOPP criteria (duplicate drug classes not applied) to identify prescribing appropriateness. Oral and written recommendations were made to ward physician who decided to accept recommendations and implement change. Reassessment at discharge and 1 year following Patients received usual care or care by a nursing home physician involved in educational intervention delivered by an expert in drug use in older people. Education included general drug use in geriatric patients, workshop on STOPP START and on-demand support for 6 months. STOPP/START was applied to a subgroup of patients. Outcomes measured at baseline and 3 months following Patients received usual pharmaceutical care or had medications screened by research pharmacist using STOPP/START. Recommendations were made to chief physician, who decided to accept recommendations. Review, screening and recommendations occurred at baseline and 6 months after. Outcomes measured at baseline and 12 months following Primary: Appropriateness of prescribing as measured by MAI and AOU indexes. Secondary: LOS in Hospital, hospital re-admission, falls frequency of primary care visits and mortality, measured in the period between discharge and 6-month postdischarge Primary: Proportion of PIMs discontinued between admission and discharge. Secondary: Characteristics associated with discontinuation of PIMs, proportion of PIMs still discontinued 1 year after discharge, and the clinical significance of the STOPP-related recommendations Primary: Appropriateness of prescribing as measured by STOPP/START, number of drugs, number of duplicate medications and number of antipsychotics. Secondary: Incidence of selected geriatric syndromes (falls, delirium), healthcare utilization (visits to physicians and nurses, visits to ED, total number of days spent in hospital) Primary: Falls, hospitalizations, quality of life and Functional Independence Measure, Secondary: number of medications and costs of medication, appropriateness of prescribing as measured by STOPP/START AOU, Assessment of Underutilization; ED, emergency department; IGCT, Inpatient geriatric consultation team; IQR, interquartile range; LTC, long term care; LOS, length-of-stay; MAI, Medication Appropriateness Index; PIM, potentially inappropriate medication; START, Screening Tool to Alert Doctors to the Right Treatment; SD, standard deviation; STOPP, Screening Tool of Older Person s potentially inappropriate prescriptions. Table 3. Risk of bias summary: Judgement of risk of bias in studies by review authors Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Summary assessment Gallagher 2011 Low Low High Low Low Low Low risk of bias for all key domains Dalleur Low High High High Low High High risk of bias for 1 key domains Moderate to High Unclear Moderate Unclear Moderate High Unclear or moderate risk of bias for 1 key domains Frankenthal Low Low Moderate Low Low Low Low risk of bias for all key domains 162

6 Characteristics of the selected studies Overall, there were few, heterogeneous RCT studies found, with a paucity of data about relevant outcomes, resulting in only four RCTs being included in this review Participants in all four studies were at least 65 years of age, although one study restricted participants to those aged 75 years and older. 20 Healthcare systems from four nations are represented (Republic of Ireland 19, Belgium 20, Spain 21 and Israel 22 ). Two studies were similar in design and population: a healthcare practitioner reviewed medication profiles of patients in transition on admission to an acute care centre. 19,20 Both of these studies followed participants for an extended period of time following discharge from the acute care centre. The other two studies reviewed the prescribing quality for patients in long-term care homes. 21,22 The size of the studies varied from 1018 participants living in 37 private nursing homes in Spain 21 to 158 participants at a single site in Belgium. 20 The majority of participants were female, varying from 53% 19 to 73%. 21 Although one study explicitly excluded patients with no regularly prescribed medications, the population in had only marginally more medications than other studies, with an average number of medications per patient between 82 (control) and 88 (intervention). 22 All studies except one (Dalleur and colleagues) used the full 65 STOPP and the full 22 START criteria in their intervention. 20 Dalleur and colleagues also did not use the duplicate therapy STOPP criteria and did not apply the START criteria. 20 Each research group, except those from Ireland, used the criteria to assess prescribing quality. 19 Gallagher and colleagues used the full STOPP and START criteria as a screening tool in their intervention, but used the implicit Medication Appropriateness Index (MAI) and the Assessment of Underutilization (AOU) index to assess prescribing quality. Dalleur and colleagues used a panel of experts to determine the extended clinical significance of the changes in prescribing, as a result of the intervention, at a 1-year follow-up. 20 The other three studies included an assessment of long-term impact on clinical outcomes by measuring changes in fall rates, healthcare usage (e.g. length-of-stay (LOS) in hospital, re-admissions, and acute care visits), incidence of delirium, functioning, quality of life 19,21,22 and, in one study, mortality. 19 Two studies recorded changes in medication costs due to the intervention. 19,22 Table 2 presents the characteristics of the included studies. Risk of bias in included studies We found that although two studies were at a low risk of bias in all key domains, 19,22 concern existed regarding the risk of bias in multiple areas of the other two studies. 20,21 Table 3 contains the summary of the risk of bias assessments. Outcome measures Effects on the appropriateness of prescribing as a result of the intervention were reported by all studies, although the reporting and assessment were inconsistent. Clinical outcomes were reported in three of the four papers 19,21,22, economic indicators in two 19,22 and quality of life indicators in one 22. The findings of all outcomes for the included studies are presented in Table 4. Prescribing quality. 1 PIMs: Fig. 2 presents the reported rates of patients with a least one PIM at baseline and follow-up for both the intervention and control groups. The baseline PIM rates are different between the studies (with a low of 324% and a high of 668%), although within each study there was little difference in the PIM rates between the intervention and control groups. All follow-up rates showed improvement (being lower than the previous rate), even in the control groups. The variability between studies is expected based on the heterogeneity in the study interventions, specifically in the integration of the STOPP/START criteria into the clinical work flow. The Dalleur study in particular shows a noticeable decrease in the PIM rate even in the control group. 20 At every time point in every study, the intervention demonstrated some success, with intervention PIM rates being lower than control rates (grey point lower than black in Fig. 2). Table 5 presents the meta-analysis data. For each study, we looked at the PIM rate after intervention and calculated an OR for each study, then compared them using a randomeffects model, in an attempt to account for the heterogeneity of the data. Fig. 3 presents the forest plots for the metaanalysis and the sensitivity analysis. The heterogeneity of the four studies is substantial (I 2 = 867%), with ORs of 111, 205, 332 and The figure suggests that the Gallagher paper may be an outlier, so a sensitivity analysis was performed by removing the Gallagher paper and rerunning the metaanalysis, also in Fig. 3. The results of the two meta-analyses present notably different ORs, making it difficult to draw conclusions about the overall effect of the STOPP criteria on PIM rates. 2 PPOs: Three studies reported the change in PPO prevalence as a result of the intervention. 19,21,22 All studies reported a significant and sustained drop in PPOs in the intervention group. Interestingly, there was also a reduction in PPOs in all control groups on follow-up, similar to the learning effect with the PIMs as described above. 3 Other measures of prescribing appropriateness: Gallagher and colleagues reported on the number needed to screen to yield improvement in PIMs as identified by MAI (28) and PPOs as identified by AOU (47). 19 Dalleur s team categorized the potential clinical severity of a subgroup of 84 PIMs detected at admission into major, moderate, minor or deleterious. 20 The largest number of PIMs were identified as moderate (37%), but a significant 29% were designated as major. One study reported the change in the number of drugs, the number of duplicate medications and the use of antipsychotics prior to, and following the intervention. 21 Improvements were seen in all outcomes between the baseline and follow-up in the intervention group. Clinical outcomes, healthcare utilization and quality-of-life indicators:. Clinical outcomes reported by at least one of the four studies were as follows: fall rates, delirium episodes, hospital LOS, readmission to hospital, primary care visits (to nurses or physicians), emergency care visits, quality-of-life indicators, and mortality. One study found a trend to lower primary care visits in the intervention group, but no significant difference with regard to other parameters. 19 In another study, incidence of falls, delirium episodes, hospital LOS and visits to the emergency department all increased in the control group, whereas the intervention group showed either an decrease or no significant change. 20 Visits to both physicians and nurses were found to remain unchanged in the control group and to decline in the intervention group. 20 There was no difference between control and intervention with regard to 163

7 Table 4. Summary of findings of included studies Measures of Appropriateness of Prescribing Study ID Prevalence or incidence of at least one PIM n(%) Prevalence or incidence of PPO n(%) Gallagher 2011 Control: Admission 85 (443%), discharge 93 (484%), 2 months 92 (492%), 4 months 90 Control: Admission 64 (333%), discharge 61 (318%), 2 months 55 (294%), (491%), 6 months 90 (506%) Admission 82 (432%), discharge 7 (37%), 4 months 52 (284%), 6 months 47 (264%) Admission 62 (326%), 2 months 11 (6%), 4 months 17 (94%), 6 months 22 (122%) discharge 7 (37%), 2 months 6 (33%), 4 months 6 (33%), 6 months 6 (33%) Dalleur Control: Admission 37 (514%), discharge 31 (419%) Admission 39 (527%), discharge 30 (405%) Control: Baseline 108 (624%), follow-up 106 (613%) Baseline 141 (668%), follow-up 92 (436%) Frankenthal Control: Baseline 114 (647%), 6 months 89 (56%),12 months 79 (541%) Baseline 129 (705%), 6 months 65 (374%), 12 months 36 (225%) Control: Baseline 120 (486%), follow-up 117 (474%) Baseline 135 (55%), follow-up 25 (101%) Control: Baseline 57 (324%), 6 months 40 (252%), 12 months 32 (219%), 12 months 32 (219%) Baseline 65 (355%), 6 months 16 (92%), 12 months 10 (63%) Study ID Other measures of prescribing appropriateness Gallagher At discharge in the intervention group: PIM as identified by MAI 4 was lower (absolute risk reduction 357% (95% CI ), # needed to screen to yield improvement in MAI: 28 (95% CI 22 38). PPO as identified by AOU 5 was lower (absolute risk reduction 212% (95% CI ), # needed to screen to yield reduction in AOU: 47 (95% CI 34 75). 2. Significant improvements in prescribing were sustained for 6 months after discharge with a slight increase was in the prevalence of PIMs and PPOs (91%) STOPP and 69 (97%) START recommendations were accepted following screening Dalleur 1. Discontinuation of PIMs present on admission by discharge: Control 193%, intervention 397%, OR 275 (95% CI ), P = At 1 year, a subgroup of PIMs from 50 (34%) of total patients or 658% of patients with PIMs identified were accessed: (i) characteristics of patients in control vs intervention were similar, (ii) non-significant difference in proportion of PIMs still discontinued 1 year after discharge in control vs intervention, (ii) 672% (84) of PIMs identified on admission (control 36 and intervention 48), were designated as major 29%, moderate 37%, minor 5% or deleterious 8%. 21% not assessed 1. Mean # of drugs SD (range): Control: (n = 200) baseline (1 19), follow-up (0 19), intervention: (n = 185) baseline (1 19) follow-up (0 15); 2. Polypharmacy (6 + drugs): at follow-up, reduced in intervention vs control (670% vs 765%). Similar findings in patients on 11 + drugs. 3. Between baseline and follow-up, antipsychotic use was increased in control (38% to 91%) and decreased in intervention (61% to 32%). 4. Duplicate medications: Control (n = 200): baseline (0 2) final (0 3); intervention (n = 185): baseline (0 4), final (0 4); 5. Mean # PIMs: control (n = 173): baseline (0 6), final (0 8), intervention (n = 211): baseline (0 5), final (0 4); 6. Mean # PPOs: control (n = 200): baseline (0 5), final (0 5), intervention (n = 183): baseline (0 9), final (0 3) Frankenthal Mean # of drugs: Control: baseline 82 3, 6 months 9 33, 12 months baseline 88 34, 6 months 81 32, 12 months (continued) 164

8 Table 4 (continued) Study ID Falls Episodes of Delirium LOS in Hospital Re-Admission to Hospital Primary Care Visits Emergency Care Visits Quality of Life Mortality Costs of Medication Gallagher 2011 No significant difference between groups Dalleur Frankenthal Control: increased (P = 0003); unchanged Control: unchanged; decreased (P = 0006) Control: increased (P = 0001); decreased (P = 0035) No significant difference between groups Control: increased (P = 0011); unchanged No significant difference between groups No significant difference between groups Trend to lower primary care visits in the intervention group (P = 0063) # visits to a physician Control: unchanged; decreased (P = 0010) # visits to nurse: Control: unchanged; decreased (P = 0000) # visits to ED Control: increased (P = 0022); unchanged No significant difference between groups No significant difference between groups 49 Accepted recommendations to use the least expensive available medications in the Intervention group The average drug cost in the intervention group decreased by 103 shekels (US$29) per participant per month (P < 0001) AOU, Assessment of Underutilization; ED, emergency department; LOS, length-of-stay; MAI, Medication Appropriateness Index; OR, odds ratio; PIM, potentially inappropriate medication; PPO, potential prescribing omission; SD, standard deviation; #, number. 165

9 Fig. 2. Potentially inappropriate medication (PIM) rates over time, by study. Study Time post-intervention Pre-intervention Post-intervention PIM No PIM Rate PIM No PIM Rate Table 5. Improvement in potentially inappropriate medication (PIM) rates after intervention; For control and intervention groups. Gallagher Control Discharge Intervention Dalleur Control Discharge Intervention Control 3 months Intervention Frankenthal Control 6 months Intervention PIM, potentially inappropriate medication. re-admission to hospital as reported by the study in Israel. 22 However, the average number of falls in the intervention group dropped significantly. Frankenthal and colleagues did not report a difference in quality of life, nor was Gallagher s study powered to discover mortality differences between groups. 19,22 Medication costs. Two studies reported cost outcomes and found cost efficiencies in medication choices in the intervention group compared with the control group. 19,22 Impact As shown by Figs. 2 and 3, and Table 5, all interventions produced improvements in prescribing appropriateness. However, the impact of the intervention differed between studies, due perhaps to the variation in the implementation of the STOPP/START criteria, and its integration into the clinical workflow. The studies differed in the health professional communication structure used to screen patients and make recommendations. The strongest intervention effect was seen in the study performed by Gallagher and colleagues, in which the criteria were applied by a physician who was also one of the original developers of the STOPP/START criteria. 19 This is in contrast to the impact of the intervention led by a research pharmacist who conveyed the results of the medication review through a chief physician 22, or the intervention in which a team of geriatric healthcare professionals made recommendations to the ward physician. 20 In these two latter cases, interprofessional barriers, as well as additional communication steps, may have lessened the impact of the intervention. Intervention fidelity No authors addressed the issue of intervention fidelity directly, nor did they report the use of a conceptual framework, protocol, or policy and procedure statements to guide the intervention development, implementation or evaluation. Strengths and weakness of the review The main strength is the robust systematic review methodology applied by the reviewers. By complementing the electronic with manual and grey literature searches, we believe we ensured a comprehensive retrieval, given our inclusion criteria. Additionally, we only included RCTs, ensuring that our review 166

10 Fig. 3. Forest plot of odds ratios for improvement in potentially inappropriate medication rates after intervention. Note: The first plot includes all four papers, while the second investigates the effect of Gallagher as an outlier. Cl, confidence interval. provides the best available evidence of effectiveness. Having one of the original developers of the criteria as a review author permitted an additional level of awareness into the use of the criteria in new studies. There are limitations associated with this review at the study level, between studies and at the review level. Three of the studies had populations that were restricted to a single facility. 19,20,22 We did not access papers published in any language except English. The interventions performed in the included studies varied in implementation, populations, outcomes and duration. Due to this heterogeneity, caution with interpreting the results of the meta-analysis is advised. WHAT IS NEW AND CONCLUSION Our original systematic review on the application of the criteria retrieved one RCT. 12 That study 19, along with 12 observational studies documenting the prevalence or incidence of PIP represented the best available evidence at the time. To this review, we add three RCTs. Our meta-analysis adds to our understanding of the effect of the criteria on PIM rates. Our inability to provide a single summary statistic of the effect is reflective of the heterogeneous implementation plans of STOPP/START in included studies. The effect is strongly dependent on the implementation of the tool, and further research into the appropriate method of integrating STOPP/START into the clinical workflow may make the effect of the intervention more consistent. Our methods revealed that the global reach and volume of research on the application of the STOPP/START criteria is expanding. A second version of the criteria has recently been published. 23 With regard to the use of the STOPP/START criteria, there are healthcare contexts where knowledge gaps remain. More study is needed using STOPP/START in interventions to detect PIP in community-dwelling patients prior to entrance into acute care facilities or emergency wards. One of the papers in this review focused on the frail elderly 19 : this rapidly growing demographic requires ongoing quality research. The use of STOPP/START in the medication review of patients with dementia and other psychiatric illness has had limited research. 24 The STOPP/START criteria may be able to offer concrete, systematic, actionable ways of improving prescribing in these complex prescribing groups. Improvement in the quality of interventions, evaluations and presentations is required. The standardization of measuring and reporting prescribing indicators and outcomes could facilitate our ability to extract more useful comparative data from heterogeneous populations and settings. Ways of reducing the negative impact of interprofessional barriers on intervention outcomes needs further research. 25 Practitioners and decision makers need to more fully understand the mechanisms that lead to success in the intervention and the contexts in which the intervention has taken place. 26 With standardization, innovation and improvements, primary studies using the STOPP/START criteria will help us to optimize the prescribing environment of ageing adults in a global context. CONFLICT OF INTEREST S.B. holds a patent, with others, called A Prescription Decision Support System (based on STOPP & START prescribing guidelines), lodged with the European Patent Office (Munich); patent No He also possesses a shareholding in Clinical Support Information Systems â, a software company established for the purpose of developing and marketing STOPP & START 167

11 criteria as a set of software products. No other authors reported a conflict of interest. Philanthropies (Dublin, Ireland) and conducted this research as part of the SPHeRE Programme under Grant No. SPHeRE/2013/1. FUNDING Funding for this research was supplied by a research grant received from the Drug Evaluation Alliance of Nova Scotia (DEANS), Halifax, Nova Scotia, Canada. KW received funding from the Health Research Board (Dublin, Ireland) and Atlantic SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Appendix S1 Data Abstraction Tool developed for the Systematic Review of STOPP/START Criteria. REFERENCES 1. O Mahony D, Gallagher PF. Inappropriate prescribing in the older population; need for new criteria. Age Ageing, 2008;37: Turner G, Clegg A. British Geriatrics Society, Age UK, Royal College of General Practioners. 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