Pharmacists interventions in the management of patients with chronic kidney disease: a systematic review

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1 Nephrol Dial Transplant (2012) 27: doi: /ndt/gfr287 Advance Access publication 30 June 2011 Pharmacists interventions in the management of patients with chronic kidney disease: a systematic review Teresa M. Salgado 1, Rebekah Moles 2, Shalom I. Benrimoj 2 and Fernando Fernandez-Llimos 1 1 Research Institute for Medicines and Pharmaceutical Sciences (imed.ul), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal and 2 Faculty of Pharmacy, University of Sydney, Sydney New South Wales, Australia Correspondence and offprint requests to: Fernando Fernandez-Llimos; f-llimos@ff.ul.pt Abstract Background. Patients with chronic kidney disease have multiple comorbidities and require complicated therapeutic regimens. The role of pharmacists caring for these patients has been documented, but no review of the impact of these interventions has occurred to date. The aim of this work is to assess the impact of pharmacists interventions in patients with chronic kidney disease. Methods. Medline, International Pharmaceutical Abstracts, Pharmacy Abstracts and the Cochrane Library were searched for quantitative studies addressing the contribution of pharmacists interventions in patients with chronic kidney disease. Quality of controlled studies was assessed using the Downs and Black scale. Results. The search identified 37 studies (38 articles), involving 4743 participants, eligible for inclusion in the review. An uncontrolled design corresponded with 80% of the studies. Twenty-one articles (55.3%) reported outcome measures and process indicators, 4 (10.5%) reported only outcome measures and 13 (34.2%) reported only process indicators. Pharmacists identified 2683 drug-related problems in 1209 patients. The results from eight controlled studies (average quality score 0.57, SD ¼ 0.10) demonstrated that pharmacists interventions reduced all-cause isations [ 1.8 (2.4) versus 3.1 (3.0), P ¼ 0.02] and cumulative time ised [ 9.7 (14.7) versus 15.5 (16.3) days, P ¼ 0.06], reduced the incidence of end-stage renal disease or death in patients with diabetic nephropathy (14.8 versus 28.2 per 100 patient-years, adjusted relative risk 60%, P < 0.001), improved management of anemia (mean 69.8 versus 43.9%, P ¼ and 64.8 versus 40.4%, P ¼ patients on goal hemoglobin and transferrin saturation, respectively), blood pressure [systolic (16.8) versus (33.9) mmhg, P ¼ 0.029; diastolic mean (SD) 77.0 (10.2) versus 91.8 (12.0) mmhg, P ¼ 0.020], calcium and phosphate parameters [serum phosphate levels 1.81 (0.54) versus 2.07 (0.25) mmol/l, P ¼ 0.03; calcium-phosphate product 4.43 (1.20) versus 4.80 (0.51) mmol 2 /L 2,P¼ 0.04] and lipid management [total cholesterol 4.4 (1.1) versus 5.0 (1.4) mmol/l, P ¼ 0.06; low density lipoprotein cholesterol 2.3 (0.9) versus 2.8 (1.0) mmol/ L, P ¼ 0.013]. Results from uncontrolled studies revealed positive impact of pharmacists interventions on reduced number of transplant rejections [ 0.22 (0.42) versus 0.50 (0.51) episodes, P ¼ 0.008] and adverse events (49 in 16.0% patients versus 73 in 21.3% patients, P < 0.05). Conclusions. The evidence of pharmacists interventions in patients with chronic kidney disease is sparse, of variable quality and with heterogeneous outcomes. On the basis of best available evidence, pharmacists interventions may have a positive impact on outcomes of patients with chronic kidney disease. Keywords: chronic kidney disease; pharmacist intervention; systematic review Introduction Chronic kidney disease is a major public health problem, which requires early detection and treatment to delay progression. When disease progresses to a stage where kidney failure occurs, patients are required to start renal replacement therapies, either through dialysis or transplantation [1]. The incidence of end-stage renal disease in the USA in 2009 was 354/million population (p.m.p.) and the prevalence was estimated in 1665 p.m.p. [2]. In Australia, the incidence of end-stage renal disease in 2008 was 116 p.m.p. and the prevalence was reported to be 822 p.m.p. [3]. In European countries, the prevalence of patients on renal replacement therapies in 2008 ranged from 421 to 1152 p.m.p. [4]. Diabetes was the primary cause for 54% of new end-stage renal disease patients in 2007, and one in three patients had a primary diagnosis of hypertension [2]. In 2008, 22% of new renal disease patients in Australia had a delayed referral to nephrological care and the most common causes of end-stage renal disease were diabetic nephropathy (34%), glomerulonephritis (22%) and hypertension (15%). Analgesic nephropathy accounted for 2% of new end-stage renal disease cases [3]. Ó The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Pharmacists interventions in patients with CKD 277 Patients with end-stage renal disease undergoing haemodialysis are prescribed an average of 12 medications and present around six comorbidities [5, 6]. Patients who have undergone organ transplantation are also required to take a multitude of drugs [7] and adherence to these medications is essential to avoid graft rejection [8] and medical costs [9]. Drug-related problems are common among dialysis patients [10]. Non-adherence to prescribed oral medication is also a common issue with mean rates of non-adherence being reported as high as 67% [11]. Over the last decades, pharmacists have seen their potential competencies broadened beyond the traditional dispensing role [12]. The effect of pharmacist-delivered services has been reported for heart failure [13], asthma management [14], antithrombotic use [15] and opiod substitutes supply [16]. Furthermore results of pharmacists interventions were reported in meta-analysis for several physician-pharmacist collaborative practice models in diabetes [17], hypertension [18] and hyperlipidemia [19]. However, to date, there has not been a systematic review describing the impact of interventions carried out by pharmacists in patients with chronic kidney disease. The aim of this review is therefore to address the impact of pharmacists interventions in patients with chronic kidney disease. Materials and methods A literature search was conducted in March 2010 in PubMed, International Pharmaceutical Abstracts (Ovid), Pharmacy Abstracts and The Cochrane Library (CENTRAL), without time limits. Inclusion criteria for this systematic review were studies addressing pharmacists interventions in patients with chronic kidney disease, reporting outcome measures or process indicators as a result of that intervention. The following queries were used: PubMed: ( pharmaceutical services [mh] OR pharmacists[mh] OR pharmacies[mh]) AND ( renal insufficiency, chronic [mh] OR renal dialysis [mh] OR kidney transplantation [mh]); International Pharmaceutical Abstracts (Ovid): ( renal disease OR kidney disease OR dialysis OR renal transplant ) AND ( pharmacist OR pharmacists ); Pharmacy Abstracts: (pharmacy OR pharmacist) AND (dialysis OR kidney transplant ); The Cochrane Library (CENTRAL): kidney AND pharmacist plus renal AND pharmacist. Additionally, references of retrieved articles and reviews on the topic were checked for other studies not identified by the previous search strategies. Two authors (T.M.S. and F.F.L.) independently analysed titles and abstracts of the merged pool of references to remove irrelevant reports, with an interrater agreement value k ¼ Full-text of potentially relevant articles was analysed in depth and the following exclusion criteria were sequentially applied: (1) Articles written in a language other than English, French, Italian, Portuguese or Spanish; (2) Articles without an abstract; (3) Articles not mentioning any intervention performed by pharmacists in patients with chronic kidney disease; (4) Articles without a methods section, review articles or case reports. Data extracted from selected articles included year of publication, country, study design, duration, setting, aim, participants demographics, pharmacists interventions and process and outcomes measured. Donabedian s SPO paradigm (Structure, Process, and Outcome) was used to define process as what is actually done in giving and receiving care, including the patient s activities in seeking care and carrying it out, as well as the practitioner s activities in making a diagnosis and recommending or implementing treatment [20] and outcomes as changes in health status that can be attributed to that care [21]. Additionally, pharmacist intervention was defined as any action with the aim of modifying the process of use of drugs, either in patients activities or in medical or health care practitioners activities. The quality of controlled studies included in this review was determined using the method of Downs and Black [22]. This instrument is a validated scoring scale consisting of 27 items grouped into five subscales: reporting, external validity, internal validity bias, internal validity confounding and power. The maximum total score is 32 and scores are expressed as rates, with higher scores representing a better methodology and 1.00 being the maximum possible. For the purpose of this study, we used the classification described by Machado et al. [17] in which studies with scores below 0.5 are considered weak, between 0.50 and 0.69 fair, between 0.70 and 0.79 good and between 0.80 and 1.00 very good. Results The search returned a total of 363 potentially relevant articles eligible for assessment (Figure 1). A total of 37 studies (38 articles) [6, 23 59], including 4743 participants at baseline, were analysed in this review. The studies characteristics are summarised in Tables 1 and 2. characteristics and quality The 37 studies identified were carried out in the USA (n ¼ 24), New Zealand (n ¼ 2), India (n ¼ 2), Canada, China, Colombia, France, Japan, Malaysia, Spain, Taiwan, and the UK, with one study each. Most articles were written in English, except two which were written in Spanish. Studies included were mainly uncontrolled (n ¼ 29), although eight studies (total 744 participants) presented a controlled design: randomised (n ¼ 4), non-randomised (n ¼ 2), prospective cohort (n ¼ 1) and crossover randomised (n ¼ 1). The studies were conducted in different health care settings: 11 studies in an ambulatory environment, 20 in wards/departments and 6 in renal transplant clinics, and the follow-up time ranged from 4 weeks to 3 years. The studies included participants aged on average from years; however, 11 studies did not mention the age of patients [24, 25, 27, 29, 31, 32, 34, 41, 42, 47, 52]. The male to female ratio was 1:0.91. In terms of race and ethnicity, Black/African-American (n ¼ 717) and Hispanic (n ¼ 567) were the most frequently reported groups, followed by Caucasians (n ¼ 511), Asians (n ¼ 509), others/unknown/not stated (n ¼ 187) and Indians (n ¼ 97). Although some studies did not report precisely the number of patients included [25, 29, 34], from the data available, 2139 patients were treated by haemodialysis 86 patients by peritoneal dialysis, 1294 were patients with chronic kidney disease not on dialysis, 431 were transplant patients, 627 were patients with renal impairment admitted to critical areas of a medical center and 92 were in- patients. The quality assessment performed individually for each of the nine articles describing eight controlled studies (total 744 participants) revealed an average score of 0.57 (SD ¼ 0.10) (range ), which is considered fair [17]. No correlation between publication year and overall quality scores was found (P ¼ 0.870). The year of publication indicates an increasing trend with a slope of 0.21 articles per year (R 2 ¼ 0.46). The mean Impact Factor of

3 278 T.M. Salgado et al. Fig. 1. Results of search strategy and identification of publications included in the review (CKD, chronic kidney disease). the journals where these articles were published was 2.32 (SD ¼ 1.27) (range ; n ¼ 22); however, 12 journals (containing 16 articles) were not listed in the Journal Citation Report. Pharmacist interventions Most interventions performed by pharmacists consisted of medication profile review to address potential drug-related problems [6, 24, 26, 28, 30, 31, 36, 39, 40, 42, 44, 48, 55 57]. Other studies reported the intervention of pharmacists in adjusting and optimising drug therapy [37, 39, 41, 45, 51, 54, 56, 57]; making therapeutic recommendations and interacting with physicians [24, 28, 30, 37, 39, 44, 52, 55]; performing continuous laboratory monitoring of specific parameters [24, 34, 35, 37, 49, 51]; evaluating admission, isation and discharge medication appropriateness [30]; identifying and correcting drug record discrepancies [38, 59]; implementing anemia-managing [34, 35, 41, 45, 47], lipid-managing [37], phosphate-managing [53] and secondary hyperparathyroidism-managing [29] protocols; providing medication/disease education to patients [23, 25, 37, 40, 46, 49 51, 55, 58] and improving compliance [33, 36]. Participation of pharmacists in medical rounds was also described for some studies [25, 54], as well as communication with other health care professionals [39] or conferences on patient care and written/oral consultations [25]. The mean duration of the studies was 11.1 (SD ¼ 10.6) months. Pharmacist patient interactions reported took between 15 min [58] and 1.8 h [55] and different interventions varied from services provided monthly [38, 39] to once every 4 months [43]. In the 38 articles analysed, 21 (55.3%) reported both process indicators and outcome measures, 13 (34.2%) only process indicators and 4 (10.5%) only outcome measures. Clinical outcomes were reported in 21 (55.3%) articles, humanistic outcomes in 5 (13.2%) articles and economic outcomes in 12 (31.6%) articles. Ten (26.3%) articles reported both clinical and economic outcomes and one (2.6%) reported humanistic and economic outcomes. Clinical outcomes. Pharmacist intervention contributed to significantly reduce all-cause isations [mean (SD) 1.8 (2.4) versus 3.1 (3.0) isations, P ¼ 0.02], as well as the cumulative time ised [mean (SD) 9.7 (14.7) versus 15.5 (16.3) days, P ¼ 0.06] [57]. In addition, pharmacist intervention in a 2-year prospective cohort with Type 2 diabetic nephropathy patients produced a relative risk reduction for end-stage renal disease of 55% (P ¼ 0.007; number needed to treat (NNT) ¼ 5.3) and a relative risk reduction of all-cause death of 78% (P ¼ 0.001; NNT ¼ 6.1) [43]. Episodes of graft rejection [mean (SD) 0.22 (0.42) versus 0.50 (0.51), P ¼ 0.008] [48] and number of adverse drug events (49 in 16.0% of patients versus 73 in 21.3% of patients, P < 0.05) [54] were also positively affected by the intervention of pharmacists. Anemia management by pharmacists resulted in a nonsignificant decrease in the time required for erythropoieticnaive patients to attain hemoglobin target [47, 49] but a significant higher percentage of patients achieving hemoglobin and transferrin saturation values target range (69.8 versus 43.9%, P ¼ and 64.8 versus 40.4%, P ¼ 0.043, respectively) [47]. The number of patients with hematocrit under 31% also decreased during a 4-year period after pharmacist intervention (14 versus 21%, P < 0.002) [34]. Other studies, however, reported a nonsignificant increase in hematocrit [35], transferrin saturation [35, 45], hemoglobin and ferritin [45]. Only one study to date has shown pharmacist intervention resulting in the decrease in the overall percentage of

4 Table 1. Characteristics of controlled studies included in the systematic review a country Chisholm et al. [33] USA design (duration) Randomised Controlled (12 months) Chisholm Randomised et al. [36] Controlled USA (12 months) Leung et al. [43] Cohort China (2 years) Bucaloiu et al. [47] USA Quality Fair Fair Fair Non-randomised Weak Controlled (6 months) setting Tertiary care teaching Tertiary care teaching Universitybased public Nephrology department of a medical center Aim To compare the immuno suppressants compliance rates, patterns of compliance and serum concentrations of renal transplant patients, who had a clinical pharmacist providing direct care compared with those who had not. To determine the effect of clinical pharmacist provision of direct patient care on the diastolic and systolic blood pressures of African-American renal transplant recipients. To develop a disease management program for patients with Type 2 diabetic nephropathy and evaluate its effects on the time to onset of end-stage renal disease or all-cause death compared with usual care. To assess the effect of a pharmacist-driven anaemia management program in patients with CKD. N (at baseline) Intervention 24 TX 49.2 (10.2) Additional clinical pharmacy services, which included medication review, therapeutic recommendation, promotion of medication compliance (n ¼ 12) 23 TX Control: 47 (12.7), intervention: 51 (16.8) Control Routine clinic services (n¼ 12) Additional clinical Routine pharmacy services, clinic services which included (n ¼ 10) medication review, identification of DRPs, therapeutic recommendations, promotion of medication compliance and information provision (n ¼ 13) 160 CKD 65.1 (8.8) Pharmacist diabetes specialist structured care (n¼ 80) 134 b CKD NR Application of a pharmacist-driven protocol to manage anaemia in CKD patients (n ¼ 62) Usual care (n ¼ 80) Physicianmanaged group (n ¼ 74) Main clinical outcomes achieved Significant reduction in both systolic [ (16.8) versus (33.9) mmhg, P ¼ 0.029] and diastolic [ 77.0 (10.2) versus 91.8 (12.0) mmhg, P ¼ 0.020] blood pressure from baseline to the fourth quarter of the study. Primary end point: composite of ESRD and all-cause death (14.8 versus 28.2 per 100 patient-years, adj RR 60%, P < 0.001), Secondary end points: significant reduction of rate of change in serum creatinine (32.5 versus 82.4 lmol/l/year; P ¼ 0.032), systolic [ (20.3) versus (22.5) mmhg, P ¼ 0.015] and diastolic [ 67.6 (11.8) versus 71.8 (11.3) mmhg, P ¼ 0.03] blood pressure; total cholesterol [ 4.4 (1.1) versus 5.0 (1.4) mmol/l, P ¼ 0.06]; and LDL cholesterol [ 2.3 (0.9) versus 2.8 (1.0) mmol/l, P ¼ 0.013] Significant increase in the number of patients remaining on goal hemoglobin (mean 69.8 versus 43.9%, P ¼ ) and goal transferrin saturation (mean 64.8 versus 40.4%, P ¼ 0.043), but not in the number of days required to achieve these levels. Pharmacists interventions in patients with CKD 279

5 Table 1. country Sathvik et al. [50] India Yokum et al. [53] UK design (duration) Crossover Randomised (16 weeks) Randomised Controlled (4 months) Pai Randomised et al. [56] Controlled USA (2 years) Pai Randomised et al. [57] Controlled USA (2 years) Quality Fair Good Fair Fair Thomas Non-randomised Weak et al. [58] Controlled India (6 months) setting Dialysis centers of teaching s Haemodialysis units of a teaching and satellite units Non-profit universityaffiliated dialysis clinic Non-profit universityaffiliated dialysis clinic Nephrology department of a private Aim To assess the medication knowledge of HD patients and to evaluate the impact of education on their medication knowledge. To evaluate the effectiveness of a protocol designed to optimize serum phosphate levels in patients undergoing regular HD. To evaluate the effect of long-term clinical pharmacist interventions on HRQOL and the impact on drug use, drug costs, isation rates and DRPs in ambulatory patients undergoing HD. To evaluate the effect of long-term clinical pharmacist interventions on HRQOL and the impact on drug use, drug costs, isation rates and DRPs in ambulatory patients undergoing HD. To assess the impact of patient counselling on HRQOL of HD patients. N (at baseline) Intervention 102 HD Developing an (13.69) (Group I), educational program (17.78) (Group II) directed at patients medications 34 HD 51.1 (12.7) Phosphate management protocol group, 47.6 (14.4) standard practice 107 HD Pharmaceutical care 55.8 (15.1), standard of care 60 (15) 104 HD Pharmaceutical care 56.3 (15), standard of care 60.5 (14.7) 56 HD Control: 47.5, intervention: 50.2 (n ¼ 45) Management of serum phosphate using a specially designed phosphate management protocol (n ¼ 17) Pharmaceutical care program, including patient interview, drug reviews, identification of DRPs and drug therapy optimisation (n ¼ 61) Pharmaceutical care group consisting of one-on-one care, with in-depth drug therapy reviews conducted by a clinical pharmacist (n ¼ 57) Patient counselling regarding diet and fluid restrictions, lifestyle modifications, disease and medication (n ¼ 28) Control Control group (n ¼ 45) Standard practice group (n ¼ 17) Standard of care group consisting of periodic medication profile updates by dialysis nursing staff (n ¼ 46) Standard of care group consisting of periodic medication profile updates by dialysis nursing staff (n ¼ 47) Main clinical outcomes achieved Significant reduction in serum phosphate levels [ 1.81 (0.54) versus 2.07 (0.25) mmol/l, P ¼ 0.03] and calcium-phosphate product [mean (SD) 4.43 (1.20) versus 4.80 (0.51) mmol 2 /L 2, P ¼ 0.04], but not in corrected calcium and parathyroid hormone levels. Control group receiving no patient counselling (n ¼ 28) Significant reduction in all-cause isations [ 1.8 (2.4) versus 3.1 (3.0) isations, P = 0.002] and cumulative time ised [ 9.7 (14.7) versus 15.5 (16.3) days, P = 0.06]. a Adj RR, adjusted relative risk; CKD, chronic kidney disease; DRPs, drug-related problems; ESRD, end-stage renal disease; HRQOL, health-related quality of life; HD, hemodialysis; LDL, low density lipoprotein; NA, not applicable; NR, not reported; PD, peritoneal dialysis; TX, transplant patients. Quality scores: <0.5 / weak, 050 and 0.69 / fair, 070 and 0.79 / good and 080 and 1.00 / very good. b This study presents an inconsistency in the number of patients included. 280 T.M. Salgado et al.

6 Pharmacists interventions in patients with CKD 281 patients with secondary hyperparathyroidism (31 versus 42%, P ¼ 0.052) and the percentage of patients with moderate to severe hyperparathyroidism (7 versus 14%, P ¼ 0.042) [29]. The implementation of a serum phosphate management protocol by a renal dietitian and a renal pharmacist showed a significantly greater reduction in serum phosphate levels [ 1.81 (0.54) versus (0.25) mmol/l, P ¼ 0.03] and a greater improvement in calcium-phosphate product [ 4.43 (1.20) versus 4.80 (0.51) mmol 2 /L 2,P¼ 0.04] compared to standard practice. However, this study could not show any difference in the number of patients achieving Kidney Disease Outcomes Quality Initiative targets [53]. Regarding glucose management, pharmacist interventions produced a highly significant decrease in fasting blood glucose in both chronic kidney disease [mean 163 versus 209 mg/dl (SD not presented), P < 0.001] [51] and renal transplant patients [ (17.43) versus (18.25) mg/dl, P ¼ 0.001] [48]. Furthermore, A1C hemoglobin was also decreased in patients at high risk of developing chronic kidney disease [mean 8 versus 10% (SD not presented), P < 0.001] [51] and renal transplant patients [ 7.42 (0.61) versus 8.07 (0.81)%, P ¼ 0.002] [48]. After 6 months of pharmacist intervention, the number of patients achieving low density lipoprotein (LDL) cholesterol targets were significantly higher than baseline (88 versus 58%, P ¼ 0.015) [37]. Additionally, lipid values decreased significantly in several studies [37, 43, 48, 51], e.g. LDL [ 2.3 (0.9) versus 2.8 (1.0) mmol/l, P ¼ 0.013] [43]; total cholesterol levels [ 4.4 (1.1) versus 5.0 (1.4) mmol/l, P ¼ 0.06] [43] and triglycerides [ (36.93) versus 290 (90.74) mg/dl, P < 0.001] [48]. Similarly, a significant decrease in blood pressure was found across the studies [36, 43, 48, 51], e.g. systolic [mean (SD) (20.3) versus (22.5) mmhg, P ¼ 0.015] and diastolic blood pressure [ 67.6 (11.8) versus 71.8 (11.3) mmhg, P ¼ 0.03] [43]. Conversely, albumin levels did not show any improvement [37] and body mass index values worsened [mean 33.8 versus 32.7 kg/m 2 (SD not presented), P ¼ 0.04] [51]. Humanistic outcomes. An increase in health-related quality-of-life scores subsequent to pharmacy intervention was reported for the dimensions of general health [ (8.88) versus (13.86), P < 0.001], social functioning [ 50.4 (6.05) versus (12.11), P < 0.001], role emotional [ (6.32) versus (6.18), P < 0.001], mental health scales [mean (SD) (5.23) versus (5.13), P < 0.001] and on the physical component summary [ (6.27) versus (7.74), P ¼ 0.008] and mental component summary [ (4.62) versus (6.42), P < 0.001] [48]. Additionally, it has also been reported a statistical improvement in energy [ 7.1 (1.7) versus 3.3 (1.7), P < 0.05], daily activities [ 7.7 (1.9) versus 4.9 (2.1), P < 0.05] and general well-being [ 7.5 (1.6) versus 4.6 (2.2), P < 0.05], using linear analog scales [46]. One study conducted to assess the relationship between health-related quality of life and pharmaceutical care provision used the effect size to measure the impact of the intervention and resulted in a small to medium impact of the pharmacist at Year 2 between intervention and control groups [56]. An increase in 3% in the Karnofsky Performance Status Scale was detected after pharmacist patient counselling; however, no P-values were presented in this study [58]. Regarding patient satisfaction, 89% of patients found the information provided by the pharmacist very useful or useful and 81% of patients expressed a desire to talk to a pharmacist about their medications in the future [40]. Economic outcomes. Economic outcomes obtained as a result of pharmacists interventions were reported in 12 articles [24, 27, 29, 32, 34, 35, 41, 45, 47, 54, 56, 57]. Cost avoidance reported amounted to USD in 1992 [24]; USD between 1992 and 1995 [27]; USD between 1995 and 1998 [34]; 3000 USD [45] and 3860 USD [47] per patient per year in 2002 and between 2003 and 2006, respectively, and 2250 USD during a period of 4 months in 2007 [54]. The number of epoetin alpha units decreased nonsignificantly from 8.5 to 7.7 million when a pharmacist became responsible for anemia management [35]. A Japanese study showed that pharmacist intervention reduced the monthly costs of erythropoietin from 1.86 to 1.37 million Japanese yen (the equivalent to USD and USD) in 9 months of the year 2002 [41]. Another study calculated the benefit-to-cost ratio, described as medication cost avoided : cost of pharmacist time. These ratios were 4.16:1 and 7.5:1 for drugs with and without Medicare reimbursement in 1998, respectively [32]. Finally, one study reported a nonsignificant 6 USD drug cost reduction in a group of patients receiving pharmaceutical care compared to patients assigned to the standard of care group between 2003 and 2005 [57]. Process indicators. In total, pharmacists identified 2683 drug-related problems in 1209 patients and made 1849 recommendations to physicians, achieving an acceptance rate ranging from 40.9 [44] to 100% [44, 56, 57]. The clinical significance of the recommendations was classified as significant in 57.5 [54] to 78.0% [28] of the cases, very significant in 4.9 [28] to 21.8% [52] and insignificant in 0 [52] to 16.3% [54]. Some of the consequences of pharmacists interventions were modifications in drug therapy during the follow-up period [24, 27, 35 37, 41, 43, 45, 47 49, 51, 53, 54, 56, 57] and resolution of drug record discrepancies [24, 28, 38, 40, 55, 59]. One study reported a statistically significant improvement in compliance rates [ 96.1 (4.7) versus 81.6 (11.5)%, P < 0.001] and duration of compliance 1 year post-transplantation (75 versus 33.3%, P < 0.05), as well as a greater percentage of patients achieving target serum drug concentrations of immunosuppressants in the group with the pharmacist intervention (64 versus 48% patients, P < 0.05) [33]. Conversely, another study reported a decrease in compliance 3 months after pharmacist educational sessions (P-value not shown) [46]. Another study highlighted the importance of pharmacists in calculating glomerular filtration rates using serum creatinine levels available in medical records, contributing to

7 Table 2. Characteristics of uncontrolled studies included in the systematic review a country Thomas et al. [23] USA Golightly et al. [24] USA Tang et al. [25] USA Kaplan et al. [26] USA Soler Company et al. [27] Spain Grabe et al. [28] USA design (duration) setting Aim (unclear) Retrospective (36 months) Retrospective (6 months) (2 months) (4 years) Retrospective (1 month) University s Non-profit community Outpatient haemodialysis unit of a non-profit tertiary teaching University based outpatient haemodialysis unit Dialysis center and the pharmaceutical services of a general University-affiliated non-profit chronic haemodialysis unit To evaluate the effectiveness of a self-medication program in reducing the incidence of non-comprehension in renal transplant patients. To establish and evaluate the effectiveness of a program for monitoring drug prescription in renal patients. To assess the role of a clinical pharmacist as a member of a team responsible for the care of patients receiving chronic HD. To test the value and measure the impact of a medication review program in patients with end-stage renal disease on HD. To evaluate the clinical and economic benefits of collaboration between the pharmacy services and a dialysis center to control de use of epoetin. To identify DRPs in HD outpatients by performing medication reviews; make appropriate recommendations and determine the significance of any interventions. N (at baseline) Pharmacist interventions Main clinical outcomes achieved 20 TX 31.4 Patient education. 627 patients with renal impairment NR Daily assessment of creatinine levels and recommendations to physicians on dose adjustments of renally eliminated drugs HD NR Participation in medical rounds and weekly conferences on patient care, oral and written consultations, laboratory monitoring and patient education. 30 HD 40.5 Written consultation forms communicated to the prescriber reporting DRPs. 22 HD (baseline), 29 HD (Jun 1991), 38 HD (Jan 1994), 40 HD (Dec 1995) NR Implementation of a protocol to manage the dispensing and utilisation of epoetin. 45 HD 52 (16) Medication review, identification of DRPs and recommendations to physicians. In 5 out of 20 records evaluated, one negative outcome appeared (not specified). - Positive patient outcome: 82.6% interventions; - No change observed: 6.7% interventions; - No effect expected: 0.5% interventions; - Negative patient outcome: 1.5% interventions (hypnotic did not relieve insomnia, antitussive did not reduce cough, phosphate binder did not reduce phosphate levels). No P-values presented; there seems to be a trend in increased levels of hematocrit, hemoglobin and ferritin and decreased levels of iron and transferrin saturation. 282 T.M. Salgado et al.

8 Table 2. country Anonymous [29] USA Possidente et al. [30] USA Chisholm et al. [31] USA Chisholm et al. [32] USA Quercia et al. [34] USA design (duration) setting Aim (12 months) Retrospective (14 weeks) (18 months) (12 months) (1995, 1998) Haemodialysis unit of a tertiary medical center University teaching with patients from affiliated dialysis units Tertiary care teaching Tertiary care teaching Tertiary care community To develop a protocol to allow for pharmacist management of the IV administration of calcitriol and to manage hypocalcemia and hyperphosphatemia. To evaluate the continuity of drug therapy in long-term dialysis patients who required isation and to identify and resolve DRPs during the transition between the outpatient and inpatient settings. To document the number and types of recommendations made by a pharmacist to the multidisciplinary renal transplant team and to determine the rate of acceptance and their potential impact on patient care. To determine the cost savings resulting from a clinical pharmacistmanaged patient medication assistance program which consisted of assisting patients to procure immunosuppressants from pharmaceutical manufacturers. 1) To determine methods of epoetin alpha preparation and distribution that reduced waste; 2) to initiate a continuing pharmacy service that results in safe and effective management of anemia in HD patients; 3) to determine if a pharmacistmanaged anemia program leads to cost avoidance with regard to epoetin alpha; 4) to determine the effect of increasing the target hematocrit per new guidelines on the pharmacy drug budget. N (at baseline) Pharmacist interventions ~160 HD (1996) b, ~175 HD (1997) b NR The pharmacy department prepared IV calcitriol for each patient on a daily basis in labeled unit-dose syringes. 31 HD, 6 PD 65.9 (12.7) Review of admission, in- and discharge medication records. DRPs identification and discussion with the nephrologist. 201 TX NR Medication review, identification of DRPs, therapeutic recommendations, patient interviews and drug information provision. 61 TX NR To help patients who were not able to purchase their immunosuppressants enroll in manufacturers medication assistance programs. NR NR Formulation of an anemia management drug-use evaluation protocol, iron status monitoring of epoetin alpha patients and ordering of intravenous iron dextran. Main clinical outcomes achieved Significant decrease in the number of patients with moderate to severe hyperparathyroidism [ 12 (7) versus 23 (14)%, P ¼ 0.042]. Identification of 62 (7.6%) adverse reactions. Significant decrease in the number of patients with hematocrit under 31% during a 4-year period (14 versus 32%, P < 0.002). Pharmacists interventions in patients with CKD 283

9 Table 2. country To et al. [35] USA Viola et al. [37] USA Manley et al. [38] USA Manley et al. [39] USA Manley et al. [6] USA Mirkov et al. [40] New Zealand design (duration) setting Aim Retrospective (6 months) Retrospective (6 months) (5 months) (10 months) Retrospective (4 weeks) (6 months) Veterans dialysis clinic Tertiary care military Non-profit outpatient haemodialysis center Non-profit outpatient haemodialysis center Non-profit outpatient haemodialysis center In-center dialysis unit at tertiary teaching s To compare the effectiveness of an anemia management protocol used by pharmacists with that of physician-based management in patients undergoing long-term HD. To describe the effectiveness and feasibility of a multidisciplinary lipid management program using the specific skills of pharmacist, dietitian and nephrologist in HD patients. To evaluate the frequency, type and potential impact of drug record discrepancies in an outpatient electronic medical record. To determine the number, type, severity, and appearance rate of DRPs, as identified through pharmaceutical care activities, in ambulatory HD patients. To describe the number, type and factors associated with medication-related problems at an ambulatory HD clinic. To establish a medication review clinic and undertake a preliminary evaluation of the benefits of providing this service to dialysis patients. N (at baseline) Pharmacist interventions 49 HD 60 (12) Implementation of an anemia-management protocol: initiation and adjustment of epoetin alfa and iron therapy and ordering of monitoring tests. 26 HD 55.7 (11) Prescription and dosage adjustments, laboratory tests orders, patient education and reporting to physicians. 63 HD 61.9 (14.5) Drug interviews to determine which drug patients were taking and how they were taking them. Comparison of information with the electronic medical records. 145 HD 62.6 (15.9) c Review of all medications and electronic medical records, communication with other health care disciplines about the health status of the patient, evaluation of medical therapy appropriateness, identification of DRPs and communication of interventions to the nephrologist. 133 HD 60.5 (15.2) Identification of DRPs through medical records review. 51 HD 61.5 Medication reviews, identification of DRPs, medication education to patients, update of medication profiles. Main clinical outcomes achieved No significant changes in hematocrit and transferrin saturation. Significant reduction in LDL [ 80 (3) versus 96 (5) mg/dl, P < 0.001] and total cholesterol [ 151 (4) versus 170 (7) mg/dl, P ¼ 0.004] levels and significant increase in the number of patients reaching target LDL (88 versus 58%, P ¼ 0.015). 284 T.M. Salgado et al.

10 Table 2. country Kimura et al. [41] Japan Salcedo et al. [42] Colombia Patel et al. [44] USA Walton et al. [45] USA Allenet et al. [46] France design (duration) setting Aim (9 months) (4 months) (6 months) (6 months) (12 weeks) Outpatient haemodialysis unit of a Non-profit private clinic Network of federally qualified primary care clinics Hospital-based dialysis unit Nephrology department of a public To evaluate the impact of a pharmacist-implemented anemia management in outpatients with ESRD and to assess the pharmacoeconomic outcome. To describe the incidence and frequency of resolution of DRPs in solid organ transplant patients. To characterise CKD in high-risk indigent patients and evaluate opportunities for pharmacists to work collaboratively with physicians to improve medication use and CKD patient outcomes. To describe a pharmacistmanaged anaemia program in an outpatient HD clinic. Assessment of a pharmacist-run anemia educational program for patients with chronic renal insufficiency. N (at baseline) Pharmacist interventions 45 HD NR Drug information to physicians on renal anaemia, performance of a medication-use evaluation and proposal of plans to change prescriptions based on that evaluation. 18 TX NR Medication reviews and identification of DRPs. 119 CKD 57.5 (12.2) Identification of CKD patients; evaluation of potential DRPs and therapeutic recommendations. 278 HD 46.2 (13.4) Adjustment of epoetin and iron therapy on a monthly basis in the outpatient HD unit. 14 Predialysis (including 11 TX) 52.3 (15.4) Patient education regarding medical and therapeutic information on anaemia and training with the device used for epoetin injections. Main clinical outcomes achieved No P-values presented. There seems to be a trend in increased mean hematocrit and number of patients with hematocrit >30%. No P-values presented. There seems to be a trend in increased hemoglobin ferritin and transferrin saturation, as well as in the number of patients with an initial hemoglobin >11 g/dl. No P-values presented. There seems to be a trend in increased mean hemoglobin levels. Pharmacists interventions in patients with CKD 285

11 Table 2. country Chisholm et al. [48] USA Joy et al. [49] USA design (duration) setting Aim (2 years) (28 months) Tertiary care teaching University-affiliated division of Nephrology To study the effects of a medication assistance program with medication therapy management on the clinical outcomes and HRQOL of renal transplant recipients. To describe the clinic design, clinical evaluations and treatment approaches used in a multidisciplinary clinic for management of anemia of CKD and to evaluate several selected clinical outcomes. N (at baseline) Pharmacist interventions 36 TX (13.37) Medication review; identification, resolution and prevention of DRPs; patient interviews; drug information; therapeutic recommendations. 166 CKD 62 (16) Coordering anemia therapies and other drugs, basic clinical assessments during patient visits, laboratory tests order, patient education and coordination of the drug program entry for patients receiving erythropoietic agents. Main clinical outcomes achieved Significant reduction in fasting blood glucose [ (17.43) versus (18.25) mg/dl, P ¼ 0.001], A1C hemoglobin [mean (SD) 7.42 (0.61) versus 8.07 (0.81)%, P ¼ 0.002], LDL [ (27.39) versus (66.20) mg/dl, P < 0.001], total cholesterol [mean (SD) (47.24) versus (108.33) mg/dl, P < 0.001], triglycerides [ (36.93) versus (90.74) mg/dl, P < 0.001], systolic [ (7.54) versus (7.81) mmhg, P < 0.001] and diastolic [ (4.24) versus (3.97) mmhg, P < 0.001] blood pressure and episodes of graft rejection [mean (SD) 0.22 (0.42) versus 0.50 (0.51), P ¼ 0.008]. No P-values presented. There seems to be a trend in increased number of patients achieving target hemoglobin. 286 T.M. Salgado et al.

12 Table 2. country Leal et al. [51] USA Ledger et al. [59] Canada Wang et al. [52] Taiwan design (duration) setting Aim (not reported) (12 weeks) (15 months) Community health center Tertiary care Medical center To evaluate a pharmacist-based disease-state management service to improve the care of indigent patients at high risk to develop CKD. To evaluate the potential impact of medication reconciliation and optimisation in the ambulatory care setting at the time of patient transfer from an in-center dialysis unit to a satellite dialysis unit. To investigate the effects on treatment outcomes by clinical pharmacists joining renal transplant clinics to provide pharmaceutical care. N (at baseline) Pharmacist interventions 601 CKD 57.7 (13.5) Modification of drug therapy, laboratory monitoring, patient education. 19 HD 64.6 (11.4) Medication reconciliation, correction of discrepancies and suggestions to optimise pharmacotherapy. 37 TX NR Provision of information to patients, therapeutic recommendations to physicians and evaluation of their influence on prescriptions and patient outcomes. Main clinical outcomes achieved Significant reduction in fasting blood glucose [mean 163 versus 209 mg/dl (SD not presented), P < 0.001], A1C hemoglobin [mean 8 versus 10% (SD not presented), P < 0.001], LDL [mean 91 versus 107 mg/dl (SD not presented), P < 0.001], total cholesterol [mean 170 versus 198 mg/dl (SD not presented), P < 0.001], triglycerides [mean 187 versus 247 mg/dl (SD not presented), P < 0.001], systolic [mean 117 versus 124 mmhg (SD not presented), P < 0.001] and diastolic [mean 70 versus 75 mmhg (SD not presented), P < 0.001] blood pressure. Improvement in 94.2% patient outcomes (not specified). Pharmacists interventions in patients with CKD 287

13 288 T.M. Salgado et al. Table 2. Main clinical outcomes achieved Pharmacist interventions N (at baseline) design (duration) setting Aim country Significant reduction in the number of adverse drug reactions (49 in 16.0% patients versus 73 in 21.3% patients, P < 0.05). Participation in rounds with the nephrology unit team and dosing adjustment recommendations when needed. Preintervention (14.15), Postintervention (14.37) Preintervention: 56 no dialysis, 163 HD, 35 PD, 46 in; postintervention: 55 no dialysis, 154 HD, 45 PD, 46 in- To assess the rate of inappropriate dosing in patients with CKD in a nephrology unit and to evaluate the impact on dose adjustment, adverse drug events and drug cost of having a pharmacist accompany a team of physicians on their rounds. Nephrology unit at a general public (8 months) Hassan et al. [54] Malaysia 64 HD 65 Clinical medication review, patient education and recommendations to physicians. To implement a pharmacist medication review clinic and establish a sustainable clinical pharmacy service. In-center dialysis unit of tertiary teaching s (8 months) Mirkov [55] New Zealand a CKD, chronic kidney disease; DRPs, drug-related problems; ESRD, end-stage renal disease; HRQOL, health-related quality of life; HD, haemodialysis; LDL, low density lipoprotein; NA, not applicable; NR, not reported; PD, peritoneal dialysis; TX, transplant patients. b Calculated from percentages presented in the article c This study presents an inconsistency in the age of participants (Table 1 versus text). the identification of more patients with chronic kidney disease previously not documented in those records [44]. Pharmacists also contributed to adjustments of medication records [24, 28, 38, 40, 55, 59], to increase medication disposals, to remind patients of physician appointments [55] and to increase patient knowledge [23, 46, 50]. Discussion Methodological considerations The search strategy used in this systematic review appeared to be sufficiently broad to include the studies of interest, as demonstrated by the reduced number of additional references picked from retrieved articles and reviews. Almost 80% of the 37 studies included had an uncontrolled design, which poses a serious threat to the validity of these works. To measure the impact of pharmacists interventions randomised controlled studies should be conducted and they should contain a clear description of the pharmacy practice setting, patient demographics and the intervention performed [60]. Some of the studies analysed refer to control and intervention groups, but no comparison analysis was presented [39]. A question arising is whether the effect observed can be isolated and attributed to pharmacist care or to a particular component of pharmacist care [61]. This is especially critical in studies where a redefinition of the roles of several health care professionals took place [49]. The use of the Downs and Black instrument [22] allowed a comparative analysis of controlled studies, both randomised and non-randomised. The average quality score was 0.57 (fair) and the low quality of studies could be a result of the difficulty in blinding pharmacists interventions, the lack of adverse events reporting and the difficulty in measuring adherence to the interventions [22, 61]. Some research studies often fail to provide in-depth details of the intervention, limiting the reproducibility of the findings [61]. In some of the studies included in this review, the duration of the study, date of patients entry, follow-up reassessment time [51] or even the number of participants in the study were lacking [25, 29, 34]. Several studies did not report outcome measures but only process measures [6, 23, 26, 28, 30, 33, 38, 39, 42, 44, 50, 55, 59]. Using process measures as a proxy indicator of potential outcomes poses some uncertainty, as a clear association between a good process and a positive outcome does not always exist [61]. It is even more difficult to assess the impact of pharmacists interventions when process variables measured are not closely related to patient outcomes, such as physician appointment reminders or medication disposals [55]. Also, clinically meaningful outcomes should be clearly presented [61] and outcomes presentation should, when possible, follow the Economic, Clinical, and Humanistic Outcomes (ECHO) model to provide a broader picture of the impact of pharmacy services [62]. Some of the studies also presented statistical concerns such as lack of P-values presentation [27, 41, 45, 46, 49]; absence of measures of statistical dispersion [45]; P-values presentation with no statistical analysis sufficiently

14 Pharmacists interventions in patients with CKD 289 described in the Materials and methods section [51] and lack of multivariate analysis performance when the aim of the study was to evaluate factors associated with medication-related problems [6]. Impact of pharmacist interventions In our analysis, controlled studies yielded similar results when compared to studies conducted under an uncontrolled design. All of the five controlled studies reporting clinical outcomes found a positive association between pharmacist intervention and clinical outcomes improvement such as reduction in blood pressure, decrease in LDL and total cholesterol levels, time on goal hemoglobin time on goal transferrin saturation, reduction in serum phosphate levels and calcium-phosphate product and all-cause isations. Six of 16 uncontrolled studies reporting clinical outcomes showed statistical improvement in reducing the number of patients with moderate to severe hyperparathyroidism, increasing hematocrit and decreasing LDL, total cholesterol, triglycerides, blood glucose, A1C hemoglobin blood pressure, graft rejection, body mass index and number of adverse drug events. Both controlled and uncontrolled studies reporting pharmacist interventions in anemia failed to demonstrate a significant impact on anemia parameters in six of eight studies, except for the time on goal haemoglobin and transferrin saturation [47] and hematocrit in a 4-year period [34]. Anaemia correction has been associated with an improvement in health-related quality of life in dialysis and nondialysis patients [63, 64] and patients with better health-related quality of life have a significantly more favourable survival rate [65]. Correcting anaemia has the potential to improve other clinical and economic outcomes in patients with chronic kidney disease [66], namely left ventricular hypertrophy [67], rate of progression of chronic kidney failure [68] and mortality [69]. Pharmacists contributed to a significant reduction in the number of patients with secondary hyperparathyroidism in an uncontrolled study [29], as well as a reduction in serum phosphate levels and calcium-phosphate product in a controlled study [53]. It is of paramount importance to control phosphate and calcium levels since arterial media calcification is a strong prognostic marker of all-cause and cardiovascular mortality in haemodialysis patients [70]. In relation to humanistic outcomes, the two controlled studies could not find a significant difference in quality of life after pharmacist intervention [56, 58]. This is in line with results reported in a previous review which showed that patients quality of life did not seem to change after pharmacist intervention [12]. The remaining two uncontrolled studies [46, 48] present some serious concerns in their design which could result in misleading conclusions. In one of them, in which a significant improvement in quality of life was reported, a confounder was not taken into consideration, as these were de novo epoetin patients with hemoglobin levels <10 mg/dl [46]. In this study, quality-of-life dimensions such as energy, general wellbeing and ability to perform daily activities were likely to be improved as a result of the epoetin treatment and not necessarily as a result of the pharmacist intervention. Cost-savings achieved as a consequence of pharmacist interventions were reported in several of the studies analysed and resulted from savings in costs with medication. Only one study reported a substantial benefit-to-cost ratio resulting from pharmacists interventions [32]. In addition, isation is the major component of the cost of care for patients on dialysis [71, 72] therefore reducing isation rates [57] is associated with cost savings; however, this has not been reported. The most frequent variable measured in the studies analysed was the so-called drug-related problems. The definition of drug-related problems has been subject to an extensive debate and a clear consensual concept has not yet been achieved [73]. Drug-related problems have been associated with increased admissions [74], increased health care utilisation [75] and increased costs with drug-related morbidity and mortality [76]. One study reported 28% of admissions being due to drugrelated problems [77]. Provision of pharmaceutical care to dialysis patients is a cost-effective way to identify, resolve and avoid drug-related problems [78]. Limitations and future research A limitation that frequently arises in systematic reviews is the selection bias produced by the lack of sensitivity in the queries used. In this review, the evidence indicates that selection bias was minimal due to the reduced number of additional articles retrieved from other articles references lists. Another bias frequently reported is related with language selection [79]. Although 10 articles were excluded on the basis of language, according to their titles and abstracts, it appears that none of these studies reported pharmacist interventions in patients with chronic kidney disease, and therefore, they may have been excluded on other criteria. An important issue that can limit the implementation of pharmacy services is funding. Comments regarding the role of pharmacists within dialysis facilities on the scope of a document produced by the Center for Medicare and Medicaid Services evidenced that pharmacist participation was desirable but not practical absent funding [80]. In addition, pharmacists perceived financial or reimbursement issues as barriers for collaborative drug therapy management in the setting, and only 11% of s received insurance reimbursement for this service [81]. Conducting randomised controlled trials may also pose difficulties [82], particularly related to recruitment [83]. Inadequate recruitment can lead to failure to conclude trials [84], and therefore, strategies to increase recruitment and ensure success of randomised controlled trials should be employed [85, 86]. Only four studies included in this review had a randomised controlled design, which constitutes the most reliable evidence for evaluating the effects of health care interventions [87]. In line with this finding is a study reporting the number of randomised controlled trials published in nephrology being fewer than other specialties of internal medicine and low in quality [88]. Systematic reviews are commonly used in evidencebased policy making. However, systematic reviews of public health interventions usually include an important amount of observational studies, producing evidence