Study protocol: systematic review and meta-analysis on the effectiveness of pharmacist intervention on health related quality of life and clinical outcomes among patients with heart failure

Background: Heart failure (HF) is associated with severe complications, hospitalization, and poor quality of life. Patients with heart failure had poor physical and emotional symptoms, functional status and worse health outcomes. Objective: The aim of this systematic review and meta-analysis will be to investigate whether pharmacist intervention is effective in improving health related quality of life (HRQoL) and clinical outcomes among patients with heart failure. Method: Systematic review and meta-analysis will be conducted. Published journals in English and indexed in Medline (PubMed), Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Google scholar will be searched from 1990 to December 2019. Data will be extracted by one author and will be approved by other two authors independently. Data will be analyzed in accordance with the Cochrane handbook. Standardized mean differences will be used as an estimate of the effect size. Quality of included studies will be assessed using the modied Downs and Black checklist. Analysis for the dichotomous outcome studies will be converted into standardized mean difference and present with 95% condence intervals. The review is approved in the International Prospective Register of Systematic Reviews (PROSPERO) with registration ID CRD42020158236. Discussion: Currently there are important gaps on the effectiveness of pharmacist intervention in improving health-related quality of life and clinical outcomes. We believe this review will provide comprehensive evidence on the effectiveness of pharmacist intervention among patients with HF.

author and will be approved by other two authors independently. Data will be analyzed in accordance with the Cochrane handbook. Standardized mean differences will be used as an estimate of the effect size. Quality of included studies will be assessed using the modi ed Downs and Black checklist. Analysis for the dichotomous outcome studies will be converted into standardized mean difference and present with 95% con dence intervals. The review is approved in the International Prospective Register of Systematic Reviews (PROSPERO) with registration ID CRD42020158236.
Discussion: Currently there are important gaps on the effectiveness of pharmacist intervention in improving health-related quality of life and clinical outcomes. We believe this review will provide comprehensive evidence on the effectiveness of pharmacist intervention among patients with HF.

Background
Heart failure (HF) is a cardiac structural and/or functional abnormality leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues [1]. Diagnosis of HF is con rmed based on clinical history, physical examination (Framingham criteria), chest X-ray and echocardiography ndings and laboratory exams speci cally plasma B-type Natriuretic Peptide and Nterminal B-type Natriuretic Peptide measurement [2,3]. Clinical outcomes among patients with HF were mortality (all-cause and HF speci c death), hospitalization, readmission and morbidity endpoints used in different trials and taken as de nition by the European Society of Cardiology HF association consensus document [4].
Globally, about 26 million people were living with HF with poor patient outlook and worse survival [5]. HF put signi cant stress on patients, caregivers and the health care system. The ve year mortality rate of systolic HF patients ranged from 25% to 75% due to sudden death from ventricular arrhythmia [6]. In a longitudinal study on community-living older persons from Cardiovascular Health Study, the rate of hospitalization was 7.9/10 person-years [7].
Multidisciplinary health professionals including nurses, pharmacists and dietitian's intervention on patient education, medication teaching and nutrition guidance, respectively, proved to have positive outcomes and lowered mortality [8]. Lower educational status was associated with an increased hospitalization of HF patients [9]. Low health literacy, which can be de ned as Brief Health Literacy Screen ≤ 9, was associated with higher risk of mortality and increased risk of hospital readmission [10]. Heart failure patients who have higher literacy have better understanding of their disease state, self e cacy and self care, thus patients with low literacy level were associated with worse HF related quality of life (QoL) [11].
Comparison of QoL among the healthy old age group versus ill old age HF patients showed a lesser QoL in the later ones. Using physical symptom as strongest measure, older adults with HF had poorer physical and emotional symptoms, poorer functional status and more worse health perception [12]. Using the German version generic QoL measure (SF-36) containing eight dimensions, scores of ve of the eight QoL domains were reduced to around one-third in NYHA class III patients [13]. In the study conducted in Serbia, the poor QoL were due to lower income, longer history of chronic HF, longer hospital stay, multiple medications, higher NYHA class, depression and cognitive impairment [14].
Communicating hospitalized HF patients effectively at the time of discharge regarding their future clinical status improved QoL of patients [15]. In this case, the involvement of pharmacists demonstrated better medication adherence compared to other health professionals and had greater impact on the ability to inform, solve problem and support patients directly [16]. The pooled data of the systematic review and meta-analysis study on the pharmacist-led medication reconciliation programs, showed a signi cant reduction in adverse drug event-related hospital and emergency department visits, reduction in hospital readmissions and improved medication adherence [17,18]. Overall, pharmacists signi cantly improved health related quality of life (HRQoL) through pharmaceutical care interventions in terms of general health, social and physical functioning [19] Importance of this review Pharmacists can review medication charts and make interventions such as medication reconciliation for discharged patients and correct medication discrepancies, dealing with barriers to medication documentation and interdisciplinary communication [20]. Pharmacist-led medication review and reconciliation were effective in improving medication adherence and patient outcomes, as well as in reducing hospitalization improving post-hospital medication safety and health care utilization [17,18]. Pharmacists play signi cant roles in handling HF patients by minimizing disease symptoms, improving medication compliance and enhancing chronic disease management [21].
Clinical pharmacists can identify and resolve pharmaceutical care issues and provide optimal care when working in collaboration with other health care professionals [22]. Clinical pharmacists lower prescription errors and medication discrepancies through the discharge service to HF patients. The clinical pharmacist's activities includes: review of medications, communication with cardiologists, general practitioners and community pharmacists, providing patient information and preparing written overview of discharge medication [23].
Pharmacists decreased readmission of HF patients and improved care through continuum of care such as discharge counseling services and resolving medication reconciliation discrepancies. Patients discharged with the diagnosis of HF who received continuum of care had lower 30-day all-cause readmission rate [24].
Providing pharmaceutical care service to patients with HF had signi cant clinical and humanistic bene ts. Pharmacist-led pharmaceutical care programs were shown to improve exercise tolerance (2-min walk test), forced vital capacity, medication adherence and HRQoL measured by the Minnesota living with heart failure questionnaire [25].
The systematic review and meta-analysis study demonstrated multidisciplinary interventions for HF reduced both hospital admission and all-cause mortality [26]. Pharmaceutical care interventions signi cantly improved HRQoL measures. However, the pooled data on HF-speci c measures indicated no signi cant impact of pharmaceutical care utilization [19]. Therefore the aim of this systematic review and meta-analysis is to investigate whether pharmacist intervention is effective on quality of life and clinical outcomes among patients with HF.

Objective
The aim of this study protocol is to provide a clear way to review systematically from various indexing databases and synthesize the data that whether pharmacist intervention is effective on HRQoL and clinical outcomes compared to usual/standard care. This review will address systematic literature search strategy, describe data sources identi ed in the review, set inclusion and exclusion criteria for the study, describe data extraction process, assess quality measures for the systematic review, and describe statistical procedures for the quantitative analysis. We aim to address our key research question that whether pharmacist intervention is effective on improving HRQoL and clinical outcomes (in terms of reduced hospitalization and mortality) among patients with HF compared to usual/standard care.

Study protocol
In order to include all relevant information the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) checklist will be employed as a tool [27]. The PRISMA ow diagram will be used for identi cation, screening, eligibility and inclusion of studies at different stages of the review process (www.prisma-statement.org). The review is approved in the International Prospective Register of Systematic Reviews (PROSPERO) with registration ID CRD42020158236.

Research question
Is pharmacist intervention effective on health related quality of life among patients with HF compared to usual/standard care? Is pharmacist intervention improves clinical outcomes (reduces patient hospitalization and mortality) among patients with HF compared to usual/standard care?
We believe these questions are highly relevant to policy makers and service providers. Our review will focus on the journals that are randomized controlled trial only.

Search strategy and data source
Databases indexed in Medline (PubMed), Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus and Google scholar will be conducted to retrieve journals. Original peer reviewed articles published in English language from 1990 to December, 2019 will be identi ed using the terms heart failure, pharmacist intervention, health related quality of life and clinical outcomes. In our search medical subject heading (MeSH) and Boolean operators will be employed to search journals using 'heart failure' (MeSH) OR 'cardiac failure' (MeSH) AND 'pharmacist intervention' OR 'clinical pharmacist intervention' OR 'pharmaceutical care' AND 'health related quality of life' OR 'quality of life' AND 'clinical outcome' OR 'health outcome' OR 'patient outcome'. We limited the studies to randomized controlled trials using the term 'randomized controlled trial'. Titles of all retrieved studies will be screened and abstracts of the selected articles will be further evaluated. Article screening and the selection process will be carried out by the primary author and then independently reviewed by two other authors.

Eligibility criteria
Studies that reported pharmacist intervention and provided data on health related quality of life (or quality of life) and clinical outcomes (mortality, hospitalization) will be included in this review. Additionally, studies that reported pharmacist-led multidisciplinary team interventions will be included. The following studies will be excluded: case reports and case series, case-controls, cohorts, observational and non-research articles and commentaries. Abstracts from conference and journals whose full-text cannot be retrieved will be excluded. In addition, studies that will not report primarily pharmacist intervention such as nurse-led multi-disciplinary team interventions, interventions requiring telephone monitoring, telemedicine, and web-based interventions will be excluded. Therefore, original peer-reviewed articles of randomized controlled trial that report pharmacist intervention and consider HRQoL and clinical outcomes among patients with HF will be eligible for inclusion.
Data extraction Data will be extracted by one author and will be approved by other two authors independently. Any discrepancy will be resolved by agreement. The following information will be extracted from included studies: name of rst author, year of publication, study setting/country, study design, number of participants, follow-up/duration, type of intervention and main outcomes of the study. For data management, we will use the ENDNOTE reference software version 7 (Thomson Reuters, Stamford, CT, USA) in title review, abstract screening, and removal of duplicates.
Quality assessment Studies will be reviewed independently to assess the quality of included studies to minimize the risk of bias using the modi ed Downs and Black checklist designed to evaluate both randomized controlled trials and nonrandomized studies. The check list contains 27 items covering quality of reporting, confounding, bias, and representativeness of sample size [28].

Data synthesis and analysis
We will analyze data in accordance with the Cochrane handbook [29]. We will pool data from studies which are su ciently similar. Meta-analysis will be performed when we nd at least two studies that report the same HRQoL and clinical outcome measures to see the pooled effect of pharmacist intervention. When this is not possible due to insu cient number of studies, we will conduct narrations of the study results. Heterogeneity of included studies will be assessed using the standard Cochrane Q statistics and the I 2 statistics. Publication bias will be assessed using funnel plots, and forest plot will be constructed using a random effect model. Because of variability in reporting among studies, standardized mean differences will be used as an estimate of the effect size. Analysis for the dichotomous outcome studies will be converted into standardized mean difference and will be presented with 95% con dence intervals. The analyses will be conducted using the Cochrane Review Manager (RevMan) V.5.3 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The study will be reported utilizing Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) 2015 statement [27].

Discussion
Heart failure is a syndrome associated with higher rates of hospitalization, morbidity, mortality and poor quality of life. Pharmacist interventions have improved quality of life on speci c diseases; however, the systematic review and meta-analysis study of pharmaceutical care intervention on HRQoL proved no statistically signi cant impact of pharmaceutical care intervention on HF [19]. Currently there are important gaps on the effectiveness of pharmacist intervention. We believe this review will provide comprehensive evidence on the effectiveness of pharmacist intervention among patients with HF. Currently we have screened more than 1820 abstracts and identi ed more than 145 potential studies which we will intend to retrieve their full text review.