The Effect of Pharmacist Services on Patient Health Outcomes in a Low Middle-income Country: a Systematic Review


 Background: The pharmacist's role is shifting from dispensing to bedside care, resulting in better patient health outcomes. However, pharmacist services on healthcare utilization in low- and middle-income countries such as Pakistan are unclear. As a result, we intend to conduct a systematic review of pharmacists' roles in improving Pakistani patients' health outcomes.Methods: We searched PubMed, Scopus, EMBASE, CINAHIL, and Cochrane Library for relevant articles published from inception to February 2021. Original studies investigating the therapeutic, humanistic, safety, and economic impact of pharmacists in Pakistani patients (hospitalized or outpatients) were selected. Two reviewers independently assessed the bias in studies, and mutual consensus resolved discrepancies. Results: The literature search found 751 articles from which ten studies were included; seven were randomized controlled trials (RCTs), and three were observational studies. Three RCTs included were having a low risk of bias (ROB), two RCTs were having an unclear ROB, while two RCTs were having high ROB. Pharmacist interventions comprised one or more components like provision of education about the disease, medication adherence counselling, medication therapy management, and consultation with a physician regarding change of prescription. In most studies, pharmacists provided therapeutic care, followed by humanistic and safety outcomes with significant improvements. Intervention effect on cost-effectiveness and long-term outcomes were unclear.Conclusions: Positive but not always statistically significant pharmacist effects on therapeutic, humanistic, and safety outcomes have been reported. Therefore, the results favour adding on the benefit of pharmacist services but lack evidence of economic feasibility and long-term impact of pharmacist interventions.


Background
Since 1990, with pharmaceutical care introduction, pharmacists' careers have evolved from single dispensary positions to patient-oriented health care [1,2]. Pharmacists are su ciently empowered to play a vital role in pharmaceutical care [3,4]. However, pharmacists' role in developing countries is gradually moving towards direct cooperation with other health professionals [5,6]. In the meantime, they remain primarily responsible for the production, distribution, and dispensing of medicines [3,7].
To improve pharmacy services across the country, the Federal Government of Pakistan has established a regulatory body, the Drug Regulatory Authority of Pakistan (DRAP) Act 2012 [8]. Under the DRAP Act 2012, pharmacy services include pharmacy services that range from existing basic services (i.e., dispensing, procurement, storage, distribution of therapeutic products and counselling) to enhanced drug services (pharmaceutical care, pharmacovigilance, pharmacoepidemiology, pharmacoeconomic and drug management services) at all levels [9]. The pharmacy curriculum underwent a transition from four years of Bachelor of Pharmacy to ve years of Doctor of Pharmacy degree in 2004 by the Higher Education Commission (HEC) of Pakistan [10] Currently, 21 public sector and 25 private sector universities are offering Pharm D degrees to more than 3000 pharmacists each year [11]. Moreover, as of 2019, the number of community pharmacies in Pakistan has also increased to more than 40,000 [12]. In 2014, to strengthen pharmacists' expertise in clinical roles, HEC introduces the Department of Pharmacy Practice in Pakistan's private and public sector universities [13]. As a result, studies have begun to highlight potential clinical pharmacy progress, including further bedside activities, patient consultation, and therapy optimization in Pakistan [14][15][16].
The inclusion of pharmacy workers in primary care has been seen as an effective means of improving patient health outcomes [17,18]. Published literature reviews of the effects and outcomes of pharmacists' interventions in the United States and west showed various outcomes, health care settings, and disease states could bene t through pharmacists' direct care [19][20][21][22][23]. Pande et al. systematically reviewed the impact of pharmacist interventions on patient outcomes, health service utilization and costs in low-and middle-income countries in 2013 [24]. Pande et al. concluded that the pharmacist's services positively impact treatment outcomes such as hyperglycaemia and systolic/diastolic blood pressure (BP), the control of cholesterol, and the quality of life of chronic diseases such as asthma, diabetes, and hypertension [24]. However, the authors were uncertain about the implications of a lack of evidence on health services and costs. All the studies used in the review were from middle-income countries such as South East Asia, Africa and Eastern Europe. These results were heterogeneous as each study measured different outcomes with different clinical conditions using different measurement methods, which requires careful interpretation. As a result, the results may not apply to countries with varying healthcare systems, such as Pakistan, which has recently been classi ed as one by the World Bank, with low, middle incomes in southern Asia. The real impact of clinical pharmacists and, therefore, the use of services is not well established in Pakistan. There may be a lack of knowledge of clinical pharmacists' added bene ts and drivers to support the practice among stakeholders and service users. The objective of this systematic review is therefore to synthesise the therapeutic, safety, humanistic and cost-effective consequences of pharmacist intervention compared to standard treatments without the involvement of pharmacists in direct patient care in Pakistani population.

Scope of review: eligibility criteria
This systematic review was conducted following the Cochrane Handbook for Systematic Reviews of the Intervention Guidelines [25], and the reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [26]. Studies were included if they were 1) randomized controlled trials (RCTs), pre-post, follow up; 2) involved pharmacist intervention either alone or in a multidisciplinary team 3); measuring any health outcome (humanistic, safety, economic and therapeutic effects); 4) conducted among outpatients or inpatients in the hospital or community pharmacy settings; 5) had a control or comparison group (with healthcare professionals other than a pharmacist); 6) published in a peer-reviewed journal in English language only and available in full-text.

Information sources
We used a population, intervention, comparator, and outcome (PICO) search strategy to identify relevant records from PubMed, Scopus, OVIDEmbase, CINAHIL Plus, and Cochrane Libraries. The initial search was done on 14 February 2021, and follow-up searches were done on 28 February 2021

Database searching
The search strategy identi ed original research on the effect of pharmacists' interventions on therapeutic, safety, humanistic and cost-effective consequences of pharmacist intervention compared to standard treatments without the involvement of pharmacists in direct patient care in Pakistani Population. An extensive literature search was carried out using different search term combinations. . The search terms used were Pharmacist OR Pharmacy OR "Clinical Pharmacy" OR PharmD OR "Pharmacist-led") AND (Adherence OR "Health outcomes" OR "Medication management" OR "Patient outcomes" OR outcome OR "Quality of life" OR "clinical outcome" OR Pharmacovigilance OR Economics OR "drug interactions" AND "drug safety") AND (Pakistan OR Pakistani). Due to each database's technical differences and limitations, the search mechanism in each database has been subsequently adapted and slightly modi ed. Case reports, expert opinions, systematic reviews, letters to editors, comments, correspondence, news articles and qualitative studies were excluded from the study.
Conference abstracts were excluded from the study if they were not available in full text and non-English studies.

Data extraction
The titles and abstracts of all the studies collected were examined separately by two authors, AA and MS. The full-text screening was carried out independently by the reviewers for each potential research, and the differences were resolved by consensus. If a discrepancy remained, a third reviewer (MT) helped to develop a mutual agreement. Using a standardized extraction form, the AA extracted the data independently after selecting the eligible studies. The extracted data were checked for accuracy and consistency by the second author (MS). Article details (objective, year of publication and rst authors), study design, country of study, sample size and study characteristics (age, follow-up duration, pharmacist intervention, intervention strategy, control group, intervention group, type of outcome measure, main health outcomes) were extracted.

Risk of bias
Two reviewers (AA and MS) independently assessed the quality of RCTs using the Cochrane Risk of Bias Tool (ROB.2) [27]. The mutual consensus resolved discrepancies. In non-RCTs, a Risk of Bias in non-Randomized Intervention Studies (ROBINS-I) tool was used for quality evaluation [28]. These studies have been assessed as being of low risk (if no bias), unclear risk (if any doubts affect results), and high risk (if bias has affected the results severely).

Study Selection
After an initial literature search, a total of 751 research items were identi ed. As depicted in the PRISMA ow diagram, 44 duplicate records were removed ( Figure 1). Following the exclusion of 662 citations found to be irrelevant to the primary research question based on title and abstract view, 45 full-text publications were retrieved and evaluated for eligibility. Thirty ve studies were excluded due to following reasons: Editorial/letter to editor = (n=5), study protocol = (n=1), review articles = (n=1), conference paper / proceedings = (n=7), commentary/short report = (n=4), qualitative studies (n=6), not met inclusion criteria = (n=11). Ten studies were selected for analysis.
Pharmacist provided a variety of interventions broadly classi ed into six categories 1) Provision of education regarding disease stages with booklets; 2) exploring adherence barriers and motivational interviewing to improve adherence; 3) lifestyle modi cation guidance; 4) pharmaceutical care consisting of pharmacovigilance, drug-drug interactions, drug-food interactions; 5) interacting with the physician to change the drug regimen 6) maintain patient follow up care. Detailed characteristics of individual studies and their outcomes are shown in Table 1.
Three RCTs included were having a low ROB [31,33,34], two RCTs were having an unclear ROB [29,32], while two RCTs were having a high ROB [30,35]. The most common reasons for bias were problems in randomization of participants, measurement of outcomes, and handling of missing data. One observational study had an unclear risk [38], while two had a high ROB [36,37] due to bias in outcome measurement and handling of missing data. Details of Bias in each study are shown in Figures 2 and 3.  Ali et al. reported that HRQoL was signi cantly improved in both the usual care and pharmaceutical care groups, but no statistically signi cant change was observed between them. While there was a signi cant difference in VAS score between both groups at follow-up as patients in the pharmaceutical care group had higher scores than the usual care group (P<0.001) [33].

Discussion
To the best of the authors' knowledge, this is the rst systematic review to include widespread evidence of pharmacists' role in Southern Asia, particularly in a low-medium-income country like Pakistan. Clinical pharmacy education in Pakistan is evolving, but still at the root level, and the value of these services for patients and healthcare systems is not well understood. To endorse changes in practice, policymakers must understand pharmacist bene t add-ons for patients and health systems. This review highlights potential consequences for pharmacists in better disease management and patient outcomes and likely drivers of future professional development and research for decision-makers and scientists.
There was variation in health outcome measurements as well as heterogeneity in pharmacist interventions. Provision of simple education was the most common intervention by the pharmacist. Few studies evaluated complete pharmaceutical care follow-up, which included optimizing medication therapy, monitoring disease progression, assessing adherence, identifying and resolving drug-related problems, and maintaining manual records for each patient. Interventions were delivered (for example, at outpatient departments or inpatient departments), frequency of intervention range from 2 to 6 times during follow up (range 2 to 10 months), length of pharmacist intervention sessions (First session range 15 to 60min, follow up sessions range from 10 to 45min) reported in the studies.
The reviewed studies included were of moderate quality, demonstrating methodological heterogeneity, versatility in the measurement of outcomes, reporting of selected outcomes, and adequacy of power of studies with differential interventions. Nonetheless, clinical pharmacists played an important role in identifying and addressing therapy-related issues in chronic diseases (diabetes, Hepatitis C, CKD, hypertension, tuberculosis, and HIV) and pharmacovigilance in neonatal care. These ndings are comparable with the study conducted in a similar Jordanian LMIC setting [3]. However, we could not nd any research that evaluated the cost-effectiveness of pharmacist intervention. Similarly, a Cochrane review also reported limited evidence of the cost of pharmacist interventions [24]. Likewise, minimal safety evidence was generated and reported from the growing literature from the UK, the USA, and European countries [20,[39][40][41].

Implications for Practice and research
Clinical pharmacy services are emerging and are feasible in the Pakistan context. Pharmacists interact with patient consultations and medication therapy management. However, acceptance of their clinical roles by other healthcare workers is challenging [9,10]. There should be multidisciplinary group discussions to advance clinical pharmacy services in Pakistan. There is no professional body that certi es the pharmacist specialities, like the board of pharmacy specialities (BPS) of America certi es pharmacists in specialized services [42]. Govt of Pakistan should start initiatives like forming a council at a state level to begin clinical residency and certi cation program to strengthen pharmacist to take better responsibility for patient pharmaceutical care. Moreover, govt should start continuous education programs like in the UK 30 hours of continuous professional development are necessary to complete per year [43].
There was little evidence of pharmacist intervention in terms of safety outcomes, and no study assessing the cost-effectiveness of pharmacist interventions was discovered. Future research should focus on the safety and cost-effectiveness of pharmacist interventions to further develop pharmacist roles. In the future, adequately powered randomized studies with standardized outcome measurements, longer intervention duration, and equal baseline between groups will be required. Research is also needed on the time, frequency, and content of pharmacist interventions to improve clinical outcomes [44]. Furthermore, this study concludes essential insight for future research focusing on a tailored intervention and cost of delivering future cost-effective interventions. The result will be bene cial for the policymakers to choose pharmacist interventions based on the availability of their resources.

Limitations
First, to avoid bias, only peer-reviewed published studies were included in this review; unpublished studies were not included. Second, we found one or a maximum of two studies for each outcome, so it was practically impossible to apply meta-analysis due to variation in follow-up and differences in intervention content. Third, only evidence from Pakistan was included; Other data from neighbouring countries were not included due to different healthcare systems.

Conclusion
The review underlined the role of the clinical pharmacist services in improving patient outcomes and medication therapy management. Pharmacist interventions showed a positive impact on therapeutic, humanistic, and safety outcomes. However, much remains to be understood in safety, cost, and longterm intervention impact. Future studies must be more rigorous in terms of evaluating multidimensional and long-term outcomes. Evidence of Costseffectiveness must also be sought to allow informed decision-making and allocation of resources.  PRISMA ow diagram of included studies