Clinical and economic outcomes of hospital pharmaceutical care: a systematic review and meta-analysis

Background Hospital clinical pharmacists have been working in many countries for many years and clinical pharmaceutical care have a positive effect on the recovery of patients. In order to evaluate the clinical effectiveness and economic outcomes of clinical pharmaceutical care, relevant clinical trial studies were reviewed and analysed. Methods Two researchers searched literatures published from January 1992 to October 2019, and screened them by keywords like pharmaceutical care, pharmaceutical services, pharmacist interventions, outcomes, effects, impact, etc. Then, duplicate literatures were removed and the titles, abstracts and texts were read to screen literatures according to inclusion and exclusion criteria. Key data in the literature were extracted, and Meta-analysis was conducted using the literature with common outcome indicators. Results A total of 3299 articles were retrieved, and 42 studies were finally included. Twelve of them were used for meta-analysis. Among the 42 studies included, the main results of pharmaceutical care showed positive effects, 36 experimental groups were significantly better than the control group, and the remaining 6 studies showed mixed or no effects. Meta-analysis showed that clinical pharmacists had significant effects on reducing systolic blood pressure and diastolic blood pressure and shortening hospitalization days (P < 0.05), but no statistical significance in reducing medical costs (P > 0.05). Conclusion Clinical pharmacists’ pharmaceutical care has a significant positive effect on patients’ clinical effects, but has no significant economic effect.


Background
Pharmaceutical care is the direct, responsible provision of medication-related care for the purpose of achieving definite outcomes [1]. Though identifying, solving and preventing medication problems, finding out prescription errors and medication-related injuries by clinical pharmacists, incidence of adverse events and rehospitalization rates could be reduced. Patient adherence of the treatment could be significantly improved and possible harm due to medication problems had been reduced after patients received their medication instructions [2]. Medication education and treatment advice from clinical pharmacists could also shorten hospital stay [3].
Studies have shown that hospital pharmaceutical care had great value in clinical and economic aspects. In a diabetes management team, participation of clinical pharmacists led to the reduction of hemoglobin, cholesterol and blood pressure in patients as well as the significantly lower cost of medication for each patient [4]. A study showed the implementation of antifungal practice guidelines by a clinical pharmacist, member of an ICU team, resulted in a 50% cost reduction in expenditure on antifungal agents [5]. However, whether there was a direct connection between this service and the improvement of patient health had been discussed. Meanwhile, costs of running pharmacy service and its economic benefits were at issue in some countries. These worries impeded the development of hospital clinical pharmacy and its universal implement. Among factors mentioned above, lack of strong, direct evidence is one potential barrier.
Although many studies noticed the clinical and economic outcomes of hospital pharmaceutical care, few systematically demonstrated and validated the effectiveness of hospital pharmaceutical care. Due to flaws in experimental design and source of literature, nonrandomized controlled trials, low methodological quality of included studies or unconvincing experimental data, evidence on effectiveness and validity are still insufficient. Therefore, it is necessary to explore its clinical and economic outcomes from the scope of a more general perspective. In the present study, a systematic review and meta-analysis for pooling statistical power was conducted to systematically evaluate the clinical and economic outcomes of hospital pharmaceutical care.

Search strategy
Two researchers searched for relevant articles published in databases including Pubmed by Medline, Embase, Cochrane and CINAH (January 1992 to October 2019). Key words included pharmaceutical service/care/intervention, pharmacy service/care/intervention, pharmacist service/care/intervention and clinical outcomes, evaluations, effects, assessment, outcomes, practice. And it is supplemented by such truncated words as "service *", "analysis *", "evaluate *", "effect *", "Pharmac *", "intervene *", "practi *", "impact *". The retained researches were supplemented by access to monographs, reviews, references to published articles, and recently published Chinese and English journal articles. Two reviewers independently searched and discussed and resolved discrepancies.

Inclusion and exclusion criteria
Studies would be included when interventions or participation of clinical pharmacists were considered with detailed descriptions of services they provided. The research setting should be conducted in hospitals. The research conducted should involve intervention groups and control groups who received routine care or noninterventions from clinical pharmacists. The clinical outcomes or economic outcomes of the interventions should be evaluated. Studies only abstracts available were excluded.

Data extraction and validity assessment
The data extraction was independently carried out by the researchers using a standard electronic form Microsoft Excel 2016 and the extracted data was checked by two researchers. According to the Cochrane systematic review guidelines, combined with the aim of this study and quality assessment requirements, extracted data in the feature tables included: (1) For numbered lists Literature characteristics (Table 1): author, publication year, country, sample source, interventions, primary outcomes and effects. (2) Methodological quality assessment table: correct randomization method, hidden allocation scheme, blindness method, whether there is bias due to missing data.
When comparing the main outcomes of experimental groups and control groups, p < 0.05 was viewed statistically significant. When the primary outcomes of the experimental group were significantly better than the control group, it was marked as "positive"; and when there were no significant difference between the two groups, it was viewed as "no effect". For studies evaluating multiple primary outcomes and not positive outcomes, those who presented at least one major positive outcome were considered as "mixed".

Meta-analysis
In this study, Stata 15 was used for meta-analysis. After calculating the number of studies with common outcomes, systolic blood pressure (SBP), diastolic blood pressure (DBP), medical cost, and hospitalization days remained for meta-analysis. The standard mean difference (SMD) was used as the effect quantity, the significance level (or) of the combined effect quantity test was 0.05, the significance level of the heterogeneity test was 0.1, and the overall estimate was expressed by the point estimate and 95% confidence interval (95% CI). If there is significant heterogeneity such as research subjects and interventions in the studies used to perform metaanalysis, these studies would not be directly combined. Statistical consistency was assessed using chi-square tests and I 2 statistics for heterogeneity. If p > 0.1, no heterogeneity was considered. If p < 0.1, heterogeneity between studies was considered.

Search and study selection
Three thousand two hundred thirty-eight documents were obtained through database searching with a manual search of 61 added references related to empirical researches on hospital pharmaceutical care. After removing duplicate articles, 2284 articles remained. Through     After strict screening, 120 patients were randomly divided into two groups. And one hundred ninety-nine patients completed the study Interviews included face-to-face interviews (once every other month) and telephone follow-up (every month) until the end of the study. During the interview, the pharmacist discussed about their medication compliance, self-monitoring of blood sugar control, and exercise; explained side effects and possible drug interactions; and reminded them to see the doctor next time. review the following aspects of the patient's medication: (a) the indications of each drug are related to the patient's condition; (b) the suitability, dose, plan, and treatment time of each drug are related to the patient's age and / or clinical status (renal or liver function). In addition, therapeutic drug monitoring was carried out for drugs with narrow drug-related negative outcomes Possitive reviewing titles and abstracts, 1634 irrelevant articles were excluded. After reading full texts, 577 articles inconsistent with this study were excluded. And 73 studies deemed suitable were assessed and excluded after screening (Fig. 1). Finally, 42 studies were included for the meta-analysis.

Summary of included studies
Relevant studies were published mainly in Europe countries and America. There were 16 studies from the United States and 5 studies from the United Kingdom; 5 studies from China; 3 studies from Australia; 2 studies from Germany and Netherlands; other studies from Singapore, Iran, France, Jordan, etc. Diseases interfered included hypertension, diabetes, nephropathy, etc. Since 2010, researches on effectiveness of hospital pharmaceutical care have greatly increased, especially in 2014. And diseases concerned shifted from traditional diseases with highincidence to epidemic, chronic diseases. For observing changes after receiving pharmaceutical care from clinical pharmacists, most samples were inpatients. In terms of interventions, most pharmacist interventions were diverse. Patient education programs, physician advice, disease state monitor and management were referred to in most researches provided. As for effects of hospital pharmaceutical care, among the 42 articles included, 36 studies had positive effects, 5 studies had mixed effects, and one study had no effect.

Methodological quality of studies
Of the 42 studies included, 17 studies belonged to high quality studies with scores of 3-4, and the remaining 23

Meta-analysis
Meta-analysis of hospital pharmaceutical care on SBP A total of nine studies included blood pressure data, one of which missed standard deviation of the sample, and one experiment had an uneven baseline. Results of the meta-analysis of SBP by random effects model are shown in Table 2, Fig. 2. The results of SBP heterogeneity test were significant (I 2 = 82.1%, p = 0.000 < 0.1). The test results showed p = 0.000 < 0.05, indicating that hospital pharmaceutical care had a significant effect on the reduction of SBP, compared to usual care. The mean difference of SBP between the intervention groups and control groups was − 0.573 (95% CI, − 0.851 to − 0.295).

Meta-analysis of hospital pharmaceutical care on DBP
A total of nine studies included blood pressure data, one of which missed the standard deviation of the sample, and one experiment had an uneven baseline. Results of the meta-analysis of DBP by random effects model are shown as Table 3, Fig. 3. Heterogeneity test results on DBP were significant (I 2 = 67.3%, p = 0.005 < 0.1). The  test results showed that p = 0.002 < 0.05. It was shown that compared with usual care, hospital pharmaceutical care had significant effect on DBP. The average DBP difference between intervention group and control group was − 0.329 (95% CI, − 0.532 to − 0.125).

Meta-analysis of hospital pharmaceutical care on medical cost
A total of 15 studies included outcomes on patient medical costs, of which four experimental data missed sample standard deviations. Also, studies which had uneven baselines and did not report baselines were excluded.
Here is the meta-analysis of the random effects model of medical cost indicators. The heterogeneity test of medical cost was significant (I 2 = 98.3%, p = 0.000 < 0.1). The test results showed that p = 0.078 > 0.05, indicating that compared with usual care, hospital pharmaceutical care was not statistically significant on reducing medical cost. Therefore, it is not strong enough to support positive economic effect of this care on reducing the cost of patient care ( Table 4, Fig. 4).

Meta-analysis of hospital pharmaceutical care on hospitalization days
A total of 11 studies covered patient days of hospitalization, of which four experimental data missed sample standard deviations and four experiments had an uneven baseline. The following is the result of a metaanalysis on the random effects model of hospital stay days. The heterogeneity test of the hospitalization days

Discussion
This study systematically evaluated the clinical and economic outcomes of hospital pharmaceutical and conducted a meta-analysis. This study conducted a systematic review and meta-analysis of the clinical and economic outcomes of hospital pharmaceutical care. From Table 1, the vast majority of the studies showed that clinical pharmacy interventions could improve the economic and clinical outcomes, playing a significant role in improving medication errors, reducing readmission rates, and reducing medication costs. Among the 42 studies included, the primary outcomes of this service showed positive effects, among which 36 experimental groups were significantly better than their control groups, and the remaining 6 studies showed mixed or no effect. Overall, hospital pharmaceutical care showed positive clinical outcomes. Results of the meta-analysis showed that the intervention of pharmaceutical care had a significant effect on the reduction of SBP and DBP. Meanwhile, results of the meta-analysis showed that hospital pharmaceutical care had a significant impact on hospitalization days, but no significant effect on reducing medical cost. In an academic medical intensive care unit, a randomized controlled trial was conducted on 202 patients before the intervention and 162 patients after the intervention. This study showed that the administration of medications by the pharmacist team effectively reduced inappropriate stress of ulcer prophylaxis use [20], finally leading to reduced medical cost (p = 0.000). It might be attributed to insufficient number of relevant  studies, or different calculation methods and scope for medical cost in various studies. In Carter's research, costs associated with prescriptions and visits as well as the total cost per patient were evaluated, but no specific cost items were listed. While in Gallagher's study [34], medical expenses covered expenses of pharmacist, nonconsultant hospital physicians, senior staff nurses, inpatient days, software costs and training costs. Although studies of Carter et al. [9] and Gum [13] reported positive economic effects, their sample sizes were not large enough to support its effectiveness. The small sample size was also one of the reasons for the lack of significant results. This study has certain limitations. First, high-quality studies and total number of studies included for metaanalysis is insufficient. Researches on pharmaceutical care carried out in hospitals with strict study design are to be updated. Second, it is difficult to determine which intervention(s) of hospital pharmaceutical care caused specific effects. How much beneficial certain pharmacy services are than other pharmacy services might be the potential problem to be settled in the future.

Conclusion
The results of meta-analysis showed that the hospital pharmaceutical care had a significant effect on reducing SBP, DBP and hospital stay, but no significant reduction on medical cost. In addition, because the data available for meta-analyses are not sufficient, a false-negative conclusion could be easily drawn. Therefore, hospital pharmaceutical care have a positive clinical and economic elimination in terms of reducing SBP, DBP and improving patient hospital stay, but follow-ups on medical cost as well as other outcomes need more experimental data to support.