The effectiveness and cost of integrating pharmacists within general practice to optimize prescribing and health outcomes in primary care patients with polypharmacy: a systematic review.

BACKGROUND: Polypharmacy and associated potentially inappropriate prescribing (PIP) place a considerable burden on patients and represent a challenge for general practitioners (GPs). Integration of pharmacists within general practice (herein 'pharmacist integration') may improve medications management and patient outcomes. This systematic review assessed the effectiveness and costs of pharmacist integration. METHODS: A systematic search of ten databases from inception to January 2021 was conducted. Studies that evaluated the effectiveness or cost of pharmacist integration were included. Eligible interventions were those that targeted medications optimization compared to usual GP care without pharmacist integration (herein 'usual care'). Primary outcomes were PIP (as measured by PIP screening tools) and number of prescribed medications. Secondary outcomes included health-related quality of life, health service utilization, clinical outcomes, and costs. Randomised controlled trials (RCTs), non-RCTs, interrupted-time-series, controlled before-after trials and health-economic studies were included. Screening and risk of bias using Cochrane EPOC criteria were conducted by two reviewers independently. A narrative synthesis and meta-analysis of outcomes where possible, were conducted; the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: In total, 23 studies (28 full text articles) met the inclusion criteria. In ten of 11 studies, pharmacist integration probably reduced PIP in comparison to usual care (moderate certainty evidence). A meta-analysis of number of medications in seven studies reported a mean difference of -0.80 [-1.17, -0.43], which indicated pharmacist integration probably reduced number of medicines (moderate certainty evidence). It was uncertain whether pharmacist integration improved health-related quality of life because the certainty of evidence was very low. Twelve health-economic studies were included; three investigated cost effectiveness. The outcome measured differed across studies limiting comparisons and making it difficult to make conclusions on cost effectiveness. CONCLUSIONS: Pharmacist integration probably reduced PIP and number of medications however, there was no clear effect on other patient outcomes; and while interventions in a small number of studies appeared to be cost-effective, further robust, well-designed cluster RCTs with economic evaluations are required to determine cost-effectiveness of pharmacist integration. TRIAL REGISTRATION: CRD42019139679.

Integrating clinical pharmacists within general practice: protocol for a pilot cluster randomised controlled trial.

INTRODUCTION: Managing patients with multiple conditions (multimorbidity) is a major challenge for healthcare systems internationally, particularly in older patients. Multimorbidity and subsequent polypharmacy increase treatment burden and the risk of potentially inappropriate prescribing, and both are complex to manage in primary care. Limited evidence suggests integration of pharmacists into general practice teams could improve medication management for patients with multimorbidity and polypharmacy. Building on findings from a non-randomised, uncontrolled General Practice Pharmacist (GPP) feasibility study conducted in Irish primary care, the aim of this study is to conduct a pilot cluster randomised controlled trial (cRCT) of the GPP study, to assess feasibility, intervention impact, costs and appropriateness of continuing to a definitive cRCT. METHODS AND ANALYSIS: This pilot cRCT will involve 8 general practitioner (GP) practices and 120 patients. Practices will identify and recruit patients aged ≥65 years, who are taking ≥10 regular medications. Practices will be allocated to intervention or control after baseline data collection. Intervention practices will have a pharmacist integrated within their service, working with GPs, patients and practice staff to optimise prescribing and other medication-related activities. Control practices will provide standard GP care. The primary feasibility outcomes will include recruitment rate, uptake of medication reviews and study retention. For the primary clinical outcome, the number of potentially inappropriate prescribing incidences per patient will be collected. Secondary outcomes will include medication-related outcomes, patient-reported outcome measures, and data pertaining to the role and impact of the pharmacist on prescribing. In addition, economic and process evaluations will be conducted. ETHICS AND DISSEMINATION: This trial has been approved by the Irish College of General Practitioners Research Ethics Committee and will be performed in accordance with the Declaration of Helsinki. The results will be reported in peer-reviewed journals and be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN Registry (https://doi.org/10.1186/ISRCTN18752158).

The effectiveness of integrating clinical pharmacists within general practice to optimise prescribing and health outcomes in primary care patients with polypharmacy: A protocol for a systematic review.

Introduction: Coordinating prescribing for patients with polypharmacy is a challenge for general practitioners. Pharmacists may improve management and outcomes for patients with polypharmacy. This systematic review aims to examine the clinical and cost-effectiveness of pharmacist interventions to optimise prescribing and improve health outcomes in patients with polypharmacy in primary care settings.  Methods: The review will be reported using the PRISMA guidelines. A comprehensive search of 10 databases from inception to present, with no language restrictions will be conducted. Studies will be included where they evaluate the clinical or cost-effectiveness of a clinical pharmacist in primary care on potentially inappropriate prescriptions using validated indicators and number of medicines. Secondary outcomes will include health related quality of life measures, health service utilisation, clinical outcomes and data relating to cost effectiveness. Randomised controlled trials, non-randomised controlled trials, controlled before-after, interrupted-time-series and health economic studies will be eligible for inclusion.  Titles, abstracts and full texts will be screened for inclusion by two reviewers. Data will be extracted using a standard form. Risk of bias in all included studies will be assessed using the Effective Practice and Organisation of Care (EPOC) criteria. Economic studies will be assessed using the Consensus Health Economic Criteria (CHEC) list as per the Cochrane Handbook for critical appraisal of methodological quality. A narrative synthesis will be performed, and the certainty of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Where data support quantitative synthesis, a meta-analysis will be performed. Discussion: This systematic review will give an overview of the effectiveness of pharmacist interventions to improve prescribing and health outcomes in a vulnerable patient group. This will provide evidence to policy makers on strategies involving clinical pharmacists integrated within general practice, to address issues which arise in polypharmacy and multimorbidity.  PROSPERO Registration:  CRD42019139679 (28/08/19).

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance.

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (ß-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected ß-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead ß-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and ß-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.