Implementation of medication reviews in community pharmacy: reaching consensus on stakeholders' recommendations for mechanisms of change using the nominal group technique.

BACKGROUND: Since 2022, patients with five or more medicines are eligible for a medication review (MR) in a community pharmacy remunerated by the German health system. However, implementation has been slow, with few pharmacies providing MRs. Stakeholders' input is necessary to detail how implementation strategies can be executed effectively on a national level. Prior research identified "external facilitation" and "altering incentives" as crucial strategies to achieve implementation outcomes. AIM: To gather stakeholders' recommendations for, and obtain consensus on, mechanisms of change that allow implementation strategies to work in practice. METHOD: The consensus method used was the nominal group technique (NGT) with NGT-discussions held separately with pharmacy owners and pharmacy chambers employees. Votes were summed and the relative importance (rI) calculated, defined as (score achieved for a mechanism)/(maximum possible score) × 100. Content analysis provided context for the highest ranked mechanisms and allowed linking to implementation outcomes. RESULTS: Four NGT-discussions were held in 2023 (n = 2 owners; n = 2 chamber employees) with a total of 17 participants. The overall highest ranked mechanisms were fit-for-purpose software (rI = 154.7) detailed process support (rI = 104.9) and an expert support line (rI = 77.7). These together with financial viability (rI = 40.0) were prioritised by both participant groups. Three mechanisms were favoured for both implementation strategies, namely software, process support and materials (rI = 34.3). CONCLUSION: This study identified stakeholders' priorities for mechanisms of change to implement MRs in community pharmacies. Focusing efforts on the prioritised mechanisms is likely to significantly advance a national implementation plan for countries which are at an early implementation stage.

Medication complexity, prescription behaviour and patient adherence at the interface between ambulatory and stationary medical care.

PURPOSE: A hospital stay is often accompanied by changes in medication therapy. The purpose of this study was to investigate the impact of a transfer across the interfaces on the complexity of therapeutic regimens and patient adherence as well as the attitudes of patients and general practitioners (GPs) towards pharmacotherapies. METHODS: This was a prospective observational study that analysed the complexity of medication therapies and the adherence and attitudes of internal medicine and urology patients towards their medication(s) at three time points (hospital admission, discharge and 6 weeks after discharge). GPs of the patients recruited to the study were questioned about the follow-up medication therapy and their opinion on the medication prescribed in hospital. RESULTS: At the time of hospital admission, 60.2 % of the study population were nonadherent. During hospitalization, the number decreased to 37.6 %, but increased to 61.2 % 6 weeks after discharge. Changes in the overall complexity of the therapy regimens were marginal and not statistically significant. Of the long-term medication regimens, 48.6 % were modified during hospital stay. The patients preferred regimens with a minimum of drug administrations. GPs stated to be willing to continue hospital prescriptions but were restricted by financial budgets. CONCLUSION: The results of this study confirm that an increase in adherence during a hospital stay is only transient, underlining the need for interventions to ameliorate medication adherence. They also suggest that patients prefer simple regimens. Although GPs are willing to consider their patient's preferences on pharmacotherapy, they state limitations due to financial budgets. Further studies are needed that investigate the extent to which medication therapies can be simplified and the effect of simplification on adherence.

Effect of patient education videos on modifying medication-related health behaviours: A systematic review using the behaviour intervention functions.

OBJECTIVE: This systematic review appraises, synthesises, and presents the published evidence on the effect of patient education videos in modifying medication-related health behaviours. METHODS: A systematic literature review was conducted across 12 databases. Title, abstract and full-text screening was done independently using PICOS. Data extraction results were mapped directly to the Behaviour Change Intervention Functions. Results are reported in accordance with PRISMA 2020. RESULTS: Out of 583 studies 12 articles from 4 countries were included. Interventions focus on improving patient's knowledge. Modelling, Enablement, Persuasion, and Training are used in video education development. PASS analysis showed very few well designed studies that allow the reliable determination of behaviour changes. CONCLUSIONS: A reliable or sustained effect of patient education videos in modifying medication-related health behaviours could not be reported due to a lack of robust study design. Modelling, Enablement, Persuasion, and Training are all intervention designs used to target behaviour change often resulting either in a narrative (real people acting) or practice (demonstrating) presentation format. PRACTICE IMPLICATIONS: With the increased use of health education technology, robust, theoretically underpinned studies are urgently needed to evaluate the effectiveness of these interventions in the context of their impact on patient medication-related behaviour change.

Just a 'romantic idea'? A theory-based interview study on medication review implementation with pharmacy owners.

BACKGROUND: Recent legal changes in Germany entitle patients on multiple medications to receive a medication review (MR). However, the provision of MRs is not mandatory and pharmacy owners decide whether to implement this service in their pharmacies. AIM: To determine pharmacy owners' attitudes towards MRs, explore their experiences with MR implementation and examine their perceptions of barriers and facilitators towards implementation of MRs in community pharmacies. METHOD: Pharmacy owners were invited to participate in semi-structured interviews. Purposive sampling was used with selection criteria being MR-implementation stage, and geographical location of the pharmacy. The topic guide was based on a systematic review and the Framework for Implementation of Services in Pharmacy (FISpH). Interviews were recorded, transcribed verbatim and coded directly against the FISpH. RESULTS: Twenty-one pharmacy owners were interviewed. Despite participants' consistent positive attitude towards MRs, most believed that providing MRs on an economically viable basis would be challenging. Several practical suggestions emerged which would enable community pharmacies a smoother implementation of MRs. Suggestions included employing 'change facilitators', who visit and support implementing pharmacies; national awareness campaigns targeting patients and health professionals; reducing bureaucracy; continuing professional development; involving technicians in some MR-tasks; and offering an additional incentive to lower the initial implementation threshold. CONCLUSION: This research identified numerous factors that are likely to increase owners' and managers' support to the idea of MRs. This may be of interest to any country planning implementation of MRs.

Experiences of key stakeholders with the implementation of medication reviews in community pharmacies: A systematic review using the Consolidated Framework for Implementation Research (CFIR).

BACKGROUND: Though medication reviews have shown positive patient outcomes, they are still not widely implemented in community pharmacies. Published reviews on their implementation often include several other pharmacy services, making them non-specific. Using the Consolidated Framework for Implementation Research (CFIR) to focus solely on the experiences of different stakeholders with the implementation of medication reviews will help to better understand relevant facilitators and barriers. OBJECTIVES: To critically appraise, synthesise and present the available evidence on experiences of key stakeholders with the implementation of medication reviews and to identify barriers and facilitators to its implementation in community pharmacies. METHODS: A systematic literature search was conducted in four databases for studies published in English, Spanish or German. Key search terms included: implementation, pharmac*, medication review, facilitator, barrier. Study selection, quality assessment and data extraction were performed by two independent reviewers. Findings were mapped directly against the constructs of the CFIR. RESULTS: Out of 924 retrieved records 24 articles from 9 countries met the inclusion criteria. Key facilitators identified included pharmacists' openness to practice change and a high degree of patient satisfaction post medication review. Attracting patients to the service was stated as challenging due to an unawareness of the scope and potential benefit of a medication review. The dominant barrier was inadequate remuneration, as it impacted all additional resourcing and ultimately the viability of the service. Further barriers included difficult professional relationships with doctors and little mandate from health authorities. Most reports were from the employed pharmacists' perspective and concerned the inner setting, other perspectives were under-reported. CONCLUSIONS: Results of this systematic review illustrate different stakeholders' experiences and add to the understanding of challenges in the implementation process. Nevertheless, findings also highlight how scarce reporting of external stakeholders' views is and that filling this gap can unveil hidden barriers and facilitators. REGISTRATION: PROSPERO register (CRD 42019122836).

Ku70 and Rad51 vary in their importance for the repair of doxorubicin- versus etoposide-induced DNA damage.

For DNA targeting anticancer drugs, cellular DNA repair mechanisms may cause resistance and hamper the therapeutic outcome. DNA damage induced by topoisomerase IIα inhibitors like etoposide and anthracyclines, which are a mainstay of cancer therapy, is also repaired in many cell types, but the impact and precise mechanisms of this repair are still obscure. To investigate the DNA damage response of human adenocarcinoma HT29-cells to doxorubicin and to compare the involvement of Ku70 and Rad51 in the repair of doxorubicin- versus etoposide-induced DNA damage, we assessed cell cycle distribution and cell death, DNA damage, proteins relevant for repair by homologous recombination and non-homologous end-joining, and clonogenicity following exposure to doxorubicin at clinically achievable concentrations. Also, we assessed changes in the repair kinetics after siRNA-mediated attenuation of Ku70 or Rad51 expression. We found that exposure to doxorubicin for 24 h induced a substantial amount of DNA damage that was largely repaired when doxorubicin was removed and the cells were maintained in drug-free medium. Nevertheless, a pronounced G(2)/M arrest occurred at times when repair was maximal. This was followed by a distinct increase in cell death and loss of clonogenicity. In this regard, responses to doxorubicin and etoposide were similar. However, distinct differences in the repair process following doxorubicin versus etoposide were seen in concentration dependency, time-course and requirement of Ku70 and Rad51 proteins. In spite of the shared molecular target of doxorubicin and etoposide, DNA lesions induced by these compounds are repaired differently.

Cellular responses to etoposide: cell death despite cell cycle arrest and repair of DNA damage.

The topoisomerase IIalpha inhibitor etoposide is a 'broad spectrum' anticancer agent and a potent inducer of DNA double strand breaks. DNA damage response of mammalian cells usually involves cell cycle arrest and DNA repair or, if unsuccessful, cell death. We investigated these processes in the human colon cancer cell line HT-29 treated with three different etoposide regimens mimicking clinically relevant plasma concentrations of cancer patients. Each involved a period of drug-free incubation following etoposide exposure to imitate the decline of plasma levels between the cycles of chemotherapy. We found a massive induction of double strand breaks that were rapidly and nearly completely fixed long before the majority of cells underwent apoptosis or necrosis. An even greater percentage of cells lost clonogenicity. The occurrence of double strand breaks was accompanied by a decrease in the levels of Ku70, Ku86 and DNA-PK(cs) as well as an increase in the level of Rad51 protein. Twenty-four hours after the first contact with etoposide we found a pronounced G(2)/M arrest, regardless of the duration of drug exposure, the level of double strand breaks and the extent of their repair. During the subsequent drug-free incubation period, the loss of clonogenicity correlated well with the preceding G(2)/M arrest as well as with the amount of cell death found several days after exposure. However, it correlated neither with early apoptosis or necrosis nor with any of the other investigated parameters. These results suggest that the G(2)/M arrest is an important determinant in the cytostatic action of etoposide and that the removal of DNA double strand breaks is not sufficient to ensure cell survival.

Repair of idarubicin-induced DNA damage: a cause of resistance?

Idarubicin, a widely used anticancer drug inhibits topoisomerase (topo) IIalpha and induces DNA double strand breaks. The finding that idarubicin-induced DNA damage is repaired before cell death is initiated encouraged us to examine the role of DNA repair for the cytotoxicity of idarubicin in human promyelocytic HL60 leukaemia cells. We found that DNA double strand breaks induced by a 90 min transient exposure to 0.5 microgml(-1) idarubicin were rapidly repaired throughout the whole population, while topo IIalpha itself was degraded. In spite of DNA repair, the vast majority of cells died within 40 h. Using differential staining of the chromatids and microscopic evaluation of DNA break points, we found evidence for a high number of false ligations of loose DNA strands arising from the inhibition of topo IIalpha action by idarubicin. If mainly actively transcribed genes are affected, this results in a disruption of vital genetic information, of regulatory sequences and, ultimately, in induction of the cell death pathway. Our results confirm the hypothesis that misrepair of DNA damage is a decisive event in idarubicin-induced cell death. They are discussed in the context of topo IIalpha-function and the currently known mechanisms of DNA double strand break repair.

Reducing cardiovascular medication complexity in a German university hospital: effects of a structured pharmaceutical management intervention on adherence.

BACKGROUND: Patient adherence is necessary for successful medication therapy. However, highly complex medication regimens may lead to poor adherence, which decreases the effectiveness of treatment and often results in treatment failure, excessive morbidity and mortality, and higher costs.  OBJECTIVE: To examine whether patient adherence can be increased indirectly through reducing medication complexity by (a) pharmaceutical counseling of hospital medical staff and (b) additional information in the discharge letter for the primary care provider (PCP) about the simplified discharge medication.  METHODS: At the Medical Center Hamburg-Eppendorf, a tertiary care university hospital in Germany, 240 chronically ill inpatients with hypertension, diabetes, and/or dyslipidemia were enrolled in this prospective, semirandomized study. For the intervention group, hospital doctors were counseled by a clinical pharmacist on feasible simplifications of cardiovascular and antidiabetic medications. In 1 randomized subgroup, the PCP received additional explanatory information in the discharge letter. Adherence (self-reporting using the Medication Adherence Rating Scale [MARS-D]) and medication complexity (using the Medication Regimen Complexity Index [MRCI-D]) were recorded at admission to the hospital, discharge from the hospital, and 6 weeks after discharge. Patient quality of life (QoL) and satisfaction with information about medications were assessed at admission and after discharge.   RESULTS: At discharge, the medication regimen in the intervention group was significantly less complex than in the comparison group. Yet, 6 weeks  after discharge, the complexity of the outpatient medication had increased to values similar to the comparison group, unless the PCP received additional information in the discharge letter. Propensity adjusted complete adherence rates at discharge were slightly, but not significantly, higher in the intervention group than in the comparison group. Within the intervention group, complete adherence was more frequent in the subgroup with additional information for the PCP. Patient QoL and satisfaction with information were comparable in both groups.   CONCLUSION: The complexity of cardiovascular and antidiabetic hospital medications can be reduced by counseling the hospital doctors. However, for a sustainable simplification of outpatient medication, the PCPs must receive explicit information about the modifications. Patient adherence was not significantly influenced by this intervention. To verify these results, further research with objective measures of adherence and in patients with other diseases is needed. 

Incomplete medication adherence of chronically ill patients in German primary care.

BACKGROUND: Incomplete medication adherence is a major problem in health care worldwide. Patients who adhere to medical treatment have a better prognosis and create fewer costs. OBJECTIVE: To assess the degree of incomplete adherence of chronically ill routine primary care patients in a German setting and analyze the association between incomplete medication adherence, as well as clinical and sociodemographic patient characteristics. METHODS: In a cross-sectional survey, chronically ill patients were asked to assess their adherence in primary care retrospectively using the Medication Adherence Report Scale (MARS-D) questionnaire. To investigate the association of incomplete adherence with sociodemographic and clinical data, univariate and multivariate analyses were conducted. RESULTS: In total, 62.1% of 190 patients were categorized as incompletely adherent. The mean MARS-D score was 23.5 (standard deviation = 2.7). Analyses revealed no statistically significant associations at P < 0.05 between degree of adherence and patient characteristics. The total explained variance amounted to 11.8% (Nagelkerke's R(2) = 0.118) in the multivariate analysis. CONCLUSION: Previously reported results regarding associations of sociodemographic and clinical data with incomplete medication adherence could not be confirmed for this sample of chronically ill patients. In order to be able to provide guidelines for the reduction of incomplete medication adherence in German primary care, further research is needed.

Development and psychometric evaluation of the German version of the Medication Regimen Complexity Index (MRCI-D).

BACKGROUND: Several factors contribute to the complexity of pharmacotherapeutic regimens, like the total number of medications to be taken, the number of dosage units to take at a time, dosage frequency, as well as specific directions concerning the administration. The Medication Regimen Complexity Index (MRCI) is a validated instrument developed in English for the measurement of the complexity of a given pharmacotherapeutic regimen. OBJECTIVES: Translation of the MRCI into German and evaluation of the translated instrument (MRCI-D) in order to make it more easily accessible for use in German practice and research. METHODS: The process of validation included the translation of the English version to German, back-translation into English, comparison of the back-translated and the original versions, pre-tests, and pilot-testing of the German version by three raters using 20 medication regimens for inpatients. The subsequent psychometric evaluation included the calculation of inter-rater and test-retest reliability, as well as the assessment of convergent validity. RESULTS: The number of medications correlated highly and statistically significantly with the MRCI-D score (0.91, P < 0.001), indicating sufficient convergent validity of the instrument. Both inter-rater and test-retest reliability were very high (intraclass correlation coefficients above 0.80 in all cases). CONCLUSION: Our results demonstrate that the German version of the MRCI reflects the complexity of therapeutic regimens with similar validity and reliability as the established English version. Thus, it may be a valuable tool to analyse therapeutic regimens in both clinical practice and science.

Cisplatin resistance induced in germ cell tumour cells is due to reduced susceptibility towards cell death but not to altered DNA damage induction or repair.

To identify factors involved in cisplatin (CDDP) resistance of germ cell tumours (GCTs), we exposed NTERA-2 cells, and the platinum-adapted subline NTERA-2R to CDDP and compared their response. While both cell lines showed comparable proliferation, NTERA-2R cells were clearly more resistant to the drug than the parental NTERA-2 cell line. Interestingly, the two lines showed identical extent of DNA adduct formation and elimination, indicating that neither changes in CDDP uptake, nor altered drug efflux, DNA binding, or repair caused the difference in resistance. Similarly, no difference occurred in the time-course of γH2AX formation, which was not linked to 53BP1 accumulation. In contrast, NTERA-2R cells showed a more pronounced dose-dependent S phase delay, a transient G(2)/M-block, and subsequent release into immediate cell death. We thus conclude that the enhanced resistance against CDDP is linked to reduced susceptibility to cell death rather than to an altered DNA adduct formation or adduct removal.

Do centrally pre-prepared solutions achieve more reliable drug concentrations than solutions prepared on the ward?

PURPOSE: To compare the concentration conformity of infusion solutions manually prepared on intensive care units (ICU) with solutions from pharmacy-based, automated production. METHODS: A prospective observational study conducted in a university hospital in Germany. Drug concentrations of 100 standardised infusion solutions manually prepared in the ICU and 100 matching solutions from automated production containing amiodarone, noradrenaline or hydrocortisone were measured by high-performance liquid chromatography analysis. Deviations from stated concentrations were calculated, and the quality of achieved concentration conformity of the two production methods was compared. RESULTS: Actual concentrations of 53% of the manually prepared and 16% of the machine-made solutions deviated by >5% above or below the stated concentration. A deviation of >10% was measured in 22% of the manually prepared samples and in 5% of samples from automated production. Of the manually prepared solutions, 15% deviated by >15% above or below the intended concentration. The mean concentration of the manually prepared solutions was 97.2% (SD 12.7%, range 45-129%) and of the machine-made solutions was 101.1% (SD 4.3%, range 90-114%) of the target concentration (p < 0.01). CONCLUSIONS: In this preliminary study, ward-based, manually prepared infusion solutions showed clinically relevant deviations in concentration conformity significantly more often than pharmacy-prepared, machine-made solutions. Centralised, automated preparation of standardised infusion solutions may be an effective means to reduce this type of medication error. Further confirmatory studies in larger settings and under conditions of routine automated production are required.