A Trial-Based Cost-Utility Analysis of a Medication Optimization Intervention Versus Standard Care in Older Adults.

BACKGROUND: Older adults are at greater risk of medication-related harm than younger adults. The Integrated Medication Management model is an interdisciplinary method aiming to optimize medication therapy and improve patient outcomes. OBJECTIVE: We aimed to investigate the cost effectiveness of a medication optimization intervention compared to standard care in acutely hospitalized older adults. METHODS: A cost-utility analysis including 285 adults aged ≥ 70 years was carried out alongside the IMMENSE study. Quality-adjusted life years (QALYs) were derived using the EuroQol 5-Dimension 3-Level Health State Questionnaire (EQ-5D-3L). Patient-level data for healthcare use and costs were obtained from administrative registers, taking a healthcare perspective. The incremental cost-effectiveness ratio was estimated for a 12-month follow-up and compared to a societal willingness-to-pay range of €/QALY 27,067-81,200 (NOK 275,000-825,000). Because of a capacity issue in a primary care resulting in extended hospital stays, a subgroup analysis was carried out for non-long and long stayers with hospitalizations < 14 days or ≥ 14 days. RESULTS: Mean QALYs were 0.023 [95% confidence interval [CI] 0.022-0.025] higher and mean healthcare costs were €4429 [95% CI - 1101 to 11,926] higher for the intervention group in a full population analysis. This produced an incremental cost-effectiveness ratio of €192,565/QALY. For the subgroup analysis, mean QALYs were 0.067 [95% CI 0.066-0.070, n = 222] and - 0.101 [95% CI - 0.035 to 0.048, n = 63] for the intervention group in the non-long stayers and long stayers, respectively. Corresponding mean costs were €- 824 [95% CI - 3869 to 2066] and €1992 [95% CI - 17,964 to 18,811], respectively. The intervention dominated standard care for the non-long stayers with a probability of cost effectiveness of 93.1-99.2% for the whole willingness-to-pay range and 67.8% at a zero willingness to pay. Hospitalizations were the main cost driver, and readmissions contributed the most to the cost difference between the groups. CONCLUSIONS: According to societal willingness-to-pay thresholds, the medication optimization intervention was not cost effective compared to standard care for the full population. The intervention dominated standard care for the non-long stayers, with a high probability of cost effectiveness. CLINICAL TRIAL REGISTRATION: The IMMENSE trial was registered in ClinicalTrials.gov on 28 June, 2016 before enrolment started (NCT02816086).

Is anticholinergic and sedative drug burden associated with postdischarge institutionalization in community-dwelling older patients acutely admitted to hospital? A Norwegian registry-based study.

PURPOSE: Investigate the association between anticholinergic (AC) and sedative (SED) drug burden before hospitalization and postdischarge institutionalization (PDI) in community-dwelling older patients acutely admitted to hospital. METHODS: A cross-sectional study using data from the Norwegian Patient Registry and the Norwegian Prescription Database. We studied acutely hospitalized community-dwelling patients ≥70 years during 2013 (N = 86 509). Patients acutely admitted to geriatric wards underwent subgroup analyses (n = 1715). We calculated drug burden by the Drug Burden Index (DBI), use of AC/SED drugs, and the number of AC/SED drugs. Piecewise linearity of DBI versus PDI and a knot point (DBI = 2.45) was identified. Statistical analyses included an adjusted multivariable logistic regression model. RESULTS: In the total population, 45.4% were exposed to at least one AC/SED drug, compared to 52.5% in the geriatric subgroup. AC/SED drugs were significantly associated with PDI. The DBI with odds ratios (ORs) of 1.11 (95% CI 1.07-1.15) for DBI < 2.45 and 1.08 (95% CI 1.04-1.13) for DBI ≥ 2.45. The number of AC/SED drugs with OR of 1.07 (95% CI 1.05-1.09). The AC component of DBI with OR 1.23 and the number of AC drugs with OR 1.13. In the subgroup, ORs were closer to 1 for AC drugs. CONCLUSIONS: The use of AC/SED drugs was highly prevalent in older patients before acute hospital admissions, and significantly associated with PDI. The number, or just using AC/SED drugs, gave similar associations with PDI compared to applying the DBI. Using AC drugs showed higher sensitivity, indicating that to reduce the risk of PDI, a clinical approach could be to reduce the number of AC drugs.

Interdisciplinary collaboration across secondary and primary care to improve medication safety in the elderly (The IMMENSE study) - a randomized controlled trial.

BACKGROUND: Suboptimal medication use contributes to a substantial proportion of hospitalizations and emergency department visits in older adults. We designed a clinical pharmacist intervention to optimize medication therapy in older hospitalized patients. Based on the integrated medicine management (IMM) model, the 5-step IMMENSE intervention comprise medication reconciliation, medication review, reconciled medication list upon discharge, patient counselling, and post discharge communication with primary care. The objective of this study was to evaluate the effects of the intervention on healthcare use and mortality. METHODS: A non-blinded parallel group randomized controlled trial was conducted in two internal medicine wards at the University Hospital of North Norway. Acutely admitted patients ≥ 70 years were randomized 1:1 to intervention or standard care (control). The primary outcome was the rate of emergency medical visits (readmissions and emergency department visits) 12 months after discharge. RESULTS: Of the 1510 patients assessed for eligibility, 662 patients were asked to participate, and 516 were enrolled. After withdrawal of consent and deaths in hospital, the modified intention-to-treat population comprised 480 patients with a mean age of 83.1 years (SD: 6.3); 244 intervention patients and 236 control patients. The number of emergency medical visits in the intervention and control group was 497 and 499, respectively, and no statistically significant difference was observed in rate of the primary outcome between the groups [adjusted incidence rate ratio of 1.02 (95% CI: 0.82-1.27)]. No statistically significant differences between groups were observed for any of the secondary outcomes, neither in subgroups, nor for the per-protocol population. CONCLUSIONS: We did not observe any statistical significant effects of the IMMENSE intervention on the rate of emergency medical visits or any other secondary outcomes after 12 months in hospitalized older adults included in this study. TRIAL REGISTRATION: The trial was registered in clinicaltrials.gov on 28/06/2016, before enrolment started (NCT02816086).

Intervention fidelity and process outcomes of the IMMENSE study, a pharmacist-led interdisciplinary intervention to improve medication safety in older hospitalized patients.

WHAT IS KNOWN AND OBJECTIVE: The majority of hospitalized older patients experience medication-related problems (MRPs), and there is a call for interventions to solve MRPs and improve clinical outcomes like medical visits. The IMMENSE study is a randomized controlled trial investigating the impact of a pharmacist-led interdisciplinary intervention on emergency medical visits. Its multistep intervention is based on the integrated medicines management methodology and includes a follow-up step with primary care. This study aims to describe how the intervention in the IMMENSE study was delivered and its process outcomes. METHODS: The study includes the 221 intervention patients in the per-protocol group of the IMMENSE study. Both intervention delivery, reasons for not performing interventions and process outcomes were registered daily by the study pharmacists in a Microsoft Access® database. Process outcomes were medication discrepancies, MRPs and how the team solved these. RESULTS AND DISCUSSION: A total of 121 (54.8%) patients received all intervention steps if appropriate. All patients received medication reconciliation (MedRec) and medication Review (MedRev) (step 1 and 2), while between 10% and 20% of patients were missed for medication list in discharge summary (step 3), patient counselling (step 4), or communication with general practitioner and nurse (step 5). A total of 437 discrepancies were identified in 159 (71.9%) patients during MedRec, and 1042 MRPs were identified in 209 (94.6%) patients during MedRev. Of these, 292 (66.8%) and 700 (67.2%), respectively, were communicated to and solved by the interdisciplinary team during the hospital stay. WHAT IS NEW AND CONCLUSION: The fidelity of the single steps of the intervention was high even though only about half of the patients received all intervention steps. The impact of the intervention may be influenced by not implementing all steps in all patients, but the many discrepancies and MRPs identified and solved for the patients could explain a potential effect of the IMMENSE study.

The impact of hospitalisation to geriatric wards on the use of medications and potentially inappropriate medications - a health register study.

BACKGROUND: The use of potentially inappropriate medications (PIMs) are associated with negative health effects for older adults. The purpose of this study was to apply national register data to investigate the impact of hospitalisation to geriatric wards in Norway on the use of medications and PIMs, and to compare two explicit PIM identification tools. METHODS: We included 715 patients ≥65 years (mean 82.5, SD = 7.8) admitted to Norwegian geriatric wards in 2013 identified from The Norwegian Patient Registry, and collected their medication use from the Norwegian Prescription Database. Medication use before and after hospitalisation was compared and screened for PIMs applying a subset of the European Union (EU)(7)-PIM list and the Norwegian General Practice - Nursing Home (NORGEP-NH) list part A and B. RESULTS: The mean number of medications increased from 6.5 (SD = 3.5) before to 7.5 (SD = 3.5) (CI:1.2-0.8, p < 0.001) after hospitalisation. The proportion of patients with PIMs increased from before to after hospitalisation according to the EU(7)-PIM list (from 62.4 to 69.2%, p < 0.001), but not according to The NORGEP-NH list (from 49.9 to 50.6%, p = 0.73). The EU(7)-PIM list and the NORGEP-NH list had more than 70% agreement on the classification of patients as PIM users. CONCLUSIONS: Medication use increased after hospitalisation to geriatric wards. We did not find that geriatric hospital care leads to a general improvement in PIM use after hospitalisation. According to a subset of the EU(7)-PIM list, PIM use increased after hospitalisation. This increase was not identified by the NORGEP-NH list part A and B. It is feasible to use health register data to investigate the impact of hospitalisation to geriatric wards on medication use and PIMs.

Interdisciplinary collaboration across secondary and primary care to improve medication safety in the elderly (IMMENSE study): study protocol for a randomised controlled trial.

INTRODUCTION: Drug-related problems (DRPs) are common in the elderly, leading to suboptimal therapy, hospitalisations and increased mortality. The integrated medicines management (IMM) model is a multifactorial interdisciplinary methodology aiming to optimise individual medication therapy throughout the hospital stay. IMM has been shown to reduce readmissions and drug-related hospital readmissions. Using the IMM model as a template, we have designed an intervention aiming both to improve medication safety in hospitals, and communication across the secondary and primary care interface. This paper presents the study protocol to explore the effects of the intervention with regard to healthcare use, health-related quality of life (HRQoL) and medication appropriateness in elderly patients. METHODS AND ANALYSIS: A total of 500 patients aged ≥70 years will be included and randomised to control (standard care) or intervention group (1:1). The intervention comprises five steps mainly performed by pharmacists: (1) medication reconciliation at admission, (2) medication review during hospital stay, (3) patient counselling about the use of medicines, (4) a comprehensible and patient-friendly medication list with explanations in discharge summary and (5) postdischarge phone calls to the primary care level. The primary outcome is the difference between intervention and control patients in the rate of emergency medical visits (acute readmissions and visits to emergency department) 12 months after discharge. Secondary outcomes include length of index hospital stay, time to first readmission, mortality, hip fractures, strokes, medication changes, HRQoL and medication appropriateness. Patient inclusion started in September 2016. ETHICS AND DISSEMINATION: The trial was approved by the Norwegian Centre for Research Data and the Norwegian Data Protection Authority. We aim to publish the results in international peer-reviewed open access journals, at national and international conferences, and as part of two PhD theses. TRIAL REGISTRATION NUMBER: NCT02816086.

[Post-exposure varicella prophylaxis]. / Profylaktisk behandling etter varicellaeksponering.

BACKGROUND: Varicella may have a serious and sometimes fatal course, especially in immunocompromised patients. Some patient groups may need prophylaxis after exposure to the varicella-zoster-virus. In this article we review the evidence for usefulness of prophylactic measures after such exposure. MATERIAL AND METHODS: The article is based on a non-systematic literature search in Medline, the Cochrane Library, UpToDate and Clinical Evidence. RESULTS: The effect of post-exposure varicella prophylaxis on disease rate and severity of varicella is only weakly documented. There is some evidence that passive immunisation with varicella-zoster immunoglobulin (VZIG) reduces the risk of serious disease when it is administered within 72-96 hours after exposure. Several studies of mostly healthy children have shown that prophylactic acyclovir is better than control treatment, but the studies are small and they are not properly designed. Post-exposure vaccination is shown to reduce disease rate and severity in otherwise healthy children. INTERPRETATION: We believe that acyclovir or valacyclovir can be used as post-exposure varicella prophylaxis in risk patients for whom the time window for VZIG-use has expired.

Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice.

Cardiovascular complications, characterized by endothelial dysfunction and accelerated atherosclerosis, are the leading cause of morbidity and mortality associated with diabetes. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Overproduction and/or insufficient removal of these free radicals result in vascular dysfunction, damage to cellular proteins, membrane lipids and nucleic acids. Despite overwhelming evidence on the damaging consequences of oxidative stress and its role in experimental diabetes, large scale clinical trials with classic antioxidants failed to demonstrate any benefit for diabetic patients. As our understanding of the mechanisms of free radical generation evolves, it is becoming clear that rather than merely scavenging reactive radicals, a more comprehensive approach aimed at preventing the generation of these reactive species as well as scavenging may prove more beneficial. Therefore, new strategies with classic as well as new antioxidants should be implemented in the treatment of diabetes.

Vascular dysfunction of venous bypass conduits is mediated by reactive oxygen species in diabetes: role of endothelin-1.

Diabetes is associated with increased risk for complications following coronary bypass grafting (CABG) surgery. Augmented superoxide (*O2*) production plays an important role in diabetic complications by causing vascular dysfunction. The potent vasoconstrictor endothelin-1 (ET-1) is also elevated in diabetes and following CABG; however, the effect of ET-1 on *O2* generation and/or vascular dysfunction in bypass conduits remain unknown. Accordingly, this study investigated basal and ET-1-stimulated *O2* production in bypass conduits and determined the effect of *O2* on conduit reactivity. Saphenous vein specimens were obtained from nondiabetic (n = 24) and diabetic (n = 24) patients undergoing CABG. Dihydroethidium staining and NAD(P)H oxidase activity assays (5380 +/- 940 versus 16,362 +/- 2550 relative light units/microg) demonstrated increased basal *O2* levels in the diabetes group (p < 0.05). Plasma ET-1 levels were associated with elevated basal *O2* levels, and treatment of conduits with exogenous ET-1 further increased *O2* production and augmented vasoconstriction. Furthermore, vascular relaxation was impaired in the diabetic group (75 versus 40%), which was restored by *O2* scavenger superoxide dismutase. These findings suggest that ET-1 causes bypass conduits dysfunction via stimulation of *O2* production in diabetes. Novel therapies that attenuate *O2* generation in bypass conduits may improve acute and late outcome of CABG in diabetic patients.