Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

The potential role of cost-utility analysis in the decision to implement major system change in acute stroke services in metropolitan areas in England

BACKGROUND: The economic implications of major system change are an important component of the decision to implement health service reconfigurations. Little is known about how best to report the results of economic evaluations of major system change to inform decision-makers. Reconfiguration of acute stroke care in two metropolitan areas in England, namely London and Greater Manchester (GM), was used to analyse the economic implications of two different implementation strategies for major system change. METHODS: A decision analytic model was used to calculate difference-in-differences in costs and outcomes before and after the implementation of two major system change strategies in stroke care in London and GM. Values in the model were based on patient level data from Hospital Episode Statistics, linked mortality data from the Office of National Statistics and data from two national stroke audits. Results were presented as net monetary benefit (NMB) and using Programme Budgeting and Marginal Analysis (PBMA) to assess the costs and benefits of a hypothetical typical region in England with approximately 4000 strokes a year. RESULTS: In London, after 90 days, there were nine fewer deaths per 1000 patients compared to the rest of England (95% CI -24 to 6) at an additional cost of £770,027 per 1000 stroke patients admitted. There were two additional deaths (95% CI -19 to 23) in GM, with a total costs saving of £156,118 per 1000 patients compared to the rest of England. At a £30,000 willingness to pay the NMB was higher in London and GM than the rest of England over the same time period. The results of the PBMA suggest that a GM style reconfiguration could result in a total greater health benefit to a region. Implementation costs were £136 per patient in London and £75 in GM. CONCLUSIONS: The implementation of major system change in acute stroke care may result in a net health benefit to a region, even one functioning within a fixed budget. The choice of what model of stroke reconfiguration to implement may depend on the relative importance of clinical versus cost outcomes

Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations

Chronic Opioid Use in Women Following Hysterectomy: Patterns and Predictors

Background: Most women are prescribed an opioid after hysterectomy. The goal of this study was to determine the association between initial opioid prescribing characteristics and chronic opioid use after hysterectomy. Methods: This study included women enrolled in a commercial health plan who had a hysterectomy between 1 July 2010 and 31 March 2015. We used trajectory models to define chronic opioid use as patients with the highest probability of having an opioid prescription filled during the 6 months post‐surgery. A multivariable logistic regression was applied to examine the association between initial opioid dispensing (amount prescribed and duration of treatment) and chronic opioid use after adjusting for potential confounders. Results: A total of 693 of 50 127 (1.38%) opioid‐naïve women met the criteria for chronic opioid use following hysterectomy. The baseline variables and initial opioid prescription characteristics predicted the pattern of long‐term opioid use with moderate discrimination (c statistic = 0.70). Significant predictors of chronic opioid use included initial opioid daily dose (≥60 MME vs \u3c40 MME, aOR: 1.43, 95% CI: 1.14‐1.79) and days\u27 supply (4‐7 days vs 1‐3 days, aOR: 1.28, 95% CI: 1.06‐1.54; ≥8 days vs 1‐3 days, aOR: 1.41, 95% CI: 1.05‐1.89). Other significant baseline predictors included older age, abdominal or laparoscopic/robotic hysterectomy, tobacco use, psychiatric medication use, back pain, and headache. Conclusion: Initial opioid prescribing characteristics are associated with the risk of chronic opioid use after hysterectomy. Prescribing lower daily doses and shorter days\u27 supply of opioids to women after hysterectomy may result in lower risk of chronic opioid use

Distinguishing patterns in the dynamics of long-term medication use by Markov analysis: beyond persistence

<p>Abstract</p> <p>Background</p> <p>In order to accurately distinguish gaps of varying length in drug treatment for chronic conditions from discontinuation without resuming therapy, short-term observation does not suffice. Thus, the use of inhalation corticosteroids (ICS) in the long-term, during a ten-year period is investigated. To describe medication use as a continuum, taking into account the timeliness and consistency of refilling, a Markov model is proposed.</p> <p>Methods</p> <p>Patients, that filled at least one prescription in 1993, were selected from the PHARMO medical record linkage system (RLS) containing >95% prescription dispensings per patient originating from community pharmacy records of 6 medium-sized cities in the Netherlands.</p> <p>The probabilities of continuous use, the refilling of at least one ICS prescription in each year of follow-up, and medication free periods were assessed by Markov analysis. Stratified analysis according to new use was performed.</p> <p>Results</p> <p>The transition probabilities of the refilling of at least one ICS prescription in the subsequent year of follow-up, were assessed for each year of follow-up and for the total study period.</p> <p>The change of transition probabilities in time was evaluated, e.g. the probability of continuing ICS use of starters in the first two years (51%) of follow-up increased to more than 70% in the following years. The probabilities of different patterns of medication use were assessed: continuous use (7.7%), cumulative medication gaps (1–8 years 69.1%) and discontinuing (23.2%) during ten-year follow-up for new users. New users had lower probability of continuous use (7.7%) and more variability in ICS refill patterns than previous users (56%).</p> <p>Conclusion</p> <p>In addition to well-established methods in epidemiology to ascertain compliance and persistence, a Markov model could be useful to further specify the variety of possible patterns of medication use within the continuum of adherence. This Markov model describes variation in behaviour and patterns of ICS use and could also be useful to investigate continuous use of other drugs applied in chronic diseases.</p

Impact and sustainability of centralising acute stroke services in English metropolitan areas: retrospective analysis of hospital episode statistics and stroke national audit data

OBJECTIVES: To investigate whether further centralisation of acute stroke services in Greater Manchester in 2015 was associated with changes in outcomes and whether the effects of centralisation of acute stroke services in London in 2010 were sustained. DESIGN: Retrospective analyses of patient level data from the Hospital Episode Statistics (HES) database linked to mortality data from the Office for National Statistics, and the Sentinel Stroke National Audit Programme (SSNAP). SETTING: Acute stroke services in Greater Manchester and London, England. PARTICIPANTS: 509 182 stroke patients in HES living in urban areas admitted between January 2008 and March 2016; 218 120 stroke patients in SSNAP between April 2013 and March 2016. INTERVENTIONS: Hub and spoke models for acute stroke care. MAIN OUTCOME MEASURES: Mortality at 90 days after hospital admission; length of acute hospital stay; treatment in a hyperacute stroke unit; 19 evidence based clinical interventions. RESULTS: In Greater Manchester, borderline evidence suggested that risk adjusted mortality at 90 days declined overall; a significant decline in mortality was seen among patients treated at a hyperacute stroke unit (difference-in-differences -1.8% (95% confidence interval -3.4 to -0.2)), indicating 69 fewer deaths per year. A significant decline was seen in risk adjusted length of acute hospital stay overall (-1.5 (-2.5 to -0.4) days; P0.05), length of hospital stay declined (P<0.01), and more than 90% of patients were treated in a hyperacute stroke unit. Achievement of evidence based clinical interventions generally remained constant or improved in both areas. CONCLUSIONS: Centralised models of acute stroke care, in which all stroke patients receive hyperacute care, can reduce mortality and length of acute hospital stay and improve provision of evidence based clinical interventions. Effects can be sustained over time

Evaluation of reconfigurations of acute stroke services in different regions of England and lessons for implementation: a mixed-methods study

Background: Centralising acute stroke services is an example of major system change (MSC). ‘Hub and spoke’ systems, consisting of a reduced number of services providing acute stroke care over the first 72 hours following a stroke (hubs), with a larger number of services providing care beyond this phase (spokes), have been proposed to improve care and outcomes. Objective: To use formative evaluation methods to analyse reconfigurations of acute stroke services in different regions of England and to identify lessons that will help to guide future reconfigurations, by studying the following contrasting cases: (1) London (implemented 2010) – all patients eligible for Hyperacute Stroke Units (HASUs); patients admitted 24 hours a day, 7 days a week; (2) Greater Manchester A (GMA) (2010) – only patients presenting within 4 hours are eligible for HASU treatment; one HASU operated 24/7, two operated from 07.00 to 19.00, Monday to Friday; (3) Greater Manchester B (GMB) (2015) – all patients eligible for HASU treatment (as in London); one HASU operated 24/7, two operated with admission extended to the hours of 07.00–23.00, Monday to Sunday; and (4) Midlands and East of England – planned 2012/13, but not implemented. Design: Impact was studied through a controlled before-and-after design, analysing clinical outcomes, clinical interventions and cost-effectiveness. The development, implementation and sustainability of changes were studied through qualitative case studies, documentation analysis (n = 1091), stakeholder interviews (n = 325) and non-participant observations (n = 92; ≈210 hours). Theory-based framework was used to link qualitative findings on process of change with quantitative outcomes. Results: Impact – the London centralisation performed significantly better than the rest of England (RoE) in terms of mortality [–1.1%, 95% confidence interval (CI) –2.1% to –0.1%], resulting in an estimated additional 96 lives saved per year beyond reductions observed in the RoE, length of stay (LOS) (–1.4 days, 95% –2.3 to –0.5 days) and delivering effective clinical interventions [e.g. arrival at a Stroke Unit (SU) within 4 hours of ‘clock start’ (when clock start refers to arrival at hospital for strokes occurring outside hospital or the appearance of symptoms for patients who are already in-patients at the time of stroke): London = 66.3% (95% CI 65.6% to 67.1%); comparator = 54.4% (95% CI 53.6% to 55.1%)]. Performance was sustained over 6 years. GMA performed significantly better than the RoE on LOS (–2.0 days, 95% CI –2.8 to –1.2 days) only. GMB (where 86% of patients were treated in HASU) performed significantly better than the RoE on LOS (–1.5 days, 95% CI –2.5 to –0.4 days) and clinical interventions [e.g. SU within 4 hours: GMB = 79.1% (95% CI 77.9% to 80.4%); comparator = 53.4% (95%CI 53.0% to 53.7%)] but not on mortality (–1.3%, 95% CI –2.7%to 0.01%; p = 0.05, accounting for reductions observed in RoE); however, there was a significant effect when examining GMB HASUs only (–1.8%, 95% CI –3.4% to –0.2%), resulting in an estimated additional 68 lives saved per year. All centralisations except GMB were cost-effective at 10 years, with a higher net monetary benefit than the RoE at a willingness to pay for a quality-adjusted life-year (QALY) of £20,000–30,000. Per 1000 patients at 10 years, London resulted in an additional 58 QALYs, GMA resulted in an additional 18 QALYs and GMB resulted in an additional 6 QALYs at costs of £1,014,363, –£470,848 and £719,948, respectively. GMB was cost-effective at 90 days. Despite concerns about the potential impact of increased travel times, patients and carers reported good experiences of centralised services; this relied on clear information at every stage. Planning change – combining top-down authority and bottom-up clinical leadership was important in co-ordinating multiple stakeholders to agree service models and overcome resistance. Implementation – minimising phases of change, use of data, service standards linked to financial incentives and active facilitation of changes by stroke networks was important. The 2013 reforms of the English NHS removed sources of top-down authority and facilitative capacity, preventing centralisation (Midlands and East of England) and delaying implementation (GMB). Greater Manchester’s Operational Delivery Network, developed to provide alternative network facilitation, and London’s continued use of standards suggested important facilitators of centralisation in a post-reform context. Limitations: The main limitation of our quantitative analysis was that we were unable to control for stroke severity. In addition, findings may not apply to non-urban settings. Data on patients’ quality of life were unavailable nationally, clinical interventions measured changed over time and national participation in audits varied. Some qualitative analyses were retrospective, potentially influencing participant views. Conclusions: Centralising acute stroke services can improve clinical outcomes and care provision. Factors related to the service model implemented, how change is implemented and the context in which it is implemented are influential in improvement. We recommend further analysis of how different types of leadership contribute to MSC, patient and carer experience during the implementation of change, the impact of change on further clinical outcomes (disability and QoL) and influence of severity of stroke on clinical outcomes. Finally, our findings should be assessed in relation to MSC implemented in other health-care specialties. Funding: The National Institute for Health Research Health Services and Delivery Research programme

Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

The advent of the 5HT3 receptor antagonists (5HT3 antagonists) in the 1990s and the combination with dexamethasone has resulted in acute emesis protection in 70% of patients receiving highly emetogenic chemotherapy. Despite complete protection in the acute phase, however, 40% of patients as yet have symptoms in the delayed phase, 5HT3 antagonists and dexamethasone are only modestly effective in this delayed phase. Moreover, the antiemetic protection over repeated cycles is not sustained. Neurokinine 1 receptor antagonists (NK1 antagonists) belong to a new class of antiemetic agents that specifically target the NK1 receptor, which is involved in both the acute and, particularly, the delayed phase of emesis. Clinical studies have demonstrated that the addition of NK1 antagonists to dual therapy with a 5HT3 antagonist plus dexamethasone improves the acute emesis protection by a further 10-15%. In the delayed phase, the proportion of patients remaining free of emesis increases by even 20-30%. Since the effectiveness of this triplet combination was found to be sustained over six cycles of chemotherapy, the chance for an individual patient to remain completely protected during both the acute and the delayed phase over six chemotherapy cycles is nearly doubled

Effects of centralizing acute stroke services on stroke care provision in two large metropolitan areas in England

BACKGROUND AND PURPOSE In 2010, Greater Manchester and London centralized acute stroke care into ‘hyperacute’ units (Greater Manchester=3, London=8), with additional units providing ongoing specialist stroke care nearer patients’ homes. Greater Manchester patients presenting within four hours of symptom onset were eligible for hyperacute unit admission; all London patients were eligible. Research indicates that, post-centralization, only London’s stroke mortality fell significantly more than elsewhere in England. This paper attempts to explain this difference by analyzing how centralization affects provision of evidence-based clinical interventions. METHODS Controlled before and after analysis was conducted, using national audit data covering Greater Manchester, London, and a non-centralized urban comparator (38,623 adult stroke patients, April 2008-December 2012). Likelihood of receiving all interventions measured reliably in pre- and post-centralization audits (brain scan; stroke unit admission; receiving antiplatelet; physiotherapist, nutrition, and swallow assessments) was calculated, adjusting for age, sex, stroke-type, consciousness, and whether stroke occurred in-hospital. RESULTS Post-centralization, likelihood of receiving interventions increased in all areas. London patients were overall significantly more likely to receive interventions, e.g. brain scan within three hours: Greater Manchester=65.2%[95% Confidence Interval=64.3-66.2]; London=72.1%[71.4-72.8]; comparator=55.5%[54.8-56.3]. Hyperacute units were significantly more likely to provide interventions, but fewer Greater Manchester patients were admitted to these (Greater Manchester=39%; London=93%). Differences resulted from contrasting hyperacute unit referral criteria, and how reliably they were followed. CONCLUSIONS Centralized systems admitting all stroke patients to hyperacute units, as in London, are significantly more likely to provide evidence-based clinical interventions. This may help explain previous research showing better outcomes associated with fully-centralized model

Impact of centralising acute stroke services in English metropolitan areas on mortality and length of hospital stay: difference-in-differences analysis.

To investigate whether centralisation of acute stroke services in two metropolitan areas of England was associated with changes in mortality and length of hospital stay