Global access to affordable direct oral anticoagulants

Poor control of cardiovascular disease accounts for a substantial proportion of the disease burden in developing countries, but often essential anticoagulant medicines for preventing strokes and embolisms are not widely available. In 2019, direct oral anticoagulants were added to the World Health Organization's WHO Model list of essential medicines. The aims of this paper are to summarize the benefits of direct oral anticoagulants for patients with cardiovascular disease and to discuss ways of increasing their usage internationally. Although the cost of direct oral anticoagulants has provoked debate, the affordability of introducing these drugs into clinical practice could be increased by: price negotiation; pooled procurement; competitive tendering; the use of patent pools; and expanded use of generics. In 2017, only 14 of 137 countries that had adopted national essential medicines lists included a direct oral anticoagulant on their lists. This number could increase rapidly if problems with availability and affordability can be tackled. Once the types of patient likely to benefit from direct oral anticoagulants have been clearly defined in clinical practice guidelines, coverage can be more accurately determined and associated costs can be better managed. Government action is required to ensure that direct oral anticoagulants are covered by national budgets because the absence of reimbursement remains an impediment to achieving universal coverage. Tackling cardiovascular disease with the aid of direct oral anticoagulants is an essential component of efforts to achieve the World Health Organization's target of reducing premature deaths due to noncommunicable disease by 25% by 2025

Clinical Evidence: a useful tool for promoting evidence-based practice?

Background: Research has shown that many healthcare professionals have problems with guidelines as they would prefer to be given all relevent information relevent to decision-making rather than being told what they should do. This study assesses doctors' judgement of the validity, relevance, clarity and usability of the Italian translation of Clinical Evidence (CE) after its free distribution launched by the Italian Ministry of Health. Methods: Opinions elicited using a standardised questionnaire delivered either by mail or during educational or professional meetings. Results: Twenty percent (n = 1350) doctors participated the study. Most of them found CE's content valid, useful and relevant for their clinical practice, and said CE can foster communications among clinicians, particularly among GPs and specialists. Hospital doctors (63%) more often than GPs (48%) read the detailed presentation of individual chapters. Twenty-nine percent said CE brought changes in their clinical practice. Doctors appreciated CE's nature of an evidence-based information compendium and would have not preferred a collection of practice guidelines. Conclusions: Overall, the pilot initiative launched by the Italian Ministry of Health seems to have been well received and to support the subsequent decision to make the Italian edition of Clinical Evidence concise available to all doctors practising in the country. Local implementation initiatives should be warranted to favour doctor's use of CE

Time from adenosine di-phosphate receptor antagonist discontinuation to coronary bypass surgery in patients with acute coronary syndrome: meta-analysis and meta-regression

BACKGROUND: Adenosine di-phosphate receptor antagonists (ADPRAs) blunt hemostasis for several days after administration. This effect, aimed at preventing cardiac ischemic complications particularly in patients with acute coronary syndromes (ACS), may increase perioperative bleeding in the case of cardiac surgery. Practice Guidelines recommend withholding ADPRAs for at least 5days prior to surgery, though with a weak base of evidence. The purpose of this study was to systematically review observational and experimental studies of early or late preoperative discontinuation of ADPRAs prior to coronary artery bypass grafting (CABG) for patients with ACS. METHODS: MEDLINE, EMBASE, the Cochrane Library databases up to December 2011; and reference lists. Observational and experimental studies that compared early ADPRA discontinuation with late discontinuation, or no discontinuation, in patients with ACS undergoing CABG. RESULTS: There were 19 studies, including 14,046 participants, 395 deaths and 309 reoperations due to bleeding. ADPRA late discontinuation up to CABG was associated with an increased risk of postoperative mortality (OR 1.46, 95% confidence interval (CI) 1.10 to 1.93) and reoperations due to bleeding (OR 2.18; 95% CI 1.47 to 2.62). Between-study heterogeneity was low. Meta-analysis limited to high quality or prospective studies gave consistent results. In most instances, the 95% prediction intervals for summary risk estimates confirmed the risk across study groups. CONCLUSIONS: ADPRA late discontinuation prior to CABG is associated with an increased risk of death and reoperations due to bleeding in patients with ACS. The confidence in the estimates of risk for late discontinuation is moderate to high

Guideline recommendations and antimicrobial resistance : The need for a change

Objectives Antimicrobial resistance has become a global burden for which inappropriate antimicrobial use is an important contributing factor. Any decisions on the selection of antibiotics use should consider their effects on antimicrobial resistance. The objective of this study was to assess the extent to which antibiotic prescribing guidelines have considered resistance patterns when making recommendations for five highly prevalent infectious syndromes. Design We used Medline searches complemented with extensive use of Web engine to identify guidelines on empirical treatment of community-acquired pneumonia, urinary tract infections, acute otitis media, rhinosinusitis and pharyngitis. We collected data on microbiology and resistance patterns and identified discrete pattern categories. We assessed the extent to which recommendations considered resistance, in addition to efficacy and safety, when recommending antibiotics. Results We identified 135 guidelines, which reported a total of 251 recommendations. Most (103/135, 79%) were from developed countries. Community-acquired pneumonia was the syndrome mostly represented (51, 39%). In only 16 (6.4%) recommendations, selection of empirical antibiotic was discussed in relation to resistance and specific microbiological data. In a further 69 (27.5%) recommendations, references were made in relation to resistance, but the attempt was inconsistent. Across syndromes, 12 patterns of resistance with implications on recommendations were observed. 50% to 75% of recommendations did not attempt to set recommendation in the context of these patterns. Conclusion There is consistent evidence that guidelines on empirical antibiotic use did not routinely consider resistance in their recommendations. Decision-makers should analyse and report the extent of local resistance patterns to allow better decision-making

2019 Community-acquired Pneumonia Treatment Guidelines: There Is a Need for a Change toward More Parsimonious Antibiotic Use.

International audienc

Progress towards antibiotic use targets in eight high-income countries.

Objective: To compare antibiotic sales in eight high-income countries using the 2019 World Health Organization (WHO) Access, Watch and Reserve (AWaRe) classification and the target of 60% consumption of Access category antibiotics. Methods: We analysed data from a commercial database of sales of systemic antibiotics in France, Germany, Italy, Japan, Spain, Switzerland, United Kingdom of Great Britain and Northern Ireland, and United States of America over the years 2013-2018. We classified antibiotics according to the 2019 AWaRe categories: Access, Watch, Reserve and Not Recommended. We measured antibiotic sales per capita in standard units (SU) per capita and calculated Access group sales as a percentage of total antibiotic sales. Findings: In 2018, per capita antibiotic sales ranged from 7.4 SU (Switzerland) to 20.0 SU (France); median sales of Access group antibiotics were 10.9 SU per capita (range: 3.5-15.0). Per capita sales declined moderately over 2013-2018. The median percentage of Access group antibiotics was 68% (range: 22-77 %); the Access group proportion increased in most countries between 2013 and 2018. Five countries exceeded the 60% target; two countries narrowly missed it (> 55% in Germany and Italy). Sales of Access antibiotics in Japan were low (22%), driven by relatively high sales of oral cephalosporins and macrolides. Conclusion: We have identified changes to prescribing that could allow countries to achieve the WHO target. The 60% Access group target provides a framework to inform national antibiotic policies and could be complemented by absolute measures and more ambitious values in specific settings

La produzione di raccomandazioni cliniche con il metodo GRADE: l'esperienza sui farmaci oncologici

Questo Dossier \ue8 dedicato alla presentazione del background scientifico e dei risultati del Progetto AFO (Appropriatezza farmaci oncologici) sviluppato dall\u2019Agenzia sanitaria e sociale della Regione Emilia-Romagna nell\u2019ambito del Programma Ricerca e innovazione (PRI E-R). Dal punto di vista del background scientifico l\u2019elemento di originalit\ue0 del progetto \ue8 stato la sperimentazione dell\u2019uso del metodo GRADE (Grading of Recommendations Assessment, Development and Evaluation) per la produzione e graduazione di raccomandazioni cliniche relative all\u2019effetto degli interventi sanitari. Il metodo GRADE \ue8 nato dall\u2019attivit\ue0 avviata nel 2000 di un gruppo di lavoro internazionale che ha ritenuto necessario mettere a punto un approccio unificato alla produzione di raccomandazioni cliniche in presenza di una molteplicit\ue0 di sistemi di grading tra loro non sempre coerenti e la cui variabilit\ue0 mette in serio pericolo la fruibilit\ue0 dello strumento linee guida/raccomandazioni. Dal punto di vista dei contenuti e delle modalit\ue0 operative, il Progetto AFO - che ha anche ottenuto un finanziamento da parte del Ministero del Lavoro, della salute e delle politiche sociali nell\u2019ambito del Programma Ricerca finalizzata (Fondo ex art. 12 DLgs 502/1992) - \ue8 nato con l\u2019obiettivo di sperimentare la possibilit\ue0 di coinvolgere gruppi multidisciplinari di clinici nella produzione di raccomandazioni sull\u2019uso appropriato di farmaci oncologici, sia nuovi sia gi\ue0 registrati ma in evoluzione per quanto riguarda le indicazioni cliniche. Nella prima parte del Dossier, dopo una breve introduzione relativa alla filosofia del programma PRI E-R e agli scopi del progetto AFO, viene presentato il metodo GRADE, le sue assunzioni e le tappe operative di applicazione. Nella seconda parte vengono presentati i risultati del lavoro dei tre panel multisciplinari che hanno prodotto complessivamente 32 raccomandazioni per la terapia adiuvante e la fase avanzata del trattamento dei tumori della mammella, del colon retto e del polmone. Conclude la seconda parte del Dossier una discussione circa le criticit\ue0 di applicazione del metodo e le potenzialit\ue0 e i limiti del suo utilizzo per la produzione di strumenti utili al miglioramento dell\u2019appropriatezza d\u2019uso dei farmaci. Nell\u2019Appendice viene infine riportato, a scopo esemplificativo, il testo di due raccomandazioni relative all\u2019uso del trastuzumab nella terapia adiuvante del tumore della mammella e delle fluoropirimidine nella terapia adiuvante del tumore del colon.This report is devoted to the presentation of the scientific background and results of the AFO (an acronym standing for Appropriateness of Oncologic Drugs) project developed by the Health Care and Social Agency of Emilia-Romagna region in the framework of the Research and Innovation program (PRI E-R). From the methodological standpoint the novelty of the project stems from the utilisation of the GRADE method (Grading of Recommendation, Assessment, Development and Evaluation) for the production and grading of clinical recommendations on the effects of health care interventions. The GRADE method originated from the work of an international working group that, starting 2001, was convened to go beyond the variations in the existing methods for producing and grading clinical recommendations. These variations were mostly due to conceptual inconsistencies that, if not properly recognised and addressed, would jeopardise the credibility of the entire guidelines movement. From the subject matter standpoint the AFO project - which was also partially supported by a research grant from the Italian Ministry of Welfare, Health and Social Affairs - was conceived to test the feasibility of a working methodology where multidisciplinary panels of clinicians would be convened to produce clinical recommendations on newly registered drugs as well as those already in widespread use but whose indications change over time. In the first part of the report, after a brief introduction on the working hypotheses and objectives of the PRI ER program and the AFO project, the GRADE method is presented and discussed. In the second part the results of the activities of the three panels that produced a total of 32 recommendations for the adjuvant and advanced treatment of breast, colorectal and lung cancer are reported. The final session of the report addresses some open issues relative to the application of the GRADE method to the production of clinical recommendations construed with the explicit aim of improving quality and appropriateness of care in oncology. In the Appendix, two examples of the recommendations produced though this project are presented: they refer to Trastuzumab in the treatment of early breast cancer and Fluoropirimide in the adjuvant therapy of colon cancer

Pharmacokinetics of acute tryptophan depletion using a gelatin-based protein in male and female Wistar rats

The essential amino acid tryptophan is the precursor of the neurotransmitter serotonin. By depleting the body of tryptophan, brain tryptophan and serotonin levels are temporarily reduced. In this paper, several experiments are described in which dose and treatment effects of acute tryptophan depletion (ATD) using a gelatin-based protein–carbohydrate mixture were studied in male and female Wistar rats. Two or three doses of tryptophan depleting mixture resulted in 65–70% depletion after 2–4 h in males. ATD effects were similar in females, although females may return to baseline levels faster. Treatment effects after four consecutive days of ATD were similar to the effects of 1 day of treatment. Object recognition memory was impaired 2, 4, and 6 h after the first of two doses of ATD, suggesting that the central effects occurred rapidly and continued at least 6 h, in spite of decreasing treatment effects on plasma tryptophan levels at that time point. The method of acute tryptophan depletion described here can be used to study the relationship between serotonin and behaviour in both male and female rats

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research