Patterns of utilisation of specialist care after SARS-Cov-2 infection: a retrospective cohort study.

OBJECTIVE: To explore the pattern of health services utilisation of people who had had a documented SARS-Cov-2 infection. DESIGN: Retrospective cohort study. SETTING: The Italian province of Reggio Emilia. PARTICIPANTS: 36 036 subjects who recovered from SARS-CoV-2 infection during the period September 2020-May 2021. These were matched for age, sex and Charlson Index with an equal number of subjects never found positive at the SARS-Cov-2 swab test over the study period. MAIN OUTCOME MEASURES: Hospital admissions for all medical conditions and for respiratory or cardiovascular conditions only; access to emergency room (for any cause); outpatient specialist visits (pneumology, cardiology, neurology, endocrinology, gastroenterology, rheumatology, dermatology, mental health) and overall cost of care. RESULTS: Within a median follow-up time of 152 days (range 1-180), previous exposure to SARS-Cov-2 infection was always associated with higher probability of needing access to hospital or ambulatory care, except for dermatology, mental health and gastroenterology specialist visits. Post-COVID subjects with Charlson Index≥1 were hospitalised more frequently for heart disease and for non-surgical reasons than subjects with Charlson index=0, whereas the opposite occurred for hospitalisations for respiratory diseases and pneumology visits. A previous SARS-CoV-2 infection was associated with 27% higher cost of care compared with people never infected. The difference in cost was more evident among those with Charlson Index>1. Subjects who had anti-SARS-CoV-2 vaccination had lower probability of falling in the highest cost quartile. CONCLUSIONS: Our findings reflect the burden of post-COVID sequelae, providing some specific insight on their impact on the extra-use of health services according to patients' characteristics and vaccination status. Vaccination is associated with lower cost of care following SARS-CoV-2 infection, highlighting the favourable impact of vaccines on the use of health services even when they do not prevent infection.

Feasibility of contextualizing the Informed Health Choices learning resources in Italy: A pilot study in a primary school in Florence.

Background The Informed Health Choices (IHC) project team developed learning resources for primary school children to teach critical thinking about treatments claims and health choices and evaluated their effect in a randomized controlled trial of 120 schools in Uganda. Children taught with these resources showed a better ability to think critically about treatments claims and health choices than children not taught with these resources. Teams in multiple countries are contextualising the IHC resources for use in other languages and settings; in this pilot we describe contextualization for use in Italian primary school.  Methods After translating the IHC resources to Italian and holding an introductory workshop with participating schoolteachers, we piloted the resources with two classes of a primary school in Florence over nine lessons. Our aims were: 1) to assess the feasibility of introducing the IHC curriculum in Italian primary school; 2) to evaluate students' ability to assess health claims and make informed health choices; to explore 3) students' and 4) teachers' experiences with the IHC learning resources; 5) to identify barriers and facilitators to implementation of IHC learning resources in Italian primary school. To assess these objectives, we used qualitative and quantitative methods. Results Both qualitative and quantitative analyses consistently showed that the IHC learning resources had a positive impact on the objectives examined. The resources integrated well into the Italian primary school curriculum. Both students and teachers considered these resources comprehensible, appealing in design and content, and stimulating for the development of a critical attitude. The only barrier teachers and students expressed was using the resources in a remote learning context.  Conclusions Findings from our contextualisation of IHC learning resources in Italian primary school indicate that these resources are well-suited for Italian teachers and students in a primary school context and compatible with the Italian primary school curriculum.

End-of-life care in cancer patients: how much drug therapy and how much palliative care? Record linkage study in Northern Italy.

OBJECTIVES: Investigating end-of-life use of anticancer drugs and of palliative care services. DESIGN: Population based cohort linked to mortality registry and administrative databases. SETTING: Emilia-Romagna Region (Northern Italy). PARTICIPANTS: 55 625 residents who died of cancer between 2017 and 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: Multivariate analyses were carried out to assess the relationship between cancer drug therapy and palliative care services, and their association with factors related to tumour severity. RESULTS: In the last month of life, 15.3% of study population received anticancer drugs (from 12.5% to 16.9% across the eight Local Health Authorities-LHA) and 40.2% received palliative care services (from 36.2% to 43.7%). Drug therapy was inversely associated with receiving palliative care services within the last 30 days (OR 0.92, 95% CI 0.87 to 0.97), surgery within the last 6 months (OR 0.59, 95% CI 0.52 to 0.67), aggressive tumours (OR 0.88, 95% CI 0.84 to 0.93) and increasing age (OR 0.95, 95% CI 0.95 to 0.95). Drug therapy was more likely among those with haematologic tumours (OR 2.15, 95% CI 2.00 to 2.30) and in case of hospital admissions within the last 6 months (OR 1.63, 95% CI 1.55 to 1.72). Palliative care was less likely among those with haematologic compared with other tumours (OR 0.52, 95% CI 0.49 to 0.56), in case of surgery (OR 0.44, 95% CI 0.39 to 0.49) or hospital admissions (OR 0.70, 95% CI 0.67 to 0.72) within the last 6 months, if receiving anticancer drugs during the last 30 days (OR 0.90, 95% CI 0.85 to 0.94) and for each year of increasing age (OR 0.99, 95% CI 0.99 to 0.99). Palliative care was more likely in the presence of aggressive tumours (OR 1.12, 95% CI 1.08 to 1.16). CONCLUSION: Use of anticancer drugs and palliative care in the last month of life were inversely associated, showing variability across different LHAs. While administrative data have limits, our findings are in line with conclusions of other studies.

[About the communication of health research: generating trust through information and education.] / La comunicazione della ricerca scientifica: informare (e formare) generando fiducia.

Public communication strategies of scientific findings can be placed at various levels on a scale that originates from purely informative methods and, through increasingly persuasive methods, goes up to coercion. Institutional communication of science during the covid-19 pandemic is affected by the tension between the pursuit of the ethics of transparency and the need to achieve public health goals: a communication focused on information, that neutrally highlights both the risks and the advantages of an intervention, could reduce the acceptance of this intervention in the short term, but consolidate people's trust in institutions in the long term. On the other hand, a more persuasive communication could lead to a greater adherence to the proposed intervention in the short term, but weaken the trust of the communication's recipients towards the institutions. Whenever there is robust evidence in favor of the net benefit of an intervention, informative and persuasive communication tend to overlap, while interventions with an uncertain relation between pros and cons should orient communication towards more informative strategies: even when this is not possible, as in the case of health emergencies, transparency in communication remains decisive. In this regard, transparency is configured as the common denominator of a type of science communication that can generate trust in its recipients. But transparency alone is not enough. In fact, its effectiveness is lost if the communicated contents are not useful and if the recipients of the messages are not able to receive them adequately. Based on Italo Calvino's Six Memos, we define six requirements for transparent communication of scientific research and emphasize the importance of interventions aimed at promoting health literacy since primary school, such as the international Informed Health Choices project.

Synthesizing quantitative and qualitative information on multiple comparisons of health interventions to facilitate knowledge transfer: an example from an EUnetHTA multi-HTA.

OBJECTIVE: Presenting an approach to synthesize quantitative and qualitative information from systematic reviews of multiple health interventions. METHODS: Within the context of an EUnetHTA multi-health technology assessment of twenty-three surgical techniques, we developed synthetic single tables, using color gradients and abbreviations, with information on which technologies had been compared, estimates of the size of differences for available comparisons, their clinical relevance, and certainty of the related evidence. RESULTS: The proposed methodology provided, through a single depiction, information normally included in multiple figures/tables such as network plots, league tables, and summary of findings tables. CONCLUSION: Transferring information on benefits, risks, and certainty of the available evidence on health interventions may be challenging, especially when assessing multiple treatments: more pieces of information need to be integrated in order to show an overall picture for each of the chosen outcomes, and usual reporting tools may be targeted to researchers more than to different kinds of decision makers. While more in-depth layers of information can always be added to satisfy needs of different audiences, the proposed tools could favor a quick interpretation of articulated scientific data by both decision makers and researchers.

[Thirty years of EBM: what has changed, what has yet to change.] / Trent'anni di EBM: cosa è cambiato, cosa deve ancora cambiare.

Evidence-based medicine and clinical practice should not be seen as opposing entities. Evidence-based medicine suggests some rules to design and interpretation of clinical research, with the aim of improving population and individual health. The set of data produced and their transferability to general context must be considered taking into account the clinical setting, and the characteristics of the patient and his values. Furthermore, the author considers the problems related to clinical guidelines, useful tools as long as they transparently combine the available evidence with the assessment of validity and relevance limiting risks related to conflicts of interest. Finally, the article underlines the importance of educational programs aimed at promoting critical thinking offered not just to health professionals, but also to children and adolescents.

[Access to anti-covid vaccines: research, development and role of patents.] / Accesso ai vaccini anticovid: ricerca, sviluppo e ruolo dei brevetti.

Access to vaccines against covid-19 is a very topical issue. On the one hand, we are suffering from supply problems and inadequate availability of doses both nationally and internationally. On the other hand, public health needs do not coincide with those of the market economy: the need to vaccinate the entire world population to overcome the pandemic cannot be satisfied due to market rules and limits in production processes. The result is a radical inequality in access to vaccines. We are aware of the delicate balance between health and economy: the latter cannot ignore the former. Also for this reason, the demand for greater equity in access to vaccines is growing: the race for innovation may not be hindered by a targeted relaxation of the rules on intellectual property during a pandemic health emergency.

[Vitamin D and coronavirus: a new field of use?] / Viramina D e coronavirus: un nuovo campo di impiego?

Given the succession of communications in scientific and popular circuits, tending to take for granted a role for vitamin D in the control of the coronavirus pandemic, the authors conducted an analysis of the literature currently available in order to recognize what is supported by opinions personal and what evidence of effectiveness. At the end of the bibliographic survey there is the current absence of evidence of efficacy in favor of vitamin D in the treatment of coronavirus infection in its various expressions. The diffusion of personal opinions as if they were evidence can be a disturbing factor for adequate assistance and for correct research.

Hadrontherapy for cancer. An overview of HTA reports and ongoing studies

Introduction: There is growing interest in the use of both proton beam therapy (PBT) and carbon ion radiation therapy (CIRT), which are types of hadrontherapy. Although neither are new technologies they have been subject to assessment by several Health Technology Assessment (HTA) agencies over the past years. The main claimed benefit of PBT and CIRT is a reduction in toxicity compared to conventional radiation therapy, resulting in fewer harms and a lower risk of induced secondary malignancies. Such an advantage would be particularly relevant to children and young adults. Sizeable hadrontherapy centres expansion is underway worldwide, while evidence supporting claims of superiority over conventional radiation therapy is thought to be currently insufficient. Objectives: The report is aimed at presenting the state of the art of clinical research in both PBT and CIRT, by summarising the evidence findings from most recent and uptodate HTA reports and by providing a description of all currently ongoing clinical studies. Methods: The search for HTA reports was carried out on 3 databases to identify reports published between January 2011 and June 2019. The quality of the identified reports was assessed using the AMSTAR instrument. The search for ongoing studies was carried out on four public registers in July 2019. All identified ongoing studies were included. Results: The overview of available evidence for PBT is drawn from five HTA reports on a total of 16 oncology indications, including 295 primary studies of any study design. One HTA report also included eight guidelines. All included HTA reports concluded that the quality of research is low and that there is insufficient evidence to support the claimed benefits of PBT. Seventytwo non-comparative ongoing studies and 25 comparative ongoing studies were identified. Seventeen were randomized controlled studies comparing Proton Beam Therapy with current practice. The search for HTA reports assessing the use of CIRT in oncology identified five reports, two of which were up to date and of good quality reporting data from primary studies. The largest report identified 56 studies on 13 indications, but only 27 studies (including only one randomised trial) could be included in a qualitative synthesis, providing no evidence of differences in efficacy and safety of CIRT compared to photontherapy. The other report focused on the effects of CIRT on chordomas and chondrosarcomas, highlighting the heterogeneity and inconsistency of available data mostly coming from low-quality studies. Thirtyseven ongoing studies were identified, 5 of which were RCT versus conventional treatment and 32 were single-arm studies. Table A summarises the findings, by clinical indication, from the included HTA reports and from the overview of ongoing clinical research. The Table reports the current level of certainty on superiority of PBT or CIRT compared to photon radiation therapy and the likelihood that future research results would resolve current uncertainty. Conclusions. Despite the growing number of studies being published and the growing number of PBT and/or CIRT centres opening or at a planning stage, there is persistent uncertainty on the added clinical benefit of hadrontherapy treatments over conventional radiation therapy. Clinical research currently underway may not contribute to solve this uncertainty. There is a lack of agreement on the appropriate study design to assess the effects of hadrontherapies and lack of coordination between centres in the production of joint research protocols to generate the necessary evidence. This has led to the production of numerous small, poorly designed and reported studies. These shortcomings might confine the use of PBT and CIRT to experimental treatments and require that patients willing to undergo PBT or CIRT be fully informed of the risks and uncertainties of the outcomes.

Inhaled Corticosteroid Use in Chronic Obstructive Pulmonary Disease and Risk of Pneumonia: A Nested Case-Control Population-based Study in Lazio (Italy)-The OUTPUL Study.

Inhaled corticosteroid (ICS) use in chronic obstructive pulmonary disease (COPD) patients is associated with a reduction of exacerbations and a potential risk of pneumonia. The objective was to determine if ICS use, with or without long-acting ß2-agonist, increases pneumonia risk in COPD patients. A cohort study was performed using linked hospital and drug prescription databases in the Lazio region. Patients (45+) discharged with COPD in 2006-2009 were enrolled and followed from cohort entry until first admission for pneumonia, death or study end, 31 December, 2012. A nested case-control approach was used to estimate the rate ratio (RR) associated with current or past use of ICS adjusted for age, gender, number of exacerbations in the previous year and co-morbidities. Current users were defined as patients with their last ICS prescribed in the 60 days prior to the event. Past users were those with the last prescription between 61 and 365 days before the event. Current use was classified into three levels (high, medium, low) according to the medication possession ratio. Among the cohort of 19288 patients, 3141 had an event of pneumonia (incidence rate for current use 87/1000py, past use 32/1000py). After adjustment, patients with current use were 2.29 (95% confidence interval [CI]: 1.99-2.63) times more likely to be hospitalised for pneumonia with respect to no use; for past use RR was 1.23 (95% CI: 1.07-1.42). For older patients (80+), the rate was higher than that for younger patients. ICS use was associated with an excess risk of pneumonia. The effect was greatest for higher doses and in the very elderly.

[Medicines: if their added value is not made explicit.] / Nuovi farmaci: è necessario conoscere il valore aggiunto.

Information on added therapeutic value of medicines should represent the basis for therapeutic decisions and ideally, before of that, for drug registration. A recent study assessed the availability and quality of such information provided by Medicines Regulatory Authorities and other national public health institutions in 8 European countries, and of tools facilitating the implementation of such information. This study highlighted for UK and Germany quite an advanced framework of evidence-based, comparative drug information for health professionals, decision-makers and for the general public. Other countries (including Italy) seem far behind. More efforts are warranted to make this information available and to develop sharp formats to make it easier to understand and put in context. Coordinated efforts at European level can help in the efficient production of evidence-based material. Specific plans would then be necessary to favor its local implementation.

Drug information by public health and regulatory institutions: Results of an 8-country survey in Europe.

PURPOSE: To evaluate the framework of drug information produced by public health and regulatory institutions in Europe. MATERIALS AND METHODS: We carried out a short survey asking editors of ISDB bulletins of the European region to indicate the main sources of drug information provided by public health and regulatory authorities in their countries, the specific kind of information produced and their opinions about strengths and weaknesses of such information. The availability of evaluations about the added therapeutic value of drugs and of tools facilitating the implementation of such information were particularly addressed and checked on the websites of those institutions. RESULTS: Answers pertaining to eight countries were available. Regulatory information and safety alerts are generally available, but just UK and Germany stand out by showing quite an advanced framework of evidence-based, comparative drug information for health professionals, decision-makers and for the general public. National plans to implement evidence-based drug information seem lacking. CONCLUSION: More efforts are warranted to develop sharp formats to make evidence-based drug information easier to access, understand and put in context, showing the place in therapy of medicines and their added therapeutic value. Harmonization of different sources, also at European level, would be important to favor their access and limit dispersion. Appropriate tools and specific plans are then necessary to favor implementation of information materials.

Short-term and long-term effects of tibolone in postmenopausal women.

BACKGROUND: Tibolone is a synthetic steroid used for the treatment of menopausal symptoms, on the basis of short-term data suggesting its efficacy. We considered the balance between the benefits and risks of tibolone. OBJECTIVES: To evaluate the effectiveness and safety of tibolone for treatment of postmenopausal and perimenopausal women. SEARCH METHODS: In October 2015, we searched the Gynaecology and Fertility Group (CGF) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO (from inception), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinicaltrials.gov. We checked the reference lists in articles retrieved. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing tibolone versus placebo, oestrogens and/or combined hormone therapy (HT) in postmenopausal and perimenopausal women. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures of The Cochrane Collaboration. Primary outcomes were vasomotor symptoms, unscheduled vaginal bleeding and long-term adverse events. We evaluated safety outcomes and bleeding in studies including women either with or without menopausal symptoms. MAIN RESULTS: We included 46 RCTs (19,976 women). Most RCTs evaluated tibolone for treating menopausal vasomotor symptoms. Some had other objectives, such as assessment of bleeding patterns, endometrial safety, bone health, sexuality and safety in women with a history of breast cancer. Two included women with uterine leiomyoma or lupus erythematosus. Tibolone versus placebo Vasomotor symptomsTibolone was more effective than placebo (standard mean difference (SMD) -0.99, 95% confidence interval (CI) -1.10 to -0.89; seven RCTs; 1657 women; moderate-quality evidence), but removing trials at high risk of attrition bias attenuated this effect (SMD -0.61, 95% CI -0.73 to -0.49; odds ratio (OR) 0.33, 85% CI 0.27 to 0.41). This suggests that if 67% of women taking placebo experience vasomotor symptoms, between 35% and 45% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with greater likelihood of bleeding (OR 2.79, 95% CI 2.10 to 3.70; nine RCTs; 7814 women; I2 = 43%; moderate-quality evidence). This suggests that if 18% of women taking placebo experience unscheduled bleeding, between 31% and 44% of women taking tibolone will do so. Long-term adverse eventsMost of the studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Breast cancerWe found no evidence of differences between groups among women with no history of breast cancer (OR 0.52, 95% CI 0.21 to 1.25; four RCTs; 5500 women; I2= 17%; very low-quality evidence). Among women with a history of breast cancer, tibolone was associated with increased risk (OR 1.5, 95% CI 1.21 to 1.85; two RCTs; 3165 women; moderate-quality evidence). Cerebrovascular eventsWe found no conclusive evidence of differences between groups in cerebrovascular events (OR 1.74, 95% CI 0.99 to 3.04; four RCTs; 7930 women; I2 = 0%; very low-quality evidence). We obtained most data from a single RCT (n = 4506) of osteoporotic women aged 60 to 85 years, which was stopped prematurely for increased risk of stroke. Other outcomesEvidence on other outcomes was of low or very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 2.04, 95% CI 0.79 to 5.24; nine RCTs; 8504 women; I2 = 0%.• Cardiovascular events: OR 1.38, 95% CI 0.84 to 2.27; four RCTs; 8401 women; I2 = 0%.• Venous thromboembolic events: OR 0.85, 95% CI 0.37 to 1.97; 9176 women; I2 = 0%.• Mortality from any cause: OR 1.06, 95% CI 0.79 to 1.41; four RCTs; 8242 women; I2 = 0%. Tibolone versus combined HT Vasomotor symptomsCombined HT was more effective than tibolone (SMD 0.17, 95% CI 0.06 to 0.28; OR 1.36, 95% CI 1.11 to 1.66; nine studies; 1336 women; moderate-quality evidence). This result was robust to a sensitivity analysis that excluded trials with high risk of attrition bias, suggesting a slightly greater disadvantage of tibolone (SMD 0.25, 95% CI 0.09 to 0.41; OR 1.57, 95% CI 1.18 to 2.10). This suggests that if 7% of women taking combined HT experience vasomotor symptoms, between 8% and 14% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with a lower rate of bleeding (OR 0.32, 95% CI 0.24 to 0.41; 16 RCTs; 6438 women; I2 = 72%; moderate-quality evidence). This suggests that if 47% of women taking combined HT experience unscheduled bleeding, between 18% and 27% of women taking tibolone will do so. Long-term adverse eventsMost studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Evidence was of very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 1.47, 95% CI 0.23 to 9.33; five RCTs; 3689 women; I2 = 0%.• Breast cancer: OR 1.69, 95% CI 0.78 to 3.67; five RCTs; 4835 women; I2 = 0%.• Venous thromboembolic events: OR 0.44, 95% CI 0.09 to 2.14; four RCTs; 4529 women; I2 = 0%.• Cardiovascular events: OR 0.63, 95% CI 0.24 to 1.66; two RCTs; 3794 women; I2 = 0%.• Cerebrovascular events: OR 0.76, 95% CI 0.16 to 3.66; four RCTs; 4562 women; I2 = 0%.• Mortality from any cause: only one event reported (two RCTs; 970 women). AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests that tibolone is more effective than placebo but less effective than HT in reducing menopausal vasomotor symptoms, and that tibolone is associated with a higher rate of unscheduled bleeding than placebo but with a lower rate than HT.Compared with placebo, tibolone increases recurrent breast cancer rates in women with a history of breast cancer, and may increase stroke rates in women over 60 years of age. No evidence indicates that tibolone increases the risk of other long-term adverse events, or that it differs from HT with respect to long-term safety.Much of the evidence was of low or very low quality. Limitations included high risk of bias and imprecision. Most studies were financed by drug manufacturers or failed to disclose their funding source.

Knowledge transfer: what drug information would specialist doctors need to support their clinical practice? Results of a survey and of three focus groups in Italy.

BACKGROUND: The wide offer of information on pharmaceuticals does not often fulfill physicians' needs: problems of relevance, access, quality and applicability are widely recognized, and doctors often rely on their own experience and expert opinions rather than on available evidence. A quali-quantitative research was carried out in Italy to provide an overview on information seeking behavior and information needs of doctors, in particular of infectious disease specialists, and to suggest an action plan for improving relevance, quality and usability of scientific information. METHODS: We did a quantitative survey and three focus groups. Two hundred infectious disease specialists answered a 24-item questionnaire aimed at investigating features of scientific information they receive and their ratings about its completeness, quality and usability. Subsequent focus groups, each involving eight specialists, investigated their opinions on information sources and materials, and their suggestions on how these could better support their information needs. RESULTS: The quantitative survey indicated doctors' appreciation of traditional channels (especially drug representatives) and information materials (brochures), but also their attitude to autonomous search of information and their wish to have more digital channels available. Focus groups provided more depth and, not surprisingly, revealed that physicians consider critical to get complete, comparative and specific information quickly, but also that they would like to discuss their doubts with expert colleagues. Quite strikingly, limited concerns were expressed on information validity, potential biases and conflicts of interests, as scientific validity seems to be related to the perceived authoritativeness of information sources rather than to the availability of a transparent evaluation framework. Although this research investigated views of infectious disease specialists, we believe that their opinions and perceived needs should not substantially differ from those of other clinicians, either in primary or in secondary care. CONCLUSIONS: In participants' view, the ideal information framework should provide quick and tailored answers through available evidence and favor the exchange of information between practitioners and trusted experts. The general consensus existing within the scientific and medical community on the need for integrating available evidence and experience is confirmed, although the issues of information validity and conflicts of interests seem definitely overlooked.

The impact of adherence to inhaled drugs on 5-year survival in COPD patients: a time dependent approach.

PURPOSE: Whether inhaled medications improve long-term survival in Chronic Obstructive Pulmonary Disease (COPD) is an open question. The purpose of this study is to assess the impact of adherence to inhaled drug use on 5-year survival in COPD. METHODS: A population-based cohort study in three Italian regions was conducted using healthcare linked datasets (hospitalization, mortality, drugs). Individuals (45+ years) discharged after COPD exacerbation in 2006-2009 were enrolled. Inhaled drug daily use during 5-year follow-up was determined through Proportion of Days Covered on the basis of Defined Daily Doses. Five levels of time-dependent exposure were identified: (i) long-acting ß2 agonists and inhaled corticosteroids (LB/ICS) regular use; (ii) LB/ICS occasional use; (iii) LB regular use; (iv) LB occasional use; and (v) respiratory drugs other than LB. Cox regression models adjusted for baseline (socio-demographic, comorbidities, drug use) and time-dependent characteristics (COPD exacerbations, cardiovascular hospitalizations, cardiovascular therapy) were performed. RESULTS: A total of 12 124 individuals were studied, 46% women, mean age 73,8 years. Average follow-up time 2,4 year. A total of 3415 subjects died (mortality rate = 11.9 per 100 person years). In comparison to LB/ICS regular use, higher risks of death for all remaining treatments were found, the highest risk for respiratory drugs other than LB category (HR = 1.63, 95%CI 1.43-1.87). Patients with regular LB use had higher survival than those with LB/ICS occasional use (HR = 0.89, 95%CI 0.79-0.99). CONCLUSIONS: These findings support clinical guidelines and recommendations for the regular use of inhaled drugs to improve health status and prognosis among moderate-severe COPD patients. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Role of Tiotropium in Reducing Exacerbations of Chronic Obstructive Pulmonary Disease When Combined With Long-Acting ß2 -Agonists and Inhaled Corticosteroids: The OUTPUL Study.

Combined inhaled therapy in chronic obstructive pulmonary disease (COPD) is commonly used, but its benefits remain controversial. We assessed the effect of tiotropium in reducing COPD exacerbations when combined with long-acting ß2 agonists (LABA) and/or inhaled corticosteroids (ICS). This new-user cohort study is based on administrative data from 3 Italian regions. We identified adults hospitalized for COPD from 2006 to 2009 who were newly prescribed a fixed LABA/ICS combination (double therapy). We classified patients according to whether tiotropium was also prescribed (triple therapy), using both intention-to-treat and as-treated approaches, and followed them for 1 year. COPD exacerbations were measured as outcomes. Multivariate and propensity score-adjusted hazard ratios (HRs, 95%CI) were calculated with Cox regression models. We identified 5717 new users of LABA/ICS of which 31.9% initiated triple therapy. In the intention-to-treat analysis, the multivariate adjusted HR for moderate, severe, and any exacerbations were 1.02 (95%CI 0.89-1.16), 0.92 (95%CI 0.76-1.12), and 1.08 (95%CI 0.91-1.28), respectively. The propensity score adjustment produced similar results. In the subcohort of patients with previous exacerbations, triple therapy was significantly associated with reduced risk of moderate exacerbations, compared to double therapy (HR 0.68, 95%CI 0.48-0.98 in intention-to-treat approach). In conclusion, the addition of tiotropium to LABA/ICS did not reduce COPD exacerbations compared to LABA/ICS alone. A protective role for moderate exacerbations was found in patients at risk of frequent exacerbations. Given the impact of exacerbations on health status and prognosis, it is crucial to target COPD patients for optimal treatment.

One-year mortality associated with COPD treatment: a comparison of tiotropium and long-acting beta2-agonists in three Italian regions: results from the OUTPUL study.

PURPOSE: Long-acting bronchodilators, i.e. beta-2-agonists (LABA) and tiotropium are commonly used in COPD treatment. Choice of a specific agent is based on effectiveness and safety. Evidence yields controversial results with respect to mortality. The present study compared one-year mortality associated to treatment with tiotropium versus LABA. METHODS: A population-based cohort study using data from Italian health information systems was performed. Patients aged 45+ years, discharged with COPD diagnosis in 2006-2009 were identified. Through record linkage with drug claims, patients who received a first prescription of LABA or tiotropium within 6 months after discharge were enrolled. The main analysis was restricted to naïve users (no prior use of either LABA or tiotropium). We used 'intention to treat' (ITT) and 'as treated' (AT) approaches. We followed patients for a maximum of 12 months. Hazard ratios (HRs) were calculated by Cox regression including quintiles of propensity score. In sensitivity analysis patients receiving tiotropium + LABA combination were included in the tiotropium group. RESULTS: Among the 33 891 enrolees, 28% were exposed to Tio, 56% to LABA, 16% to both. Overall mean age was 74 years and the mortality rate was 122/1000 person-years (py) at the ITT analysis and 108/1000 py at the AT analysis. The adjusted HR for tiotropium only compared with LABA only was 1.06 (95%CI: 0.94-1.20) at the ITT analysis and 1.00 (95%CI: 0.93-1.08) at the AT analysis. Results were robust in sensitivity analysis. CONCLUSIONS: In this real-world study use of tiotropium was not associated with an increased risk of one-year mortality compared with LABA. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.