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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 β 2 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., (© 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Purpose: There are some methodological concerns regarding results from observational studies about the effectiveness of evidence-based (EB) drug therapy in secondary prevention after myocardial infarction. The present study used a nested case–control approach to address these major methodological limitations., Methods: A cohort of 6880 patients discharged from hospital after acute myocardial infarction (AMI) in 2006–2007 was enrolled and followed-up throughout 2009. Exposure was defined as adherence to each drug in terms of the proportion of days covered (cutoff ≥ 75%). Composite treatment groups, that is, groups with no EB therapy or therapy with one, two, three, or four EB drugs), were analyzed. Outcomes were overall mortality and reinfarction. Nested case–control studies were performed for both outcomes, matching four controls to every case (841 deaths, 778 reinfarctions) by gender, age, and individual follow-up. The association between exposure to EB drug therapy and outcomes was analyzed using conditional logistic regression, adjusting for revascularization procedures, comorbidities, duration of index admission, and use of the study drugs prior to admission., Results: Mortality and reinfarction risk decreased with the use of an increasing number of EB drugs. Combinations of two or more EB drugs were associated with a significant protective effect (p < 0.001) versus no EB drugs (mortality: 4 EB drugs: ORadj = 0.35; 95%CI: 0.21–0.59; reinfarction: 4 EB drugs: ORadj = 0.23; 95%CI: 0.15–0.37)., Conclusions: These findings of the beneficial effects of EB polytherapy on mortality and morbidity in a population-based setting using a nested case–control approach strengthen existing evidence from observational studies.

Aims: We conducted a population-based cross-sectional study to assess the prevalence of both preclinical and clinical heart failure (HF) in the elderly., Methods and Results: A sample of 2001 subjects, 65- to 84-year-old residents in the Lazio Region (Italy), underwent physical examination, biochemistry/N-terminal pro brain natriuretic peptide (NT-proBNP) assessment, electrocardiography, and echocardiography. Systolic left ventricular dysfunction (LVD) was defined as left ventricular ejection fraction (LVEF) <50%. Diastolic LVD was defined by a Doppler-derived multiparametric algorithm. The overall prevalence of HF was 6.7% [95% confidence interval (CI) 5.6-7.9], mainly due to HF with preserved LVEF (HFpEF) (4.9%; 95% CI 4.0-5.9), and did not differ by gender. A systolic asymptomatic LVD (ALVD) was detected more frequently in men (1.8%; 95% CI 1.0-2.7) than in women (0.5%; 95% CI 0.1-1.0; P = 0.005), whereas the prevalence of diastolic ALVD was comparable between genders (men: 35.8%; 95% CI = 32.7-38.9; women: 35.0%; 95% CI = 31.9-38.2). The NT-proBNP levels and severity of LVD increased with age. Overall, 1623 subjects (81.1% of the entire studied population) had preclinical HF (Stage A: 22.2% and stage B: 59.1% respectively). A large number of subjects in stage B of HF showed risk factor levels not at target., Conclusions: In a population-based study, the prevalence of preclinical HF in the elderly is high. The prevalence of clinical HF is mainly due to HFpEF and is similar between genders.

Background: Several types of medications have been used for stabilizing heroin users: Methadone, Buprenorphine and levo-alpha-acetyl-methadol (LAAM.) The present review focuses on the prescription of heroin to heroin-dependent individuals., Objectives: To compare heroin maintenance to methadone or other substitution treatments for opioid dependence regarding: efficacy and acceptability, retaining patients in treatment, reducing the use of illicit substances, and improving health and social functioning., Search Methods: A review of the Cochrane Central Register of Trials (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to november 2009), EMBASE (1980 to 2005) and CINAHL until 2005 (on OVID) was conducted. Personal communications with researchers in the field of heroin prescription identified ongoing trials., Selection Criteria: Randomised controlled trials of heroin maintenance treatment (alone or combined with methadone) compared with any other pharmacological treatment for heroin-dependent individuals., Data Collection and Analysis: Two reviewers independently assessed trial quality and extracted data., Main Results: Eight studies involving 2007 patients met the inclusion criteria. Five studies compared supervised injected heroin plus flexible dosages of methadone treatment to oral methadone only and showed that heroin helps patients to remain in treatment (valid data from 4 studies, N=1388 Risk Ratio 1.44 (95%CI 1.19-1.75) heterogeneity P=0.03), and to reduce use of illicit drugs. Maintenance with supervised injected heroin has a not statistically significant protective effect on mortality (4 studies, N=1477 Risk Ratio 0.65 (95% CI 0.25-1.69) heterogeneity P=0.89), but it exposes at a greater risk of adverse events related to study medication (3 studies N=373 Risk Ratio 13.50 (95% CI 2.55-71.53) heterogeneity P=0.52). Results on criminal activity and incarceration were not possible to be pooled but where the outcome were measured results of single studies do provide evidence that heroin provision can reduce criminal activity and incarceration/imprisonment. Social functioning improved in all the intervention groups with heroin groups having slightly better results. If all the studies comparing heroin provision in any conditions vs any other treatment are pooled the direction of effect remain in favour of heroin., Authors' Conclusions: The available evidence suggests an added value of heroin prescribed alongside flexible doses of methadone for long-term, treatment refractory, opioid users, to reach a decrease in the use of illicit substances, involvement in criminal activity and incarceration, a possible reduction in mortaliity; and an increase in retention in treatment. Due to the higher rate of serious adverse events, heroin prescription should remain a treatment for people who are currently or have in the past failed maintenance treatment, and it should be provided in clinical settings where proper follow-up is ensured.

Purpose: Define patients treated with evidence-based drugs in a cohort discharged after acute myocardial infarction (AMI) in absence of prescribed daily doses (PDD). To compare different drug use measures and analyze their impact on the effect estimate of risk factors related to drug use., Methods: AMI patients discharged in Rome during 2006-2007 were selected from the Hospital Information System. Drugs claimed during the 12 months after discharge were retrieved. Measures of drug use were defined as: 'continuity' (one prescription each follow-up quarter-year) and the 'proportion of days covered' calculated by defined daily doses (DDDs) or pill counts (PCs) (≥ 80% of individual follow-up). Poly-therapy was defined through the same drug use measure for all drug groups. Kappa index was calculated to analyze the concordance between measures. For each measure we estimated the effect of age, gender and Percutaneous Transluminal Coronary Angioplasty (PTCA) on poly-therapy., Results: Poly-therapy rates varied between 11.5 and 37.8% in the cohort and between 17.3 and 56.9% in patients with at least one prescription for all drugs. Concordance between all measures was high for antiplatelets (k=0.74) and very low for beta-blockers (k=0.22). According to measures used, gender and older age effects slightly varied, while PTCA remained a strong determinant of drug use., Conclusions: Different measures of exposure to drug treatment may affect the estimate of the proportion of treated patients and the effect estimates of risk factors. Drug dispense registries are useful, but it is necessary to develop and validate methodologies in absence of PDD., (Copyright © 2010 John Wiley & Sons, Ltd.)

Background: Several types of medications have been used for stabilizing heroin users: Methadone, Buprenorphine and levo-alpha-acetyl-methadol (LAAM.) The present review focuses on the prescription of heroin to heroin-dependent individuals., Objectives: To compare heroin maintenance to methadone or other substitution treatments for opioid dependence regarding: efficacy and acceptability, retaining patients in treatment, reducing the use of illicit substances, and improving health and social functioning., Search Strategy: A review of the Cochrane Central Register of Trials (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to 2008), EMBASE (1980 to 2005) and CINAHL until 2005 (on OVID) was conducted. Personal communication with researchers in the field of heroin prescription identified other ongoing trials., Selection Criteria: Randomised controlled trials of heroin maintenance treatment (alone or combined with methadone) were compared with any other pharmacological treatment for heroin-dependent individuals., Data Collection and Analysis: Two reviewers independently assessed trial quality and extracted data., Main Results: Eight studies involving 2007 patients were included. Results show marginal significance in favour of heroin for remaining in treatment until the end of the study (8 studies, N= 2007, RR=1.23, 95%CI=0.96-1.57; heterogeneity P < 0.01). Adverse events are significantly more frequent in the heroin group. Heroin plus methadone prescription for maintenance treatment in adult chronic opioid users who failed previous methadone treatment attempts decreases the use of other illicit substances (3 Studies, N=1289, RR=0.63, 95%CI=0.49, 0.81, heterogeneity P=0.21), and reduces the risk of being incarcerated (2 studies, N=1103, RR=0.64, 95%CI=0.51-0.79, heterogeneity P=0.31). In addition, we also found a marginally significant protective effect of heroin prescription plus methadone for the use of street heroin (3 studies, N=1512, RR=0.70, 95%CI=0.49-1.00, heterogeneity P < 0.01) and for criminal activity (4 studies, N=1377, RR=0.80, 95%CI=0.61-1.04, heterogeneity P=0.31). There was not enough power to detect statistically significant results for the risk of death (5 studies, N=1817, RR=0.77, 95%CI=0.32-1.87, heterogeneity P=0.79)., Authors' Conclusions: The available evidence suggests a small added value of heroin prescribed alongside flexible doses of methadone for long-term, treatment-refractory opioid users, considering a decrease in the use of street heroin and other illicit substances, and in the probability of being imprisoned; and an increase in retention in treatment. Due to the higher rate of serious adverse events, heroin prescription should remain a treatment of last resort for people who are currently or have in the past failed maintenance treatment.

Background: Many medications have been used for stabilizing heroin users: Methadone, Buprenorphine and LAAM. The present review focus on the prescription of heroin to heroin dependents., Objectives: To assess the efficacy and acceptability of heroin maintenance versus methadone or other substitution treatments for opioid dependence, in retaining patients in treatment; reducing the use of illicit substances and improving health and social functioning., Search Strategy: The Cochrane Central Register of Trials (CENTRAL) issue 1, 2005; MEDLINE 1966-2005, EMBASE 1980-2005 and CINAHL till 2005 (on OVID) were searched. There was no language or publication year restrictions. Many researchers were contacted for information., Selection Criteria: Randomised controlled trials of heroin (alone or combined with methadone) maintenance treatment compared with any other pharmacological treatments for heroin dependents., Data Collection and Analysis: The trials were independently assessed for inclusion and methodological quality by the reviewers. Data were extracted independently and double checked. Studies were not pooled together because of heterogeneity., Main Results: 2400 references were obtained and 20 studies were eligible, 4 met the inclusion criteria for a total of 577 patients. The studies could not be analysed cumulatively because of heterogeneity of interventions and outcomes. Retention in treatment: no groups difference was found in two studies; one study (N=96) found RR=2.82 (95% CI 1.70-4.68) favouring heroin; one study (N=235) found RR 0.79 (95%CI 0.68-0.90) favouring methadone. Relapse to illegal heroin use (self- reported): in one study people using heroin in treatment was 64% (heroin group)and 59% (methadone group); in the other study the RR of heroin use was 0.33 (95%CI 0.15-0.72) favouring heroin. Criminal offence: one study showed the potential of heroin prescription in reducing the risk of being charged RR 0.32 (95% CI 0.14-0.78). Social functioning: two studies did not show statistical difference between intervention groups, and two studies considered criminal offence and social functioning as part of a multidomain outcome measure showing improvements among those treated with heroin plus methadone over those on methadone only., Authors' Conclusions: No definitive conclusions about the overall effectiveness of heroin prescription is possible. Results favouring heroin treatment come from studies conducted in countries where easily accessible Methadone Maintenance Treatment at effective dosages is available. In those studies heroin prescription was addressed to patients who had failed previous methadone treatments. The present review contains information about ongoing trials which results will be integrated as soon as available.

Background: Dependent heroin users are characterised by the persistence of use in spite of the difficulties they experience with health, law, social achievements and personal relationships. The present review will consider maintenance treatment in which the patients enter programs of pharmacological administration tailored to achieve patient stabilisation. Many medications have been used for this purpose such as: Methadone, Buprenorphine and LAAM. The present review will focus on maintenance treatment through the prescription of heroin., Objectives: To assess the efficacy and acceptability of heroin maintenance versus methadone or other substitution treatments for opioid dependence, in retaining patients in treatment; reducing the use of illicit substances and improving health and social functioning., Search Strategy: The Cochrane Central Register of Trials (CENTRAL) issue 4, 2002; MEDLINE (on Silver Platter) 1966-2002; EMBASE (on OVID) 1980-2000 and CINAHL till 2000 were searched. There was no language or publication year restrictions. Many researchers were contacted for information., Selection Criteria: Randomised controlled trials of heroin (alone or combined with methadone) maintenance treatment compared with any other pharmacological treatments., Data Collection and Analysis: The trials were independently assessed for inclusion and methodological quality by the reviewers. Data were extracted independently and double checked. Studies were not pooled together because of heterogeneity., Main Results: 2400 references were obtained and 20 studies were eligible, 4 met the inclusion criteria for a total of 577 patients. The studies included could not be analysed cumulatively because of heterogeneity of interventions and outcomes considered. Two studies compared injected heroin to oral methadone for 1 year (270 patients) but considered different outcomes; one study compared injected heroin and methadone to oral methadone for 6 months (51 patients); and one compared inhaled heroin and methadone to oral methadone for 1 year (235 patients). Retention in treatment: in two studies there was no statistical difference between groups; one study (N=90) had a RR=2.49 (95% CI 1.51-4.10) in favour of heroin; one study (N=235) had a RR 0.79 (95%CI 0.68-0.90) in favour of methadone. Relapse to illegal heroin use, based on self report: in one study the proportion of people still using heroin were 64% in the heroin group, 59% methadone group; in the other study the RR was 0.33 (95%CI 0.15-0.72) in favour of heroin. The remaining studies did not provide the data. Criminal offence: one of the two studies which provided details about this showed the potential of heroin prescription in reducing the risk of being charged RR 0.32 (95% CI 0.14-0.78). Social functioning: the two studies reporting this outcome did not show statistical difference between intervention groups. The two most recent studies considered criminal offence and social functioning as part of a multidomain outcome measure and showed higher improvement among those treated with heroin plus methadone over those on methadone only., Reviewer's Conclusions: No definitive conclusions about the overall effectiveness of heroin prescription is possible because of non-comparability of the experimental studies available to be included in this review. Results favouring heroin treatment come from studies conducted in countries where the treatment system is comprehensive and easy accessible Methadone Maintenance Treatment at effective dosages is available. In those studies heroin prescription was addressed to patients who had failed previous methadone treatments.

Background: Dependent heroin users are characterised by the persistence of use in spite of the difficulties they experience with health, law, social achievements and personal relationships. The present review will consider maintenance treatment in which the patients enter programs of pharmacological administration tailored to achieve patient stabilisation. Many medications have been used for this purpose such as: Methadone, Buprenorphine and LAAM. The present review will focus on maintenance treatment through the prescription of heroin., Objectives: To assess the efficacy and acceptability of heroin maintenance versus methadone or other substitution treatments for opioid dependence, in retaining patients in treatment; reducing the use of illicit substances and improving health and social functioning., Search Strategy: The Cochrane Central Register of Trials (CENTRAL) issue 4, 2002; MEDLINE (on Silver Platter) 1966-2002; EMBASE (on OVID) 1980-2000 and CINAHL till 2000 were searched. There was no language or publication year restrictions. Many researchers were contacted for information., Selection Criteria: Randomised controlled trials of heroin (alone or combined with methadone) maintenance treatment compared with any other pharmacological treatments., Data Collection and Analysis: The trials were independently assessed for inclusion and methodological quality by the reviewers. Data were extracted independently and double checked. Studies were not pooled together because of heterogeneity., Main Results: 2400 references were obtained and 20 studies were eligible, 4 met the inclusion criteria for a total of 577 patients. The studies included could not be analysed cumulatively because of heterogeneity of interventions and outcomes considered. Two studies compared injected heroin to oral methadone for 1 year (270 patients) but considered different outcomes; one study compared injected heroin and methadone to oral methadone for 6 months (51 patients); and one compared inhaled heroin and methadone to oral methadone for 1 year (235 patients). Retention in treatment: in two studies there was no statistical difference between groups; one study (N=90) had a RR=2.49 (95% CI 1.51-4.10) in favour of heroin; one study (N=235) had a RR 0.79 (95%CI 0.68-0.90) in favour of methadone. Relapse to illegal heroin use, based on self report: in one study the proportion of people still using heroin were 64% in the heroin group, 59% methadone group; in the other study the RR was 0.33 (95%CI 0.15-0.72) in favour of heroin. The remaining studies did not provide the data. Criminal offence: one of the two studies which provided details about this showed the potential of heroin prescription in reducing the risk of being charged RR 0.32 (95% CI 0.14-0.78). Social functioning: the two studies reporting this outcome did not show statistical difference between intervention groups. The two most recent studies considered criminal offence and social functioning as part of a multidomain outcome measure and showed higher improvement among those treated with heroin plus methadone over those on methadone only., Reviewer's Conclusions: No definitive conclusions about the overall effectiveness of heroin prescription is possible because of non-comparability of the experimental studies available to be included in this review. Results favouring heroin treatment come from studies conducted in countries where the treatment system is comprehensive and easy accessible Methadone Maintenance Treatment at effective dosages is available. In those studies heroin prescription was addressed to patients who had failed previous methadone treatments.

Cluster randomization is often used in intervention trials, yet when individuals nested within clusters are considered as the units of analysis for outcome evaluation, it cannot be assumed that the observations are statistically independent. Observations that are not statistically independent also result when repeated measures are taken over time for the same individual. Ignoring clustered observations when performing data analysis can lead to the erroneous conclusion that the intervention under study had a statistically significant effect. Moreover, individual responses are often collected on ordinal scales; thus models for continuous or categorical data are usually not appropriate. We applied a random effect ordinal regression model to data sets from two randomized controlled intervention trials that measured graded scale non-independent responses. The first trial compared two school programmes for AIDS prevention in terms of impact (i.e., changes in the frequency of condom use). The second trial used the MOS-HIV questionnaire to measure the quality of life of new AIDS cases four times over a one-year follow-up period (only results of the role-functioning scale are reported). Regarding the first data set, the effect of the intervention was not significant, and the post-intervention frequency of condom use was mainly attributable to the pre-intervention frequency (p<0.01), with no differences among schools. Regarding the second data set, a borderline significant increase in the role-functioning scale scores was observed over the follow-up period; the results differed only slightly by intervention group; a significant (p<0.01) intra-individual correlation of 0.4 was found., (Copyright 2001 John Wiley Sons, Ltd.)

Data gathered through the Latium HIV Surveillance System were used in conjunction with a compartmental mathematical model to describe the transmission dynamics of HIV-1 in Italy. In the Latium region, as in the rest of Italy, fewer than 1 in 5 cumulative cases of AIDS are attributable to male homosexual transmission, while 55-60 per cent of the cases have been observed among intravenous drug users (IVDUs). Moreover, the number of non-drug-using heterosexual cases is increasing (14 per cent of cumulative cases). Anonymous notification of positive HIV-1 tests, mandatory in Latium since 1985, were used to produce a time series of new HIV-1 diagnoses; just over 400 new cases of infection per quarter were diagnosed from mid 1989 to mid 1990, with no evidence of increasing incidence. A minimum of 6009 and a maximum of 10,000 individuals with HIV-1 as of the end of 1989 were estimated, 80 per cent of adult cases occurring among IVDUs. The model included two main subgroups: IVDUs and non-drug-using heterosexuals, both with behavioural heterogeneities. Sharing of needles among IVDUs and heterosexual contact were considered as possible ways of transmitting HIV-1. A mathematical framework was developed to reproduce different mixing patterns within and between subgroups. A scenario analysis of the model showed incident cases of HIV-1 among IVDUs peaking early, then declining dramatically and stabilising at low values, with a stable-state prevalence higher than 0.75. Heterosexual interaction with IVDUs resulted in a significant, but non-self-sustaining, virus spread in the general population, affecting females more than males. The extent of this spread is associated with the assortativeness of the sexual mixing pattern adopted. The qualitative features of the Italian epidemic are well represented by the model, which highlights the role of IVDUs as an infection reservoir. However, the need emerges for more accurate information on the key parameters influencing the transmission dynamics of HIV-1.