Comparative cardiovascular safety of strontium ranelate and bisphosphonates: a multi-database study in 5 EU countries by the EU-ADR Alliance.

Strontium ranelate use, compared with oral bisphosphonates, is not associated with increased risk of AMI in patients with no contraindications for SR use. However, current strontium ranelate (compared with current bisphosphonate) appears associated with 25-30% excess risk of VTE and 35% excess risk of CVDeath. INTRODUCTION: Evaluate the risk of cardiac and thromboembolic events among new users of SR and oral BPs without contraindications for SR. METHODS: We conducted three multi-national, multi-database (Aarhus-Denmark, HSD-Italy, IPCI-Netherlands, SIDIAP-Spain, THIN-UK) case-control studies nested within a cohort of new users of SR/BP. We matched cases of acute myocardial infarction (AMI), venous thromboembolism (VTE), and cardiovascular death (CVDeath), up to 10 controls on gender, year of birth, index date, and country. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) according to current SR vs current BP use and current vs past SR use, adjusting for potential confounders. Data were pooled using random effects meta-analysis. RESULTS: No excess risk of AMI (5477 cases/54,674 controls) was found with current SR vs current BP (OR 0.89 (95%CI 0.70, 1.12)) nor with current vs past SR use (0.71(0.56, 0.91)). For VTE (5614 cases/6036 controls), an excess risk was found with current SR compared with current BP use, 1.24 (0.96, 1.61), and current vs past SR use, 1.30 (1.04, 1.62). For CVDeath (3019 cases/29,871 controls), an increased risk was seen with current SR vs current BP use, 1.35 (1.02, 1.80), but not with current vs past SR use (0.68 (0.48, 0.96)). CONCLUSION: In patients without contraindications for SR, we found no evidence of an increased risk of AMI but a 25-30% excess risk of VTE and a 35% excess risk of CVDeath with current SR vs current BP users. This is despite a reduction in risk in CVDeath with current vs past SR users. The latter disparity could still be partially explained by cessation of preventative therapies in end-of-life or residual confounding by indication.

Correction to: Impact of risk minimisation measures on the use of strontium ranelate in Europe: a multi-national cohort study in 5 EU countries by the EU-ADR Alliance.

The original version of this article, published on 26 November 2019 contained a mistake.

Impact of risk minimisation measures on the use of strontium ranelate in Europe: a multi-national cohort study in 5 EU countries by the EU-ADR Alliance.

INTRODUCTION: In May 2013 and March 2014, the European Medicines Agency (EMA) issued two decisions restricting the use of strontium ranelate (SR). These risk minimisation measures (RMM) introduced new contraindications and limited the indications of SR therapy. The EMA required an assessment of the impact of RMMs on the use of SR in Europe. Methods design: multi-national, multi-database cohort Setting: electronic medical record databases based on hospital (Denmark) and primary care provenance (Italy, Spain, the Netherlands, UK). PARTICIPANTS: the database source populations were included for population-based analyses, and SR users for patient-level analyses. INTERVENTION: New RMMs included contraindications (ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, uncontrolled hypertension) and restricted SR indication to severe osteoporosis with initiation by experienced physician and not as first line anti-osteoporosis therapy. METHODS: Prevalence and incidence rates of SR use in the population; prevalence of contraindications and restricted indications in SR users, plus 1-year therapy persistence. Drug use measures were calculated in three periods for comparison: reference (2004 to May 2013), transition (June 2013 to March 2014) and assessment (from April 2014 to end 2016). RESULTS: The study population included 143 million person-years(PY) of follow-up and 76,141 incident episodes of SR treatment. Average monthly prevalence rates of SR use dropped by 86.4% from 62.6/10,000 PY (95 CI 62.4-62.9) in the reference to 8.5 (8.5-8.6) in the assessment period. Similarly, the incidence rate of SR use fell by 97.3% from 7.4/10,000 PY (7.4-7.4) to 0.2 (0.2-0.2) between the reference and assessment period. The prevalence of any contraindication decreased, whilst the prevalence of restricted indications increased in these periods. One-year persistence decreased in the assessment compared with reference period. CONCLUSIONS: Our study demonstrates a substantial impact of the regulatory action to restrict use of SR in Europe: SR utilisation overall decreased strongly. The proportion of patients fulfilling the restricted indications, without contraindications, increased after the proposed RMMs.

Prevalence and control of hypertension in the general practice in Italy: updated analysis of a large database.

Systematic assessment of blood pressure (BP) control rates may help to improve the clinical management of hypertension in clinical practice. This approach had limited application in Europe over the last three decades and only recently has been implemented in some countries. The present study is aimed at evaluating hypertension prevalence and control among adult outpatients followed by a large, representative sample of general practitioners (GPs) in Italy. We retrospectively analysed the data derived from the GP Health Search-CSD database in 2013. Hypertension prevalence and control were estimated within the overall population sample and in hypertensive outpatients, respectively, according to age and gender. Hypertension diagnosis was defined according to the International Classification of Diseases 9. Clinic BP levels were measured according to the European guidelines. BP control was defined as systolic/diastolic BP <140/90 mm Hg. Data from 911 753 individuals (52.2% females) were scrutinized. Hypertension was diagnosed in 236 377 (25.9%) patients, being higher in male aged <70 years than age-matched female. Hypertension control was recorded in 60.6% of hypertensive patients, being higher in female than male individuals aged <70 years. Our current analysis demonstrates that about 26% of adult outpatients followed in the GP setting had hypertension and that about 61% had controlled BP levels. Both prevalence and control of hypertension appear to be higher when compared with the data reported from the analysis of the same database in 2005, thus confirming a positive trend in BP control in the GP clinical setting in Italy.

How to early recognize mood disorders in primary care: A nationwide, population-based, cohort study.

BACKGROUND: Mood disorders are managed predominantly in primary care. However, general practitioners' (GPs) ability to detect and diagnose patients with mood disorders is still considered unsatisfactory. The aim of the present study was to identify predictors for the early recognition of depressive disorder (DD) and bipolar disorder (BD) in general practice. METHODS: A cohort of 1,144,622 patients (605,285 women, 539,337 men) was investigated, using the Health Search IMS Health Longitudinal Patient Database. Predictors of DD or BD were identified at baseline encompassing somatization-related features, lifestyle variables, medical and psychiatric comorbidities. Patients were followed up as long as the following events occurred: diagnoses of DD or BD, death, end of the registration with the GP, end of the study period. RESULTS: We found an incidence rate of DD or BD of 53.61 and 1.5 per 10,000 person-years, respectively. For both the conditions, the incidence rate grew with age. Most of the lifestyle variables and medical comorbidities increased the risk of mood disorders. The strongest effect was found for migraine/headache (HR [95% CI]=1.32 [1.26-1.38]), fatigue (1.32 [1.25-1.39]) irritable bowel syndrome (1.15 [1.08-1.23]), and pelvic inflammation disease (1.28 [1.18-1.38]). CONCLUSIONS: Several predictors, in particular somatic symptoms, could be interpreted as an early sign of a mood disorder, and represent a valid indication for the GPs diagnostic process of mental disorders.

Risk of prostate cancer in low-dose aspirin users: A retrospective cohort study.

A growing body of evidence indicates that use of low-dose aspirin (LDA) reduces the risk of certain adenocarcinomas. While there are several and consistent findings on the protective effect of LDA on colorectal and other cancers, few and conflicting evidence is available on prostate cancer (PCa). The aim of this study was to assess whether LDA reduces the incidence rate of PCa. We conducted a nationwide, population-based, retrospective cohort study by using Health Search IMS Health Longitudinal Patient Database (HSD). Patients with ischemic cardio- or cerebrovascular disease (index date) were identified. Time-dependent multivariable Cox proportional hazard models were adopted to estimate Hazard Ratios (HRs) and related 95% confidence intervals (95% CI) of PCa associated with use of LDA. The exposure was lagged by one year to consider the latency of drug effect on the outcome onset. Within a cohort 13,453 patients, the overall incidence rate of PCa was 2.5 per 1,000 person-years. Use of LDA was associated with a decreased incidence rate of PCa (HR = 0.64; 95% CI: 0.48-0.86), which was primarily driven by a frequency of LDA use equal to or higher than twice per week (HR = 0.60; 95% CI: 0.43-0.83). Such an association was more pronounced (HR = 0.43; 95% CI: 0.21-0.91) when LDA was used for five or more years. Our findings indicate that LDA use might be associated with a reduction of risk of PCa in patients with cardio- or cerebrovascular diseases.

Epidemiology of chronic spontaneous urticaria: results from a nationwide, population-based study in Italy.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common skin disease, but there is a paucity of precise epidemiological data on this disease. OBJECTIVES: To obtain information on the epidemiology of CSU in Italy. METHODS: The data source was the Health Search IMS Health Longitudinal Patient Database. The study population was formed by patients aged ≥ 15 years, registered with a total of 700 general practitioners, homogeneously distributed across Italy. An algorithm based on the International Classification of Diseases, ninth revision, Clinical Modification was used for the identification of patients with CSU. The annual prevalence and incidence rates of CSU over a 12-year period (2002-2013) were estimated, along with demographic and clinical determinants. RESULTS: The annual prevalence of CSU ranged from 0·02% in 2002 to 0·38% in 2013. The incidence was 0·10-1·50 per 1000 person-years. For both prevalence and incidence rates, female patients outnumbered male. The risk of CSU was statistically significantly higher in the presence of the following variables: obesity; anxiety, dissociative and somatoform disorders; malignancies; use of immunosuppressive drugs; and chronic use of systemic corticosteroids. History of autoimmune thyroiditis showed a trend towards an increased risk of CSU, though it was not statistically significant. Smoking was associated with a significantly reduced risk of CSU. CONCLUSIONS: Our findings on CSU prevalence are consistent with those obtained in previous studies. Furthermore, this large population-based study provides important information regarding the association of CSU with demographic and clinical determinants, which have been examined in the primary-care setting.

Risk of atrial fibrillation among bisphosphonate users: a multicenter, population-based, Italian study.

UNLABELLED: Bisphosphonate treatment is used to prevent bone fractures. A controversial association of bisphosphonate use and risk of atrial fibrillation has been reported. In our study, current alendronate users were associated with a higher risk of atrial fibrillation as compared with those who had stopped bisphosphonate (BP) therapy for more than 1 year. INTRODUCTION: Bisphosphonates are widely used to prevent bone fractures. Controversial findings regarding the association between bisphosphonate use and the risk of atrial fibrillation (AF) have been reported. The aim of this study was to evaluate the risk of AF in association with BP exposure. METHODS: We performed a nested case-control study using the databases of drug-dispensing and hospital discharge diagnoses from five Italian regions. The data cover a period ranging from July 1, 2003 to December 31, 2006. The study population comprised new users of bisphosphonates aged 55 years and older. Patients were followed from the first BP prescription until an occurrence of an AF diagnosis (index date, i.e., ID), cancer, death, or the end of the study period, whichever came first. For the risk estimation, any AF case was matched by age and sex to up to 10 controls from the same source population. A conditional logistic regression was performed to obtain the odds ratio with 95% confidence intervals (CI). The BP exposure was classified into current (<90 days prior to ID), recent (91-180), past (181-364), and distant past (≥365) use, with the latter category being used as a reference point. A subgroup analysis by individual BP was then carried out. RESULTS: In comparison with distant past users of BP, current users of BP showed an almost twofold increased risk of AF: odds ratio (OR) = 1.78 and 95% CI = 1.46-2.16. Specifically, alendronate users were mostly associated with AF as compared with distant past use of BP (OR, 1.97; 95% CI, 1.59-2.43). CONCLUSION: In our nested case-control study, current users of BP are associated with a higher risk of atrial fibrillation as compared with those who had stopped BP treatment for more than 1 year.

Allopurinol adherence among patients with gout: an Italian general practice database study.

AIMS: Allopurinol is used as long-term therapy to reduce the occurrence of gout flares. This study estimated the impact of patient adherence to allopurinol on hyperuricaemia (serum uric acid levels, sUA > 6 mg/dl) and the identification of non-adherence predictors. METHODS: The Italian Health Search-CSD Longitudinal Patient Database was accessed to identify outpatients aged ≥ 18 years with gout and prescribed with allopurinol during the years 2002-2011. Patients with a proportion of days covered ≥ 80% were considered adherent to allopurinol. Data on sUA levels over the first year of therapy were categorised in three time-windows (30-89; 90-149; 150-365 days). Logistic regressions were used to estimate the association between adherence and hyperuricaemia, as well as non-adherence predictors. RESULTS: A total of 3727 patients were included. In the interval 0-29 days, the proportion of patients adherent to allopurinol was 45.9%, while up to 89, 149 and 365 days the percentages were 16.7%, 10.0% and 3.2%, respectively. The proportions of hyperuricaemic patients for each time-window were 43.1%, 42.4%, 32.6% and 59.0%, 64.0%, 66.4% among adherent and non-adherent patients, respectively. In the multivariable analysis, adherence was associated with a significant lower risk of hyperuricaemia. The adjusted ORs were 0.49 (95% CI: 0.33-0.73), 0.40 (95% CI: 0.24-0.67) and 0.23 (95% CI: 0.15-0.34) for the first, second and third time-window, respectively. Patients with hypertension (adjusted OR = 0.64, 95% CI: 0.42-0.99) and history of gout flares (adjusted OR = 0.55, 95% CI: 0.32-0.95) were significantly adherent to allopurinol. CONCLUSIONS: Adherence monitoring in patients with gout is pivotal to ensure the effectiveness of therapy. To gain a better patient adherence, the communication between physicians and patients should be improved.

Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures.

SUMMARY: There is evidence that the use oral bisphosphonates can lead to osteronecrosis of the jaws (ONJ). Although the occurrence of ONJ appears rare among oral bisphosphonates (BPs) users, it is important to know that it exists and can be opportunely minimized. INTRODUCTION: The purpose of this study is to evaluate the association between BPs prescribed for the secondary prevention of osteoporotic fractures and the occurrence of ONJ. METHODS: An Italian record linkage claims database with a target population of around 18 million individuals (6 million over 55 years of age) constituted the data source. We conducted a nested case-control study within a cohort of individuals aged 55+ years old, who were discharged from hospitals with a primary diagnosis of incident osteoporotic fracture. The date related to the discharge diagnosis of ONJ was the index date. Conditional logistic regression for matched data was fitted to estimate the odds ratio (OR) along with 95 % confidence intervals (95 % CI) for the likely association between use of BPs and the risk of ONJ. RESULTS: Any one of the 61 ascertained cases of ONJ (incidence rate, 36.6 per 100,000 person-years) was matched to 20 controls for a total of 1120 controls. When the exposure to BPs was modeled according to recency (i.e., exposure time window prior to the index date) of use, the adjusted OR (95 % CI) for current users was 2.8 (1.3-5.9) against never users. The cumulative use of BPs has shown to increase the incidence of ONJ among patients with primary osteoporotic fractures, although not statistically significant risk has been observed. CONCLUSIONS: Although the risk of BP-related ONJ appears low in non-oncological indications, it is important to be aware that it exists and to know how it may be predicted and possibly minimized.

Anaphylaxis during the first course of high-dose methotrexate: a case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: Methotrexate (MTX) is widely used in the management of paediatric cancer with a generally favourable benefit/risk profile. We report an unusual adverse drug reaction with the first course of high-dose MTX in a paediatric patient and review the literature for similar cases. CASE SUMMARY: An 11-year-old boy with small-cell osteoblastic osteosarcoma in the lower limb experienced a case of life-threatening anaphylaxis during the first course of high-dose MTX. The adverse event occurred during the first course, likely due to an immune-mediated mechanism. We postulate that prior antineoplastic treatment might have contributed to the immune response to MTX. WHAT IS NEW AND CONCLUSION: Given that this reaction has rarely been reported, we discuss the present case with a review of other similar cases. Further studies are needed to substantiate this 'signal alarm' for serious MTX-related hypersensitivity reactions.

Assessing 5-year incidence rates and determinants of osteoporotic fractures in primary care.

PURPOSE: To assess the gender and age-related 5-year incidence rates of osteoporotic fractures, and their related predictors, in a primary care setting. METHODS: We obtained information from the Health Search-CSD Longitudinal Patients Database (HSD). This is an Italian General Practice data repository which comprises information given by computer-based patient records of a selected group of over 900 Primary Care Physicians (PCPs). We selected all patients aged 50 to 85 years, who were actively included into the PCP's list at the beginning of the enrolment period (1st January 2002-31st December 2003). We excluded individuals who were registered in the PCPs' list for less than 1 year before the entry date (Index date) into the cohort, as well as those who were diagnosed with Paget disease or malignant neoplasm. Participants were followed up until the occurrence of osteoporotic fracture, one of the exclusion criteria, or the end of the study period. RESULTS: The 5-year rates (per 1000 person-years) of any osteoporotic fracture were 11.56 (95% C.I. 11.33 to 11.77) among females, and 4.91 (95% C.I. 4.75 to 5.07) among males. For hip fractures, the overall incidence rates were 3.23 (95% C.I. 3.11 to 3.34) among females and 1.21 (95% C.I. 1.12 to 1.28) among males, respectively. Advanced age, history of fracture, use of corticosteroids, rheumatoid arthritis, BMI<=20, presence of osteoporosis, gastrointestinal and chronic hepatic disease, depression, chronic obstructive pulmonary disease, use of anticonvulsants and a higher number of co-medications, increased the risk of any osteoporotic fractures. CONCLUSIONS: The use of primary care data confirms a higher incidence of osteoporotic fractures among females vs. males as well as in older individuals. Predictors of osteoporotic fractures were consistent with FRAX® algorithm. Given the clinical utility of a simple score for the assessment of absolute fracture risk among osteoporotic patients, its assessment and validation in the Italian HSD could potentially provide an applicable prediction tool.

Is suboptimal prescribing a risk factor for poor health outcomes in community-dwelling elders? The ICARe Dicomano study.

PURPOSE: Mostly because of comorbidity and drugs consumption, older persons are often exposed to an increased risk of sub-optimal prescribing (SP). At present, few studies investigated the association between SP and long-term health outcomes. We examined the relation between SP and the risk of mortality and hospitalization in Italian older community-dwellers. METHODS: Older (65+ years) community-dwelling residents of a small town in Tuscany were enrolled in a longitudinal study. SP was defined as polypharmacy (use of 5+ drugs), prescription of inappropriate drugs (ID) according to Beers' criteria, and of potentially interacting drugs (PID), evaluated in 1995 and 1999. These three forms of SP were entered as time-dependent exposures into multivariable Cox regression analysis models, whose outcomes were mortality and hospitalizations through 2003. RESULTS: Of 1022 participants (mean age 73.0 +/- 6.8, 57% women), 220 were evaluated in 1995, 234 in 1999 and 568 in both waves. In univariate analysis, mortality was two-fold higher in participants with polypharmacy (73.4/1000 person/years, 95% CI 58.2-92.4 vs. 34.1, 95% CI 29.7-39.2; p < 0.001) or PID (72.7/1000 person/years, 95% CI 46.3-113.9 vs. 38.0, 95% CI 33.5-43.1; p < 0.001), whereas it was unrelated to the presence of ID. Hospitalization rates were independent of any form of SP. In multivariable models, polypharmacy, ID, and PID were no longer associated with an increased risk of death, and ID predicted a slightly increased risk of hospitalizations (HR 1.03, 95% CI 1.0-1.06, p = 0.048). CONCLUSIONS: In this cohort, SP was not associated with an excess risk of poor health outcomes.

Potential drug-drug interactions and radiodiagnostic procedures: an in-hospital survey.

OBJECTIVES: To evaluate the type, frequency, severity and predictors of potential Drug-Drug Interactions (DDIs) in a cohort of patients undergoing radiodiagnostic procedures. SETTING: Eight Radiology wards located in Tuscany (Italy). METHODS: All participants exposed to at least two medications were included in the analysis. DDIs were grouped according to their severity as 'minor', 'moderate' or 'major'. A logistic model was used to estimate Odds Ratios and 95% Confidence Intervals for all predictors of potential DDI. MAIN OUTCOME MEASURES: Type and predictors of potential DDI in a cohort of patients undergoing radiodiagnostic procedures. RESULTS: One-thousand-and-two subjects (57.6% females; mean age: 67.3 +/- 12.2) entered the analysis, and 46.1% of them incurred in a potential DDI (78.9% 'moderate' in severity). The combination of allopurinol and ACE-inhibitors was the most frequent (21/153) among major potential DDIs, while steroids were involved in all cases of potential DDI due to premedication. Co-morbidity, number of co-medications, advanced age and premedication use increased the risk of potential DDI; a protective role was found for positive history of allergy. When the analysis was restricted to subjects with premedication (n = 93), only 12.9% of them reported a potential DDI directly attributable to premedication drugs. CONCLUSIONS: Among patients undergoing radiological examination, types and predictors of potential DDIs appeared in agreement with other kind of in-hospital populations. Premedication revealed to be a proxy predictor for potential DDIs. Considering the poor capability of the prescriber in recognizing interactions, their systematic evaluation (using an informatics tool) in patients undergoing radiological examination might be helpful in preventing the occurrence of clinically relevant DDIs.

Increased levels of CA 125 and CA 19.9 serum tumour markers following cyclic combined hormone replacement therapy.

We report a case of increase in serum tumour markers CA 125 and CA 19.9 induced by cyclic combined hormone replacement therapy (HRT). A 52-year-old Caucasian post-menopausal woman presented with a slight enlargement of the right ovary and uterine fibromyomatosis. She was taking HRT for 4 years in a cyclic combined regimen of 2 mg oestradiol with 1 mg cyproterone acetate. The serum tumour markers occasionally measured were in normal range except CA 19.9 (997 U/mL; normal values 0.0-37) and CA 125 (85 U/mL; normal values 0.0-35). However, on one occasion, the CA 19.9 and CA 125 were high and then showed persistently high values (1005 and 81.3 U/mL, respectively). Radiodiagnostic investigations excluded any malignancies and a hysteroscopy showed endometrial thickening. After discontinuation of HRT, CA 125 levels returned to normal after 1 month, whereas CA 19.9 took 6 months to do so. Four months after the beginning subsequent therapy with over-the-counter phyto-oestrogens a new serum test showed an increase in CA 19.9 but CA 125 remained within the normal range. Phyto-oestrogen therapy was then interrupted and 1 month later CA 19.9 returned to normal. In this case, cyclic HRT was the probable cause of CA 19.9 and CA 125 increase. Positive dechallenge and subsequent CA 19.9 increase after phyto-oestrogen intake seem to confirm the role of oestrogens as the cause of the endometrial thickening through hormonal imbalance. Increased CA 19.9 and CA 125 levels in benign gynaecological conditions may be a source of misdiagnosis of malignant disease.