Ticlopidine safety profile: a case/non-case study on the basis of the spontaneous ADRs reporting in Italy.

UNLABELLED: INTRODUCTON: Ticlopidine is an antiplatelet agent available from several decades. Its most important adverse drug reactions (ADRs) involve haematological system. Our aim was to evaluate the safety profile of ticlopidine in the real life, on the basis of spontaneous ADR reporting. MATERIALS AND METHODS: Spontaneous reports from 8 Italian Regions collected from 1990 to March 2007 were analysed. According to WHO Adverse Reaction Terminology for causality assessment only "certain", "probable" or "possible" ADRs were included. Association between drugs and any ADR was assessed by using the case/non-case methodoloy. Reporting odds ratio (ROR) was computed as a measure of disproportionality. RESULTS: Overall, 478 reports concerning ticlopidine were analysed. The system organ classes with significant disproportionality for ticlopidine included White Cell Disorders (ROR=22.43, 95% CI 18.54-27.12), Red Cell Disorders (8.22; 6.03-11.18), Liver And Biliary System (6.67; 5.35-8.32), Platelet, Bleeding & Clotting (6.59; 5.16-8.40). Fifteen percent of the ADRs occurred beyond the first three months of ticlopidine therapy. In 386 reports (80.7%), ticlopidine was the only suspected drug. CONCLUSION: Safety profile of ticlopidine can be considered well-established in terms of ADRs type but their frequency and severity continue to be higher in its current use. Since this drug is still widely used in Italy, both healthcare providers and patients should be aware of its ADRs. More specifically, patients should be regularly monitored during the whole period of use and not only in the first months of treatment.

Influence of regulatory measures on the rate of spontaneous adverse drug reaction reporting in Italy.

BACKGROUND: The reporting of adverse drug reactions (ADRs) is the mainstay of post-marketing surveillance systems. Under-reporting and selective reporting are considered the main limitations of a spontaneous reporting-based pharmacovigilance system. However, excessive reporting induced by external events may also impair signal detection by increasing the noise level. OBJECTIVE: The aim of this study was to examine the influence of regulatory measures and other external factors on the rate of ADR reporting in Italy, focusing on four situations occurring in the last 10 years: ACE inhibitor-induced cough; HMG-CoA reductase inhibitors ('statins') and rhabdomyolysis; nimesulide and hepatic toxicity; and cyclo-oxygenase (COX)-2 selective inhibitors ('coxibs') and increase in cardiovascular risk. METHODS: The study was based on data from spontaneous reporting in six Italian regions collected from January 1995 to December 2005. We analysed a 10-year period as a reasonable time interval around the four situations of interest, highlighting the influence of regulatory measures on the rate of ADR reporting (number of reports per million inhabitants). Chi-squared tests were used to assess the statistical significance of any changes in ADR reporting. Drug sales data were also studied to examine possible changes in drug use. Sales data were expressed as daily defined dose per 1000 inhabitants per day. RESULTS: ACE inhibitors: a 5-fold increase in the reporting rate of ACE inhibitor-induced cough was observed in 1998 and 1999 following a restriction on reimbursement for angiotensin receptor blockers introduced in 1998 and removed at the end of 1999. Statins: after the withdrawal of cerivastatin in 2001, the ADR reporting rate increased more than 4-fold, with musculoskeletal ADRs representing about 60% of all the ADRs reported in that year, and progressively decreased in the following years. Nimesulide: an increase in hepatic ADR reporting was observed after withdrawal of the drug from the Finnish and Spanish markets in 2002. Coxibs: no important changes in the rate of cardiovascular events reporting in the period 2000-4 were observed. In 2005, after the withdrawal of rofecoxib in September 2004, both the ADR reporting rate and sales of the drug decreased drastically. CONCLUSION: Our data suggest that spontaneous ADR reporting can be influenced in different ways by external events. Our data emphasize the need for educational initiatives aimed at increasing the doctor's and patient's awareness of the usefulness and the limitations of spontaneous reporting in the pharmacovigilance system. Such initiatives should use appropriate risk communication strategies in order to avoid unnecessary alarm, which could cause unjustified interruption of therapies or misplaced confidence in new drugs.

A 3 year survey on the use of antibacterial agents in five Italian hospitals.

BACKGROUND: Misuse of antimicrobial agents in hospitals may cause the emergence of resistant microorganisms, as well as increased costs and unnecessary exposure of patients to drugs. We investigated the pattern of antibiotic consumption in 2002-04 in a sample of Italian hospitals, and compared this with antibiotic consumption data in primary healthcare in the Emilia-Romagna region. METHODS: The study was carried out in five hospitals of the Emilia-Romagna region and 2002-04 drug use data were obtained from the pharmacy services. Data were analysed by clinical areas and single wards and were expressed by ATC classification and defined daily doses (DDD)/100 bed days. Prescription data of antibacterials in primary care in the same period were also analysed. RESULTS: Antibiotic consumption increased by 18% in the 3 year period. Combinations of penicillins and beta-lactamase inhibitors were the most used drugs, followed by fluoroquinolones and third-generation cephalosporins. Penicillins plus beta-lactamase inhibitors increased in all the clinical areas by over 40%, and fluoroquinolones sharply increased in medical units (+29%). Third-generation cephalosporins remained fairly stable in paediatrics and surgery, but increased in medicine (+18%). Glycopeptides accounted for 4.3% of total antibiotic consumption with a peak of 10% in intensive care units. Antibacterial prescription in primary care showed a pattern similar to that of hospitals. CONCLUSIONS: We found a considerable increase in antibiotic use over time and a marked preference for wide-spectrum antibiotics such as penicillins plus beta-lactamase inhibitors, fluoroquinolones and third-generation cephalosporins; thus raising concern about appropriate use. These results could represent the basis for educational initiatives aimed at rationalizing the use of antibiotics in hospitals.

Adherence to statin therapy and patients' cardiovascular risk: a pharmacoepidemiological study in Italy.

AIM: To evaluate the pattern of use of statins in the Emilia Romagna Region, with a focus on the therapeutic regimens and the patient's risk profile as predictors of adherence to therapy. METHODS: All patients from Emilia Romagna (4,027,275 inhabitants) receiving statin prescriptions in January-February 2005 were selected and observed for 12 months in terms of their statin regimen and use of other drugs for cardiovascular risk prevention. Previous hospital admissions for major cardiovascular events were also obtained. Adherence to statins was evaluated in terms of coverage (covered: >or=300 tablets/year). The relationship between coverage and risk profile (age, sex, other cardiovascular drugs, previous cardiovascular events and choice of drugs/dosages) was analysed by multivariate logistic regression. RESULTS: Among the 137,217 patients receiving at least one prescription in the observation period, the rate of coverage was 46%. Coverage was statistically higher in patients with a previous hospital admission (secondary prevention) [Odds ratio (OR) 1.19; 95% confidence interval (95% CI) 1.16, 1.22], in those concomitantly treated with three to four different cardiovascular drugs (OR 2.77; 95% CI 2.66, 2.89). The coverage was also statistically higher in patients aged 50-69 years (OR 1.14; 95% CI 1.08, 1.20) and among males (OR 1.21; 95% CI 1.18, 1.23). CONCLUSIONS: Less than half of patients receiving statin therapy took their medication daily, with a coverage only slightly higher in patients at higher cardiovascular risk. Three-quarters of the patients received statin therapy in primary prevention, whereas the benefits of statins are documented mostly for patients in secondary prevention. These findings strengthen the need to sensitise physicians and patients to the correct use of statins.

Adherence to chronic cardiovascular therapies: persistence over the years and dose coverage.

AIM: To evaluate adherence to chronic cardiovascular drug treatments, in terms of long-term persistence and dose coverage. METHODS: General practice prescription data of antihypertensives, lipid-lowering agents, oral hypoglycaemic agents and nitrates were collected over a 5-year period (1998-2002) in a Northern Italian district (Ravenna, 350,000 inhabitants). We selected subjects (>40 years) receiving at least one prescription of the above drugs in December 1999. For each patient, we documented the regimen at the time of selection and evaluated adherence to treatment during the following 3 years in terms of persistence (at least one prescription per year) and daily coverage (recipients of an amount of medication consistent with daily treatment). RESULTS: Fewer than 10% of the 32 068 selected subjects were naive to treatment. Antihypertensives were the most represented therapeutic category. Among patients already on treatment in December 1999, persistence was virtually complete, whereas >40% of naive patients withdrew within 1 year, except for nitrates. The rates of coverage were always much lower than the corresponding values of persistence. Coverage was significantly higher in older patients (chi(2) for trend 69.41; P < 0.001), males (odds ratio 1.30; 95% confidence interval 1.25, 1.36) and users receiving more than one therapeutic category. CONCLUSIONS: Lack of adherence to chronic cardiovascular treatments represents an important matter of concern: although most people continued treatment over the years, less than 50% received an amount of drugs consistent with daily treatment, thus jeopardizing the proved beneficial effects of available medications.

Hepatic adverse drug reactions: a case/non-case study in Italy.

OBJECTIVE: Adverse drug reactions (ADRs) can involve all tissues and organs. Liver injuries are considered among the most serious and are a cause for concern among physicians and patients. To assess the extent of drug-induced liver injuries in Italy we compared the number of cases of hepatic ADRs with reports of all other drug-related reactions present in the same database. METHODS: Spontaneous reports from six Italian Regions collected from January 1990 to May 2005 were analysed. Adverse reactions were classified according to WHO Adverse Reaction Terminology for causality assessment, and only those with "certain", "probable" or "possible" causality assessment were included. Association between drugs and hepatic ADRs was assessed using the case/non case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. RESULTS: On May 2005, the database contained 35,767 ADR reports, of which 11,829 were excluded because they were unclassifiable or unlikely in terms of causality assessment. Therefore, the analysis was carried out on 23,938 reports, of which 1,069 concerned hepatic ADRs (cases) and 22,869 concerned non-cases. The proportion of serious ADRs was about 40% in the overall database, and about 74% among cases. The drug classes with the highest number of cases were statins (ROR = 2.9, 95% CI 2.4-3.5), antiplatelet agents (ROR = 3.5; 95% CI 2.6-4.6), NSAIDs (ROR = 2.9; 95% CI 2.1-3.9) and macrolides (ROR = 1.7; 95% CI 1.2-2.3). CONCLUSION: Hepatic adverse drug reactions remain a serious concern for several drugs widely used in clinical practice. Monitoring hepatic enzymes on a monthly basis for the first 6 months of treatment has been suggested for patients taking medications known to be hepatotoxic. A better knowledge of the epidemiology and mechanisms of hepatic ADRs may contribute to minimising their occurrence.

Initial treatment of hypertension and adherence to therapy in general practice in Italy.

BACKGROUND: Antihypertensive agents are among the most used therapeutic classes. The approach to the pharmacological treatment of hypertension is guided by international recommendations and adherence to treatment is known to result in effective prevention of cardiovascular risk. AIM: The aim of this study was to evaluate the pattern of use of antihypertensive agents in general practice in terms of drug choice for the initial treatment of hypertension and adherence to treatments among newly recruited patients. METHODS: We collected the data of all antihypertensive drugs prescribed by general practitioners (GPs) and reimbursed between January 1998 and December 2002 by a Local Health Authority of Emilia Romagna (Ravenna district, 350,000 inhabitants). We selected subjects aged 40 years and older, permanently living in the area during the whole period of the study, who received their first prescription of antihypertensives between January and December 1999, with no prescription of antihypertensive agents in the previous year. For each patient, we documented the starting regimen and evaluated adherence to treatment in terms of persistence during the years (patients were defined persistent if they received at least one prescription per year) and in terms of daily coverage (patients were defined covered if they received an amount of drugs consistent with a daily treatment). Finally, switches or addition of other therapeutic classes during the 3-year period were identified. RESULTS: A cohort of 6,043 subjects receiving their first antihypertensive treatment in 1999 was obtained. Regarding the starting regimen, monotherapies with angiotensin converting enzyme inhibitors (n = 1,597; 26%) or calcium channel blockers (n = 1126; 19%) were the most frequently prescribed. Of the patients, 21% started with a drug combination regimen. Regarding adherence to treatment, 18% of the cohort received only one prescription throughout the 3 years, 13% received more than one prescription but stopped the therapy during the first year, 69% were persistent during the second year and 60% also during the third year. Only 34% were covered during the first year and 24% also during the second year, whereas only 20% of the patients resulted covered throughout the 3 years. Among persistent patients, 41% maintained the same antihypertensive regimen throughout the 3 years, 25% added other drugs to the initial treatment and 34% switched to completely different regimens. CONCLUSIONS: Our findings reflect the lack of convergence among guidelines on the drug class(es) to be considered as first choice in the initial treatment of hypertension. Although an intervention in this field may have important implications in terms of cost savings, the ongoing debate does not allow us to draw definite conclusions on whether measures should be taken by the National Health Authority. However, the lack of adherence to antihypertensive treatment is undoubtedly a matter of concern for public health and should be addressed with appropriate interventions.