Elena Ballarín

Agranulocytosis associated with dipyrone (metamizol)

ObjectivesReported estimates of the risk of agranulocytosis associated with metamizol have varied by several orders of magnitude. We assessed this association in a large database for the surveillance of blood dyscrasias.MethodsSince 1980, all laboratory units of haematology in a defined area (3.3–4.1×106 inhabitants) contribute to the ascertainment of all cases of agranulocytosis meeting strict diagnostic criteria. These cases of patients with agranulocytosis and sex-, age-, hospital- and date-matched controls were interviewed using a structured questionnaire about previous drug exposures, and relative risks were calculated for several categories of exposure to metamizol.ResultsAfter a total follow-up of 78.73×106 person-years, 273 community cases of agranulocytosis had been found—of which 96 were excluded for various reasons and 177 were included in the case-control analysis—and were compared with 586 matched controls. Thirty cases of agranulocytosis (16.9%) and nine controls (1.5%) had been exposed to metamizol during the week before the index day. The adjusted relative risk was 25.8 [95% confidence interval (CI), 8.4–79.1], and the attributable incidence was 0.56 (0.4–0.8) cases per million inhabitants and per year. The risk disappeared after more than 10 days since the last dose of metamizol, and it increased with duration of use. Those with agranulocytosis exposed to metamizol had taken the drug for longer periods than the exposed controls. Compared with the cases recently reported from Sweden, the duration of use of metamizol by our exposed cases was substantially shorter, and the use of concomitant medications potentially causing agranulocytosis was lower.DiscussionIn our milieu, agranulocytosis attributable to metamizol is rare. Geographical disparities in its risk estimate can be partly explained by differences in its patterns of use, in terms of dose, duration and concomitant medications.

Epidemiology of aplastic anemia : a prospective multicenter study

Aplastic anemia is a rare disease whose incidence varies considerably worldwide. In this study conducted in the metropolitan area of Barcelona, the overall incidence was 2.34 per million inhabitants per year. The survival rate at 2 years was 57%, confirming the severity of this condition. See related perspective article on page 489. Background Aplastic anemia is a rare and severe disease. Its incidence varies considerably worldwide. We aimed at describing the epidemiology of this disease, including the incidence, mortality and survival trends, in a well-defined population. Design and Methods Since 1980, a case-control surveillance study of aplastic anemia has been carried out by a cooperative group, in the metropolitan area of Barcelona. Inclusion is dependent on the patient having at least two of the following features: white blood cell count ≤3.5×109/L, platelet count ≤50×109/L, hemoglobin <10 g/L or hematocrit of <30%; when only one of these last two criteria is fulfilled, a reticulocyte count of ≤30×109/L is also required. The bone marrow biopsy has to be compatible with the diagnosis of aplastic anemia. Results Between 1980 and 2003, a total of 235 cases of aplastic anemia were identified. The overall incidence was 2.34 per million inhabitants per year and the incidence increased with age. Most of the cases were classified as severe or very severe aplastic anemia. Survival rates at 3 months, and at 2 and 15 years after the diagnosis were 73%, 57%, and 51%, respectively. Advanced age and more severe disese at the time of diagnosis were associated with a lower survival rate. There was a trend to a better 2-year survival rate among patients treated with bone marrow transplantation. Forty-nine cases (20.8%) were exposed to drugs reported to be associated with aplastic anemia, and 21 (8.9%) to toxic agents. Conclusions The incidence of aplastic anemia in Barcelona is low but the case fatality rate is high. Advanced age and severe disease at the time of diagnosis were associated with decreased survival.

Randomized Clinical Trial of the Effectiveness of a Home-Based Intervention in Patients With Heart Failure: The IC-DOM Study

INTRODUCTION AND OBJECTIVES The objective of this study was to determine whether a home-based intervention can reduce mortality and hospital readmissions and improve quality of life in patients with heart failure. METHODS A randomized clinical trial was carried out between January 2004 and October 2006. In total, 283 patients admitted to hospital with a diagnosis of heart failure were randomly allocated to a home-based intervention (intervention group) or usual care (control group). The primary end-point was the combination of all-cause mortality and hospital readmission for worsening heart failure at 1-year follow-up. RESULTS The primary end-point was observed in 41.7% of patients in the intervention group and in 54.3% in the control group. The hazard ratio was 0.70 (95% confidence interval [CI] 0.55-0.99). Taking significant clinical variables into account slightly reduced the hazard ratio to 0.62 (95% CI 0.50-0.87). At the end of the study, the quality of life of patients in the intervention group was better than in the control group (18.57 vs. 31.11; P< .001). CONCLUSIONS A home-based intervention for patients with heart failure reduced the aggregate of mortality and hospital readmissions and improved quality of life.

Antiepileptic drugs and suicide: a systematic review of adverse effects.

Background: Since the FDA (Food and Drug Administration) report on antiepileptic drugs (AEDs) and suicide risk was released (2008), several studies have been published on this controversial relationship. This systematic review (SR) gives an updated approach to this health issue. Summary: We searched 6 databases. We ultimately included 11 publications: 4 cohort studies, 1 case-crossover study, 2 community case-control studies, and 4 SRs. Overall, 1 SR described studies already included; 3 studies reported a 2- to 4-fold overall increase in risk; 1 study reported an increased risk of suicide among epilepsy patients on AEDs with high risk of depression; 1study showed a protective effect among epilepsy patients; 2 studies were conducted with patients with bipolar disorder (1 showed a protective effect, whereas the other showed a 3-fold increase in risk of suicide), and the other 3 studies reported results for single AEDs. Several biases affected the published results. Key Messages: There is no clear evidence of an association between the use of AEDs and an increased risk of suicide because of the heterogeneity in the studies at the clinical and methodological level. A future study should cover all indications for use, retrieve information from a healthcare database, and include a defined set of covariates to avoid bias.

Use of granulocyte colony-stimulating factor (G-CSF) and outcome in patients with non-chemotherapy agranulocytosis.

The use of granulocyte colony‐stimulating factor (G‐CSF) in the treatment of non‐chemotherapy drug‐ induced agranulocytosis is controversial. We aimed at assessing the effect of G‐CSF on the duration of agranulocytosis.

Agranulocytosis induced by pyrithyldione, a sedative hypnotic drug

AbstractObjective: Pyrithyldione, a sedative-hypnotic drug with a poor clinical pharmacological development, was associated with anecdotal cases of agranulocytosis in the 1940s in the USA, in the 1960s and 1970s in the ex-Democratic Republic of Germany and in the 1980s in Japan. We describe the estimation of the risk of agranulocytosis associated with its use in Spain, which led to its withdrawal from the market. Methods: In collaboration with the haematology units of all the hospitals in a defined area (3.3–3.9 × 106 inhabitants), all cases of agranulocytosis meeting strict diagnostic criteria were identified. Each case – defined as an episode of agranulocytosis – was reviewed by a haematologist without knowledge of previous drug exposures. Cases and age-, gender- and hospital-matched controls were interviewed with a structured questionnaire about previous drug exposures. In addition, in order to estimate the risk of pyrithyldione-associated agranulocytosis through a case-population approach, its consumption among the cases was compared with its consumption among the general population. Results: After a follow-up of 66.5 × 106 person-years, 330 cases of agranulocytosis (230 community cases) were assembled. Reliable information on previous exposures was obtained for 204 cases. They were compared with 1314 controls. Eleven patients (14 cases, 6.9%) and zero controls had been exposed to pyrithyldione. The adjusted OR was 200.11 (CI 95% 22.62–∞). All patients were female; none had a fatal outcome; three exhibited positive rechallenge; and all had concomitantly taken other drugs. Although pyrithyldione was a prescription-only medicine, only 8% had been dispensed with medical prescriptions. Assuming the worst case, i.e. that all the exposed cases could be attributed to pyrithyldione, the incidence was 35.6 cases per 100,000 patient-years (95% CI, 18.9–60.9), which gives a risk ratio estimate of 109.6 (57.5–191.5) if compared with the incidence of agranulocytosis among the non-exposed population [3.26 cases (CI 95% 2.83–3.71) per 106 inhabitants and per year]. Discussion: Pyrithyldione was viewed by pharmacists as a mild hypnotic, and apparently this had conferred to this drug an unjustified image of safety. The National Commission of Pharmacovigilance recommended to the Ministry of Health its withdrawal from the market when eight cases of agranulocytosis had been identified. However, it took more than 2 years to withdraw it, and six additional cases occurred in the study area. This illustrates the need for quick regulatory action when pharmacoepidemiological data suggest an unfavourable benefit/risk ratio.

Inhaled beta-2-agonists/muscarinic antagonists and acute myocardial infarction in COPD patients

OBJECTIVE Empirical results indicate an increased risk for cardiovascular (CV) adverse drug events (ADE) in chronic obstructive pulmonary disease (COPD) patients treated with beta-2-agonists (B2A) and muscarinic antagonists (MA). A systematic review (including a meta-analysis for drug classes with sufficient sample size) was conducted assessing the association between B2A or MA and acute myocardial infarctions (MI) in COPD patients. METHODS Comprehensive literature search in electronic databases (MEDLINE, Cochrane database) was performed (January 1, 1946-April 1, 2013). Results were presented by narrative synthesis including a comprehensive quality assessment. In the meta-analysis, a random effects model was used for estimating relative risk estimates for acute MI. RESULTS Eight studies (two systematic reviews, two randomized controlled trials, and four observational studies) were comprised. Most studies comparing tiotropium vs. placebo showed a decreased MI risk for tiotropium, whereas for studies with active control arms no clear tendency was revealed. For short-acting B2A, an increased MI risk was shown after first treatment initiation. For all studies, a good quality was found despite some shortcomings in ADE-specific criteria. A meta-analysis could be conducted for tiotropium vs. placebo only, showing a relative risk reduction of MI (0.74 [0.61-0.90]) with no evidence of statistical heterogeneity among the included trials (I(2) = 0%; p = 0.8090). CONCLUSIONS An MI-protective effect of tiotropium compared to placebo was found, which might be attributable to an effective COPD treatment leading to a decrease in COPD-related cardiovascular events. Further studies with effective control arms and minimal CV risk are required determining precisely tiotropiums cardiovascular risk.

Fatal aplastic anaemia associated with nifedipine

Although its risk/benefit ratio has been questioned, nifedipine is still used in the treatment of hypertension and angina. We suggest that nifedipine may be associated with a risk of aplastic anaemia. Since 1980, we have done case-control surveillance on agranulocytosis and aplastic anaemia; initially part of the International Study on Agranulocytosis and Aplastic Anaemia (ISAAA). 1 With the collaboration of haematology services in the Metropolitan Area of Barcelona (4·12‐4·3010 6

Sources of European drug consumption data at a country level

AbstractObjectives This study aimed at outlining the characteristics of nationwide administrative databases monitoring drug consumption in Europe.MethodsInternet and bibliographic databases (April 2010) were searched and experts in drug utilization (DU) research interviewed to find nationwide administrative medicines consumption databases in Europe, with data for the out- and inpatient healthcare sector. A questionnaire was developed to gather additional information. We collected data providers, websites, accessibility, data sources, healthcare settings, population coverage, medicines-related data, patient and prescriber data, periods covered, and linkage to other databases.ResultsThirty-one administrative nationwide medicine consumption databases in 25 countries were identified. Questionnaires were responded for 20 databases. Eleven provided wholesalers’ sales data, 11 on reimbursed, 5 on prescribed, and 4 on dispensing medicines. Fifteen databases provided inpatient drug consumption data, mainly wholesalers’ sales.Conclusions Nationwide administrative databases are of value to all stakeholders involved in the conduct and interpretation of post-marketing safety studies, and in the conduct of DU research. The endorsement of the anatomical therapeutic chemical/defined daily dose methodology by these databases contributes to data harmonization. However, there is still a lack of information on inpatient medicines consumption at a patient-level.

A compilation of research working groups on drug utilisation across Europe

BackgroundThe assessment of the benefit-risk of medicines needs careful consideration concerning their patterns of utilization. Systems for the monitoring of medicines consumption have been established in many European countries, and several international groups have identified and described them. No other compilation of European working groups has been published.As part of the PROTECT project, as a first step in searching for European data sources on the consumption of five selected groups of medicines, we aimed to identify and describe the main characteristics of the existing collaborative European working groups.FindingsGoogle and bibliographic searches (PubMed) of articles containing information on databases and other sources of drug consumption data were conducted. For each working group the main characteristics were recorded.Nineteen selected groups were identified, focusing on: a) general drug utilisation (DU) research (EuroDURG, CNC, ISPE’S SIG-DUR, EURO-MED-STAT, PIPERSKA Group, NorPEN, ENCePP, DURQUIM), b) specific DU research: b.1) antimicrobial drugs (ARPAC, ESAC, ARPEC, ESGAP, HAPPY AUDIT), b.2) cardiovascular disease (ARITMO, EUROASPIRE), b.3) paediatrics (TEDDY), and b.4) mental health/central nervous system effects (ESEMeD, DRUID, TUPP/EUPoMMe). Information on their aims, methods and activities is presented.ConclusionsWe assembled and updated information on European working groups in DU research and in the utilisation of five selected groups of drugs for the PROTECT project. This information should be useful for academic researchers, regulatory and health authorities, and pharmaceutical companies conducting and interpreting post-authorisation and safety studies. European health authorities should encourage national research and collaborations in this important field for public health.