Ron M. C. Herings

Combining electronic healthcare databases in Europe to allow for large-scale drug safety monitoring: the EU-ADR Project

In this proof‐of‐concept paper we describe the framework, process, and preliminary results of combining data from European electronic healthcare record (EHR) databases for large‐scale monitoring of drug safety.

Hypoglycaemia associated with use of inhibitors of angiotensin converting enzyme

The use of angiotensin-converting-enzyme (ACE) inhibitors has been associated with increased insulin sensitivity in diabetic patients. Although such an effect could be beneficial in the treatment of hypertension or congestive heart failure in diabetic patients, it might also precipitate severe hypoglycaemia. To test this hypothesis we carried out a nested case-control study, using data in the Dutch PHARMO system (1986-92), among diabetic patients treated with insulin or with oral antidiabetic drugs, who were admitted to hospital with hypoglycaemia. We identified 94 patients who had been admitted with hypoglycaemia and selected 654 controls from the same cohort. With adjustment for a wide range of potential confounding factors, hypoglycaemia was significantly associated with current use of ACE inhibitors (odds ratio 2.8 [95% CI 1.4-5.7]). Both among users of insulin and among users of oral antidiabetic drugs, use of ACE inhibitors was significantly associated with an increased risk of hospital admission for hypoglycaemia (2.8 [1.2-6.4] and 4.1 [1.4-12.2], respectively). Although ACE inhibitors have several advantages over other antihypertensive drugs in diabetes, the risk of hypoglycaemia should be taken into account. Further investigation of the mechanism is needed since as many as 13.8% of all hospital admissions for hypoglycaemia might be attributable to use of ACE inhibitors.

Lower Risk of Cancer in Patients on Metformin in Comparison With Those on Sulfonylurea Derivatives Results from a large population-based follow-up study

OBJECTIVE Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives. RESEARCH DESIGN AND METHODS Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. RESULTS Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88–0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives. CONCLUSIONS In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated.

Psoriasis May Not be an Independent Risk Factor for Acute Ischemic Heart Disease Hospitalizations: Results of a Large Population-Based Dutch Cohort

Although psoriasis has been associated with components of the metabolic syndrome, its association with myocardial infarction is less clear. A cohort study was conducted using hospital and pharmacy records of 2.5 million Dutch residents between 1997 and 2008. The risk of ischemic heart disease (IHD) hospitalizations was compared between psoriasis patients and a matched reference cohort. Additional adjustments were made for healthcare consumption and use of cardiovascular drugs. A total of 15,820 psoriasis patients and 27,577 reference subjects were included, showing an incidence rate of 611 and 559 IHD per 100,000 person-years, respectively (P=0.066). The age- and gender-adjusted risk of IHD was comparable between both cohorts (hazard ratio (HR)=1.10, 95% confidence interval 0.99-1.23). Before cohort entry, psoriasis patients used more antihypertensive, antidiabetic, and lipid-lowering drugs and were more often hospitalized. Adjusting for these confounders decreased the HR for IHD, but it remained comparable between both populations. There was no different risk of IHD between the subgroup of patients who only used topicals versus those who received systemic therapies or inpatient care for their psoriasis. This study, therefore, suggests that psoriasis is not a clinically relevant risk factor for IHD hospitalizations on the population level.

Undertreatment with anti-osteoporotic drugs after hospitalization for fracture

This study assessed the proportion of patients treated with anti-osteoporotic drugs during the 1-year period after hospitalization for a fracture, and the influence of a guideline in the period 1998–2000 on the likelihood of receiving treatment for osteoporosis after a fracture. Patients were assessed retrospectively for anti-osteoporotic drug use during a 1-year period following hospitalization for non-traumatic fracture. The PHARMO system, a population-based database (n=865,000) containing drug and hospitalization data of community-dwelling inhabitants of defined areas in the Netherlands, was used. The study population comprised 1654 patients age 50 years and over who were admitted to hospital for a fracture resulting from a fall during the period 1998–2000. The treatment rate of newly treated patients and the change in treatment rate throughout the period 1998–2000 were the outcome measures. The majority of these patients were women (73%), and had femur fractures (51%). In total, 247 out of 1654 patients (15%) were prescribed anti-osteoporotic drugs within 1 year after discharge from the hospital. Of these 247 patients, 86 were newly treated, mainly with bisphosphonates in the year after discharge following the fracture, yielding a new treatment rate of 5%. The likelihood of receiving treatment for osteoporosis following fracture did not change with the calendar year of fracture (OR 0.95; 95% CI: 0.68–1.30). The result of this study shows that despite the introduction of an osteoporosis treatment guideline in 1999 recommending treatment for fracture patients, most of the time, fracture patients are not being treated for osteoporosis. Thus, to a large extent, osteoporosis remains under-treated.

Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998

OBJECTIVE Fluoroquinolone antibiotics have been associated with tendinitis and tendon rupture. In this paper we report on the followup of 42 spontaneous reports of fluoroquinolone-associated tendon disorders. METHODS This study is based on cases of fluoroquinolone-associated tendon disorders reported to the Netherlands Pharmacovigilance Foundation Lareb and the Drug Safety Unit of the Inspectorate for Health Care between January 1, 1988, and January 1, 1998. By means of a mailed questionnaire, we collected information on the site of injury, onset of symptoms, treatment, and course of the tendon disorder as well as information on possible risk factors and concomitant medication. RESULTS Of 50 mailed questionnaires, 42 (84%) were returned. The data concerned 32 patients (76%) with tendinitis and 10 patients (24%) with a tendon rupture. Sixteen cases (38%) were attributed to ofloxacin, 13 (31%) to ciprofloxacin, 8 (19%) to norfloxacin, and 5 (12%) to pefloxacin. There was a male predominance, and the median age of the patients was 68 years. Most of the reports concerned the Achilles tendon, and 24 patients (57%) had bilateral tendinitis. The latency period between the start of treatment and the appearance of the first symptoms ranged from 1 to 510 days with a median of 6 days. Most patients recovered within 2 months after cessation of therapy, but 26% had not yet recovered at followup. CONCLUSION These reports suggest that fluoroquinolone-associated tendon disorders are more common in patients over 60 years of age. Ofloxacin was implicated most frequently relative to the number of filled prescriptions in the Netherlands.

Venous thromboembolism amng new users of different oral contraceptives.

New use of third generation oral contraceptives is associated with a four-fold increased risk of venous thromboembolism compared with users of second generation oral contraceptives, particularly among young, healthy women.

Influence of question structure on the recall of self-reported drug use.

Epidemiological studies often rely on self-reported information as a source of drug exposure. Several studies have evaluated the accuracy of self-reported information on drug use. The influence of question structure on the accuracy of recall, however, has not been studied extensively in these studies. In this study we examined the recall accuracy of questionnaire information on drug use in a ongoing public health survey with special attention to the influence of question structure on sensitivity of recall. A sample of 372 hypertensive subjects for whom questionnaire information and pharmacy records were available was examined. Self-reported information on drug use was obtained through questions about medications used for a specific condition and one final open-ended question. This information was compared with the pharmacy medication history. About 71% of all drugs that were currently in use according to the pharmacy records were recalled through the self-administered questionnaire, and 94% of all drugs mentioned in the questionnaire could be traced in the pharmacy records. Recall sensitivity was higher for questions about medications used for a specific indication (88%) than for the open-ended question (41%). The type of drug that was used might have caused part of this difference in recall. We conclude that questionnaire structure might be of influence on the accuracy of recall of self-reported drug use, and more attention should be paid to the structure of questions on drug use.

Application of the ATC/DDD methodology to monitor antibiotic drug use

In order to monitor the use of antibiotics, it is essential to have comprehensive data on drug consumption. The findings of drug utilisation studies can serve to describe the pattern of drug use in a particular population, to detect areas of concern, and to evaluate the impact of interventions taken to influence the use of drugs. In the present study, the Anatomical Therapeutical Chemical Classification/Defined Daily Doses (ATC/DDD) system developed by the World Health Organisation was evaluated. The system measures the amount of drug use independentof package size and sales price, which allows comparisons not only within an institution but also within a region, a country, or even internationally. Obviously, there can be no modifications of this system. To illustrate the method, the pattern of quinolone use in the general population, in long-term care facilities, and within a single institution was analysed. These drugs were widely used in long-term care facilities in the Nijmegen region of the Netherlands, accounting for about 30% of the antibiotics used in these settings, whereas in the general population as well as in the University Hospital Nijmegen, these drugs constitute only about 6% of the total antibiotics used. These differences are large enough to warrant closer analysis of patterns of antibiotic usage in different settings to identify the reasons for the use of quinolones and to identify measures that might be taken to rationalise the prescription of these drugs.

N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease

The aim of this study was to evaluate the effect of oral N‐acetylcysteine in the prevention of re-hospitalisation for chronic obstructive pulmonary disease (COPD) exacerbations. Using the PHARmacoMOrbidity linkage (PHARMO) system the authors included all patients aged ≥55 yrs who had been dispensed medication, labelled for respiratory indications (anatomical therapeutic chemical (ATC) classification system: R03), between 1986–1998 and who had also been hospitalised for COPD (International Classification of Diseases (ICD)‐9: 491, 492, 496) in this time frame. These subjects were subsequently divided into two groups, those who had received N‐acetylcysteine following discharge from their first admission between 1986–1998 and those who had not. All the patients were studied starting from their initial discharge, until their first readmission, death or end of data collection period. The maximum follow-up period was 1 yr. A total of 1,219 patients, who were hospitalised for COPD between 1986–1998, were included in this study. After adjustment for disease severity, it was observed that the use of N‐acetylcysteine was significantly associated with a reduced risk of readmission. The readmission risk was significantly lower in patients with high average daily doses of N‐acetylcysteine. In conclusion it was observed that N‐acetylcysteine reduces the risk of re-hospitalisation for chronic obstructive pulmonary disease by ∼30% and that this risk reduction is dose-dependent.