The Nordic prescription databases as a resource for pharmacoepidemiological research--a literature review.

PURPOSE: All five Nordic countries have nationwide prescription databases covering all dispensed drugs, with potential for linkage to outcomes. The aim of this review is to present an overview of therapeutic areas studied and methods applied in pharmacoepidemiologic studies using data from these databases. METHODS: The study consists of a Medline-based structured literature review of scientific papers published during 2005-2010 using data from the prescription databases in Denmark, Finland, Iceland, Norway, and Sweden, covering 25 million inhabitants. Relevant studies were analyzed in terms of pharmacological group, study population, outcomes examined, type of study (drug utilization vs. effect of drug therapy), country of origin, and extent of cross-national collaboration. RESULTS: A total of 515 studies were identified. Of these, 262 were conducted in Denmark, 97 in Finland, 4 in Iceland, 87 in Norway, and 61 in Sweden. Four studies used data from more than one Nordic country. The most commonly studied drugs were those acting on the nervous system, followed by cardiovascular drugs and gastrointestinal/endocrine drugs. A total of 228 studies examined drug utilization and 263 focused on the effects and safety of drug therapy. Pregnant women were the most commonly studied population in safety studies, whereas prescribers' adherence to guidelines was the most frequent topic of drug utilization studies. CONCLUSIONS: The Nordic prescription databases, with their possibility of record-linkage, represent an outstanding resource for assessing the beneficial and adverse effects of drug use in large populations, under routine care conditions, and with the potential for long-term follow-up.

Benchmarking antimicrobial drug use at university hospitals in five European countries.

A point-prevalence survey of five European university hospitals was performed to benchmark antimicrobial drug use in order to identify potential problem areas in prescribing practice and to aid in establishing appropriate and attainable goals. All inpatients at the university hospitals of Rijeka (Croatia), Tartu (Estonia), Riga (Latvia), Vilnius (Lithuania) and Karolinska-Huddinge (Sweden) were surveyed for antimicrobial drug use during a single day. The frequency of antimicrobial drug use was 24% in Rijeka, 30% in Tartu, 26% in Riga, 14% in Vilnius and 32% in Huddinge. Surgical patients were treated with antimicrobial agents more often than medical patients in Riga (53% vs. 31%), Tartu (39% vs. 26%) and Vilnius (54% vs. 25%). Two-thirds of patients in Rijeka, Tartu, Riga and Vilnius, and fewer than half of the patients in Huddinge, received antimicrobial agents intravenously. Broad-spectrum antimicrobial agents were used most commonly in Rijeka. The prevalence of nosocomial infections treated with antibiotics was 9% at Huddinge, and 3-5% at the other centres. Benchmarking antimicrobial drug use at five university hospitals identified differences and problem areas. The high rates of intravenous administration, poor compliance with guidelines, and prolonged surgical prophylaxis were general problems that deserved specific attention at all centres. A change in prescription practices may reduce unnecessary drug use and decrease antimicrobial resistance.

Differences in antibiotic prescribing in three university hospitals in the Baltic region revealed by a simple protocol for quality assessment of therapeutic indications.

OBJECTIVE: To identify inexpensive and simple quality parameters for the surveillance of antibiotic use in hospital settings. METHODS: A modified point-prevalence study was conducted in three university hospitals in Huddinge, Sweden, Riga, Latvia, and Vilnius, Lithuania. Each ward was visited once during May in the year 2002. All patients receiving antibiotics were identified and their medical records were reviewed by the authors according to the same protocol. Only data from corresponding departments were evaluated and compared. RESULTS: The prevalence of antibiotic use was 35%, 25% and 24% in Huddinge, Riga and Vilnius, respectively. Almost 2/3 of antibiotics were prescribed for treatment and 1/3 for either surgical or medical prophylaxis. Parenteral administration was significantly more common in Riga and Vilnius than in Huddinge. The most commonly prescribed antibiotics were cephalosporins and fluoroquinolones. Prescription of antibiotics for different diagnoses showed large variation between and within hospitals. The first or second generation cephalosporins were prescribed in most cases of surgical prophylaxis. The duration of surgical prophylaxis exceeded one day in 57%, 63% and 87% of cases in Huddinge, Riga and Vilnius, respectively. All antibiotics in Huddinge, and all except five in Riga were supplied by the hospital pharmacy. Antibiotics bought by patients and donated made up 41% of prescribed antibiotics in Vilnius. CONCLUSION: This point-prevalence survey using a simple and inexpensive method for benchmarking demonstrated quantitative and qualitative differences in the use of antibiotics between three university hospitals in the Baltic region, differences that now calls for explanations to their rationality. We suggest that the choice of an antibiotic, rates of intravenously administered treatment and duration of surgical prophylaxis are examples of suitable indicators of rational antibiotic use within a hospital but that comparison of such rates between hospitals is less meaningful.

Antimicrobial use at a university hospital: appropriate or misused? A qualitative study.

OBJECTIVE: To evaluate the quality of antimicrobial drug use in a university hospital medical department (Department of Medicine, University Hospital Rijeka, Croatia) with 279 hospital-beds in wards containing patients from endocrinology, gastroenterology, hematology, clinical immunology, cardiology and coronary care unit, nephrology and pulmonology sections of the hospital. METHODS: The appropriateness of antimicrobial treatment for all in-patients in the Department of Medicine was assessed in a prospective, longitudinal survey carried out during a 21-week period using Kunin's criteria where Categories I and II indicate "appropriate therapy", Categories III and IV indicate major deficiency in the choice or use of antimicrobials. Category V indicates unjustified antimicrobial administration. RESULTS: During the study period, a total of 438 patients were treated with antimicrobials in the Department of Medicine. Of these, 159 (36%) received antimicrobials appropriately (Category I and II), 180 (41%) needed antimicrobials (Category III and IV) but they should have been prescribed differently. The main reason for inappropriate antimicrobial treatment was the wrong choice of antimicrobials (broad-spectrum where a narrow spectrum antibiotic would have been sufficient). In the case of 99 patients (23%) an indication for antimicrobial therapy did not exist (Category V). CONCLUSION: The main reason for suboptimal use of antimicrobials was the over-prescribing of broad-spectrum antimicrobials. This situation should be corrected e.g. by changes in the post-graduate medical teaching program.

Healthcare associated infections in university hospitals in Latvia, Lithuania and Sweden: a simple protocol for quality assessment.

Surveillance of healthcare associated infections is an overlooked parameter of good clinical practice in most healthcare institutions, due to the workload demanded in the absence of adequate IT-systems. The aim of the present study was to investigate whether a simple protocol could be used to estimate the burden of healthcare associated infections in three university hospitals in Huddinge in Sweden, Riga in Latvia and Vilnius in Lithuania and form the basis for initiating a long term follow up system. The medical records of all patients receiving antibiotics were reviewed according to a standardised protocol, focusing on the indications for the drugs and on the frequency of hospital acquired infection (HAI) in a point-prevalence survey. Only comparable specialties were included. The proportion of patients treated with antibiotics (prophylaxis not included) were 63/280 (22%) in Huddinge, 73/649 (11%) in Riga and 99/682 (15%) in Vilnius. The proportion of admitted patients treated for a HAI were 15%, 3% and 4%, respectively, (both comparisons Huddinge versus other centres P <0.001). Surgical site infections were most common, followed by infections with an onset more than 2 days after admission without any of the other registered risk factors present. Our inexpensive and simple method showed that healthcare associated infections were a significant problem among patients admitted to Huddinge. The figures obtained can be used for further discussion and form a baseline for follow up at the local level. The comparison of figures between centres was far less relevant than the process the study created.

Healthcare associated infections in university hospitals in Latvia, Lithuania and Sweden: a simple protocol for quality assessment.

Surveillance of healthcare associated infections is an overlooked parameter of good clinical practice in most healthcare institutions, due to the workload demanded in the absence of adequate IT-systems. The aim of the present study was to investigate whether a simple protocol could be used to estimate the burden of healthcare associated infections in three university hospitals in Huddinge in Sweden, Riga in Latvia and Vilnius in Lithuania and form the basis for initiating a long term follow up system. The medical records of all patients receiving antibiotics were reviewed according to a standardised protocol, focusing on the indications for the drugs and on the frequency of hospital acquired infection (HAI) in a point-prevalence survey. Only comparable specialities were included. The proportion of patients treated with antibiotics (prophylaxis not included) were 63/280 (22%) in Huddinge, 73/649 (11%) in Riga and 99/682 (15%) in Vilnius. The proportion of admitted patients treated for a HAI were 15%, 3% and 4%, respectively, (both comparisons Huddinge versus other centres P<0.001). Surgical site infections were most common, followed by infections with an onset more than 2 days after admission without any of the other registered risk factors present. Our inexpensive and simple method showed that healthcare associated infections were a significant problem among patients admitted to Huddinge. The figures obtained can be used for further discussion and form a baseline for follow up at the local level. The comparison of figures between centres was far less relevant than the process the study created.

Increased prescribing of antidepressants subsequent to beta-blocker therapy.

Using records of the Saskatchewan Prescription Drug Plan, we determined the incidence of antidepressant use (a marker for depressive symptoms) in patients who received beta-blockers or other treatments for chronic diseases (diuretics, antihypertensives, and hypoglycemics) during 1984, but not in the previous 6 months. Antidepressants initiated within 12 months after the study drug were counted. Of the 3218 new beta-blocker users, 6.4% received concurrent prescriptions (ie, within 34 days) for an antidepressant and beta-blocker. Only 2.8% of the reference group (no study drug use) received an antidepressant. A greater proportion of patients prescribed propranolol (9.5%) received an antidepressant than those prescribed other "lipophilic" (3.9%) or "hydrophilic" (2.5%) beta-blockers. Incidence ratios for propranolol revealed the overall risk antidepressant use was 4.8 (95% confidence interval [CI], 4.1 to 5.5) times that of the reference group and 2.1 (95% CI, 1.7 to 2.5) times that of all other study drug users. For propranolol, relative risk of antidepressant use (drug/reference group) varied with age and was greatest in the 20- to 39-year-old group (17.2; 95% CI, 13.7 to 21.5).

Metabolic control in diabetic subjects in three Swedish areas with high, medium, and low sales of antidiabetic drugs.

OBJECTIVE: The relationship between use of antidiabetic drugs and metabolic control was studied in Swedish diabetic populations in areas with high (Gotland), medium (Tierp), and low (Skellefteå) sales of antidiabetic drugs. RESEARCH DESIGN AND METHODS: The study population consisted of 405 drug-treated diabetic subjects aged 50-74 yr. In all three areas, glyburide comprised approximately 75% of the oral treatment. RESULTS: In accordance with sales, Gotland was found to be a heavy-use area, characterized by a high prevalence of insulin treatment (43%), combination therapy with sulfonylureas and biguanide (28%), and high prescribed daily doses (PDDs) of glyburide (15.5 +/- 0.8 mg) compared with other areas. In Skellefteå, 38% were on insulin, 4% were on combination therapy, and the PDD of glyburide was 7.1 +/- 0.6 mg. In Tierp, 27% were on insulin, 26% were on combination therapy, and the PDD of glyburide was 11.4 +/- 0.7 mg. In Gotland, both men and women had significantly lower HbA1c levels, regardless of treatment mode, and a tendency to be more overweight compared with the area with the least pharmacological intensity (Skellefteå). CONCLUSIONS: In the three diabetic populations, good metabolic control, defined as an HbA1c level of less than 7% and acceptable weight control (body mass index less than 27 for men and less than 25 for women), was achieved among only 16% in Gotland, 17% in Skellefteå, and 12% in Tierp.

Pharmacoepidemiological perspectives.

Parallel with increasing concerns about drug safety, the importance of drug surveillance and the application of epidemiologic techniques have grown rapidly during the past decades. The increasing use of computerized health care data facilitates the establishment of populations large enough (millions) to allow epidemiological studies. Such extensive studies are now being done routinely in North America. By the use of computerized pharmacy or billing records, drug exposure is linked to files which include diagnoses. These record-linkage systems provide "objective" drug histories for pharmacoepidemiological cohort and case-control studies and these large databases offer powerful tools for drug evaluation. A number of new drug-disease associations, many of potential importance for European populations, will be discovered through the increased use of large databases in North America. The European community needs to develop a strategy to respond to these overseas findings to protect society from either overreaction or underreaction to drug safety issues.

Prescribing patterns for elderly community-dwelling heavy medicinal drug users in Manitoba, Canada and Jämtland, Sweden.

Patterns of drugs prescribed for elderly community-dwelling heavy medicinal drug users were determined from random samples of data bases and compared between Manitoba, Canada and Jämtland, Sweden for the year 1981. Qualitatively, there was 80% concordance between the 20 most frequently prescribed drugs in Manitoba and in Jämtland. Gender differences were rare, but there were notable quantitative differences for prescription of specific drugs between the two jurisdictions. Drugs to treat cardiovascular diseases were prominent in both groups with thiazides, triamterene and alpha-methyldopa more frequently prescribed for Manitoba patients, and furosemide, potassium supplements and digoxin more frequently prescribed for patients from Jämtland. The frequent prescribing of codeine in combination analgesics in Manitoba and phenothiazines in Jämtland appears to represent geographically disparate approaches to the use of these drugs. Overall, the concordance of prescribed drugs for elderly heavy medicinal drug users from these two jurisdictions appears to outweigh the differences. These results indicate that data from studies of heavy medicinal drug users, at least in the industrialized world, may be more widely applicable than to the geographical location from where they were obtained.

Long-term use of benzodiazepines in a Swedish community: an eight-year follow-up.

Use of benzodiazepines in a Swedish community with a general population of about 20,000 was studied using data from a research registry on prescriptions. A cohort of all benzodiazepine users in 1976, aged 15-84 years, was identified and followed for 8 years with respect to continued benzodiazepine use. A strong tendency towards continuous use was observed. Nearly 70% of the cohort continued use of benzodiazepines during the first follow-up year, 56% used benzodiazepines during the second year as well. One third continued using benzodiazepines during all 8 years of follow-up. Heavy use, previous use of benzodiazepines and age were of great importance for predicting long-term use while sex and type of benzodiazepine were of minor importance. However, after 3 or 4 years of use the pattern was very much the same in all subgroups, about 90% of users continued irrespective of user characteristics.

Fatal upper gastrointestinal hemorrhage or perforation among users and nonusers of nonsteroidal anti-inflammatory drugs in Saskatchewan, Canada 1983.

We report a cohort study of fatal upper GI hemorrhage and/or perforation in relation to use of nonsteroidal anti-inflammatory drugs (NSAIDs) among the one million residents of Saskatchewan Canada in 1983. All hospitalized cases of GI hemorrhage and/or perforation with a fatal outcome were identified using the records linkage system of the Saskatchewan Department of Health. Discharge summaries and autopsy records were reviewed to select the cases of upper GI hemorrhage or upper GI perforation and to exclude cases in which known risk factors were present. The 134,060 residents who filled one or more prescriptions for an NSAID in 1983 were identified and individually linked to their hospital records by patient identification number. The age- and gender-specific incidence of fatal upper GI hemorrhage and/or perforation in the absence of risk factors in users was compared to that in nonusers, controlling for recent history of upper GI disease. Fatal upper GI hemorrhage or perforation in temporal association with NSAIDs is extremely rare in persons younger than 75 years of age. No temporally-related cases occurred in male NSAID users age 75 and older, but NSAID usage in this group was limited. Among women age 75 and older, the rate in users was higher than in nonusers, with the highest rate being in female NSAID users age 75 and older with a recent history of upper GI disease. Total mortality among women age 75 and older was slightly lower among users than among nonusers. Physicians who prescribe NSAIDs to patients age 75 and older should be aware of the potential risks, particularly in those with predisposing factors such as a history of upper GI disease.

Marked differences in antibiotic use and resistance between university hospitals in Vilnius, Lithuania, and Huddinge, Sweden.

Antibiotic use and antimicrobial resistance was compared between Vilnius and Huddinge University hospitals. Drug use data were expressed in number of defined daily doses/100 bed-days; antimicrobial resistance were given as percentages of resistant isolates. Thirty-five and 48 different antibiotic drugs were used in Vilnius and Huddinge, respectively. The overall consumption of antibiotics was 15 DDD/100 bed-days in Vilnius and 43 DDD/100 bed-days in Huddinge. Benzylpenicillin, ampicillin, and aminoglycosides were the major antibiotics in Vilnius; beta-lactamase-resistant penicillins, cefalosporins, and quinolones in Huddinge. In Vilnius, gentamicin made up one-quarter of the use. Staphylococcus aureus and Gram-negative isolates from wounds and blood were more resistant to gentamicin in Vilnius. S. aureus was more often methicillin resistant in Vilnius than in Huddinge. There was no S. aureus-resistant to vancomycin in either hospital. The vancomycin-resistant enterococci made up from 4% to 10% in Vilnius hospital, but they were not detected in Huddinge hospital (0%). The majority of Streptococcus pneumoniae isolates were sensitive to benzylpenicillin in both hospitals. The higher resistance of microorganisms to some antibiotics in Vilnius may be explained by heavy use of few antibiotics. Lower level of hygiene procedures, sampling bias, and other methodological issues may also have contributed. Guidelines for antibiotic use and hygienic procedures are now under development in Vilnius.

Septic complications in relation to factors influencing the gastric microflora in patients undergoing gastric surgery.

Postoperative septic complications and micro-organisms found in primary infections were studied in 750 gastric operations performed between 1972 and 1986. The overall rate of primary infections was 23%. The infection rates were related to the diagnosis and to factors that could influence the colonization of the stomach. No significant differences in the rates of postoperative infections were found between patients who had received preoperative antibiotic prophylaxis and those who had not. In all groups of patients, aerobic and anaerobic gram-positive and gram-negative bacteria and yeasts were isolated in primary infections. Enterobacteriaceae, enterococci and Bacteroides fragiis were more frequent in patients with gastric bleeding or carcinoma.

Relative abuse of diazepam and oxazepam: prescription forgeries and theft/loss reports in Sweden.

Results of previous laboratory studies in humans suggest that the benzodiazepine diazepam has greater abuse liability than the benzodiazepine oxazepam. The validity of these laboratory-based experimental data were examined by analyzing Swedish data on drug abuse. Sales and prescription data showed that use of diazepam was somewhat lower than oxazepam, but of the same general order of magnitude (0.8:1). Prescription data showed that the drugs were prescribed for the same diagnostic indications. After adjustment for differences in use, 'prescription forgeries' and 'mentions in theft and loss reports' were found to be more frequent for diazepam than for oxazepam (2.3:1 and 2.5:1 for forgeries and theft/loss reports, respectively). This effect was consistent for each year examined (1982, 1983, 1984) and occurred when the data were recalculated to exclude Valium, the original and most widely known brand of diazepam. Finally, this pattern with prescription forgeries occurred across different geographical regions in Sweden (1982, 1983).

Epidemiological data suggest antidepressants reduce suicide risk among depressives.

In spite of the availability of antidepressant medication for several decades, it has not been shown that such medication lowers the risk for suicide in depressed patients. This report explores this apparent paradox by means of pharmacoepidemiological methods. Data on the prevalence of depression in the population and among suicides as well as data on the prevalence of antidepressant medication in depressed suicides were obtained from a review of the literature. Data on the prevalence of antidepressant medication in the population in 1990-1991 were obtained from the statistics of the Swedish National Corporation of Pharmacies. It was found that only one in five depressed individuals with major depression were treated with antidepressants in Sweden. The calculated risk for suicide among depressed patients who were treated with antidepressants was 141 per 100,000 person years and, among the untreated, 259 per 100,000 person years (i.e., 1.8 times higher among the untreated). This supports the hypothesis that antidepressant medication decreases the risk for suicide in depressed patients. The reason this has not been obvious in the general suicide statistics seems to be that so few depressed people are treated with antidepressants. Effective suicide prevention strategies should include intensive efforts to recognize and treat more depressed people.

Antidepressants, depression and suicide: an analysis of the San Diego study.

Depression has been consistently reported in 40-50% of suicides. Previous toxicologic studies of suicides have not included diagnostic information, however. This report includes 247 (87%) of 283 suicides in whom it was possible to perform toxicological analyses for tricyclic antidepressants. We wanted to see if any relationships existed among the presence of antidepressants at autopsy, diagnosis of Depression, recent contact with physicians and prescription of antidepressant medication. Toxicology was positive in 19 (8%) subjects. Only 12% of the subjects with a DSM-III diagnosis of Major or Atypical Depression were positive. Lethal blood levels of antidepressants were found in only 4% of all subjects and most of those involved multiple drugs. Also, most of those subjects had co-morbid Depression and Substance Abuse. More than half of the Depressed subjects had seen a physician within 90 days from suicide but less than half of these were prescribed antidepressants and only one-third of the latter were positive for antidepressants in toxicology. These data suggest that more suicides might be averted by decisively treating Depressed patients with ADs, including strict monitoring of dosage and compliance, than by not treating them to avoid AD overdoses. Diagnostic caution should be observed to identify co-morbid Substance Abuse when treating patients with Depression and suicidal ideation.

Selective serotonin reuptake inhibitors have broadened the utilisation of antidepressant treatment in accordance with recommendations. Findings from a Swedish prescription database.

BACKGROUND: With the advent of the selective serotonin reuptake inhibitors (SSRIs), the use of antidepressants has increased drastically in Sweden. The use of tricyclic antidepressants (TCAs) has, however, decreased. METHODS: We surveyed a prescription database in the Swedish county of Jämtland and compared prescription patterns for patients prescribed SSRIs with those prescribed TCAs. RESULTS: The incidence of treatments of antidepressants increased from 0.76% to 1.33% during the period 1991-1996. There were no significant differences between SSRIs and TCAs with regard to patients having only one prescription dispensed within three months from the index prescription, or patients who switched class of antidepressant. Only a minority of the treatments were continued for at least six months, but significantly more SSRI than TCA treatments (42% and 27%). A second treatment period suggesting recurrence was three-times more common in the TCA group than in the SSRI group. CONCLUSION: Provided that the increased use of SSRIs is mainly for depression, these drugs appear, despite a lower efficacy in severe depression, to have enabled a broader utilisation of antidepressants with regard to incidence, dosage and duration, in accordance with recommendations. Further analyses of this phenomenon relative to diagnostic criteria and outcome measures are required.

Transfer of some carboxylic acids in the olfactory system following intranasal administration.

The uptake of [14C]benzoic acid, 4-chloro[14C]benzoic acid, [3H]phthalic acid and [14C]salicylic acid in the nasal passages and brain was determined following a unilateral intranasal instillation in mice. An uptake of radioactivity from the nasal mucosa to the ipsilateral olfactory bulb was observed up to 4 h after administration following intranasal instillation of these carboxylic acids whereas the level was low in the contralateral olfactory bulb. Autoradiography of mice given [14C]benzoic acid and [14C]salicylic acid by intranasal instillation showed a preferential localization of radioactivity in the axonal and glomerular layer of the olfactory bulb 1 h after the administration. Four hours after administration the radioactivity was present as a gradient from the axonal layer towards the center of the olfactory bulb. Pretreatment of mice with a compound known to damage the olfactory neuroepithelium resulted in a decreased uptake of [14C]benzoic acid in the olfactory bulb. Thin layer chromatography of supernatants from the ipsilateral olfactory bulbs of mice given [14C]benzoic acid by nasal instillation indicated that the radioactivity in the bulbs represented unchanged compound. These results suggest that there is a transfer of some aromatic carboxylic acids in the olfactory pathways.

Evaluation of the BioRID P3 and the Hybrid III in pendulum impacts to the back--a comparison to human subject test data.

The BioRID P3 (Biofidelic Rear Impact Dummy) and the Hybrid III were evaluated in pendulum impacts to the back and compared to data from previous cadaver tests. The test setup impacting seated cadavers was reproduced with a pendulum impacting seated dummies at the level of T6 (6th thoracic vertebra). The pendulum mass was 23 kg and the impact velocity 4.6 m/s. The results showed that the BioRID P3 was more biofidelic than the Hybrid III in terms of the peak responses and the temporal window of the head and head relative to T1 horizontal, vertical, and angular displacement. This study is an evaluation of both the BioRID P3 and the Hybrid III against a recently available set of human subject data. The study meets the need for validation of the BioRID P3 at a higher impact severity than has been previously accomplished.