Jesper Hallas

The Danish National Prescription Registry

Introduction: Individual-level data on all prescription drugs sold in Danish community pharmacies has since 1994 been recorded in the Register of Medicinal Products Statistics of the Danish Medicines Agency. Content: The register subset, termed the Danish National Prescription Registry (DNPR), contains information on dispensed prescriptions, including variables at the level of the drug user, the prescriber, and the pharmacy. Validity and coverage: Reimbursement-driven record keeping, with automated bar-code-based data entry provides data of high quality, including detailed information on the dispensed drug. Conclusion: The possibility of linkage with many other nationwide individual-level data sources renders the DNPR a very powerful pharmacoepidemiological tool.

Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study

Abstract Objectives To assess the risk of serious upper gastrointestinal bleeding associated with the newer antithrombotic agents used alone or in combination with other antithrombotic drugs; to describe the trends in use of antithrombotic drugs in the background population. Design Population based case-control study. Setting Funen County, Denmark (population 470 000). Subjects 1443 cases of serious upper gastrointestinal bleeding identified during 2000-4; 57 720 age and sex matched controls. Main outcome measure Exposure to low dose aspirin, clopidogrel, dipyridamole, vitamin K antagonists, and combined antithrombotic treatment. Results Adjusted odds ratios associating drug use with upper gastrointestinal bleeding were 1.8 (95% confidence interval 1.5 to 2.1) for low dose aspirin, 1.1 (0.6 to 2.1) for clopidogrel, 1.9 (1.3 to 2.8) for dipyridamole, and 1.8 (1.3 to 2.4) for vitamin K antagonists. Corresponding figures for combined use were 7.4 (3.5 to 15) for clopidogrel and aspirin, 5.3 (2.9 to 9.5) for vitamin K antagonists and aspirin, and 2.3 (1.7 to 3.3) for dipyridamole and aspirin. Other combinations were used too infrequently to allow estimation. The number of treatment years needed to produce one excess case varied from 124 for the clopidogrel-aspirin combination to 8800 for clopidogrel alone. During the study period, exposure to combined antithrombotic regimens increased by 425% in the background population. Conclusion Antithrombotic treatment is becoming increasingly aggressive. Combined antithrombotic treatment confers particular risk and is associated with high incidence of gastrointestinal bleeding.

Drug related hospital admissions: the role of definitions and intensity of data collection, and the possibility of prevention.

Abstract. Three hundred and thirty‐three consecutive patients in a medical ward were evaluated in a high‐intensity monitoring scheme for drug events as a cause of hospitalization. Taking into consideration only ‘definite’ and ‘probable’ drug events, we found 36 cases (10.8%) of all admissions to be drug‐related hospitalizations (DRH). Of these, 8.1% were adverse drug reactions and 2.7% were therapeutic failures due to ineffective dosage. In 8 cases (2.4%) the drug event could definitely have been avoided, and a further 13 cases (3.9%) were considered to have been potentially avoidable if appropriate measures had been taken by the health service. In 19 cases (53%) the referring physician was unaware of the drug‐related problem. Those patients admitted because of a drug event were taking significantly more drugs than other individuals. The avoidable drug events pointed to the primary health care physicians as the appropriate targets for preventive measures in terms of intensified drug education.

Statins and risk of polyneuropathy A case-control study

BackgroundSeveral case reports and a single epidemiologic study indicate that use of statins occasionally may have a deleterious effect on the peripheral nervous system. The authors therefore performed a population-based study to estimate the relative risk of idiopathic polyneuropathy in users of statins. Method The authors used a population-based patient registry to identify first-time-ever cases of idiopathic polyneuropathy registered in the 5-year period 1994 to 1998. For each case, validated according to predefined criteria, 25 control subjects were randomly selected among subjects from the background population matched for age, sex, and calendar time. The authors used a prescription register to assess exposure to drugs and estimated the odds ratio of use of statins (ever and current use) in cases of idiopathic polyneuropathy compared with control subjects. Results The authors verified a diagnosis of idiopathic polyneuropathy in 166 cases. The cases were classified as definite (35), probable (54), or possible (77). The odds ratio linking idiopathic polyneuropathy with statin use was 3.7 (95% CI 1.8 to 7.6) for all cases and 14.2 (5.3 to 38.0) for definite cases. The corresponding odds ratios in current users were 4.6 (2.1 to 10.0) for all cases and 16.1 (5.7 to 45.4) for definite cases. For patients treated with statins for 2 or more years the odds ratio of definite idiopathic polyneuropathy was 26.4 (7.8 to 45.4). Conclusions Long-term exposure to statins may substantially increase the risk of polyneuropathy.

Polypharmacy: correlations with sex, age and drug regimen A prescription database study

AbstractObjective: To analyse the occurrence of multiple drug use (polypharmacy, PP) in the population and to identify individuals particularly prone to PP. Methods: Data were derived from the Odense Pharmacoepidemiological Database (OPED) and covered all subsidised prescriptions during 1994 presented by inhabitants in the county of Funen (n= 466 567). The number of individuals concurrently using two to four drugs (minor PP) and five or more drugs (major PP) was calculated on a random day in 1994. Drugs were classified according to the Anatomical Therapeutical Chemical (ATC) classification index. The main therapeutic class (second level of the ATC code) was used as an indicator for the type of health problem. A stepwise backwards logistic regression was used to identify predictors of major PP. Odds ratios were calculated for different drug classes, and the age and sex of all drug users. Results: On a random day, 8.3% of the population were exposed to minor PP and 1.2% to major PP. The prevalence of PP increased with age, and from the age of 70 years, two thirds of all drug users were PP users. Drug use was 50% more prevalent among women than men, but over the age of 70, the sexes did not differ in the prevalence of major PP. Many different drug combinations were found, and among major PP users (n= 5443), two thirds had their own unique drug regimen, different from all other drug users. Cardiovascular drugs and analgesics were often involved in PP among the elderly, while asthma drugs, psychotropic drugs and anti-ulcer drugs were predominant among young individuals exposed to PP. The odds ratio (OR) for major PP was substantially increased for individuals treated for cardiovascular diseases (OR, 4.5), anaemia (OR, 4.1) and respiratory diseases (OR, 3.6). Conclusions: PP is widespread in the population. Clinicians and organisers who are responsible for quality assurance programmes should intensify their surveillance of the groups most prone to PP (the elderly and those using analgesics or drugs for cardiovascular disease, anaemia, asthma and diabetes).

The relationship between paroxetine and the sparteine oxidation polymorphism

The relationship between the selective serotonin reuptake inhibitor paroxetine and the sparteine oxidation polymorphism was investigated in a combined single‐dose (30 mg) and steady‐state (30 mg/day for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of sparteine. The median area under the plasma concentration‐time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol · hr/L), whereas at steady state the median AUCsst interphenotype difference was only twofold (4410 versus 2550 nmol · hr/L). Plasma half‐life and steady‐state plasma concentration were significantly longer and higher, respectively, in poor metabolizers than in extensive metabolizers (41 versus 16 hours and 151 versus 81 nmol/L). Paroxetine pharmacokinetics were linear in poor metabolizers and nonlinear only in extensive metabolizers. Sparteine metabolic ratio (MR = 12 hour urinary ratio of sparteine/de‐hydrosparteine), increased during treatment with paroxetine in subjects who were extensive metabolizers, and after 14 days treatment two extensive metabolizers were phenotyped as poor metabolizers and the remaining extensive metabolizers were changed into extremely slow extensive metabolizers with sparteine MRs of 5.7 to 16.5. The inhibition of sparteine metabolism was rapidly reversed after cessation of paroxetine administration. In the poor metabolizers there were no significant changes in MRs during the study. It is concluded that paroxetine and sparteine metabolism cosegregates, but the interphenotype difference in metabolism was less prominent at steady state than after a single dose, presumably because of saturation of the sparteine oxygenase (CYP2D6) in subjects who were extensive metabolizers. Paroxetine is a potent inhibitor of sparteine oxidation by CYP2D6 in vivo.

Lipid-lowering drugs and risk of myopathy: a population-based follow-up study.

We conducted a population-based cohort study to estimate the risk of myopathy associated with use of lipid-lowering drugs. Using data from general practices in the United Kingdom in 1991 through 1997, we identified three cohorts of individuals 40 to 74 years of age. One cohort comprised 17,219 persons who had received at least one prescription for lipid-lowering drugs in the period; a second cohort consisted of patients with a hyperlipidemia diagnosis who had not been prescribed lipid-lowering drugs (N = 28,974); and a third cohort comprised 50,000 individuals from the general population with no diagnosis of hyperlipidemia. The incidence rate of myopathy in the cohort of users of lipid-lowering drugs was 2.3 per 10,000 person-years [95% confidence interval (95% CI) = 1.2–4.4], which exceeded the incidence rates observed in the nontreated hyperlipidemia cohort [0 per 10,000 person-years (95% CI = 0.0–0.4)] and the general population [0.2 per 10,000 person-years (95% CI = 0.1–0.4)]. The relative risks of myopathy in current users of fibrates and statins compared with nonusers were 42.4 (95% CI = 11.6–170.5) and 7.6 (95% CI = 1.4–41.3), respectively. Potential risk factors other than drug use could not explain our findings in the nested case-control analysis. We conclude that use of lipid-lowering drugs is associated with a substantially greater risk of myopathy, which is most pronounced for fibrates. The absolute risk of myopathy in users of lipid-lowering drugs is, however, small.

Evidence of Depression Provoked by Cardiovascular Medication: A Prescription Sequence Symmetry Analysis

&NA; Many cardiovascular drugs have been implicated as causes of depression. With the exception of beta‐blockers, few have been studied in formal epidemiologic designs. I present a new approach to such analyses that effectively controls for confounders that are stable over time. 1 analyzed the exposure histories of 11,244 incident antidepressant users, using the Odense University PharmacoEpidemiologic Database. All persons starting both beta‐blockers and antidepressants during a predefined period were identified. If beta‐blockers do not cause depression, this particular population should show equal numbers of persons starting either drug first. A depression‐provoking effect of beta‐blockers would generate an excess of persons starting beta‐blockers first, that is, a nonsymmetrical distribution of prescription orders. Confounders causing the two drugs to be co‐prescribed would rarely be expected to affect the symmetry. The initial screening showed nonsymmetrical prescription orders for a wide range of cardiovascular drugs. After adjustment for an increasing incidence of antidepressant prescribing, I found a depression‐provoking effect only for angiotensin‐converting enzyme (ACE) inhibitors (rate ratio = 1.29; 95% confidence interval = 1.08‐1.56) and calcium channel blockers (rate ratio = 1.31; 95% confidence interval = 1.14‐1.51). This prescription sequence symmetry analysis may be useful as a screening tool.

Complicated and uncomplicated peptic ulcers in a Danish county 1993-2002: a population-based cohort study.

Peptic ulcer epidemiology changes as the proportion of Helicobacter pylori infected people decreases, use of nonsteroidal anti-inflammatory drugs (NSAID) increases, and the proportion of elderly persons increases.OBJECTIVES:To describe incidence and prognosis of uncomplicated and complicated peptic ulcer patients in Funen County 1993–2002.METHODS:Data on endoscopies, gastric and duodenal operations, and related peptic ulcer diagnoses were extracted from four population-based databases covering a period from 1974 to 2002. All citizens of Funen County (population 470,000) who between 1993 and 2002 had a peptic ulcer diagnosed for the first time were identified.RESULTS:Between 1993 and 2002 the incidence of uncomplicated duodenal ulcer decreased from 0.55/1,000 person-years (95% CI 0.49–0.62) to 0.37 (0.31–0.43), uncomplicated gastric ulcer decreased from 0.56 (0.49–0.63) to 0.40 (0.34–0.46), and perforated ulcer decreased from 0.14 (0.11–0.18) to 0.08 (0.06–0.11). The incidence of bleeding peptic ulcer was stable with 0.55 (0.49–0.62) in 1993 and 0.57 (0.51–0.64) in 2002. The proportion of possible NSAID-related incident peptic ulcers increased from 320/827 (39%) in 1993 to 363/686 (53%) in 2002 (p < 0.01). A total of 3,233 patients with incident complicated peptic ulcer (9,927 person-years) and 4,421 patients with incident uncomplicated peptic ulcer (17,773 person-years) was followed for up to 10 yr. The first month following newly diagnosed complicated ulcer the standardized mortality rate was 37.1 (33.4–41.1) during the next 11 months it was 5.1 (4.6–5.6), and in the following years it was 2.6 (2.4–2.8). The corresponding figures for incident uncomplicated peptic ulcer was 11.6 (9.6–13.9), 4.0 (3.6–4.4), and 2.5 (2.3–2.7).CONCLUSION: During the period, incidence of peptic ulcers decreased and an increasing proportion was related to NSAID. Mortality is high.

Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-inflammatory drugs: A case-control study

BACKGROUND & AIMS Peptic ulcer complications related to use of nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common serious adverse drug reactions. Whether Helicobacter pylori infection potentiates this gastrointestinal toxicity of NSAIDs is still unresolved. In this study, we investigated the role of H. pylori as a cause of bleeding peptic ulcer among NSAID users. METHODS A case-control study of current users (n = 132) of NSAIDs (including acetylsalicylic acid), admitted because of bleeding peptic ulcer, was performed. Controls were 136 NSAID users without gastrointestinal complications. H. pylori was diagnosed by either increased levels of serum immunoglobulin G or by 13C-urea breath test. RESULTS Fifty-eight (44%) case subjects had a bleeding gastric ulcer, 54 (41%) had a bleeding duodenal ulcer, 12 (9%) had both gastric and duodenal ulcers, and 8 (6%) had hemorrhagic gastritis. H. pylori was present in 75 (57%) cases compared with 59 (43%) controls. The adjusted odds ratio of bleeding peptic ulcer among NSAID users associated with H. pylori infection was 1.81 (95% confidence interval, 1.02-3.21). H. pylori accounted for approximately 24% of bleeding peptic ulcers among elderly NSAID users. CONCLUSIONS NSAID users infected with H. pylori have an almost twofold increased risk of bleeding peptic ulcer compared with NSAID users without H. pylori.