Patrick C. Souverein

Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case–control study

Objective: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. Design and setting: Nested case–control study within a cohort of patients (⩾ 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. Patients: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430–436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. Main outcome measure: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. Results: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose–response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). Conclusions: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes.

Use of antiepileptic drugs and risk of fractures Case–control study among patients with epilepsy

Objective: To study the association between use of antiepileptic drugs (AEDs) and risk of fractures. Methods: The authors obtained data from the General Practice Research Database (GPRD). A case–control study was nested within a cohort of patients with active epilepsy. Cases were patients with a first fracture after cohort entry. Up to four controls were matched to each case by practice, sex, year of birth, timing of first epilepsy diagnosis, index date, and duration of GPRD history. Cumulative exposure to AEDs was assessed by summing the duration of all AED prescriptions. A distinction was made between AEDs that induce the hepatic cytochrome P-450 enzyme system and AEDs that do not. Medical conditions and drugs known to be associated with bone metabolism or falls were evaluated as potential confounders. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% CIs. Results: The study population comprised 1,018 cases and 1,842 matched controls. The risk of fractures increased with cumulative duration of exposure (p for trend < 0.001), with the strongest association for greater than 12 years of use: adjusted OR 4.15 (95% CI 2.71 to 6.34). Risk estimates were higher in women than in men. There was no difference between users of AEDs that induce and AEDs that do not induce the hepatic cytochrome P-450 system. Conclusions: Long-term use of AEDs was associated with an increased risk of fractures, especially in women. More research on mechanisms of AED-induced bone breakdown and female vulnerability to the effects of AEDs on bone health is warranted.

Incidence of fractures among epilepsy patients: a population-based retrospective cohort study in the General Practice Research Database.

Summary:  Purpose: To compare the incidence of various fractures in a cohort of patients with epilepsy with a reference cohort of patients not having epilepsy.

Antipsychotic Drug Use and Risk of Pneumonia in Elderly People

OBJECTIVES: To investigate the association between antipsychotic drug use and risk of pneumonia in elderly people.

Statin treatment and reduced risk of pneumonia in patients with diabetes.

Background: Recent prognostic studies have shown that previous treatment with statins is associated with a better outcome in patients admitted to hospital with pneumonia. Because of an increased risk of pneumonia in patients with diabetes, we assessed the effects of statin use on the occurrence of pneumonia in adult diabetic patients. Methods: All patients with a diagnosis of diabetes (types 1 and 2) enlisted in the UK General Practice Research Database between 1 June 1987 and 21 January 2001 were included. A case-control study was performed with cases defined as patients with a first recorded diagnosis of pneumonia. For each case up to four controls were matched by age, sex, practice, and index date. Patients were classified as current users when the index date was between the start and end date of statin treatment. Conditional multiple logistic regression analysis was used to estimate the strength of the association between statin treatment and the occurrence of pneumonia. Results: Statins were used in 1.1% of 4719 cases and in 2.1% of 15 322 matched controls (crude odds ratio (OR) 0.51, 95% CI 0.37 to 0.68). After adjusting for potential confounders, treatment with statins was associated with a significant reduction in the risk of pneumonia (adjusted OR 0.49, 95% CI 0.35 to 0.69). The association was consistent among relevant subgroups (cardiovascular diseases, pulmonary diseases) and independent of the use of other prescription drugs. Conclusions: The use of statins is associated with a considerable reduction in the risk of pneumonia in diabetic patients. In addition to lowering the risk of cardiovascular disease, statins may be useful in preventing respiratory infections.

Use of antidepressant drugs and risk of osteoporotic and non-osteoporotic fractures

AIM Both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of fractures. The serotonin transporter (5-HTT) has been located in the bone and may play a role in bone physiology. We assessed the association between antidepressant drug use, categorized in a therapeutical-based way and on basis of their affinity for the 5-HTT, and the risk of both osteoporotic and non-osteoporotic fractures. METHODS A case-control study was conducted using the PHARMO RLS. Cases were patients with a first hospital admission for a fracture during the study period. Up to four controls were matched to each case on gender, age, geographical area, and index date. RESULTS We identified 16,717 cases, of whom 59.5% had an osteoporotic fracture, and 61,517 controls. Compared to no use, current use of SSRIs was associated with a statistically significant increased risk of osteoporotic fractures (OR 1.95, 95% CI 1.69-2.26), as was current use of TCAs and non-SSRI/non-TCA antidepressant drugs (ORs 1.37, 95% CI 1.16-1.63 and 1.40, 95% CI 1.06-1.85, respectively). The risk of an osteoporotic fracture was statistically significantly higher for antidepressants with a high affinity for the 5-HTT (OR 1.86, 95% CI 1.63-2.13) compared to antidepressants with a medium or low affinity (OR 1.43, 95% CI 1.19-1.72 (medium) and OR 1.32 95% CI 0.98-1.79 (low) (p<0.05 for trend). The risk of non-osteoporotic fractures did not show the same trend. CONCLUSIONS The extent of affinity for the 5-HTT may contribute to the increased risk of osteoporotic fractures related to antidepressant drug use. The pharmacological mechanism-based classification could to be an appropriate alternative for traditional classification to study the association between the use of antidepressants and the risk of fractures.

Use of beta-blockers and the risk of hip/femur fracture in the United Kingdom and The Netherlands.

Data from in vivo studies have indicated a role for β-blockers in the prevention of bone loss. Some epidemiological studies have found protective effects of β-blockers on fracture risk. However, there is limited information on the association with cumulative dose and type of β-blockers used. We conducted two case-control studies using data from the UK General Practice Research Database (GPRD) and the Dutch PHARMO Record Linkage System (RLS). Cases were patients with a first hip or femur fracture; controls were individually matched on practice/region, gender, year of birth, and calendar time. Current use of β-blockers was defined as a prescription in 90 days before the index date. We adjusted for medical conditions and drugs associated with falling or bone mineral density. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression analysis. The study population included 22,247 cases and controls in the GPRD and 6,763 cases and 26,341 controls in the PHARMO RLS. Current use of β-blockers was associated with a reduced risk of hip/femur fracture in both the GPRD (adjusted OR = 0.82, 95% CI 0.74–0.91) and PHARMO RLS (adjusted OR = 0.87, 95% CI 0.80–0.95) study populations. However, this reduction of risk was not associated with cumulative dose, lipophilicity, or receptor selectivity of β-blockers. The protective effect of β-blockers was only present among patients with a history of use of other antihypertensive agents (GPRD adjusted OR = 0.72, 95% CI 0.64–0.83; PHARMO RLS adjusted OR = 0.76, 95% CI 0.67–0.86) but not in patients using β-blockers only (GPRD adjusted OR = 0.97, 95% CI 0.82–1.14; PHARMO RLS adjusted OR = 1.01, 95% CI 0.90–1.14). Also, in patients with a history of use of other antihypertensive agents, no dose-response relationship with β-blocker use was found. The effect was constant with cumulative dose and the OR was below 1.0 even among patients who just started treatment with β-blockers. As the mechanism by which β-blockers could influence bone mineral density is likely to need some time to exert a clinically relevant effect, all these finding suggests that the association between β-blockers and fracture risk is not causal.

Risk of aplastic anemia in patients using antiepileptic drugs.

Summary:  Purpose: To assess the association between exposure to antiepileptic drugs (AEDs) and the occurrence of aplastic anemia.

Drug Treatment of Benign Prostatic Hyperplasia and Hospital Admission for BPH-Related Surgery

OBJECTIVE To investigate whether there is a difference in the risk of progressing to BPH-related prostatic surgery between patients using alpha-blockers and patients using the 5-alpha-reductase inhibitors (5-ARIs). METHODS A population-based cohort study was conducted, using data from the PHARMO Record Linkage System. We identified 5671 patients (> or =50 years old, no history of using both alpha-blockers and 5-ARIs, more than one year of database history prior to the first date of BPH drug-dispensing), who filled at least one prescription for either alpha-blockers (alfuzosin, tamsulosin, terazosin) or 5-ARIs (finasteride). The incidence of BPH-related surgery was compared between patients treated with alpha-blockers and patients treated with 5-ARIs. RESULTS The cumulative incidence of BPH-related prostatic surgery was 15.2% and mainly involved transurethral resection of the prostate (TURP) (13.4%). Patients using alpha-blockers had a significantly increased risk of BPH-related prostatic surgery compared to patients using 5-ARIs, which remained after adjusting for age, calendar time, type of prescriber and chronic disease score (adjusted HR: 1.52, 95% CI: 1.24-1.88). The difference between alpha-blockers and 5-ARIs was sustained after stratification of time period (<1995, > or =1995) and exclusion of patients with prostatic surgery within one month of treatment initiation. CONCLUSIONS It is concluded that alpha-blocker treated patients had a higher risk of BPH-related surgery compared to 5-ARI treated patients. Additional research on the long-term outcomes and risk factors for the natural progression of BPH is necessary to identify the optimal medical treatment for BPH patients according to their baseline characteristics.

Construction of drug treatment episodes from drug-dispensing histories is influenced by the gap length

OBJECTIVES When constructing drug treatment episodes using drug-dispensing databases, duration and the number of prescriptions belonging to a single treatment episode need to be defined. We investigated how different methods used to construct antidepressant treatment episodes influence their median estimated length. STUDY DESIGN AND SETTING A follow-up study among adult antidepressant drug users, identified from the Dutch PHARMO RLS, starting selective serotonin reuptake inhibitor (SSRI) use in 2001 was conducted. The influence of varying lengths of the prescription overlap and the gap between prescriptions (number of days or percentage of prescription duration) on the median antidepressant treatment episode length were investigated. RESULTS Of the 16,053 SSRI starters, 65.1% were female and mean age was 45.7 (SD: 17.2) years. Median antidepressant treatment episode length doubled when the gap length was expanded from 0 to 10 days. For short gap lengths the episode interquartile range was 40% to 200% larger when overlap was accounted for and when percentage of prescription duration gap length was used. CONCLUSION Differences in median episode length exist between methods that account for or disregard prescription overlap. These differences are of importance for studies that focus on drug exposure-outcome relationships and could have consequences for epidemiological analysis.