Rene Schade

Long-Term Use of Antidepressants for Depressive Disorders and the Risk of Diabetes Mellitus

OBJECTIVE Use of antidepressants has been reported to cause considerable weight gain. The aim of this study was to assess the risk of diabetes mellitus associated with antidepressant treatment and to examine whether the risk is influenced by treatment duration or daily dose. METHOD This was a nested case-control study in a cohort of 165,958 patients with depression who received at least one new prescription for an antidepressant between January 1, 1990, and June 30, 2005. Data were from from the U.K. General Practice Research Database. Patients were at least 30 years of age and without diabetes at cohort entry. RESULTS A total of 2,243 cases of incident diabetes mellitus and 8,963 matched comparison subjects were identified. Compared with no use of antidepressants during the past 2 years, recent long-term use (>24 months) of antidepressants in moderate to high daily doses was associated with an increased risk of diabetes (incidence rate ratio=1.84, 95% CI=1.35-2.52). The magnitude of the risk was similar for long-term use of moderate to high daily doses of tricyclic antidepressants (incidence rate ratio=1.77, 95% CI=1.21-2.59) and selective serotonin reuptake inhibitors (incidence rate ratio=2.06, 95% CI=1.20-3.52). Treatment for shorter periods or with lower daily doses was not associated with an increased risk. CONCLUSIONS Long-term use of antidepressants in at least moderate daily doses was associated with an increased risk of diabetes. This association was observed for both tricyclic antidepressants and selective serotonin reuptake inhibitors.

Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior

Background: A recent meta-analysis of randomized trials revealed that antiepileptic drugs (AEDs) as a class increase the risk of suicidal thoughts and behavior. We conducted an observational study with data from the United Kingdom General Practice Research Database to investigate if an increase in risk for different groups of AEDs is also evident in clinical practice. Methods: This was a nested case-control study in a cohort of 44,300 patients with epilepsy who were treated with AEDs. Patients with self-harm or suicidal behavior were identified by predefined codes. We included 453 cases and 8,962 age-matched and sex-matched controls. AEDs were classified into 4 groups: barbiturates, conventional AEDs, and newer AEDs with low (lamotrigine, gabapentin, pregabalin, oxcarbazepine) or high (levetiracetam, tiagabine, topiramate, vigabatrin) potential of causing depression. Adjusted odds ratios (OR) were calculated using conditional logistic regression. Results: Current use of newer AEDs with a high potential of causing depression was associated with a 3-fold increased risk of self-harm/suicidal behavior (OR = 3.08; 95% [CI] 1.22–7.77) as compared with no use of AEDs during the last year. Use of barbiturates (OR = 0.66; 95% CI 0.25–1.73), conventional AEDs (OR = 0.74; 95% CI 0.53–1.03), or low-risk newer AEDs (OR = 0.87; 95% CI 0.47–1.59) was not associated with an increased risk. Conclusions: Newer AEDs with a rather high frequency of depressive symptoms in clinical trials may also increase the risk of self-harm or suicidal behavior in clinical practice. For the most commonly used other groups of AEDs, no increase in risk was observed.

Cyclooxygenase-2 Selective Nonsteroidal Anti-Inflammatory Drugs and the Risk of Ischemic Stroke: A Nested Case-Control Study

Background and Purpose— Several randomized trials and a large number of epidemiological studies have provided evidence of an increased risk of acute myocardial infarction associated with the use of cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs). Few data are available concerning the risk of ischemic stroke associated with COX-2 inhibitors. Methods— We performed a nested case-control study in a cohort of 469 674 patients registered within the UK General Practice Research Database (GPRD), who had at least 1 prescription of an NSAID between June 1, 2000 and October 31, 2004. A total of 3094 cases with ischemic stroke were identified and 11 859 controls were matched on age, sex, year of cohort entry and general practice. Odds ratios (ORs) of ischemic stroke associated with the use of COX-2 selective NSAIDs were calculated by conditional logistic regression. Results— Current use of rofecoxib (OR=1.71; 95% CI, 1.33 to 2.18), etoricoxib (OR=2.38; 95% CI, 1.10 to 5.13), but not of celecoxib (OR=1.07; 95% CI, 0.79 to 1.44) was associated with a significantly increased risk of ischemic stroke. For rofecoxib and etoricoxib, ORs tended to increase with higher daily dose and longer duration of use and were also elevated in patients without major stroke risk factors. Conclusions— Our study suggests that COX-2 selective NSAIDs differ in their potential to cause ischemic cerebrovascular events. An increased risk of ischemic stroke may be influenced by additional pharmacological properties of individual COX-2 inhibitors.

Suboptimal gastroprotective coverage of NSAID use and the risk of upper gastrointestinal bleeding and ulcers: an observational study using three European databases

Background Gastro-protective agents (GPA) are co-prescribed with non-steroidal anti-inflammatory drugs (NSAID) to lower the risk of upper gastrointestinal (UGI) events. It is unknown to what extent the protective effect is influenced by therapy adherence. Aim To study the association between GPA adherence and UGI events among non-selective (ns) NSAID users. Methods The General Practice Research Database (UK 1998–2008), the Integrated Primary Care Information database (the Netherlands 1996–2007) and the Health Search/CSD Longitudinal Patient Database (Italy 2000–2007) were used. A nested case-control design was employed within a cohort of nsNSAID users aged ≥50 years, who also used a GPA. UGI event cases (UGI bleeding and/or symptomatic ulcer with/without obstruction/perforation) were matched to event-free members of the cohort for age, sex, database and calendar time. Adherence to GPA was calculated as the proportion of nsNSAID treatment days covered by a GPA prescription. Adjusted OR with 95% CI were calculated. Results The cohort consisted of 618 684 NSAID users, generating 1 107 266 nsNSAID episodes. Of these, 117 307 (10.6%) were (partly) covered by GPA, 4.9% of which with a GPA coverage <20% (non-adherence), and 68.1% with a GPA coverage >80% (full adherence). 339 patients experienced an event. Among non-adherers, the OR was 2.39 (95% CI 1.66 to 3.44) for all UGI events and 1.89 (95% CI 1.09 to 3.28) for UGI bleeding alone, compared to full adherers. Conclusions The risk of UGI events was significantly higher in nsNSAID users with GPA non-adherence. This underlines the importance of strategies to improve GPA adherence.

The risk of new onset heart failure associated with dopamine agonist use in Parkinson's disease.

The aim of present study was to investigate the risk of heart failure associated with dopamine agonist use in patients with Parkinsons disease. The data sources of this study were four different population-based, healthcare databases in United Kingdom, Italy and Netherlands. A case control study nested within a cohort of Parkinsons disease patients who were new users of either dopamine agonist or levodopa was conducted. Incident cases of heart failure were identified and validated, using Framingham criteria. Controls were matched to cases on age, gender and database. To estimate the risk of newly diagnosed heart failure with ergot and non-ergot derived dopamine agonists, as compared to levodopa, odds ratios and 95% confidence intervals were calculated through conditional logistic regression. In the cohort of 25,459 Parkinsons disease patients (11,151 new users of dopamine agonists, 14,308 new users of levodopa), 518 incident heart failure cases were identified during follow-up. Compared to levodopa, no increased risk of heart failure was found for ergot dopamine agonists (odds ratio: 1.03; 95% confidence interval: 0.69-1.55). Among non-ergot dopamine agonists, only pramipexole was associated with an increased risk of heart failure (odds ratio: 1.61; 95%confidence interval: 1.09-2.38), especially in the first three months of therapy (odds ratio: 3.06; 95% confidence interval: 1.74-5.39) and in patients aged 80 years and older (odds ratio: 3.30; 95% confidence interval: 1.62-7.13). The results of this study indicate that ergot dopamine agonist use in Parkinsons disease patients was not associated with an increased risk of newly diagnosed heart failure. Among non-ergot dopamine agonists, we observed a statistically significant association between pramipexole use and heart failure, especially during the first months of therapy and in very old patients.

Adherence to gastroprotection during cyclooxygenase 2 inhibitor treatment and the risk of upper gastrointestinal tract events: A population-based study

OBJECTIVE Guidelines recommend coprescription of gastroprotective agents (GPAs) in patients receiving cyclooxygenase 2 inhibitors (coxibs) who are at high risk of upper gastrointestinal (UGI) tract complications (i.e., patients with a previous complicated ulcer or with multiple risk factors). Suboptimal GPA adherence has been shown to diminish the gastroprotective effect during use of nonselective nonsteroidal antiinflammatory drugs, but little is known about the effect of GPA adherence during coxib treatment. We undertook this study to determine the association between GPA adherence and UGI tract events among patients receiving coxibs. METHODS Using primary care data from 3 databases, we conducted a case-control study in a cohort of patients age ≥50 years who were newly starting treatment with coxibs and concomitantly taking GPAs. Patients who had a UGI tract event (bleeding or symptomatic ulcer) were matched to event-free controls for age, sex, database, and calendar date. Coxib treatment intervals were defined as consecutive coxib prescriptions with intervening gaps not exceeding the duration of the previous coxib prescription. Adherence to GPAs was calculated as the proportion of days of coxib treatment covered by a GPA prescription. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using conditional logistic regression analysis. RESULTS The coxib plus GPA-treated cohort consisted of 14,416 coxib-treated patients who received GPAs for at least 1 day, yielding 16,442 coxib treatment intervals in which a GPA was coprescribed. Most patients were treated with coxibs for <30 days. Seventy-four patients had a UGI tract event during or shortly after a coxib treatment interval in which a GPA was coprescribed, with an incidence rate of 11.9 (95% CI 9.4-14.8) per 1,000 years of coxib treatment. The risk of UGI tract events was 1.97 (95% CI 0.84-4.60) for patients with <20% adherence to GPAs compared to patients with >80% adherence to GPAs. For every 10% decrease in GPA adherence, the risk of UGI tract events increased by 9% (OR 1.09 [95% CI 1.00-1.18]). CONCLUSION Decreasing GPA adherence among coxib-treated patients is associated with an increased risk of UGI tract events.

Cyclo-oxygenase-2 inhibitors or nonselective NSAIDs plus gastroprotective agents: what to prescribe in daily clinical practice?

Two strategies for prevention of upper gastrointestinal (UGI) events for nonselective nonsteroidal anti‐inflammatory drug (nsNSAID) users are replacement of the nsNSAID by a cyclo‐oxygenase‐2‐selective inhibitor (coxib) or co‐prescription of a gastroprotective agent (GPA).

Time-Trends in Use of Gastroprotective Strategies With NSAID Treatment in the United Kingdom, Italy, and the Netherlands; A Comparative Study

Background: To reduce the risk of upper gastrointestinal (UGI) complications related to non-steroidal anti-inflammatory drugs (NSAIDs), gastroprotective strategies (GPS) are recommended in patients at risk. Aim: To compare GPS prescription behaviour by general practitioners (GP) in 3 European countries. Methods: We conducted a population-based cohort study in 3 GP databases: 1) United Kingdoms (UK) GP Research Database (1998-2008), 2) Italys (IT) Health Search/Thales Database (2000-2007), and 3) the Dutch (NL) Integrated Primary Care Information database (1996-2006). Study cohorts comprised all incident NSAID users ≥50 yrs. As preventive strategies we considered: 1) co-prescription of proton pump inhibitors, double dose H2-receptor antagonists, or misoprostol, or 2) use of a cyclooxygenase-2-specific inhibitor (coxib). Consistent with American College of Gastroenterology treatment guidelines, appropriate prescription was defined as the use of a GPS in NSAID users with≥1 UGI risk factor (history of UGI bleeding/ulceration, age≥ 65 yrs, concomitant use of anticoagulants, aspirin, or corticosteroids) and also no GPS in patients without UGI risk factors. Under-prescription was defined as no GPS in patients with ≥1 UGI risk factor. Over-prescription was the presence of a GPS in patients with no UGI risk factors. Results: The study populations comprised of 384,649 UK (mean age: 64.8 yrs, 41% male), 179,030 IT (mean age: 64.6 yrs, 41.7% male) and 55,005 NL NSAID users (mean age: 63.4 yrs, 42.6% male). In the UK, appropriate prescription increased from 51% in 1998 to 59% in 2008 (linear trend (lt) p<0.001) and over-prescription from 3% to 7% (lt p=0.04). Underprescription fell from 46% to 34% (lt p<0.001). In IT, appropriate prescription rose from 46% in 2000 to 60% in 2007 (lt p<0.001) and over-prescription from 3% to 8% (lt p= 0.74), while under-prescription fell from 51% to 32% (lt p=0.01). In the NL, appropriate prescription rose from 53% in 1996 to 63% in 2006 (lt p<0.001) and over-prescription from 4% to 14% (lt p<0.001). Under-prescription decreased from 43% to 23% (lt p<0.001). Between 2000 and 2006, appropriate prescription was significantly higher and underprescription significantly lower in NL compared to UK and IT (p<0.001). Conclusions: The appropriate prescription of GPS has increased over the past years in all three countries assessed. Although under-prescription of GPS use has decreased, it still occurred in 23-34% of NSAID users with upper GI risk factors. This still requires major improvement. The variability across countries was smaller than expected, considering the cultural and structural differences between national health care systems. However, differences across countries are likely to influence the incidence of NSAID-related UGI complications and health care costs.

Adherence to Gastroprotective Agents and the Risk of Upper Gastrointestinal Complications in Coxib Users

Background: Little is known about the upper gastrointestinal (UGI) protective effect of gastroprotective agents (GPAs) in COX-2-specific inhibitors (coxib)-users. Objectives: To study the association between GPA adherence and UGI complications among coxib-users. Methods: We used primary care data from the United Kingdoms (UK) General Practice Research Database , the Dutch (NL) Integrated Primary Care Information database, and the Italian (IT) Health Search/Thales Database. A case-control study was conducted within a cohort of coxib+GPA users aged ≥ 50 yrs. Episodes of coxib use were defined as a period of coxib use with gaps between subsequent prescriptions that were no longer than 100% of the duration of the previous coxib prescription. Patients could have more than one episode of coxib use during follow-up, but only if at least a 180-days NSAID-free period was present prior to the start of each episode. Cases with UGI complications (UGI bleeding and diagnosed symptomatic UGI ulcers) during or within 60 days after coxib use were matched to controls on age, gender, database, and calendar time. Adherence to GPAs was calculated over the most recent episode of coxib use prior to the index date as the proportion of coxib treatment days covered (PDC) by a GPA prescription. Adherence was expressed as a continuous variable as well as categorical (low (PDC 80%)). Adjusted odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using conditional logistic regression. Results: 98,940 coxib episodes were counted in the coxib user cohort (UK: 52,698; NL: 7,201, IT: 39,041). In 16,442 (16.6%) of the eligible coxib episodes a GPA was prescribed (UK: 21.2%; NL: 13.4%, IT: 11.0%). Of the GPA users, 7.2% had low adherence (PDC 80%). Overall, mean pooled adherence was 0.76±0.30 (UK: 0.79±0.29; NL: 0.85±0.27; IT: 0.66±0.30). Only 18% used coxibs >90 days. In those patients, mean adherence dropped to 0.65 ± 0.34. Within the coxib+GPA users, we identified 74 cases with an UGI complication (30 UGI bleedings and 44 (un)complicated UGI ulcers). Mean adherence (PDC) to GPA was 0.72±0.32 for UGI complication cases compared to 0.78±0.30 for controls. Among low adherers, the risk was 1.97 (95%CI 0.84-4.60) for all UGI complications, compared with high adherers. For every 10% decrease in adherence, the risk of all UGI complications increased by 9% (OR: 1.09, 95%CI: 1.001.18). Conclusions: The risk of UGI complications increased by 9% in all coxib users ≥ 50 years for every 10% decrease in adherence of GPAs. Patients benefit from GPAs in addition to coxibs to lower their increased risk of UGI complications.

Risk of ischemic stroke and the use of individual non-steroidal anti-inflammatory drugs: A multi-country European database study within the SOS Project

Background and purpose A multi-country European study using data from six healthcare databases from four countries was performed to evaluate in a large study population (>32 million) the risk of ischemic stroke (IS) associated with individual NSAIDs and to assess the impact of risk factors of IS and co-medication. Methods Case-control study nested in a cohort of new NSAID users. For each case, up to 100 sex- and age-matched controls were selected and confounder-adjusted odds ratios for current use of individual NSAIDs compared to past use calculated. Results 49,170 cases of IS were observed among 4,593,778 new NSAID users. Use of coxibs (odds ratio 1.08, 95%-confidence interval 1.02–1.15) and use of traditional NSAIDs (1.16, 1.12–1.19) were associated with an increased risk of IS. Among 32 individual NSAIDs evaluated, the highest significant risk of IS was observed for ketorolac (1.46, 1.19–1.78), but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam. IS risk associated with NSAID use was generally higher in persons of younger age, males, and those with a prior history of IS. Conclusions Risk of IS differs between individual NSAIDs and appears to be higher in patients with a prior history of IS or transient ischemic attack (TIA), in younger or male patients. Co-medication with aspirin, other antiplatelets or anticoagulants might mitigate this risk. The small to moderate observed risk increase (by 13–46%) associated with NSAIDs use represents a public health concern due to widespread NSAID usage.