Benzodiazepine therapy in psychiatric outpatients is associated with deliberate self-poisoning events at emergency departments—a population-based nested case–control study

Rationale

Deliberate self-poisoning (DSP), the most common form of deliberate self-harm, is closely associated with suicide. Identifying risk factors of DSP is necessary for implementing prevention strategies.

Objectives

This study aimed to evaluate the relationship between benzodiazepine (BZD) treatment in psychiatric outpatients and DSP cases at emergency departments (EDs).

Methods

We performed a retrospective nested case–control study of psychiatric patients receiving BZD therapy to evaluate the relationship between BZD use and the diagnosis of DSP at EDs using data from the nationwide Taiwan National Health Insurance Research Database.

Results

Regression analysis yielded an odds ratio (OR) and 95 % confidence interval (95 % CI) indicating that the use of BZDs in psychiatric outpatients was significantly associated with DSP cases at EDs (OR?=?4.46, 95 % CI?=?3.59–5.53). Having a history of DSP, sleep disorders, anxiety disorders, schizophrenia, depression, or bipolar disorder was associated with a DSP diagnosis at EDs (OR?=?13.27, 95 % CI?=?8.28–21.29; OR?=?5.04, 95 % CI?=?4.25–5.98; OR?=?3.95, 95 % CI?=?3.32–4.70; OR?=?7.80, 95 % CI?=?5.28–11.52; OR?=?15.20, 95 % CI?=?12.22–18.91; and OR?=?18.48, 95 % CI?=?10.13–33.7, respectively). After adjusting for potential confounders, BZD use remained significantly associated with a subsequent DSP diagnosis (adjusted OR?=?2.47, 95 % CI?=?1.93–3.17). Patients taking higher average cumulative BZD doses were at greater risk of DSP.

Conclusion

Vigilant evaluation of the psychiatric status of patients prescribed with BZD therapy is critical for the prevention of DSP events at EDs.     

Effect of cardiovascular drug classes on all-cause mortality among atrial fibrillation patients treated in primary care in Sweden: a cohort study

Background

Risk factors for stroke are well known in atrial fibrillation (AF) patients, while less is known on the effect of these factors on total mortality.

Objective

Our aim was to study the impact of cardiovascular drug classes on mortality in AF patients treated in primary care.

Methods

The study population was chosen based on patient data from 75 primary care centres in Sweden compiled in a database. Individuals diagnosed with AF who were older than 45 years were enrolled (n?=?12,302, of whom?6,660 were men). Cox regression analysis with mortality (years to death) as outcome was conducted in the men and women separately, as well in the age categories <80 and ≥80 years, with cardiovascular drugs as independent factors, and age, cardiovascular diagnoses and educational level as covariates.

Results

Lower mortality was shown for anticoagulant treatment among men, both younger (<80 years) [adjusted hazard ratio (HR) 0.43, 95 % confidence interval (CI) 0.31–0.61] and older (≥80 years) (adjusted HR 0.47, 95 % CI 0.32–0.69), and among younger women (adjusted HR 0.46, 95 % CI 0.29–0.74), and for antiplatelet treatment in older men (adjusted HR 0.51, 95 % CI 0.35–0.74). Treatment with thiazides was associated with lower mortality among younger men (adjusted HR 0.68, 95 % CI 0.48–0.96), older men (adjusted HR 0.67, 95 % CI 0.46–0.98) and older women (adjusted HR 0.70, 95 % CI 0.52–0.94). Statins were associated with lower mortality among younger patients, in both men (adjusted HR 0.47, 95 % CI 0.32–0.68) and women (adjusted HR 0.54, 95 % CI 0.35–0.82).

Conclusions

The differences in age and gender patterns need further exploration.     

Statin use among older Finns stratified according to cardiovascular risk

Purpose

Statin use has increased in older age groups, although there is little evidence for the benefits of statin therapy in the elderly, especially in low-risk persons. The aim of this paper is to describe recent trends in the prevalence and incidence of statin use among the Finnish older population, according to the person’s estimated cardiovascular (CV) event risk.

Methods

We conducted a register study covering the whole community-dwelling population of Finland, aged >70 years in 2000–2008 (N?=?883,051). Data on reimbursed purchases of statins, antidiabetic and CV drugs, and pre-existing CV diseases were retrieved from comprehensive national registers. We stratified each person into low, moderate or high CV risk category, and according to age (70–74, 75–79, and >80 years) and sex.

Results

Between 2000 and 2008, the age-sex-standardized prevalence of statin use tripled from 12.2 % to 38.7 % (rate ratio 3.0, 95 % CI 3.0–3.1), and the incidence almost doubled (from 3.7 % to 6.8 %; rate ratio 1.8, 95 % CI 1.8–1.9). The prevalence and incidence of statin use were consistently highest among high-risk persons. The greatest relative increases were observed in persons aged >80 years and in those at low risk; however, the proportion of statin users at low CV risk remained the same (～7 % of all users).

Conclusions

Statin prescribing is shifting towards older age groups. A substantial increase in prevalence and incidence was seen across all risk categories, but the channeling of statin use towards high-risk persons remained unchanged.     

Dyspnea and Reversibility Profile of P2Y12 Antagonists: Systematic Review of New Antiplatelet Drugs

Background

Dyspnea has been consecutively reported in some trials evaluating new P2Y₁₂ inhibitors.

Objective

We aimed to review and quantify the global risk of dyspnea of recent P2Y₁₂ inhibitor drugs, and evaluate its association with the reversibility profile of P2Y₁₂ inhibitors.

Methods

A database search (March 2013) retrieved randomized controlled trials (RCTs) comparing new antiplatelet drugs (ticagrelor, prasugrel, cangrelor, elinogrel) with clopidogrel. The primary outcome was the incidence of dyspnea. Placebo-controlled trials were excluded. Meta-analysis was performed and estimates were expressed as risk ratio (RR) and 95 % confidence intervals (95 % CIs). Dyspnea incidence was evaluated according to the reversibility profile of P2Y₁₂ antagonists.

Results

We found eight RCTs including 41,289 patients. Prasugrel was not associated with an increased risk of dyspnea (RR 1.09, 95 % CI 0.93–1.27), whereas ticagrelor (RR 1.95, 95 % CI 1.37–2.77), cangrelor (RR 2.42, 95 % CI 1.36–4.33), and elinogrel (RR 3.25, 95 % CI 1.57–6.72) showed an increased risk of dyspnea. Reversible inhibitors significantly increased the risk of dyspnea compared with the irreversible inhibitor, prasugrel, through adjusted indirect comparison (RR 1.99, 95 % CI 1.40–2.82).

Conclusions

The reversible P2Y₁₂ antagonists ticagrelor, cangrelor, and elinogrel have an increased incidence of dyspnea in increasing order when compared with irreversible P2Y₁₂ inhibitors such as clopidogrel or prasugrel.     

Exposure to phototoxic NSAIDs and quinolones is associated with an increased risk of melanoma

Purpose

Ultraviolet radiation exposure is the most important exogenous risk factor for cutaneous malignancies. It is possible that phototoxic drugs promote the development of cutaneous melanoma (CM) by intensifying the effect of ultraviolet light on the skin. We investigated the association between the use of common systemic phototoxic drugs and development of CM.

Methods

This study was a case–control study in a Dutch population-based cohort. The drug dispensing data was obtained from PHARMO, a Dutch drug dispensing and hospital admissions registry, and linked to PALGA, the nationwide pathology network of the Netherlands. The cases were patients diagnosed with pathologically confirmed primary CM between 1991 and 2004. Controls were sampled from the PHARMO population. Exposure to systemic phototoxic drugs was measured and included antimicrobial agents, diuretics, antipsychotic drugs, antidiabetic drugs, cardiac drugs, antimalarials and nonsteroidal anti-inflammatory drugs (NSAIDs). A multivariate conditional logistic regression analysis was performed to study the association between exposure to phototoxic drugs and CM.

Results

The study population included 1,318 cases and 6,786 controls. Any phototoxic drug during the study period was dispensed for 46 % of the cases and 43 % of the controls (p?=?0.012). The use of quinolones [odds ratio (OR) 1.33, 95 % confidence interval (CI) 1.01–1.76] and propionic acid derivative NSAIDs (OR 1.33, 95 % CI 1.14–1.54) had a positive association with CM.

Conclusions

Our study shows that the use of phototoxic drugs is associated with an increased risk of developing CM. Even a short-term use of phototoxic quinolones and propionic acid derivative NSAIDs may increase the risk for CM. Patient education to promote sun-protective behaviour is essential to avoid immediate adverse effects and possible long-term effects of phototoxic drugs.     

Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors or chemotherapy alone in advanced NSCLC: a meta-analysis of randomized controlled trials

Background

Most patients with advanced non-small-cell lung cancer (NSCLC) require systemic chemotherapy. Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors (TKI; e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, axitinib) has recently been evaluated in patients with NSCLC. However, the advantage of this therapy over chemotherapy alone in patients with advanced NSCLC remains largely unknown.

Methods

A meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy and toxicity of chemotherapy plus multitargeted antiangiogenic TKI with chemotherapy alone in patients with advanced NSCLC. PubMed, the ASCO and ESMO databases, and the Cochrane Library were searched for references to published articles. Two reviewers independently assessed the quality of the trials. Data were extracted, and overall response rate (ORR), pooled progression-free survival (PFS), overall survival (OS) with 95 % confidence intervals (CI), and major toxicities/adverse effects were analyzed.

Results

Six RCTs involving 3,337 patients with advanced NSCLC were ultimately analyzed. Compared to chemotherapy alone, chemotherapy plus multitargeted antiangiogenic TKI significantly increased the ORR [relative risk (RR)?1.71, 95 % CI??1.43–2.05] and PFS [hazard ratio (HR) ?0.83, 95 % CI?0.76–0.90], but not OS (HR 0.93, 95 % CI?0.83–1.03). Patients who received chemotherapy plus multitargeted antiangiogenic TKI exhibited more rash, diarrhea and hypertension (OR?2.78, 95 % CI? 2.37–3.26; OR?1.92, 95 % CI?1.65–2.24; OR ?2.90, 95 % CI?2.19–3.84, respectively) and less nausea and vomiting (OR?0.71, 95 % CI?0.60–0.83; OR?0.75, 95 % CI?0.61–0.92, respectively). The incidence of hemorrhage, fatigue, cough, constipation, anorexia, and alopecia were comparable between the two groups.

Conclusions

Therapy consisting of chemotherapy plus multitargeted antiangiogenic TKI was found to have specific advantages over chemotherapy alone in terms of PFS and ORR. The toxicity was comparable between the two therapies. Therefore, chemotherapy plus multitargeted antiangiogenic TKI may be a safe and valid therapeutic option for patients with advanced NSCLC.     

Association between spironolactone added to beta-blockers and ACE inhibition and survival in heart failure patients with reduced ejection fraction: a propensity score-matched cohort study

Purpose

Heart failure (CHF) guidelines recommend mineralocorticoid receptor antagonists for all symptomatic patients treated with a combination of ACE inhibitors/angiotensin receptor blockers (ARBs) and beta-blockers. As opposed to both eplerenone trials, patients in RALES (spironolactone) received almost no beta-blockers. Since pharmacological properties differ between eplerenone and spironolactone, the prognostic benefit of spironolactone added to this baseline combination therapy needs clarification.

Methods

We included 4,832 CHF patients with chronic systolic dysfunction from the Norwegian Heart Failure Registry and the heart failure outpatients’ clinic of the University of Heidelberg. Propensity scores for spironolactone receipt were calculated for each patient and used for matching to patients without spironolactone.

Results

During a total follow-up of 17,869 patient-years, 881 patients (27.0 %) died in the non-spironolactone group and 445 (28.4 %) in the spironolactone group. Spironolactone was not associated with improved survival, neither in the complete sample (HR 0.82; 95 % CI 0.64–1.07; HR 1.03; 95 % CI 0.88–1.20; multivariate and propensity score adjusted respectively), nor in the propensity-matched cohort (HR 0.98; 95 % CI 0.82–1.18).

Conclusion

In CHF outpatients we were unable to observe an association between the use of spironolactone and improved survival when administered in addition to a combination of ACE/ARB and beta-blockers.     

Influence of refill adherence method when comparing level of adherence for different dosing regimens

Purpose

To examine the impact of two methods when estimating refill adherence in patients using bisphosphonates with different dosing regimens.

Methods

In the Swedish Prescribed Drug Register, 18,203 new users of bisphosphonates aged 18–85 years were identified between 1 July 2006 and 30 June 2007 and followed for a maximum of 2 years. The patients were categorised based on dosing regimen: one tablet daily, one tablet weekly, switching between these regimens, and other regimens. Refill adherence was estimated with Continuous measure of Medication Acquisition (CMA, adherent if CMA?≥?80 %) and the maximum gap method (adherent if gaps <45 days). Differences in adherence between patients in the groups were assessed with logistic regression models controlling for confounding factors.

Results

The proportion of patients classified as adherent was higher using CMA compared with patients classified as adherent using the maximum gap method. Patients on one tablet weekly had significantly lower adherence compared with patients on one tablet daily in the main analyses of both methods (the maximum gap method: 73 % vs. 80 %; adjusted OR?=?0.71; 95 % CI 0.57–0.89 and CMA: 84 % vs. 88 %, adjusted OR?=?0.75; 95 % CI 0.57–0.99). Patients using the other two dosing regimens had significantly lower adherence compared with patients on one tablet daily using both methods.

Conclusion

Choice of method has an impact on the estimates of refill adherence to bisphosphonates. Patients on one tablet weekly dosing had lower adherence compared with patients on one tablet daily dosing using both methods.     

Use of medications amongst older persons in Kaunas, Lithuania

Aim

To evaluate the associations between socio-economical factors and the use of medications in the elderly.

Methods

The data was collected in a cross-sectional study in 2009. We received 624 completed questionnaires (response rate — 48.9%) from elderly people aged 60–84 years living in Kaunas (Lithuania). For an evaluation of the impact of explanatory variables on the analyzed events (binary dependent variable), an Enter model of logistic regression was used.

Results

Our findings suggest that 50.8% (n=317) of respondents used at least one drug daily. 18.3% (n=114) of respondents indicated that they use medications regularly, but not on a day-by-day basis. One quarter (25.6%; n=160) used medication only on an “at need” basis. Only 5.3% (n=33) of older persons did not use any medications at all. Logistic regression showed that being male (OR=0.67; 95%CI:0.45–0.98) was associated with using medications “regularly + daily.” For the use of “daily” medications, older age (OR=1.33; 95%CI:1.15–1.53) was associated with using medications daily. An opposite association was observed for respondents having no paid work (OR=0.48; 95%CI:0.26–0.82).

Conclusions

Our study suggests that more than half of older persons in Lithuania use medications every day. Use was associated with socioeconomic factors (gender, age, and employment status).     

Social stratification in the dissemination of statins after stroke in Sweden

Purpose

Since 2005, statins have been recommended to patients with ischaemic stroke. The objective of this study was to analyse how statin treatment has been disseminated in different patient groups (age, sex, socioeconomic status and country of birth) in Sweden between 2004 and 2009.

Methods

The Swedish Stroke Register (Riks-Stroke) has been linked to the Longitudinal Integration Database for Health Insurance and Labour Market Studies. Approximately 85 % of stroke patients in Sweden are included in Riks-Stroke. Odds ratios for statin prescribing were calculated using a multivariable logistic regression model including age, sex, socioeconomic status and risk factors.

Results

During the study period, 108,950 ischaemic stroke patients were discharged alive from hospital. The proportion with statins at discharge increased from 32.9 % in 2004 to 60.1 % in 2009. Patients with secondary school or university education had slightly higher odds [odds ratio (OR) 1.07, 95 % confidence interval (CI) 1.04–1.11 and OR 1.05, 95 % CI 1.01–1.10 respectively] than patients with primary school education. Patients on a high income were prescribed more statins than those on a low income (OR 1.24, 95 % CI 1.19–1.28). Compared with patients born in Sweden, patients born in other countries were prescribed more statins (Nordic countries excepting Sweden: OR 1.07, 95 % CI 1.01–1.14; Europe: OR 1.31, 95 % CI 1.22–1.40; Outside Europe: OR 1.20, 95 % CI 1.08–1.34).

Conclusions

Statin prescribing after ischaemic stroke has increased from 2004 to 2009. Our results also show a social stratification in the dissemination of statins, with patients having a higher income and patients with higher education receiving statins more often than those with a lower income and education, and patients born in Sweden receiving statins less often than those born outside of Sweden.     

Association between an excess risk of acute kidney injury and concomitant use of ibuprofen and acetaminophen in children,retrospective analysis of a spontaneous reporting system

Purpose

Ibuprofen and acetaminophen are frequently alternated or simultaneously used to treat fever or pain in children, while the evidence for the safety of such a combination is lacking. In this study, we analyzed the association of acute kidney injury (AKI) with ibuprofen, acetaminophen, and the combination of both drugs in children (0–12 years) by using the FDA Adverse Event Reporting System (AERS) database between January 2004 and June 2012.

Methods

Adverse event reports in children aged 0 to ≤12 years were included in the study. Cases were defined as reports of AKI according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology, non-cases as all other reports. Exposure categories were divided into three index groups: two groups where ibuprofen or acetaminophen were used in absence of one another and another group where both drugs were used concomitantly. There was also a reference group, in which neither ibuprofen nor acetaminophen was used. These index groups were compared with the reference group using reporting odds ratios (RORs).

Results

In total, 47,803 reports were included in the study. After adjusting for year of reporting, age, and sex, the ROR for an AKI in children who used only ibuprofen or acetaminophen compared with children who used neither ibuprofen nor acetaminophen was 2.14 (95 % CI: 1.59-2.88) and 1.53 (95 % CI: 1.18-1.97), respectively, while the adjusted ROR was 4.01 (95 % CI: 2.96-5.43) when both drugs were concomitantly used.

Conclusions

The results illustrate that the concomitant use of ibuprofen and acetaminophen in children might be associated with increased risk of AKI.     

Prior Antiplatelet Use and Cardiovascular Outcomes in Patients Presenting with Acute Coronary Syndromes

Background

Although antiplatelet therapy effectively reduces ischemic events, the cardiovascular (CV) outcome in some cases is still unpredictable.

Objective

The objective of this study was to evaluate the impact of prior single or dual antiplatelet (PAP) use in patients presenting with acute coronary syndromes (ACS).

Methods

Data were collected from the 2nd Gulf Registry of Acute Coronary Events between October 2008 and June 2009. Patients were grouped according to whether they were PAP users or not (NAP). Patients’ characteristics and outcomes were analyzed and compared. Mortality was assessed at 1 and 12 months.

Results

Among 7827 consecutive ACS patients, 41% were PAP users (70% aspirin, 1% clopidogrel, and 29% dual antiplatelet agents). In comparison with NAP use, PAP use was associated with a higher rate of comorbidities, atypical presentation, severe left ventricular dysfunction, three-vessel disease, and a high GRACE risk score. After adjustment for relevant covariates, PAP use was an independent predictor for recurrent ischemia in unstable angina (odds ratio [OR] 1.7; 95% CI 1.17, 2.57) and non-ST-elevation myocardial infarction (NSTEMI) [OR 1.9; 95% CI 1.38, 2.65] and for heart failure in NSTEMI (OR 1.5; 95% CI 1.11, 2.15) and STEMI (OR 1.4; 95% CI 1.08, 1.93). Although PAP use was associated with high mortality in STEMI and NSTEMI, it was not an independent predictor for mortality. Among PAP patients, percutaneous coronary intervention independently reduced the risk of hospital (adjusted OR 0.25; 95% CI 0.20, 0.32), 1-month (OR 0.31; 95% CI 0.26, 0.37), and 12-month mortality (OR 0.28; 95% CI 0.24, 0.33).

Conclusion

PAP use identified a high-risk population across the ACS spectrum. Early coronary revascularization may improve CV outcomes in these patients.     

Adverse drug reactions in an emergency medical dispatching centre

Purpose

The purpose of this study is to assess the incidence of adverse drug reactions (ADR) leading to call an emergency medical dispatching centre.

Methods

A prospective, observational, monocentric clinical study performed over a 2-year period (2011–2012) in a French prehospital emergency dispatching centre, the Service d'Aide Médicale Urgente (SAMU) covering 1,156,000 inhabitants. All adult patients (age?≥?18) who called for any cause were included. We created an electronic trigger ‘iatrogenic event’ implemented by the dispatching physician for each suspected case of ADR, then we completed the analyses of all the cases with a chief complain represented in more than 1 % of the triggered cases. The primary outcome variable was the occurrence of any possible ADR. We then used the French method of causal relationship assessment.

Results

The SAMU dispatched 339,915 calls during the study. In total, 1,467 ADRs were identified, representing 0.95 % (CI 95 % 0.90–1.00 %) of cases. ADRs were as serious (SADR) in 51.06 % (CI 95 % 48.45–53.67 %) of cases. The major ADR observed was haemorrhage, (42.81 % (CI 95 % 40.62–45.00 %), n?=?628) followed by allergy, hypoglycaemia, vomiting, dizziness and drowsiness. The class of drugs most frequently involved was antithrombotic (43.69 % (CI 95 % 41.45–45.93 %), n?=?641), followed by insulin (17.98 % (CI 95 %:17.06–18.90 %), n?=?264).

Conclusions

Emergency calls concerning ADRs were estimated as 9/1,000, and one out of two is serious.