Triptans and vascular comorbidity in persons over fifty: Findings from a nationwide insurance database - A cohort study.

OBJECTIVE: To gather information about prescription of triptans and to evaluate whether vascular comorbidity differs in users and nonusers of triptans over the age of 50 years. BACKGROUND: Beyond the age of 50 years, migraine is still common-yet the incidence of vascular disorders increases. Triptans, medications for treating migraine attacks, are vasoconstrictive drugs and contraindicated in persons with vascular disorders. METHODS: Based on a nationwide insurance database from 2011, we compared the prescription of vascular drugs (identified by Anatomical Therapeutic Chemical codes), vascular diagnoses and hospitalizations, between triptan users greater than 50 years and a matched control group. RESULTS: Of the 3,116,000 persons over 50 years, 13,833 (0.44%) had at least one triptan prescription; 11,202 (81%) were women. Thirty percent of the triptan users (13,833/47,336 persons) were over 50 years. Of those over 50 years, 6832 (49.4%) had at least one vascular drug and 870 (6.3%) had at least one inpatient vascular diagnosis; 15.7% (2166 of 13,833 users) overused triptans. We compared triptan-users to 41,400 nonusers, using a 1:3 match. In triptan-users, prescriptions of cardiac therapies and beta blockers were significantly more common (odds ratio [OR] = 1.35, 95% confidence interval [CI] = 1.24-1.47 and OR = 1.19, 95% CI = 1.14-1.25, respectively); whereas prescriptions of calcium channel blockers and renin/angiotensin inhibitors were significantly less common (OR = 0.82, 95% CI = 0.76-0.88 and OR = 0.75, 95% CI = 0.72-0.79, respectively). The prescriptions of antihypertensive, diuretic, and antilipidemic drugs as well as platelet inhibitors and direct thrombin inhibitors did not differ in users and nonusers. Triptan users had significantly more hospital stays (OR = 1.39, 95% CI = 1.33-1.45); however, the number of days spent in the hospital and more importantly the frequency of inpatient vascular diagnoses did not differ statistically significantly between the two groups. CONCLUSION: In persons over 50 years of age, a prescription of triptans is common. Vascular comorbidity is comparable in users and nonusers of triptans showing that triptans are prescribed despite vascular comorbidity and suggesting that triptan use does not increase vascular risk in patients with migraine over the age of 50 years. Nevertheless, regular evaluation for contraindications against triptans and for vascular risk factors is recommended in this age group.

Cardiovascular safety of evogliptin in patients with type 2 diabetes: A nationwide cohort study.

AIM: To assess whether the use of evogliptin, a novel dipeptidyl peptidase-4 inhibitor (DPP-4i), was associated with an increased risk of cardiovascular events compared with glimepiride in patients with type 2 diabetes (T2D). METHODS: We conducted a population-based cohort study using South Korea's nationwide healthcare database from 1 January 2014 to 31 December 2018. We identified a base cohort of patients with T2D who newly initiated metformin monotherapy, from which we identified a study cohort of patients who either added or switched to glimepiride or DPP-4is (including evogliptin). Patients were followed up from initiation of DPP-4is or glimepiride until the earliest of either outcome occurrence or 31 December 2018. Our primary outcome was hospitalization or an emergency visit for cardiovascular events, a composite endpoint comprised of cerebrovascular events, heart failure, myocardial infarction, transient ischaemic attack, angina pectoris and revascularization procedures; secondary outcomes were the individual components of the primary outcome. A multivariable Cox proportional hazards model was used to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the risk of study outcomes associated with evogliptin compared with glimepiride. RESULTS: Our base and study cohorts had 317,307 and 128,788 patients, respectively, of which 100,038 were DPP-4i users (2946 were evogliptin users) and 28,750 were glimepiride users within the study cohort. The median follow-up was 195 days for evogliptin and 113 days for glimepiride users. Compared with glimepiride, evogliptin was associated with a reduced risk of the primary outcome (aHR 0.67, 95% CI 0.48-0.95) and cerebrovascular events (aHR 0.41, 95% CI 0.22-0.78) but showed non-significant associations for myocardial infarction (aHR 0.63, 95% CI 0.27-1.46), heart failure (aHR 0.35, 95% CI 0.09-1.47), transient ischaemic attack (aHR 0.23, 95% CI 0.03-1.72) and angina pectoris (aHR 1.35, 95% CI 0.82-2.21). CONCLUSIONS: Findings from this population-based cohort study provide novel real-world evidence that the use of evogliptin, compared with glimepiride, did not increase the risk of cardiovascular events, including cerebrovascular events, myocardial infarction, heart failure, transient ischaemic attack and angina pectoris.

Identification of risk factors and development of detection algorithm for denosumab-induced hypocalcaemia.

WHAT IS KNOWN AND OBJECTIVE: This study used electronic medical records to identify risk factors and establish a detection algorithm for denosumab-induced hypocalcaemia. METHODS: We identified 201 patients with cancer who were initially prescribed denosumab. Hypocalcaemia was defined as an adjusted serum calcium level of ≤2.13 mmol/L. A diagnosis of denosumab-induced hypocalcaemia was confirmed by two physicians after reviewing patient medical records. We evaluated patient characteristics as potential screening factors. Moreover, a retrospective cohort study was conducted to identify risk factors for denosumab-induced hypocalcaemia. Odds ratios (ORs) were estimated using logistic regression analysis. RESULTS: We analysed 164 patients with a low risk of hypocalcaemia. Among these, 29 (17.7%) patients were suspected to have denosumab-induced hypocalcaemia. The times to onset of definitive hypocalcaemia were shorter among these patients than among patients with non-denosumab-induced hypocalcaemia. Based on receiver operating characteristic curve analysis, we used time to onset of hypocalcaemia of ≤90 days as a second screening factor. The positive predictive value of this factor was 87.5%. In the retrospective cohort study, a significant difference was observed among patients with serum alkaline phosphatase (ALP) levels of >5.95 µkat/L before initial prescription (P < 0.01). Patients with higher serum ALP levels had a 6.63 times higher risk of developing hypocalcaemia than those without increased serum ALP levels (OR: 6.63, 95% confidence interval [CI]: 1.79-29.31). The same results were observed in a sensitivity analysis using another database. WHAT IS NEW AND CONCLUSION: We developed a detection algorithm for denosumab-induced hypocalcaemia based on calcium levels and time to onset of hypocalcaemia. We also identified elevated ALP levels as a risk factor for hypocalcaemia. Clinicians should carefully monitor initial serum calcium levels and screen for signs of hypocalcaemia in patients receiving denosumab who demonstrate elevated serum ALP levels.

Association between dipeptidyl peptidase-4 inhibitors and urinary tract infection in elderly patients: A retrospective cohort study.

PURPOSE: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. Although they have been reported to increase the risk of infection, the findings are controversial. Given that urinary tract infections (UTIs) are common in the elderly, we conducted a retrospective cohort study by using health care insurance claims data, to elucidate the association between the DPP-4 inhibitors and the incidence of UTI in latter-stage elderly patients. METHODS: We analyzed 25,111 Japanese patients aged 75 years and older between the fiscal years 2011 and 2016. Patients using DPP-4 inhibitors and sulfonylureas (SUs) were matched at a 1:1 ratio using propensity scoring. The Incidence rate ratio (IRR) of UTI was compared between users of SUs and users of DPP-4 inhibitors by Poisson regression. Moreover, subgroup analyses stratified by sex were conducted to evaluate whether the combination of prostatic hyperplasia and DPP-4 inhibitors is associated with the incidence of UTI in male patients. RESULTS: The use of DPP-4 inhibitors was associated with an increased risk of UTI (adjusted IRR 1.23, 95% CI [1.04-1.45]). After propensity score matching, the association remained significant (adjusted IRR 1.28, 95% CI [1.05-1.56]). Moreover, elderly male patients with prostatic hyperplasia who received DPP-4 inhibitors had a higher risk of UTI than SU users without prostatic hyperplasia (Matched: crude IRR 2.90, 95% CI [1.78-4.71]; adjusted IRR 2.32, 95% CI [1.40-3.84]). CONCLUSIONS: The long-term use of DPP-4 inhibitors by elderly patients, particularly male patients with prostatic hyperplasia, may increase the risk of UTI.

[Hyponatremia associated with SSRI/NRSI: Descriptive and comparative epidemiological study of the incidence rates of the notified cases from the data of the French National Pharmacovigilance Database and the French National Health Insurance]. / Les hyponatrémies sous ISRS/IRSNA : étude épidémiologique descriptive et comparative des taux d'incidence de cas notifiés à partir des données de la Banque nationale de pharmacovigilance et de l'Assurance maladie.

INTRODUCTION: Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are frequently prescribed. These antidepressants can potentially induce serious hyponatremia through the SIADH syndrome. That seems to concern all molecules of these classes but the individual risk of each molecule is not well known. The aims of the study were to compare the incidence rate of each molecule in order to identify the existence of molecules more at risk of inducing hyponatremia and to characterize a profile of patients at risk for hyponatremia during a treatment with a SSRI or a SNRI. METHOD: The cases of hyponatremia under SSRI/SNRI were extracted from the French pharmacovigilance database (BPNV). The exposition to the different SSRIs/SNRIs in the French population was estimated from the French National Health Insurance database (SNIIRAM) using a sampled database (Echantillon Généralistes des Bénéficiaires). The study ran from 01/01/2011 to 31/12/2013. The primary study endpoint was the incidence rate of notifications of the hyponatremia cases in patients treated by SSRI/SNRI and recorded into the BNPV database, related to the average annual number of corresponding treatments initiated during the same period. RESULTS: The number of cases of hyponatremia included in the study was 169 for 3 749 800 adult patients initiating treatment. The incidence rate of cases was 1.64 for 100 000 persons per year (PY). The standardized incidence rates between the different molecules showed no difference except for duloxetine (2.79/100 000 PY p > 0.03). Identified risk factors were age, with a large increase of incidence rate from 75 years old (incidence 12.5 higher) and female gender. CONCLUSIONS: Comparison of the incidence rates from spontaneous reports indicates a greater risk of hyponatremia for duloxetine for 2011-2013. This result needs to be confirmed by other studies. The advanced age and female sex are risk factors, irrespective of the molecule.

Thiazolidinedione Use Is Associated with a Borderline Lower Risk of Multiple Myeloma and a Significantly Lower Risk of Death in Patients with Type 2 Diabetes Mellitus in Taiwan.

BACKGROUND: Thiazolidinedione (TZD) exerts anti-proliferative effects on multiple myeloma (MM) cells. However, there has not been any human study investigating the risk of MM associated with TZD use. METHODS: We used Taiwan's National Health Insurance database to identify 423,949 patients who had been newly diagnosed with diabetes mellitus between 1999 and 2005. After excluding ineligible patients, 86,999 pairs of patients with and without the use of TZD (rosiglitazone or pioglitazone) that had been matched based on propensity score were selected for a follow-up for MM until 31 December 2011. The hazard ratios for MM were estimated using Cox regression and weighted using a propensity score. RESULTS: After a median follow-up of 4.6 years and 4.7 years in ever users and never users of TZD, 32 and 47 cases were diagnosed with MM, respectively. A 35% lower risk (though not statistically significant) was observed among ever users (hazard ratio 0.652, 95% confidence interval: 0.416-1.023, p = 0.0625). When ever users were divided by the median (15 months) cumulative duration of TZD therapy, the hazard ratios (95% confidence interval) for the lower and upper medians were 0.706 (0.394-1.264) and 0.603 (0.346-1.051), respectively. When treated as a continuous variable, the hazard ratio for every 1-month increment of the cumulative duration was 0.980 (95% confidence interval: 0.963-0.997, p = 0.0185). In the age subgroup analysis, a significantly lower risk could be seen in the older age subgroup of ≥65 years (hazard ratio 0.550, 95% confidence interval: 0.305-0.992, p = 0.0468). Additional analyses suggested that there were no interactions between TZD and some medications and between TZD and some clinical diagnoses, and that the use of TZD as a preventive drug for MM might not be cost-effective because a number-needed-to-treat of 5800 was too large. Survival analyses suggested that ever users had a significantly lower risk of death when all patients were analyzed (hazard ratio: 0.84, 95% confidence interval: 0.81-0.87, p < 0.0001 via a log-rank test) or when patients who developed MM were analyzed (hazard ratio: 0.40, 95% confidence interval: 0.19-0.86, p = 0.0153 via a log-rank test). CONCLUSIONS: In Taiwanese patients with type 2 diabetes mellitus, TZD use is associated with a borderline lower risk of MM, which is more remarkable in patients aged ≥65 years. Because of the low incidence of MM, the use of TZD for the prevention of MM may not be cost-effective. Patients who have been treated with TZD may have a survival advantage. Future research is required to confirm the findings.

Exploring public knowledge and perceptions regarding per os OTC pain-relieving medications: the case of paracetamol (acetaminophen).

BACKGROUND: Over-the-counter medications (OTC) are safe and effective when patients follow the patient's information leaflet (PIL) instructions and/or the instructions given by healthcare professionals (HCPs). However, OTC medications could be harmful and unsafe when individuals do not follow the given instructions and/or when their understanding about the proper use of OTC medications is incorrect. This study aimed to investigate the knowledge and perceptions of people regarding paracetamol use in the Republic of Cyprus. METHODS: This cross-sectional study, which belongs to quantitative research methods, included participants visiting community pharmacies in the following three cities of the Republic of Cyprus: Nicosia, Limassol and Larnaca. Participation in the study was voluntary and anonymous. Participants responded to the survey-based questionnaire, which concerned their knowledge and views on paracetamol use. After the data collection, responses were tabulated and analysed statistically. RESULTS: The original compound was shown to be more well-known compared to generics. A notable percentage of respondents-ranging between 13.0% (N = 49) and 29.8% (N = 112)-answered incorrectly that broadly used non-steroidal anti-inflammatory drugs (NSAIDs) contain paracetamol. Furthermore, a remarkable percentage of respondents (71.5%, N = 269 and 50.3%, N = 189, respectively) falsely believed that two widely used combination products in the market of Cyprus (Paracetamol and Hyoscine-N-butylbromide; Paracetamol and Codeine and Caffeine) did not contain paracetamol. A notable percentage of participants (27.6%, N = 100) believed that paracetamol causes low toxicity. More than a third of the respondents (40.2%, N = 149) drink alcohol together with or slightly after consuming paracetamol products. This viewpoint was linked with the participants' attitude towards consuming paracetamol medications after drinking alcohol (OR for consuming alcohol versus not consuming alcohol 0.100, 95% CI 0.044-0.225, p = 0.000). CONCLUSIONS: To the best of our knowledge, this is the first study conducted in the Republic of Cyprus on this topic. Paracetamol is frequently consumed by individuals, both in its generic and original forms. However, the study showed that respondents often misperceive NSAIDs and paracetamol-containing medications. In addition, it is identified that there is a lack of education among people about the safe and effective use of paracetamol, namely, indications, potential side effects, maximum daily dose, alcohol consumption, and the potential risks of hepatotoxicity. The study contributed to the current published literature as it showed that there is a significant public health issue, for which appropriate measures can be established by the respective Authorities of Cyprus.

Pioglitazone and Risk of Chronic Obstructive Pulmonary Disease in Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study.

BACKGROUND: Pioglitazone's effect on chronic obstructive pulmonary disease (COPD) has rarely been studied. PURPOSE: This retrospective observational study investigated whether the use of pioglitazone would affect the risk of COPD in patients with type 2 diabetes mellitus. PATIENTS AND METHODS: The Taiwan's National Health Insurance database was used to enroll 9487 matched pairs of ever users and never users of pioglitazone based on propensity score from a cohort of 350,536 patients. The enrolled patients had a new diagnosis of type 2 diabetes mellitus between 1999 and 2008 and were not having a diagnosis of COPD before January 1, 2009. They were then followed up for COPD, starting from January 1, 2009 until December 31, 2011. Diagnosis of COPD was based on the codes of 491 for chronic bronchitis and 492 for emphysema based on the International Classification of Diseases, Ninth Revision, Clinical Modification. Cox regression was used to estimate hazard ratios. The interactions between pioglitazone and COPD risk factors including pneumonia, pulmonary tuberculosis and tobacco abuse were also investigated. RESULTS: In 9487 never users and 9487 ever users of pioglitazone, the case numbers of incident COPD were 359 and 295, respectively. The respective incidence rates of COPD were 1484.73 and 1167.61 per 100,000 person-years. The overall hazard ratio (95% confidence interval) for COPD that compared ever to never users was 0.778 (0.667-0.908). The hazard ratios for the tertiles of cumulative duration of pioglitazone therapy (cutoffs: <11.0, 11.0-19.6 and >19.6 months) to never users were 0.904 (0.729-1.121), 0.727 (0.578-0.914) and 0.715 (0.570-0.896), respectively. No interactions between pioglitazone and COPD risk factors including pneumonia, pulmonary tuberculosis and tobacco abuse were noted. CONCLUSION: Pioglitazone use is associated with a significantly lower risk of COPD.

The Risk of Multiple Myeloma Is Reduced in Metformin Initiators: A Retrospective Cohort Study in Taiwanese Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Whether metformin might reduce the risk of multiple myeloma (MM) has not been extensively researched in humans. METHODS: The study subjects were enrolled from the reimbursement database of Taiwan's National Health Insurance. A total of 739,553 patients who had a new diagnosis of type 2 diabetes mellitus during 1999-2009 were identified. They were categorized as metformin initiators (metformin (+)) and non-metformin initiators (metformin (-)) based on the prescriptions of antidiabetic drugs that included metformin and did not include metformin within the initial 12 months, respectively. MM incidence was calculated after the initial 12 months of treatment group assignment until 31 December 2011. Hazard ratios based on intention-to-treat (ITT) and per-protocol (PP) approaches were estimated by Cox regression weighted by propensity scores. RESULTS: In the ITT analyses, the respective incidence rates for 497,248 metformin (+) and 242,305 metformin (-) were 9.97 and 14.33 per 100,000 person-years. The hazard ratio that compared metformin (+) to metformin (-) in the ITT analysis was 0.710 (95% confidence interval 0.593-0.850). In the PP analysis, the respective incidence rates were 5.14 and 13.98 per 100,000 person-years, and the hazard ratio was 0.355 (95% confidence interval, 0.270-0.466). The lower risk of MM among metformin (+) was supported by subgroup and sensitivity analyses. CONCLUSIONS: Type 2 diabetes patients who are initiated with metformin treatment have a significantly lower risk of MM, especially when they adhere to metformin treatment.

Estimating Consumers' Knowledge and Attitudes Towards Over-The-Counter Analgesic Medication in Greece in the Years of Financial Crisis: The Case of Paracetamol.

INTRODUCTION: Non-prescription over-the-counter (OTC) drugs are widely used by patients to control aches, pain, and fever. One of the most frequently used OTC medications worldwide is paracetamol (acetaminophen). The aim of the present study was to fill the current knowledge gap regarding the beliefs and attitudes of people in Greece associated with the use of paracetamol during the years of financial crisis. METHODS: The present study employed a sample of individuals visiting community pharmacies in the second largest city of Greece, Thessaloniki. All participants anonymously answered a questionnaire regarding their beliefs and characteristics of paracetamol consumption. Their answers were then statistically analyzed. RESULTS: The generic paracetamol compound was shown to be more well known than the original. A significant percentage of participants, ranging between 9.9% and 33.7%, falsely believed that certain medications [mainly non-steroidal anti-inflammatory drugs (NSAIDs)] contained paracetamol. Participants' age, level of education, and gender were shown to be predictive of this false belief. Additionally, 11.1% of participants believed that the maximum allowed daily dose of paracetamol was higher than the correct one. Better educated individuals were less likely to consume alcohol in parallel with paracetamol (odd ratio 0.230, 95% confidence interval 0.058-0.916, P = 0.037). CONCLUSION: Paracetamol is commonly used, both in its original and generic forms. However, a significant number of individuals confuse it with NSAIDs. Age, level of education, and gender are important determinants of the characteristics of paracetamol consumption. It seems that patients prefer to take paracetamol on their own decision during the financial crisis.

<b>Analysis for Trend in Pharmacoepidemiological Studies </b> / 薬剤疫学

Since the Vol.1 No.1 was published in March 1996, the journal of “Pharmacoepidemiology” has been published approximately two times per year. The current issue is Vol.18 No.1 in 2013. The number of original articles in total was forty-three. Based on these original articles, what type of pharmacoepidemiological studies were performed and the trend of study designs are demonstrated. The studies for database and methodology of pharmacoepidemiology have been constantly conducted. The number of the studies for evaluating drug usefulness and drug utilization is decreasing. In contrast, the studies for evaluating drug safety is increasing, especially, hybrid designs, such as a case-crossover study or nested case-control study are recently conducted.