Kiyoshi Kubota

Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs in Japan.

ObjectiveStudies in Western populations have shown the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and upper gastrointestinal bleeding (UGIB). The role of Helicobacter pylori infection in NSAIDs-related UGIB remains to be studied. We conducted a case-control study in Japan to investigate these related topics.MethodsCases of UGIB due to duodenal or gastric ulcer, or gastritis were identified in 14 study hospitals in various areas of Japan. For each case, two controls were identified from population registries in the same district. Information on drugs and other risk factors was obtained from 175 cases and 347 controls by telephone interviews. Anti-H. pylori antibody in the urine was measured in a single laboratory for all the cases and 225 controls.ResultsThe odds ratio (OR) of UGIB was 5.5 for aspirin and 6.1 for other NSAIDs (NANSAIDs) (p<0.01). The OR for regular use was higher than for occasional use both for aspirin (7.7 vs 2.0) and NANSAIDs (7.3 vs 4.1). Loxoprofen (5.9), frequently used in Japan as a safe ‘prodrug’, was significantly associated with UGIB. The odds ratio for H. pylori infection was 4.9 and the relative excess risk due to the interaction between H. pylori and the use of NSAID was 1.2 (95% CI: −5.8–8.1).ConclusionNSAIDs including loxoprofen increase the risk of UGIB in Japan as in Western countries, with a similar magnitude of association. There was no evidence of biological interaction between NSAIDs and H. pylori infection.

Epidemiology of psoriasis and palmoplantar pustulosis: a nationwide study using the Japanese national claims database

Objective The primary objective was to estimate the national prevalence of psoriasis and palmoplantar pustulosis (PPP) in Japan. Secondary objectives were to determine (1) whether psoriasis and PPP disease activity varies by season, and (2) whether disease severity is associated with concurrent diabetes mellitus, hyperlipidaemia and hypertension. Settings Patients with a psoriasis or PPP diagnosis code between April 2010 and March 2011 were identified using a Japanese national database. Participants 565 903 patients with psoriasis or PPP were identified. No patient was excluded. Primary and secondary outcome measures National prevalence was calculated using census data. We estimated the difference in the proportion of patients who used healthcare services, as a proxy for disease activity, between the hot and cold seasons and the difference in the standardised prevalence of comorbidities between severe and mild disease. The measures were estimated separately for the two broad disease categories of psoriasis and PPP but not in all patients as planned because the two disease categories had major differences. Results The national prevalence of psoriasis and PPP was 0.34% (95% CI 0.34% to 0.34%) and 0.12% (0.12% to 0.12%), respectively. The difference in the proportion of patients who used healthcare services in the hot compared to the cold season was −0.3% (−0.5% to −0.1%) for psoriasis and 10.0% (9.8% to 10.3%) for PPP. The difference in the standardised prevalence between severe and mild psoriasis was 3.1% (2.7% to 3.4%), 3.2% (2.8% to 3.6%) and 5.1% (4.7% to 5.6%) for concurrent diabetes mellitus, hyperlipidaemia and hypertension, respectively. No significant difference in the prevalence of comorbidity was observed for PPP. Conclusions The national prevalence, seasonal variation in disease activity and prevalence of comorbidities in Japanese patients with psoriasis and PPP estimated in this descriptive study may be used as basic information for future studies.

Survival and Prognostic Factors in Malignant Pleural Mesothelioma: A Retrospective Study of 314 patients in the West Part of Japan

OBJECTIVE The objective in our study was to examine baseline and other characteristics associated with survival in patients with malignant pleural mesothelioma in Japan. METHODS Three hundred and fourteen patients with an adjudicated diagnosis of mesothelioma were examined. Survival was evaluated by the Kaplan-Meier method with the log-rank test. The Cox model was used to estimate the hazard ratio for the possible prognostic factors. RESULTS Of 314 patients, 223 (71%) died and only 40 (13%) were still alive at the end of the observation period starting from the day of diagnosis, while 51 (16%) were transferred to other hospitals or had the last health service contact before the end of the study period yielding the median survival of 308 days. In the multivariate analysis, age older than 70 years (hazard ratio = 2.17; 95% confidence interval, 1.36-3.46), non-epithelioid type (hazard ratio = 1.58; 95% confidence interval, 1.15-2.18), poor performance status (hazard ratio = 3.22; 95% confidence interval, 1.19-8.74), high white blood cell count (hazard ratio = 1.49; 95% confidence interval, 0.99-2.26) and high C-reactive protein level (hazard ratio = 1.80; 95% confidence interval, 1.06-3.06) were negatively associated with survival, after adjustment for other factors. CONCLUSIONS Some baseline conditions including old age, poor performance status, non-epithelioid type, high white blood cell count and high C-reactive protein level were determinants of poor survival of patients with malignant mesothelioma.

The asian pharmacoepidemiology network (AsPEN): Promoting multi-national collaboration for pharmacoepidemiologic research in Asia

Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden Medical Research Collaborating Center, Seoul National University Hospital/Seoul National University College of Medicine, Seoul, South Korea Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, NJ, USA Department of Medicine, Division of Pharmacoepidemiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA Department of Medical Informatics, School of Medicine, Hamamatsu University, Shizuoka, Japan Department of Pharmacoepidemiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Institute of Clinical Pharmacy and Pharmaceutical Sciences, and Health Outcome Research Center, National Cheng Kung University, Tainan, Taiwan Department of Preventative Medicine, College of Medicine, Seoul National University, Seoul, South Korea Korea Institute of Drug Safety and Risk Management, Seoul, South Korea Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia Duke Clinical Research Institute, Durham, NC, USA Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden Karolinska University Hospital, Stockholm, Sweden Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, South Korea Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA

Multi-country rapid adverse drug event assessment: the Asian Pharmacoepidemiology Network (AsPEN) antipsychotic and acute hyperglycaemia study.

To undertake a multi‐country study to investigate the risk of acute hyperglycaemia with antipsychotic use.

Rationale and design of the Eplerenone combination Versus conventional Agents to Lower blood pressure on Urinary Antialbuminuric Treatment Effect (EVALUATE) trial: a double-blinded randomized placebo-controlled trial to evaluate the antialbuminuric effects of an aldosterone blocker in hypertensive patients with albuminuria.

Although inhibitors of the renin–angiotensin system are effective as first-line antihypertensive drugs in hypertensive patients with chronic kidney disease, they cannot completely prevent the progression of renal injury. Many animal studies, including our own, and a few human studies suggest that mineralocorticoid receptor blockade could inhibit the ongoing renal damage in chronic kidney disease. Thus, we designed this double-blinded, randomized, placebo-controlled trial to evaluate the antialbuminuric effect of a low dose (50 mg day−1) of the mineralocorticoid receptor antagonist eplerenone. The study subjects will include 340 hypertensive patients (blood pressure: 130–180/80–100 mm Hg) with albuminuria (urinary albumin/creatinine ratio: 30–600 mg g−1 in the first morning void urine), who are treated with an inhibitor of the renin–angiotensin system. Other classes of antihypertensive drugs may be added as needed to achieve the target blood pressure (<130/80 mm Hg). The primary study end point is the change in the urinary albumin/creatinine ratio after a 1-year study period. This trial is expected to show whether a low dose of mineralocorticoid receptor antagonists can exert an antialbuminuric effect in patients with chronic kidney disease.

The use of a medical dictionary for regulatory activities terminology (MedDRA) in prescription-event monitoring in Japan (J-PEM)

The Medical Dictionary for Regulatory Activities Terminology (MedDRA) version 2.1 (V2.1) was released in March 1999 accompanied by the MedDRA/J V2.1J specifically for Japanese users. In prescription-event monitoring in Japan (J-PEM), we have employed the MedDRA/J for data entry, signal generation and event listing. In J-PEM, the lowest level terms (LLTs) in the MedDRA/J are used in data entry because the richness of LLTs is judged to be advantageous. A signal is generated normally at the preferred term (PT) level, but it has been found that various reporters describe the same event using descriptions that are potentially encoded by LLTs under different PTs. In addition, some PTs are considered too specific to generate the proper signal. In the system used in J-PEM, when an LLT is selected as a candidate to encode an event, another LLT under a different PT, if any, is displayed on the computer screen so that it may be coded instead of, or in addition to, the candidate LLT. The five-level structure of the MedDRA is used when listing events but some modification is required to generate a functional event list.

Vasodilation-related adverse events in diltiazem and dihydropyridine calcium antagonists studied by prescription-event monitoring

The incidence of vasodilation-related events (flushing, headache, dizziness and oedema) was determined in a total of 37,670 patients treated with diltiazem, nicardipine, isradipine or amlodipine and studied by Prescription-Event Monitoring between 1984 and 1991.Event rates are expressed as the percentage of patients who experienced these events during the six months after the first prescription. The rates for all these events with the newer vasoselective dihydropyridines (nicardipine, isradipine and amlodipine) were higher than those with diltiazem. Among the three dihydropyridines, there were large individual differences in the rates. With nicardipine, the frequency of each of the four vasodilation-related events were similar to one another (≈3%). With isradipine, the rates were also similar to one another but all were approximately twice those measured in the nicardipine study (≈6%). These differences may have been due to confounding factors such as the publicity about adverse drug reactions, the indication for use by individual patients or the doses actually being used at the time the event occurred. With amlodipine, in contrast, the rate for oedema was two to four times larger than the rates for flushing, headache or dizziness.

ACE-inhibitor-induced cough, an adverse drug reaction unrecognised for several years: studies in prescription-event monitoring.

AbstractObjective: This study examines cough recorded in Prescription-Event Monitoring (PEM) of four ACE-inhibitors. Particular attention was paid to the study of enalapril because the drug was monitored before the causal relationship between cough and ACE-inhibitors had been widely accepted. Results: Several factors which had obscured the causal relationship in the individual cases were found to be also an obstacle in PEM. For example, cough was a common and non-serious event and was under-reported in the PEM study of enalapril and the rate was not strikingly different from that recorded for other drugs. Cough induced by ACE-inhibitors has several characteristics which reduce the chance of a recognis-able ‘signal’. The original questionnaires returned from doctors in the PEM study of enalapril have been reexamined. The observation that the rate of cough diminished after enalapril had been stopped rather than increased after starting, provided the best evidence of causality, because this was not affected by many biases such as the publicity that had occurred prior to doctors participating in PEM completed later reports.

Drug use investigation (DUI) and prescription-event monitoring in Japan (J-PEM)†

To present ethical issues and relevant problems in observational studies of drug safety in Japan.