Objective：To assess the risk for hyperkalemia caused by treatment with angiotensin Ⅱ Type 1 receptor blockers （ARB） in clinical practice with Japanese medical database.

Design：A cohort study in patients treated with ARB alone and those treated with calcium channel blockers （CCB） alone as control.

Methods：The Diagnosis Procedure Combination （DPC） database provided by Medical Data Vision Co., Ltd. was used to identify patients who received a diagnosis of hypertension (ICD-10 codes, I10 to I15) and were treated with ARB or CCB from April 2008 to June 2017. A logistic regression model was applied to estimate adjusted odds ratios （OR） and their 95％ confidence intervals （CI） in these patients. The outcome in the logistic model was hyperkalemia （serum potassium≧5.5 mEq/L） and the covariates were sex, age, renal insufficiency, hepatic insufficiency, and baseline serum potassium levels. And, subgroup analysis was also performed in patients with and without renal insufficiency.

Results：The incidence of hyperkalemia （per 1000 person-years） with ARB was 39.4 and that with CCB was 32.6. And, median periods from the index date to the date of occurrence of hyperkalemia for both exposure and control groups were 36 days （Min-Max：12-85） and 51.5 days（Min-Max：8-88）respectively. However, treatment with ARB was not associated with occurrence of hyperkalemia （OR 1.26, 95％CI： 0.58-2.75). The risk for hyperkalemia among those with renal insufficiency was higher （OR 3.31, 95％CI： 1.39-7.88）and as baseline serum potassium increased, the risk increased as well （OR 9.20, 95％CI： 3.52-24.10). And, the subgroup analysis also showed that rare occurrence of hyperkalemia by ARB and elevation risk for hyperkalemia by baseline serum potassium.

Conclusion：The clinical data showed rare occurrence of hyperkalemia caused by ARB, indicating that renal insufficiency and baseline serum potassium levels affected the onset of the disease in clinical practice. Previous studies also reported the effects of renal insufficiency and other factors on the onset of hyperkalemia. ARB should be prescribed carefully in patients with these factors, as is conventionally done.

Monitoring of the safety profile for the approved medical products consists of routine pharmacovigilance activities for all drugs and additional pharmacovigilance activities for product-specific concerns. Signal management is an important part of routine pharmacovigilance activities, so EMA and FDA have published the guidelines for signal management in various documents. The AMED Risk Management Plan （RMP） research group, which started its activities in 2018 to enhance risk management plan in Japan, reviewed the guidelines and related articles and then put together the principles of signal management. The guidelines in EU and US describes the signal detection and evaluation methods including points to consider when conducting them, responsibilities of each action, and the procedures that the regulatory authorities disclose the outcome of their activities, in addition to the principles and procedures of signal management. Through the guidelines, they establish transparency for public including pharmaceutical industry. Our group first created the Japanese definitions of signal-related terms. Based on them, we created high-level concept for a series of activities from signal detection to risk identification and discussed the future vision of signal management in Japan.