Safety study to quantify the risk of ulceration (including all sites of occurrence), and related events (including perforations, fistula, abscess and bleeding) and death among patients treated with nicorandil with and without diverticular disease

Date of ISAC Approval: 
04/07/2016
Lay Summary: 
Nicorandil belongs to a group of medicines called 'potassium channel activators'. It works by increasing the blood flow through the blood vessels of the heart. It improves the blood and oxygen supply of the heart muscle and reduces its workload. Nicorandil is used to prevent or attenuate painful, straining symptoms (angina pectoris) of heart disease. Nicorandil may cause injuries to the gastrointestinal tract such as ulcers. This can develop problems such as bleeding, fistula, holes, abscess, especially in patients with diverticular disease (a digestive condition affecting the large intestine). Regulatory authorities recommended to conduct a safety study to quantify the risk of ulceration (including all sites of occurrence), and related events (including perforations, fistula, abscess and bleeding) and identify any person with an increased risk of developing those events. We will use routinely collected health information from the Clinical Practice Research Datalink. The findings of our study are expected to help ascertain the rates of of ulceration in patients treated with nicorandil, as well as subsequent erosion, perforation, haemorrhages, abscesses formation, fistulae and delayed wound healing and, to identify other potential risk factors, thereby aiding the development of preventive measures.
Technical Summary: 
The purpose of this study is to quantify the time-related risk and patterns of erosions, ulcerations, perforations, haemorrhages, abscesses, fistulae, delayed wound healing in patients treated with nicorandil (including gastrointestinal, skin, ocular, mucosal, anal; alone or in multiple locations), and death; together with the exploration of high risk subgroups, other risk factors, and a dose and time effect assessment. This is a retrospective cohort study using the UK CPRD database. The inclusion criteria will be: patients aged 18 and older, with a diagnosis of angina pectoris between 01/01/1995 and 31/12/2014, and an initial prescription for Nicorandil. They will be longitudinally followed-up until end of observation period or death. Exposure will be determined individually for each patient. Outcomes of interest will include Perforation, Ulcer, Fistula, Abscess, Erosion, Diverticulosis, Diverticulitis, Death, Delayed wound healing, haemorrhages (PUFAEDH). Standard descriptive statistics, Kaplan-Meier time to event assessment and Cox proportional hazards modelling will be used. The main outcomes will be the incidence rates and 95% confidence intervals for the outcomes of interest, as stratified by variables. Additional descriptive analyses will be provided for specific subgroups, i.e. patients with discontinuation with and without treatment restart, and patients with sequence of events suggesting progression or reversibility.
Health Outcomes to be Measured: 
Perforations, Ulcer, Fistula, Abscesses, Erosions, Diverticulosis, Diverticulitis, Death, Delayed wound healing, Hemorrhages. Outcomes of interest have been identified using READ codes.
Collaborators: 

Sandra Guedes - Chief Investigator - Merck Group (KGaA)
Juergen Zieschang - Collaborator - Merck & Co., Inc.
Sampada Gandhi - Collaborator - Genzyme - Sanofi Company
Sandra Guedes - Corresponding Applicant - Merck Group (KGaA)
Shinichi Matsuda - Collaborator - Merck & Co., Inc.
Ulrike Gottwald-Hostalek - Collaborator - Merck Group (KGaA)