title: Nicorandil, Gastrointestinal Adverse Drug Reactions and Ulcerations: A Systematic Review.
abstract: BACKGROUND
  Nicorandil is a popular anti-anginal drug in Europe and Japan. Apart from some common adverse drug reactions (ADR), its safety is satisfactory. Several reports have suggested a link between nicorandil, gastrointestinal (GI) ulceration and fistulas. The review aims to critically appraise, synthesize and present the available evidence of all known GI ADR per anatomical location.
  
  
  METHODS
  The study complied with the PRISMA statement. Literature and pharmacovigilance databases were used to provide rate and/or calculate parameters (median age, median dose, history of symptoms, length of therapy and healing time after withdrawal of the drug). Differences in distribution of quantitative variables were analyzed via Mann-Whitney test. Correlation between quantitative variables was assessed with a Spearman's correlation coefficient. A p value <0.05 was significant.
  
  
  RESULTS
  Oral ulcerations occur in 0.2% of the subjects, anal ulcerations are present between 0.07% and 0.37% of patients. Oral and distal GI involvements are the most common ADR (28-29% and 27-31% of all GI ADR, respectively). The hepatobiliary system, the pancreas and salivary glands are not affected by nicorandil exposure. The time to develop oral ulcerations is 74 weeks among people on <30 mg/day compared to only 7.5 weeks in individuals on higher regimens (p = 0.47). There is a significant correlation between dose and ulcer healing time (Spearman's 0.525, p < 0.001).
  
  
  CONCLUSIONS
  Ulcerative disease is a very commonly reported GI ADR. A delayed ulcerative tendency supports the hypothesis of an ulcerogenic metabolite. Nicorandil seems to act as a cause of the ulcerations, but appears to also work in synergy with other promoting factors. Whether the action of the metabolites relies on a specific mechanism or a simple chemical ulceration is still to be established.
authors: Department of General Surgery, Raigmore Hospital, Inverness, UK. u.pisano@nhs.net.
authors: Umberto
authors: http://orcid.org/0000-0001-8400-1139
authors: U
authors: Pisano
authors: Department of General Surgery, Raigmore Hospital, Inverness, UK.
authors: Jordanna
authors: J
authors: Deosaran
authors: Department of Cardiology, Raigmore Hospital, Inverness, UK.
authors: Stephen J
authors: SJ
authors: Leslie
authors: Highland Pharmacy Education and Research Centre, Inverness, UK.
authors: Gordon F
authors: GF
authors: Rushworth
authors: School of Pharmacy and Life Sciences, Robert Gordon University, Aberdeen, UK.
authors: Derek
authors: D
authors: Stewart
authors: Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
authors: Ian
authors: I
authors: Ford
authors: Department of General Surgery, Raigmore Hospital, Inverness, UK.
authors: Angus J M
authors: AJ
authors: Watson
mesh_terms: D000368:Aged; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020108:Nicorandil / Q000009:adverse effects*; D019226:Oral Ulcer / Q000139:chemically induced; D010437:Peptic Ulcer / Q000139:chemically induced; D013997:Time Factors
chemical_list: D020108:Nicorandil
keywords: Cardiology; Family medicine; Gastroenterology; Pharmacology; Surgery