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Nicorandil, Gastrointestinal Adverse Drug Reactions and Ulcerations: A Systematic Review

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Abstract

Introduction

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.

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Acknowledgments

The study received the financial support from the NHS Highland Research and Development, in the sum of 1115 GBP, which sustained the generation costs of a specific WHO pharmacovigilance database and the expenses related to the dissemination of findings. UP gratefully acknowledges the support of Michael Lim, colorectal surgeon, and Ian Rudd, pharmacy director, who acted as reviewers for the endowment application. The article processing charges were funded by the NHS Highland Research and Development.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published.

UP and AJMW designed the study. The data collection was performed by UP and JD and supervised by AJMW. The analysis and interpretation of data was performed by UP and JD. GFR and IF helped towards the acquisition of additional material. The draft was written by UP and revised critically by SJL, GFR, DS, IF and AJMW. All authors approved the final version of the submitted manuscript.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Disclosures

Umberto Pisano, Jordanna Deosaran, Stephen J. Leslie, Gordon F. Rushworth, Derek Stewart, Ian Ford and Angus J. M. Watson have nothing to disclose.

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Authors and Affiliations

  1. Department of General Surgery, Raigmore Hospital, Inverness, UK

    Umberto Pisano, Jordanna Deosaran & Angus J. M. Watson

  2. Department of Cardiology, Raigmore Hospital, Inverness, UK

    Stephen J. Leslie

  3. Highland Pharmacy Education and Research Centre, Inverness, UK

    Gordon F. Rushworth

  4. School of Pharmacy and Life Sciences, Robert Gordon University, Aberdeen, UK

    Derek Stewart

  5. Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK

    Ian Ford

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  1. Umberto Pisano
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Correspondence to Umberto Pisano.

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Pisano, U., Deosaran, J., Leslie, S.J. et al. Nicorandil, Gastrointestinal Adverse Drug Reactions and Ulcerations: A Systematic Review. Adv Ther 33, 320–344 (2016). https://doi.org/10.1007/s12325-016-0294-9

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