Risk of skin ulcerations associated with oral nicorandil therapy: a population-based study.
BACKGROUND
Although healthcare products regulatory agencies have issued warnings on risk of ulceration associated with the use of nicorandil, a population-based study has not been carried out.


OBJECTIVE
To determine the relationship between use of nicorandil and skin ulceration.


METHODS
We carried out a population-based study using a cohort of 1 million people assembled from Taiwan's national health insurance database. The association between nicorandil use and skin ulcers was estimated by a Cox proportional hazards regression model adjusting for a nicorandil-specific propensity score (PS) comprising of 86 potential predictors (c-statistic = 0·91).


RESULTS
The prospective cohort was longitudinally followed from January 2005 to December 2009, during which 1268 new users of nicorandil and 771 136 nonusers were identified. A higher frequency of skin ulcers (29 of 1268; 2·3%) was observed for users of nicorandil compared with nonusers (3231 of 771 136; 0·4%). Compared with nonusers, the crude hazard ratio (HR) associating nicorandil use with skin ulcers was 5·52 [95% confidence interval (CI) 3·82-7·95] and the PS-adjusted HR was 1·85 (95% CI 1·27-2·69). A risk period analysis showed that the risk of skin ulceration among users of nicorandil was greatest in the first year. Subgroup analysis found that the interaction term reached statistical significance (P < 0·05) for age and diabetes.


CONCLUSIONS
Use of nicorandil was found to be associated with an increased risk for skin ulceration, especially in the first year after incident exposure. We suggest that regulatory agencies re-evaluate the risk for skin ulceration associated with use of nicorandil.
Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan.
M-T G
http://orcid.org/0000-0002-2648-1522
MT
Lee
Department of Dermatology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.|Hsin-Yi Lin Dermatological Clinic, Taipei, Taiwan.
H-Y
HY
Lin
Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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SH
Lee
Department of Rehabilitation and Physical Medicine, Taipei Veteran General Hospital, Taipei, Taiwan.|College of Medicine, National Yang Ming University Hospital, Taipei, Taiwan.
S-H
SH
Lee
Department of Family Medicine, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan.|College of Medicine, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, 333, Taiwan.
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SS
Chang
Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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SC
Chen
Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Emergency Medicine, National Taiwan University Hospital Yunlin Branch, Douliou, 640, Taiwan.|Department of General Medicine, National Taiwan University Hospital Yunlin Branch, Douliou, 640, Taiwan.
C-C
CC
Lee
D000284:Administration, Oral; D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D020108:Nicorandil / Q000008:administration & dosage / Q000009:adverse effects*; D011446:Prospective Studies; D012307:Risk Factors; D012883:Skin Ulcer / Q000139:chemically induced*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects*
D014665:Vasodilator Agents; D020108:Nicorandil