Four patients with nicorandil induced ulceration are described, and the literature on the subject is reviewed. Nicorandil induced ulcers are very painful and distressing for patients. Clinically they appear as large, deep, persistent ulcers that have punched out edges. They are poorly responsive to topical steroids and usually require alteration of nicorandil treatment. The ulceration tends to occur at high doses of nicorandil and all four cases reported here were on doses of 40 mg per day or greater. In these situations reduction of nicorandil dose may be sufficient to promote ulcer healing and prevent further recurrence. However, nicorandil induced ulcers have been reported at doses as low as 10 mg daily and complete cessation of nicorandil may be required.
Nicorandil, a nicotinamide ester, is a potassium channel activator used in the prevention and long term treatment of angina pectoris.1 It is the only licensed drug in its class. It is a novel drug that acts as an arteriolar vasodilator, but also as a venodilator because of its nitrate moiety. It thus reduces both cardiac preload and afterload. It is not currently a first line agent in the management of angina but it is sometimes used in combination with other antianginal drugs in refractory stable and unstable angina.2 The drug has been used in Japan for over a decade and has more recently been introduced in Europe. Initial reports from France at the end of the last decade suggested a link between oral ulceration and the use of nicorandil,3–10 and more recent reports from the UK have also demonstrated a link.11–14 However, to date, no reports have appeared in the cardiology literature in the English language and there is a need to heighten awareness among cardiologists of the distressing nature of nicorandil induced oral ulceration. This paper presents four cases of nicorandil induced oral ulceration and reviews the literature on the subject.
Case 1
A 72 year old man was referred to the oral medicine clinic by a dermatologist in relation to oral ulceration. The patient reported that he had developed large ulcers of 2–3 months' duration over the previous 12 months. He had hypertension, ischaemic heart disease, benign prostatic hypertrophy, and arthritis and had undergone coronary artery bypass graft surgery (CABG) 24 years previously. His medications included nicorandil 40 mg twice daily, bisoprolol, amlodipine, losartan, frusemide, esomeprazole, tamsulosin, and glyceryl trinitrate transdermally. Nicorandil had been commenced two years previously and the dose gradually increased to the current dose of 40 mg twice daily. He had been prescribed triamcinolone acetonide 0.1% paste and benzydamine hydrochloride mouthwash for his oral ulceration.
On examination, he had a round deep punched out ulcer on the left buccal mucosa measuring 15 mm in diameter. He had a similar ulcer measuring 10 mm by 7 mm on the left lateral border of his tongue (fig 11).). There were also several smaller ulcers on the dorsum of his tongue. An incisional biopsy of lesional and paralesional tissue was carried out in the left buccal mucosa. Tissue was sent for histopathological and direct immunofluoresence studies. The histopathologist reported non-specific ulceration and there were no positive findings on direct immunofluoresence.
The patient was commenced on betamethasone 0.05% mouthwashes and the referring dermatologist was informed of the likely association between his oral ulceration and nicorandil. The nicorandil was not stopped while awaiting consultation with his cardiologist about adjusting his medication. Unfortunately the patient had a myocardial infarction shortly after this and died from renal failure 10 days later.
Case 2
A 54 year old man attended the accident and emergency department of the dental hospital complaining of painful oral ulceration of 10 weeks' duration. He was diagnosed with angina in 1997 and had undergone CABG in 1998. He was a non-smoker. His medications included nicorandil 40 mg twice daily, bisoprolol, amlodipine, trimetazidine dihydrochloride, aspirin, atorvastatin, omeprazole, nimesulide, glyceryl trinitrate transdermally, and temazepam nocte. He used glyceryl trinitrate spray as required. His nicorandil dose had been increased from 30 mg to 40 mg twice daily nine months earlier.
Clinical examination showed a large deep oval ulcer on the left lateral border of the tongue measuring 25 mm by 10 mm and a deep linear ulcer in the lower labial sulcus measuring 10 mm by 6 mm (fig 22).). Both ulcers were surrounded by an erythematous flare. There was a strong clinical suspicion that the ulceration was caused by nicorandil. He was prescribed topical corticosteroid preparations, including betamethasone 0.05% mouth and triamcinolone acetonide 0.1% paste. His cardiologist, having been informed of the likely connection between nicorandil and his oral ulceration, discontinued the nicorandil. This was followed by rapid healing of the oral ulcers. The patient remained well with no exacerbation of his anginal symptoms or recurrence of oral ulceration.
Case 3
An 81 year old lady was referred to the oral medicine clinic by her general medical practitioner. She gave a five month history of painful oral ulceration occurring on her palate and buccal mucosa. She had ischaemic heart disease and had undergone CABG in 1991, following which she developed a deep venous thrombosis and pulmonary embolism. She also suffered from peripheral vascular disease and cervical spondylosis. She was a non-smoker. Her medications included nicorandil 30 mg twice daily, lisinopril, bisoprolol, aspirin, omeprazole, and glyceryl trinitrate transdermally. She also took glyceryl trinitrate spray and diclofenac acid as required. She was first placed on nicorandil 10 mg twice daily in October 1999; this was increased to 20 mg twice daily in December 2000 and was further increased to 30 mg twice daily in March 2001. Her ulceration developed four weeks after this last dose increase.
Clinical examination revealed the presence of a large deep ulcer measuring approximately 20 mm by 15 mm in the left buccal mucosa (fig 33).). A course of 2.5 mg hydrocortisone pellets was prescribed for topical application to the oral ulcer. The clinical appearance was suggestive of a nicorandil induced oral ulcer and liaison with her cardiologist resulted in discontinuation of the nicorandil. On review six weeks later the ulceration had resolved. Fortunately, the patient's angina remained well controlled and there were no further episodes of oral ulceration.
Case 4
A 75 year old woman was referred to the oral medicine clinic by her general medical practitioner in relation to a large ulcer on the ventral surface of her tongue of three weeks' duration. She suffered with unstable angina and had a myocardial infarction and CABG 10 years previously. She also had a pulmonary embolus 10 years previously and had ventricular ectopic beats. Her medications included nicorandil 20 mg twice daily, isosorbide mononitrate, diltiazem, amiodarone, atorvastatin, digoxin, warfarin, frusemide, and glyceryl trinitrate spray as required. She had been prescribed 2.5 mg hydrocortisone pellets and triamcinolone acetonide 0.1% paste but these had not resulted in an improvement in her symptoms.
On intra-oral examination there was a deep linear ulcer on the left side of the ventral surface of the tongue. There was no associated lymphadenopathy. The clinical appearance of the ulcer was strongly suggestive of nicorandil induced ulceration. Betamethasone 0.05% mouthwash six times daily was prescribed and this resulted in resolution of the ulcer. She had further ulcer recurrences, but the ulcers were aborted by the early use of betamethasone mouthwash and her cardiologist was reluctant to discontinue nicorandil. She suffered an exacerbation in her ulceration approximately three months after her nicorandil dose was increased to 50 mg daily and she re-presented with a large painful ulcer measuring 3 cm in diameter on the left buccal mucosa. This eventually resolved with the continued use of betamethasone mouthwashes. Unfortunately, shortly after this the patient died suddenly.
Nicorandil is, in general, a well tolerated drug. Its well recognised side effects include headache, flushing, nausea, dizziness, hypotension, and tachycardia. A total of 49 cases of nicorandil associated oral ulceration have been reported worldwide since 19973–16 (table 11),), but many of these have appeared in the French literature. Those cases in the English literature have been published in general or oral journals and this paper is an attempt to increase awareness among the cardiology community of this distressing side effect of nicorandil.
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