Nicorandil Drugs and Side-Effects

Nicorandil, marketed in the UK as Ikorel, is a powerful potassium-channel activator to treat angina pectoris (severe chest pains), and a recent study suggests it is a very effective one. As a result, it's increasingly being used as a first-line treatment.

Unfortunately, the sharper the sword, the greater the risk you run of getting cut. The study that concluded that the drug was most effective for people with stable angina also admitted that 66 per cent of those in the trial had to stop treatment because the adverse reactions were so severe. Most complained of very bad headaches (Lancet, 2002; 359: 1269-75). By any reckoning, this is an astonishingly high failure rate.

Now, doctors at Aberdeen's Royal Infirmary also suspect the drug can cause anal ulcers. They noticed that five patients suddenly developed the ulcers while taking the drug. The ulcers disappeared almost immediately after stopping treatment (Lancet, 2002; 360: 546-7).

Persistent nicorandil induced oral ulceration

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 1​1).). 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 2​2).). 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 3​3).). 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 1997^3–16 (table 1​1),), 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.

Nicorandil: a drug for many purposes: too good to be true?

Nicorandil, a drug approved for the treatment of ischaemic heart disease, is believed to have a dual properties. The intrinsic mechanism of the drug (selective activation of K+ATPchannels at the sarcolemmal and mitrochondrial level) allows coronary and peripheral vasodilatation with subsequent reduction of preload and afterload. Secondly, because of the role K+ATPchannels in ischaemic preconditioning, nicorandil has been attributed cardioprotective effects.1
The drug has been available in Europe for years, classified as a new class of therapy for coronary artery disease, but failed till now to truly penetrate on the 'European market'. The large scaled, randomized IONA trial evaluated the efficacy of nicorandil on top of 'conventional' antianginal drugs for the treatment of stable angina pectoris.2The primary end-point (a composite of cardiac death, myocardial infarction, unplanned hospital admission for chest pain) occurred significantly less in the nicorandil (13.1%) then in the placebo group (15.5%, P=0.014). Nevertheless, only about half of patients were on β-blockers and 'unplanned hospital admission for chest pain' is a very weak end-point despite the randomized character of the trial. Inherent of these limitations, nicorandil may be considered as a safe additional drug to β-blockers for angina relief in patients with stable angina pectoris. Weather, it may be an alternative to β-blockers in post myocardial infarction patients remains to be established.
Nicorandil has a long tradition in Japan, where it has been studied extensively. The present issue of the journal publishes two papers from Japan. The first study by Matsuo et al. evaluates again the efficacy of nicorandil in ischaemic preconditioning in the human angioplasty model while the second paper by Izawa et al. investigates the impact of the drug on left ventricular filling pressures in exercising patients with hypertrophic cardiomyopathy.3,4A potential benefit of the drug is demonstrated in both trials, characterized by a heavy, 'high-tech' methodology applied to small study cohort. Nevertheless, they merit our consideration as both authors have improved and extended prior research in the field, providing thereby relatively solid data.
Matsuo et al. previously demonstrated by simple ST-segment analysis that nicorandil enhances preconditioning in the human PTCA model.5However, the potential contribution of collateral blood flow was not adequately assessed. In the present study, a homogeneous group of 44 patients with isolated proximal LAD stenosis and normal left ventricular function, was randomized to intravenous nicorandil or saline prior to angioplasty.3In addition to ST-segment analysis, 99mTc tetrofosmin SPECT acquisition was performed at the end of the PCTA as a surrogate for myocardial perfusion to the related myocardium. A trend but no significant flow increase to the ischemic bed was demonstrated together with a significant attenuation of ST-segment elevation in the nicorandil group. This implies that nicorandil seems to possess acardioprotective effect independent of myocardial (collateral) blood flow to the ischaemic bed. The message is clear and easily understood.
The second paper by Izawa et al. studied the effect of nicorandil on left ventricular end-diastolic pressure during exercise in patients with non-obstructive hypertrophic cardiomyopathy.4These authors too, added an additional step to previous research. They could previously distinguish a distinct behaviour of left ventricular filling pressures during exercise in these patients depending of the severity of myocardial hypertrophy.6A continuous increase in pressure was observed in patients with severe hypertrophy, while those with mild hypertrophy experienced a biphasic pattern with an initial increase following by a decrease prior to peak exercise. Both groups could further be distinguished by more severe Thallium-201 scintigraphy perfusion defects in case of severe hypertrophy. The biphasic pattern in the mild hypertrophy group was abolished by pre-treatment with propanolol, suggesting a β-adrenergic mediated coronary vasodilatation induced by exercise. Vasodilatation may prevent myocardial ischaemia in a vascular bed that has not grown in proportion to the hypertrophy, therefore preventing further rise in filling pressures. Without providing clear anatomic cut-off values to predict these haemodynamic alterations, the authors have now conducted a second trial published in this issue of the journal. A total of 23 patients with non-obstructive hypertrophic cardiomyopathy were randomised to pre-treatment to nicorandil or propanolol prior to any knowledge of the haemodynamic conditions induced by exercise. Again, patients could be categorized according to the evolution of the pressure pattern during exercise: gradual increase (13 patients, group 1) or a biphasic pattern (10 patients, group 2). The current study further confirmed their initial observation that the pressure pattern was related to the extent of myocardial hypertrophy and perfusion defects on myocardial scintigraphy. After completion of the first exercise, the study medication was administered and exercise was repeated to analyse its impact on left ventricular filling pressures. Therefore, four subgroups were available for analysis: group 1 (nicorandil: eight patients, propanolol: five patients) and group 2 (nicorandil: four patients, propanolol: six patients). Obviously, propanolol produced the same effect as during their first study with a disappearance of the biphasic pattern in group 2. This biphasic pattern was maintained in group 2 after administration of nicorandil but more importantly four out of eight patients in group 1 converted from a gradual increase to a biphasic pattern. The authors postulated that this beneficial effect was related to an augmented left ventricular contractility as a result ofimproved ischaemia and its impact on the coronary microcirculation.
The results of this complex investigation are intriguing and many questions remain unanswered. How may we predict the haemodynamic pattern in these patients during exercise by non invasive means? One may assume that even if all patients in both studies are pooled, statistics may fail to produce clear anatomic or scintigraphic cut-off values to predict the 'bad' patients. At a second level, not all patients, who experience a gradual increase in left ventricular filling pressures during exercise, benefit from nicorandil administration. Even if a potential mechanism (improvement in contractility and decrease in ischaemia) is postulated, no single clue to this beneficial effect in particular patients is suggested. Significant epicardial coronary disease was not present but the authors do not provide any insight into a potential abnormal resistance at this level to potentially explain the failure of nicorandil in four patients in group 1.7Intracoronary pressure measurements may therefore have elucidated one of the confounding factors interacting in these patients.
What will be the clinical relevance of the studies with nicorandil in the present issue of the journal? Both papers indicate that nicorandil may act beneficial at the myocardial cellular level. The first investigation demonstrates a cardioprotective effect during angioplasty independent of collateral flow to the ischaemic bed. Tremendous progress has been achieved in interventional cardiology in recent years and interventions appear 'easier and quicker done with excellent angiographic results and few clinical complications'. There are however no 'hard' clinical data to state this common belief. As operators expand their indications to more complex clinical and angiographic conditions, one may suggest a potential role for this drug in patients with an anticipated high interventional risk. Furthermore, the drug should probably more extensively be investigated during reperfusion strategies for acute myocardial infarction. Finally, in the particular setting of minimal invasive cardiac surgery further research seems indicated. The second paper again is only a 'second' small step. Complex investigation with invasive haemodynamic assessment during exercise in patients with non obstructive cardiomyopathy might allow selection of patients who benefit 'acutely and in the experimental setting' from the drug. At present, we ignore the clinical impact of this therapy and lack non invasive tools to guide us. However, as in many success stories, we are confident that a 'third' episode will further reveal current uncertainties.