Nicorandil may be associated with gastrointestinal ulceration

 Nicorandil (Ikorel; Rhne-Poulenc Rorer, Guildford) is associated with mouth and anal ulcers,1-4 but we are not aware of any previous reports of association with gastrointestinal ulceration. A 69 year old woman had had percutaneous coronary intervention and a stent inserted into her left anterior descending artery two years before presentation. She had recurrent angina, and her general practitioner increased her dose of nicorandil to 30 mg twice a day. She had another percutaneous coronary intervention for in-stent re-stenosis, after which she presented to her general practitioner with mouth and anal ulcers and was referred for gastrointestinal evaluation. She was taking aspirin, a blocker, nitrate, and a statin. Upper and lower gastrointestinal endoscopy showed, in addition to her oral and anal ulcers, multiple ulcers of the small and large intestines and multiple biopsies showed non-specific ulceration. A provisional diagnosis of inflammatory bowel disease was made and she was due to be started on steroids and immunosuppressive treatment. She was seen in our clinic for cardiac review, and, at that time, she had anal ulcers and a large ulcer, 15 mm in diameter, at the base of her tongue. We stopped nicorandil, and her ulcers healed, and she had no further problems and remains well.

    Full investigations to rule out other pathologies and causes of ulceration are important. Ulceration related to nicorandil usually resolves itself on stopping nicorandil, but reducing the dose may promote ulcer healing.4 This is important as nicorandil is usually used as a third line treatment in patients with severe coronary artery disease, and it may not be possible to stop it completely without recurrence of anginal symptoms.

    This case suggests that nicorandil might be associated with intestinal ulceration, in addition to ulceration of the mouth and anus, because no other cause was identified, and the ulcers resolved after stopping nicorandil. The Medicines and Healthcare Products Regulatory Agency's website lists two cases with possible relation to nicorandil: one of oesophageal ulceration and another of fatal small intestinal ulceration. Similarly, a report of perforation of the terminal ileum putatively linked it to nicorandil.5

    Funding: None.

    Competing interests: None declared.

    References

    Reichert S, Antunes A, Trechot P, Barbaud A, Weber M, Schmutz J. Major aphthous stomatitis induced by nicorandil. Eur J Dermatol 1997;7: 132-3.

    Agbo-Godeau S, Joly P, Szpirglas H. Association of major aphthous ulcers and nicorandil. Lancet 1998;352: 1598-9.

    Watson A, Al Ozairi O, Fraser A, Loudon M, O'Kelly T. Nicorandil associated anal ulceration. Lancet 2002;360: 546-7.

    Healy CM, Smyth Y, Flint SR. Persistent nicorandil induced oral ulceration. Heart 2004;90: e38.

    King PM, Suttie SA, Jansen JO, Watson AJ. Perforation of the terminal ileum, a possible complication of nicorandil therapy. Surgeon 2004;2: 56-7.

Ikorel (nicorandil)

How does it work?

Ikorel tablets contain the active ingredient nicorandil, which is a type of medicine called a potassium-channel activator. It is used to help the heart work more easily.

The pain of angina is caused by too little oxygen reaching the heart when its workload increases, such as during exercise. This is usually a result of hardening of the arteries (atherosclerosis) that supply blood to the heart. This is also known as coronary heart disease. Nicorandil decreases the workload of the heart and also improves its blood and therefore oxygen supply.

Nicorandil works by acting on potassium channels that are found on muscle cells within the walls of blood vessels. It opens these channels, which causes the muscle cells to relax. When the muscle cells in the walls of blood vessels relax, it allows the blood vessels to widen.

Nicorandil widens the arteries that take blood from the heart to the rest of the body. This reduces the resistance within these arteries, which makes it easier for the heart to pump the blood around the body.

Nicorandil also widens the veins that return the blood to the heart. This decreases the volume of blood that returns to the heart with each heartbeat, and this makes it easier for the heart to pump that blood out again.

As a result of both these actions, the heart requires less energy to pump the blood around the body and therefore does not need as much oxygen. Nicorandil also widens the coronary arteries within the heart itself, and this increases the blood and oxygen supply to the heart muscle. Both these actions help to prevent the pain of angina.

Nicorandil is taken on regular basis to help the heart work more easily and thus prevent angina attacks. It has also been shown to reduce the risk of the complications of coronary heart disease and angina, such as heart attacks, angina that occurs at rest and death from heart disease.

What is it used for?

• Angina pectoris.
• Preventing the complications of coronary heart disease and angina, such as heart attack, unstable angina or death from heart disease.

Warning!

• This medicine might make you feel dizzy and so may reduce your ability to drive or operate machinery safely. Do not drive or operate machinery until you know how this medicine affects you and you are sure it won't affect your performance.
• If you drink alcohol while taking this medicine it might make you feel dizzy. Tell your doctor if this is the case.
• This medicine may very rarely cause skin ulcers, mouth ulcers, genital ulcers and ulceration or bleeding in the stomach or intestines, including anal ulceration and rectal bleeding. If it occurs, the ulceration is often severe and in a few people with ulcers in the stomach or intestines it can lead to perforation (holes appearing) in the gut. Although these types of ulcers are very rare, they usually only get better if treatment with this medicine is stopped. For this reason, it is important that you consult your doctor immediately if you get any ulcers, or notice any sign of ulceration or bleeding from the stomach or intestines, for example bleeding from the back passage, ulcers, pain, irritation or itching in the back passage, vomiting blood, or passing black/tarry/bloodstained stools. If it is decided that you should stop treatment with this medicine this should only be done under the supervision of your cardiologist, to avoid your heart condition getting worse.

Use with caution in

• People with a low volume of circulating blood (hypovolaemia), for example due to blood loss or dehydration.
• People with fluid in the lungs (pulmonary oedema).
• People taking medicines to treat high blood pressure (see end of factsheet for more information).

Not to be used in

• Failure of the heart to maintain adequate circulation of blood (cardiogenic shock).
• Left-sided heart failure (left ventricular failure with low filling pressures).
• Low blood pressure (hypotension).
• Breastfeeding.
• This medicine is not recommended for children.

This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy.If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately.

Pregnancy and breastfeeding

Certain medicines should not be used during pregnancy or breastfeeding. However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.

• The safety of this medicine during pregnancy has not been established. The manufacturer therefore advises that it should not be used during pregnancy unless there is no safer alternative. Seek medical advice from your doctor.
• It is not known if this medicine passes into breast milk. For this reason, it should not be used by breastfeeding mothers. Women who need treatment with this medicine should not breastfeed. Seek medical advice from your doctor.

Side effects

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here does not mean that all people using this medicine will experience that or any side effect.

Very common (affect more than 1 in 10 people)

• Headache, particularly in the first few days of treatment, but this usually disappears with time.

Common (affect between 1 in 10 and 1 in 100 people)

• Dizziness.
• Nausea and vomiting.
• Increased blood flow to the skin (flushing).
• Feeling of weakness.
• Rectal bleeding.

Uncommon (affect between 1 in 100 and 1 in 1000 people)

• Increased heart rate at high doses.
• Low blood pressure at high doses.
• Mouth ulcers.

Rare (affect between 1 in 1000 and 1 in 10,000 people)

• Rash.
• Abnormal liver function.
• Pain in the muscles.
• Persistant mouth ulcers that may be severe.

Very rare (affect less than 1 in 10,000 people)

• Swelling of the lips and tongue (allergic reaction called angieodema - seek medical attention straight away if you experience these symptoms).
• Ulceration and bleeding in the stomach or intestine, including anal ulceration or bleeding from the rectum (see warning above).

The side effects listed above may not include all of the side effects reported by the medicine's manufacturer.For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.

How can this medicine affect other medicines?

It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start treatment with this medicine. Similarly, check with your doctor or pharmacist before taking any new medicines while taking this one, to make sure that the combination is safe.

This medicine must not be used in combination with any of the following medicines that are used to treat erectile dysfunction (impotence):

• sildenafil (Viagra)
• tadalafil (Cialis)
• vardenafil (Levitra).

This is because the combination of these medicines and nicorandil can cause a dangerous drop in blood pressure.

If this medicine is taken with any of the following medicines, the combination might cause your blood pressure to drop. If your blood pressure falls too low it might make you feel dizzy, in which case lie down until the feeling passes. You should let your doctor know if you feel dizzy while taking this medicine with any of those listed below, in case your doses need adjusting:

• other medicines that widen the blood vessels (eg alpha-blockers, nitrates, calcium channel blockers, minoxidil, hydralazine)
• medicines to treat high blood pressure (antihypertensives)
• medicines that can decrease blood pressure as a side effect (eg tricyclic antidepressants, MAOI antidepressants, sedatives).

There may be an increased risk of ulceration or bleeding in the stomach or intestines if corticosteroids such as prednisolone are taken in combination with this medicine.

Other medicines containing the same active ingredient

There are currently no other medicines available in the UK that contain nicorandil as the active ingredient.

A Comparison of Nicorandil With Isosorbide Mononitrate in Elderly Patients With Stable Coronary Heart Disease: The SNAPE Study

Abstract

Background: Nicorandil, a potassium channel opener, is an effective antianginal drug, but its therapeutic evaluation is still limited.
Objective: The efficacy and safety of nicorandil compared with isosorbide mononitrate (ISMN) was evaluated in the treatment of elderly patients (>=65 years) with stable angina pectoris and a positive exercise test result (>=0.1 mV ST-segment depression).
Methods and Results: In a multicenter, double-blind, double-dummy, controlled trial, 194 patients were randomly assigned to 10 mg nicorandil twice daily or 20 mg ISMN twice daily. For the evaluation of ischemic variables, a symptom-limited bicycle exercise test was performed after 1 week of placebo treatment and after 4 weeks of nicorandil or ISMN treatment. Clinical assessment for safety and side effects occurred at 2-week intervals. One hundred seventy-eight patients were analyzed on an intent-to-treat basis and 145 were terminated from the study per protocol (efficacy analysis). During treatment, within both treatment groups exercise testing revealed a significant postponement of the onset of ischemia (nicorandil, P < .01; ISMN, P = .03) and angina (P =< .03 for both) and a decrease of maximum ST depression (ISMN, P < .002) compared with baseline. There were no differences between the groups for both intent-to-treat and efficacy analysis, with the exception of the rate-pressure product, which was increased (P = .03) in the nicorandil group. Safety and well-being variables were not different between groups, but the frequency of angina decreased (P = .02) in the ISMN group.
Conclusions: These data suggest that, although nicorandil seems to be as safe and effective as ISMN for the treatment of stable angina in elderly patients, ISMN may be superior to nicorandil for the symptomatic treatment of daily angina in this patient population.

Introduction

Nicorandil, a nicotinamide derivative with a nitrate moiety, combines the smooth muscle-relaxing property of both nitrates and nicotinamide with its ability to increase potassium ion conductance.^[1] As a result, nicorandil has a direct (preload and afterload) vasodilating effect on normal and diseased coronary arteries and peripheral vessels.^[1,2] These characteristics have justified its assessment as an antianginal compound in numerous experimental and clinical studies.^[1] Although nicorandil has been shown to be efficacious and safe in patients with stable angina pectoris compared with placebo^[3-5] as well as with other antianginal agents,^[6-12] its therapeutic evaluation is still limited. This international, multicenter, randomized, double-blind, double-dummy study (S) was designed to assess the efficacy and safety of nicorandil (N) compared with isosorbide mononitrate for the treatment of angina pectoris (AP) in elderly (E) patients with stable coronary heart disease (SNAPE).

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.