Safety of oral nicorandil before coronary artery bypass graft surgery{dagger}

P. Blanc1, A. Aouifi1, H. Bouvier1, P. Joseph1, P. Chiari1, M. Ovize2, C. Girard1,4, O. Jegaden3, Y. Khder5 and J. J. Lehot1

1Service d’Anesthésie-Réanimation, Hôpital Cardiovasculaire Louis Pradel, 28 avenue du Doyen Lépine, BP Lyon-Montchat, F-69394 Lyon Cedex 03, France. 2Service de Cardiologie D, Hôpital Cardio-vasculaire Louis Pradel, 28 avenue du Doyen Lépine, BP Lyon-Montchat, F-69394 Lyon Cedex 03, France. 3Service de Chirurgie Cardiaque B, Hôpital Cardiovasculaire Louis Pradel, 28 avenue du Doyen Lépine, BP Lyon-Montchat, F-69394 Lyon Cedex 03, France 4Present address: CHU Hôpital du Bocage, BP 1542, F-21034 Dijon Cedex, France. 5Present address: MERCK-LIPHA Santé, Département de Recherche Clinique, 116 rue Carnot, BP 60, F-92152 Suresnes Cedex, France*Corresponding author

{dagger}This work was presented as a poster during the Annual Meeting of the American Society of Anesthesiologists (ASA), San Francisco (USA), October 14–18, 2000.

Accepted for publication: July 16, 2001


    Abstract
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Nicorandil is a KATP channel opener used to treat angina. It is cardioprotective and a vasodilator. We conducted a prospective, randomized, double-blind, placebo-controlled study to assess oral nicorandil in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Twenty-two patients received nicorandil (10 mg twice a day) and 23 patients received placebo. Haemodynamic data were recorded before induction of anaesthesia (T0), 5 and 20 min after starting mechanical ventilation (T1, T2), before aortic cannulation (T3), after 30 min of CPB (T4), 10 min after CPB (T5) and after 3, 8 and 18 h in the intensive care unit (T6, T7, T8). Serum proteins (creatine kinase metabolite and cardiac troponin I) were measured before and 8 and 18 h after surgery. Haemodynamic values did not differ between the two groups. There was no tachycardia during the study, no significant difference in hypotensive episodes, ST segment changes and no changes in cardiac enzymes. Myocardial infarction after surgery was similar in the two groups. Vasoactive therapy was similar in the two groups. Nicorandil can be continued safely up to premedication without deleterious haemodynamic consequences, but a myocardial protective effect of nicorandil in CABG surgery was not found.

Br J Anaesth 2001; 87: 848–54

Keywords: pharmacology, nicorandil; cardiovascular system, effects; heart, myocardial function; surgery, cardiopulmonary bypass


    Introduction
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Nicorandil is an ATP-dependent potassium (KATP) channel opener used to treat angina.1 2 KATP channels are found in cardiac muscle and vascular smooth muscle. Nicorandil dilates arteries and veins: potassium channel activation leads to calcium channel blockade and arterial dilation, while the nitrate moiety dilates veins by increasing intracellular cyclic guanosine monophosphate (cGMP).3 Nicorandil dilates peripheral and coronary vessels and increases coronary blood flow, reduces preload by increasing venous capacitance and afterload by decreasing peripheral resistance.24 Nicorandil may be cardioprotective by opening KATP channels, as suggested by animal studies of ischaemia–reperfusion injury in stunned and infarcted myocardium. Nicorandil reduced infarct size and improved systolic shortening after short-term coronary occlusion.5

We conducted a prospective, randomized, double-blind, placebo-controlled study of the safety of oral nicorandil in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). We studied the effect of routine nicorandil treatment on cardiovascular changes during and after surgery, the possible cardioprotective effects of nicorandil based on the incidence of ischaemic episodes, and the effect of CPB on the pharmacokinetics of nicorandil.


    Methods
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Patients about to undergo elective CABG were recruited by a single cardiologist. Inclusion criteria were age between 18 and 75 yr, stable angina and a left ventricular ejection fraction (LVEF) >40%. Patients already taking nicorandil, nitrates, dihydropyridines and sulfonylureas were excluded. The patients were randomized into two groups: nicorandil 10 mg twice daily and placebo groups. Treatment started on the evening of recruitment up to a maximum of 1 month before surgery. All patients had a preanaesthetic consultation at least 7 days after inclusion, with baseline heart rate and arterial pressure measurements. A 12-lead ECG was recorded, biochemical and haematological tests were done, and compliance with medication was recorded.

In patients taking inhibitors of angiotensin-converting enzyme (ACE), treatment was stopped 24 h before surgery. Patients taking ß-adrenergic blocking agents received their usual dose on the morning of surgery. The study treatment was given up to the time of premedication, approximately 2 h before induction of anaesthesia.

Patients were operated on by two surgeons. CABG was done with CPB with moderate hypothermia (34°C) and intermittent, cold, anterograde, crystalloid cardioplegia (Fresenius, Bad Homburg, Germany). Cardiovascular measurements included heart rate, systemic artery, central venous, pulmonary artery and capillary wedge pressures, cardiac output and mixed venous oxygen saturation (SvO2) with a Swan–Ganz catheter (Baxter, Irvine, CA, USA). Data were recorded at the following times: before induction of anaesthesia (T0); 5 min after starting mechanical ventilation (T1); 20 min after starting mechanical ventilation (T2); immediately before aortic cannulation (T3); after 30 min of CPB (T4); 10 min after the end of CPB (T5); after 3 h in the intensive care unit (ICU) (T6); after 8 h in the ICU (T7); and after 18 h in the ICU (T8). During and after surgery, we noted hypotensive events (>=30% compared with baseline value), tachycardia (defined as any increase in heart rate of >=20% compared with baseline value), ST segment elevation >=2 mm and ST depression >=1 mm lasting more than 1 min. Vasoactive treatment, fluid administration and adverse events were noted up to 24 h after surgery. Serum glutamic oxaloacetic acid transferase, creatine kinase, creatine kinase isoenzymes (CK-MB) and cardiac troponin I (cTnI) were measured and ECGs were recorded at T6 and T8. If CK-MB was higher than 40 IU litre–1, further samples were taken at 24 and 48 h. The plasma concentration of nicorandil was measured at premedication (T–1), T0, T2, T3, T4, T5, T6, T7 and T8. Blood samples were collected in lithium heparin tubes, centrifuged at 4°C at 3500 r.p.m. and the samples stored at –20°C. Nicorandil was measured by semiselective extraction and high-performance gas chromatography.

The anaesthetic was standardized. Oral premedication was with preoperative ß-blocker, hydroxyzine 100 mg and midazolam 0.2 mg kg–1. Lidocaine-prilocaine cream (Emla; AstraZeneca, Rueil-Malmaison, France) was applied to the neck 90 min before inserting Swan-Ganz catheter into the right jugular vein. Anaesthesia was induced with midazolam 0.2 mg kg–1, fentanyl 15 µg kg–1 and pancuronium 0.1 mg kg–1, all i.v. Anaesthesia was maintained with fentanyl (250 µg) and isoflurane if necessary after 20 min (after T2), to keep arterial pressure within 30% and heart rate within 20% of the baseline values. Hypertension was first treated by additional anaesthetic agents. When this was insufficient, either nicardipine (0.5 mg) or urapidil (2.5 mg) were given. A decrease in blood pressure by more than 30% of the baseline value was treated either by an infusion of hydroxyethylstarch 6% (Elohes 6%; Fresenius Kabi, Sèvres, France) or 3–6 mg ephedrine i.v. Postoperative analgesia was with propacetamol (2 g every 6 h) and morphine was given by continuous i.v. infusion (20–40 mg 24 h–1).


    Statistics
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Results are expressed as mean and standard deviation. Patient characteristics were compared by the t-test. Cardiovascular values were compared by two-way analysis of variance for repeated measurements followed by the Tukey test when appropriate. P<0.05 was considered significant. Statistical analysis was done with SPSS 9.0 for Windows (SPSS BI, Paris, France). To assess sample size, we considered changes in arterial pressure. To demonstrate a difference of 10 mmHg in arterial pressure between the groups, given a standard deviation of 10 mmHg with a power of 90%, each group would have to contain 25 subjects.


    Results
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We enrolled 51 patients. Six patients were excluded for the following reasons: one patient in the placebo group had an LVEF <40% (inclusion mistake); one patient in the nicorandil group died from a cerebral stroke before admission for surgery; and four patients (three in the nicorandil group and one in the placebo group) had poor compliance with the study medication.

Table 1 gives patient characteristics. There was no statistically significant difference between the groups in surgical characteristics, such as the number of CABGs performed, the surgeon, or the duration of CPB or aortic cross-clamping. Anaesthetic dosage was similar in the two groups.


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Table 1 Patient characteristics. *Mean (SD). n = number of patients/or grafts; ACE = angiotensin-converting enzyme. P>0.05 for all criteria (unpaired t-test)
 
Cardiovascular changes (Table 2) did not differ between the two groups. The lowest mean arterial pressure (MAP) was observed during CPB [74 (10) mm Hg in the nicorandil group and 71 (7) mm Hg in the placebo group]. Systemic vascular resistance was lowest at T5 and T6 during the rewarming period, associated with a simultaneous increase in cardiac index in both groups.


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Table 2 Perioperative cardiovascular measurements. Results are expressed as mean (SD). HR = heart rate; MAP = mean arterial pressure; MPAP = mean pulmonary arterial pressure; CVP = central venous pressure; PCWP = pulmonary capillary wedge pressure; CI = cardiac index; SvO2 = mixed venous oxygen saturation; SVR = systemic vascular resistance; PVR = pulmonary vascular resistance; NA = not available
 
Table 3 shows the number of patients with one or none or with three or more hypotensive events recorded during the three intervals T0–T3, T3–T5 and T5–T8 and the number of therapeutic interventions to restore blood pressure (volume infusion or ephedrine treatment). There was no difference between the nicorandil and placebo groups. There were no episodes of tachycardia (as defined above, under Methods) during the study. There was no statistically significant difference in the number or pattern of distribution of ST segment changes between the groups.


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Table 3 Number of patients with hypotensive events or at least one episode of significant ST change. *Number of interventions given in parentheses. No significant difference between groups
 
Cardiac enzyme changes are shown in Figure 1. The differences between the groups were not significant. Ten patients had myocardial damage (CK-MB >40 IU litre–1 or cTnI >9 µg litre–1; three patients in the nicorandil group and seven in the placebo group). There was no significant difference between the groups. Postoperative ECGs did not show new Q waves in patients with increased cardiac enzymes.



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Fig. 1 Changes in cardiac enzymes. (A) Serum glutamic oxaloacetic acid transferase. (B) Creatine kinase. (C) Creatine kinase metabolite. (D) Troponin I. There was no statistical significant difference between groups. Black columns = nicorandil group; grey columns = placebo group; pre-AV = preanaesthesia visit; T6 = after 3 h in ICU; T8 = after 18 h in ICU.

 
Nicorandil concentrations in the nicorandil group (22 patients) are shown in Figure 2. Nicorandil was not found in the plasma of the patients of the placebo group.



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Fig. 2 Plasma concentration of nicorandil in the nicorandil group (n=22).

 
Fluid requirements were similar in the two groups, with a median volume infusion of 500 ml of hydroxyethylstarch 6% in 15 patients in the nicorandil group and 16 patients in the placebo group, administered mainly during rewarming. The only patient requiring transfusion (600 ml of red cells) in the nicorandil group needed surgical re-exploration, whereas four patients in the placebo group received transfusion [mean volume 550 (300) ml] without surgical re-exploration. Vasoactive treatment after operation, such as epinephrine infusion (one patient in the nicorandil group and two patients in the placebo group), vasodilators, such as nicardipine [11 patients in the nicorandil group (median dose 5.5 mg) vs nine patients in the placebo group (median dose 2.0 mg)] and urapidil (five patients in the nicorandil group vs three patients in the placebo group with the same median dose of 20 mg), and also drugs used to decrease heart rate (ß-blocker or diltiazem according to preoperative management) were similar in the two groups (three patients in the nicorandil group vs two patients in the placebo group).


    Discussion
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We found that nicorandil medication during cardiac surgery had neither adverse cardiovascular effects nor cardioprotective effects.

Haemodynamic tolerance
Nicorandil treatment, increased progressively up to a dose of 80 mg day–1, did not cause a symptomatic decrease in arterial blood pressure or heart rate and could be combined with other antianginal drugs.1 Total vascular resistance decreased slightly after an oral dose of 30 mg.4 The usual dose in patients with ischaemic heart disease is 20 mg day–1, but patients with heart failure may need more to obtain consistent responses because of less bioavailability.6

In the present study, there were no cardiovascular differences even in the presence of preoperative treatment with ß-blockers and/or calcium channel blockers. In dogs, giving nicorandil during isoflurane anaesthesia reduced systolic arterial pressure and caused reflex tachycardia without myocardial dysfunction.7 In the present study, the lack of nicorandil-induced haemodynamic effects can be explained by the less marked cardiovascular effects of the anaesthetic.

The number of therapeutic interventions was much lower than the number of hypotensive episodes because the baseline arterial pressure value was determined in the awake patient. A 30% reduction in arterial pressure (defined as a significant hypotensive event in the study) was not always considered to need treatment in an anaesthetized patient, particularly when the baseline systolic arterial pressure could be 150 mm Hg.

The effects of nicorandil during CPB are not well documented. Large requirements for phenylephrine and inotropic agents to maintain perfusion pressure above 55 mmHg during CPB have been reported in seven patients taking oral nicorandil preoperatively, which persisted for 4–72 h after CPB in some patients.8 The haemodynamic effects of nicorandil could be exaggerated by depletion of adenosine triphosphate, which can occur during CPB. Our study suggests that severe collapse is unlikely when chronic treatment with nicorandil is maintained until premedication.

Myocardial protection
The cardioprotective effects of nicorandil have been studied experimentally.5 9 Nicorandil gives the same degree of myocardial protection as ischaemic preconditioning, limits infarct size after irreversible ischaemic injury and attenuates myocardial ‘stunning’ after briefer, reversible periods of ischaemia.3 This protection is prevented by the administration of a potassium channel blocker, such as glibenclamide or sodium 5-hydroxydecanoate, indicating the involvement of the KATP channels.10 11 Consequently, the use of potassium channel openers such as nicorandil could enhance cardioplegic protection in cardiac surgery.12 Nicorandil also enhances cardioplegic protection by reducing ischaemic contracture during reperfusion, reducing the effects of ischaemic arrest and improving postischaemic recovery of contractile function.12 13

No protective myocardial effect was found in the present study. Despite a trend to smaller concentrations of markers of cardiac damage and less postoperative myocardial infarction in the nicorandil group, statistical significance was not found, perhaps because the sample size was too small.

A protective myocardial effect of nicorandil may not have been found for several reasons, which will be discussed below.

Plasma concentrations of nicorandil
Patients had a nicorandil concentration in the therapeutic range, with minimum values reaching almost 10 ng ml–1 and persisting until T4. The greatest concentration was at T0 [46.5 (40.1) ng ml–1], 2 h after the last dose taken with the premedication. In healthy subjects, after a single dose of oral nicorandil, the mean maximum plasma concentration was 107 (30) ng ml–1 (range 44–148), usually between 30 and 60 min after administration. The discrepancy between the apparent short elimination half-life of nicorandil (1 h) and a persistent effect on exercise angina (observed 6 h after administration) is attributed to the affinity of nicorandil for vascular tissues. This tissue distribution pattern of nicorandil may support its duration of action.14

Cardioprotective effects from nicorandil during CPB may require the higher plasma concentrations given by i.v. administration before onset of CPB or by addition to cardioplegic solutions.12 13 Clinical studies remain to be performed.

At the end of CPB (T5), mean nicorandil concentration decreased to the value found at T–1, which is the concentration 12 h after oral administration. This may have been caused by CPB dilution. Three hours after arrival in the ICU (T6), nicorandil had almost completely disappeared from the plasma.

Vasoactive treatment
ß-Adrenergic blocking agents. We gave ß-blockers routinely to all patients up to premedication. This may explain the lack of tachycardia noted experimentally7 15 or clinically.16 Perioperative myocardial infarction seems unrelated to preoperative patient characteristics, but is more frequent in patients with perioperative ECG evidence of myocardial ischaemia, particularly in association with tachycardia.17 A slow heart rate is a major goal in patients with coronary artery disease.18 Postoperative myocardial infarction was more frequent in patients receiving no antianginal therapy or treated with calcium channel-blocking drugs, than in those treated with ß-blockers alone or in combination.17 19 ß-Adrenergic blocking agents seem effective in patients undergoing either CABG surgery20 or non-cardiac surgery,21 by reducing the incidence of perioperative myocardial ischaemia and risk of death at 2 yr. Therefore, ß-blockers are commonly maintained until premedication and resumed as soon as possible after extubation. In this study, the continuation of the ß-blockers may have obscured the possible protective effects of nicorandil.

Isoflurane. Isoflurane is a commonly used halogenated anaesthetic agent with dose-related negative inotropic and vasodilatory actions, which are attributed to alterations in voltage-dependent slow calcium channel activity in the sarcolemmal membrane. The antagonization of KATP channels by glibenclamide suggests that the effect of isoflurane is mediated predominantly by the adenosine receptor activation of the KATP channels.22 Experimentally, isoflurane mimics the cardioprotective effects of ischaemic preconditioning by the activation of protein kinase C (PKC) and the opening of KATP channels, probably at the mitochondrial level.23 Isoflurane preconditioning of the human heart during cardiac surgery has been reported through a significant increased value of ecto-5'-nucleotidase activity, considered to be a marker of PKC activation, and lower cTnI in patients given isoflurane before CPB.24 Nicorandil and isoflurane given together can enhance postischaemic recovery of left ventricular function.25

Isoflurane was used in both groups as an additional agent to reduce blood pressure changes during the surgical events, such as sternotomy. Both groups could have gained from the use of isoflurane before CPB, which may limit the capacity of the study to demonstrate any cardioprotective effects of nicorandil.

ACE inhibitors. In this study, seven of the 22 patients in the nicorandil group and nine of the 23 patients in the placebo group were treated preoperatively with ACE inhibitors. This treatment is unlikely to have influenced the results of the study because the number of treated patients, although small, was similar, and the values of the haemodynamic variables did not differ significantly between the groups. The known haemodynamic effect of ACE inhibitors on anaesthetic induction led us to maintain our routine practice of stopping treatment 24 h before the scheduled time of surgery.26

General tolerance
Nicorandil can cause large and painful mouth ulcers with severe dysphagia.27 Other side-effects include headache resulting from vasodilation, usually experienced during the first days of treatment and reduced by increasing the dose slowly. Dizziness and gastrointestinal disorders have also been reported.1 2 28 Except for the patient who complained of headache 6 days after starting treatment (which could have been related to a massive cerebral ischaemic attack), no other side-effect was noticed.

Conclusion
Preoperative treatment with nicorandil, often combined with other antianginal agents, is common in patients with coronary artery disease. We found no adverse perioperative haemodynamic effects, such as hypotension or tachycardia, even when treatment was maintained until premedication. Myocardial protective effects of nicorandil in CABG surgery were not demonstrated.


    Acknowledgements
 
We thank V. Piriou and Mrs C. Castera-Raddaz (Clinical Research Associate). This study was supported by funding from Merck-Lipha Santé.


    References
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14 Frydman AM, Chapelle P, Diekmann H, et al. Pharmacokinetics of nicorandil. Am J Cardiol 1989; 63: 25–33J

15 Humphrey SJ. Cardiovascular and pharmacokinetic interactions between nicorandil and adjunctive propanolol, atenolol or diltiazem in conscious dogs. Methods Find Exp Clin Pharmacol 1998; 20: 779–91[ISI][Medline]

16 Bickel C, Rupprecht HJ, Tyrtania A, Rorig J, Meyer J. [Nicorandil: acute haemodynamic effects of two different oral doses of a potassium channel opener in patients with coronary heart disease.] Med Klin 1999; 94: 67–73[ISI][Medline]

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20 Rao PS, Brock FE, Cleary K, Mueller H, Barner HB. Effect of intraoperative propanolol on serum creatine kinase MB release in patients having elective cardiac operations. J Thorac Cardiovasc Surg 1984; 88: 562–6[Abstract]

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