potassium channel openers: clinical applications in ischemic heart disease—overview of clinical...

Cardiovascular Drugs and Therapy 1995;9:229-236 © Kluwcr Academic Publishers, Boston. Printed in U.S.A.

Potassium Channel Openers: in Ischemic Heart Disease Efficacy of Nicorandil

Clinical Applications Overview of Clinical

Charles Knight, Henry Purcell, and Kim Fox Royal Brompton National Heart and Lung Hospital, London, UK

Summary. Nicorandil is a balanced arterial and venodilator that may also possess cardioprotective properties via its activation of ATP-sensitive potassium channels. It has a number of beneficial hemodynamic effects and has been shown to be effective in treating angina with similar efficacy as the currently available antianginal agents. In addition, it may have useful effects in unstable and variant angina. In this review we examine the hemodynamic effects of nicorandil and discuss the currently available data on its cl inical efficacy, both in isolation and in comparison with other agents.

Cardiovasc Drugs Ther 1995;9:229-236

Key Words. nicorandil, angina, cardioprotection

I n everyday clinical practice it is clear that there are deficiencies in the medical management of angina. While some patients experience considerable benefit from monotherapy with one of the three major groups of antianginals, namely, nitrates, beta blockers, and calcium antagonists, many find themselves taking two or more compounds without adequate relief of syrup- toms and go on to angioplasty or coronary ar tery by- pass grafting. Any new drug that offers a significant reduction in anginal symptoms throughout the spec- trum of coronary ar tery disease will be welcomed. Nicorandil is a new compound with antianginal activity. It appears to be safe with an acceptable side effect profile. Tolerance does not seem to develop, and it does not adversely affect the patient's lipid status. It is widely applicable in a variety of patient groups, including the elderly and those with poor left ventricular function. The drug has a number of favorable hemodynamic and cardioprotective actions. In this review we examine how well this new compound fulfills its promise in the clinical arena.

Background

Nicorandil is a derivative of the nicotinamide vitamin group that is structurally combined with an organic nitrate. It has been described as a hybrid between nitrates and potassium-channel activators [1]. Potas- sium-channel activators cause smooth muscle relax- ation and subsequent vasodilatation by increasing po-

tassium flux through sacrolemmal ATP-sensitive potassium channels. The drug is therefore capable of acting as a balanced arterial dilator and venodilator; potassium-channel activation indirectly leads to calcium channel blockade and dilatation of arterial resistance vessels, while the nitrate moiety dilates venous capacitance vessels via an increase in the intracellular concentration of cyclic guanosine monophosphate (cGMP). In the clinical setting, the nitrate activity is probably predominant. In addition to these favorable hemodynamic properties, which suggest nicorandil is a potentially useful antianginal, there is also in vitro evidence that its actions on the ATP-sensitive potassium channel may have an independent cardioprotective effect following ischemia/reperfusion damage. Further in vivo studies are required to assess whether these interesting laboratory findings can be translated into an additional clinical role for nicorandil.

Hemodynamic Effects

Nicorandil has a variety of actions that contribute to its effectiveness as an antianginal. It functions as a balanced peripheral and coronary vasodilator, increasing coronary blood flow, decreasing coronary vascular resistance, and reducing both preload and afterload. Angiographic studies have shown that nicorandil dilates coronary arteries by 10-20% in patients with coronary ar tery disease. Administration of 20 mg sub- lingual nicorandil to 11 patients with coronary disease showed that both unaffected and stenotic portions of the epicardial arteries were dilated by 14% [2]. When compared with intracoronary isosorbide dinitrate, intracoronary nicorandil had a greater vasodilatory effect on stenotic areas (20% vs. 8%), although it had less effect on nonstenotic segments [3]. Interestingly, when nicorandil was infused after isosorbide in this study, there was a significant further dilatation of coronary stenoses of 13%, whereas the administration of isosorbide after nicorandil gave no additional benefit.

Address for correspondence: Dr. Charles Knight, Department of Cardiac Medicine, Royal Brompton Hospital, Sydney Street, Lon- don SW3 6NP, UK. Received I December 1993, accepted in revised fo~w~ 21 March 1994

229

230 Knight, Purcell and Fox

However, there is evidence that nicorandil's vasodilator action is primarily the result of its nitrate-like activity. In comparison with a specific potassium- channel operator, cromakalim [4], nicorandil had different selectivity for a variety of vasoconstrictor agonists in isolated porcine large coronary arteries. Whereas the effects of cromakalim were blocked by glibenclamide (a potassium-channel opener antagonist), the vasorelaxant effects of nicorandil were unaffected, suggesting that in this situation the drug was acting primarily as a nitrate.

In conjunction with its effects on larger epicardial arteries, nicorandil may also dilate coronary resistance vessels. Intravenous administration of 4 mg of nicorandil to 16 patients with ischemic heart disease caused a 9% decrease in coronary vascular resistance without a concomitant increase in coronary sinus blood flow [5]. In contrast, the effect of 0.3 mg sublin- gual nitroglycerin was to decrease coronary sinus blood flow significantly with no fall in coronary vascular resistance, although clearly these may not be ex- actly pharmacologically equivalent doses.

Hemodynamic parameters have been assessed in response to single doses of oral or intravenous nicorandil in patients with and without coronary ar tery disease. Coltart and Signy [6] studied 15 patients undergoing routine cardiac catheterization for the inves- tigation of chest pain with normal left ventricular function and showed significant hemodynamic effects within 15 minutes of administering 40 mg oral nicorandil. Preload was reduced, with a decrease in left ventricular end-diastolic pressure from 7.4 _+ 1.7 to - 2 . 6 _+ 1.5 mmHg associated with a significant increase in venous capacitance. There was also a significant decrease in afterload with a fall in peripheral resistance up to 19% at 30 minutes. The concomitant decrease in systolic (up to 34%) and diastolic (up to 21%) blood pressure may, however, be less desirable, as it could compromise diastolic coronary perfusion. There was a 17% decrease in cardiac output and a 14% increase in heart rate at 30 minutes. The effect on heart rate appears to be transient, as it was no longer significant at 60 minutes, despite persistently decreased mean blood pressure and preload. Other studies have shown different effects on cardiac output, with increases of up to 19% reported in patients with previous myocardial infarction following intravenous [7] or oral [8] nicorandil. In patients with heart failure, improvements in cardiac output have also been reported. Solal et al. [9] studied the effect of a single oral dose of nicorandil in 11 patients with New York Heart Associ- ation grade III or IV congestive heart failure and reported a maximal rise in cardiac index of 55% at 30 minutes. Changes were still significant at 3 hours. The duration of action of these favorable hemodynamic actions in heart failure are still unclear from other studies reporting shorter [10] and longer [11] periods of effectiveness.

S tab le A n g i n a

Nicorandil has been studied in a number of small placebo-controlled trials and has been shown to be effective in the t reatment of chronic stable angina. Its acute and chronic effects at various doses have been assessed both with single agents or in comparison with established antianginals. Single doses of 20, 40, and 60 mg nicorandil were evaluated in eight men with exertional angina in a double-blind, randomized crossover study using symptom-limited exercise testing ac- cording to the Bruce protocol [12]. All patients had a positive exercise test and at least a 70% stenosis in at least one coronary ar tery at angiography. Exercise testing was carried out at baseline and at 2 and 6 hours after drug administration. At 2 hours there was a significant dose-dependent increase in time to angina of 58, 96, and 125 seconds over baseline values (p < 0.01) with the 20-, 40-, and 60-mg doses. These changes were significantly greater than those ob- tained with placebo ( p < 0.05). Beneficial effects in terms of increased total duration of exercise and total work load were still significant at 6 hours with all doses. However, at higher doses there was an increased incidence of adverse effects, notably dizziness and headache, leading the authors to conclude that the 20-rag dose provided the best combination of safety and efficacy.

A larger study [13] also showed that a single oral dose of 20-mg nicorandil increased exercise duration when compared with placebo in a single-blind, randomized crossover study. Twenty-nine patients, all with effort angina and a positive exercise test (docu- mented coronary ar tery disease in 15) were studied. A significant increase in exercise duration was demon- strated at 1, 3, and 6 hours after administration.

Studies of nicorandil's antianginal efficacy involving longer term administration are probably of greater clinical relevance. Meany et al. [14] conducted a double-blind parallel-group study over a 4-week period to examine the initial and medium-term effects of twice daily nicorandil in two dosage regimes. Forty-six men with chronic stable angina and a positive exercise test were randomized, after a 2-week washout period, to one of three treatment groups for a further 2 weeks. The first group (five patients) received nicorandil 5 mg twice daily for i week and then increased to 10 mg twice daily. The second group (10 patients) received higher doses of 10 mg and t h e n 20 mg in the same manner. The third group remained on placebo. Symp- tom-limited exercise testing with the Bruce protocol was performed before and 2 hours after initial dosing, and at the end of the 2-week treatment period. After the initial dosing there were significant increases in exercise duration, time to onset of angina, and time to onset of l-mm ST-segment depression in patients treated with nicorandil compared with those receiving placebo. After the 2-week treatment period, exercise

Overview of Clinical Efficacy of Nicorandil 231

40

c-

O3 c" 30 o

o

" 20 o

o

E ~ 10 c

c -

~ 0 l- o

-10 Placebo

i

Nicorandil lOmg

Trough ~ Peak

Nicorandil 20mg

Fig. 1. Increase in time to angina in patients taking nicorandil compared with placebo. (After Meany et al. [14], with permission.)

testing was carried out 2 to 12 hours after the last dose. There was a significant 23% increase in time to angina at trough drug levels 12 hours postdosing in both the 10-rag and 20-mg nicorandil groups when compared with a 2% rise with placebo. Two hours postdosing, larger effects were seen, with 38% and 32% increases in the 10-rag and 20-rag groups, respectively, compared with - 2% in the placebo group (Fig- ure 1). There was no significant change in hemodynamic parameters at rest, peak exercise, or recovery. Thus nicorandil was shown to improve exercise capacity, not only acutely after drug administration but also at trough drug levels with chronic administration over a 2-week period.

The long-term efficacy of nicorandil in stable angina pectoris has been assessed in a larger trial of 106 patients [15]. This was not placebo controlled. Patients were exercised at regular intervals up to 12 months after beginning nicorandil therapy at a dose of 10 mg twice daily, increasing up to a maximum of 40 mg twice daily. At the end of the 12-month period there had been a small increase in exercise duration of 4% compared with baseline and an improvement in time

to ST-segment depression of 33% The number of patients experiencing more than three anginal attacks per week was reduced from 64% at baseline to 24% at twelve months, but these must be interpreted with caution in view of the uncontrolled nature of the study.

These studies taken together provide evidence that nicorandil is an effective antianginal agent, but in or- der to take its place in everyday clinical practice a new agent such as nicorandil must be compared with existing therapy. Several trials have looked at its performance with reference to established therapy with nitrates, beta blockers, and calcium antagonists.

Nitrates D5ring [16] has reported two double-blind studies comparing the antianginal and antiischemic effects of nicorandil with isosorbide-5-mononitrate and isosorbide dinitrate. One hundred and twenty-nine patients, male and female, with angina and two successive positive exercise tests were recruited. The first study compared 20 mg twice daily of either nicorandil or isosorbide-5-mononitrate for 4 weeks each in a cross-


oO

r - o m

12

10

8

6

4

2

0 ex. duration time to angina time to lmm

[ ] baseline

• 20mg Nicorandil

20mg IS-5-MN

Fig. 2. Comparison of the effects of nicorandil and isosorbide-5-mononitrate (IS-5-MN) on exercise duration, time to angina, and time to l -mm ST depression in 54 patients. (After Doring [16], with permission.)

over design in 63 patients. Results were analyzed in 54 patients. Patients were followed with exercise tests. Both drugs prolonged exercise tolerance and reduced angina attacks to a similar degree (Figure 2). The second study was a parallel study comparing increasing doses of nicorandil with increasing doses of isosorbide dinitrate (2 weeks of 10 mg three times daily, then 4 weeks of 20 mg three times daily for both compounds) after a 2-week prephase with isosorbide dinitrate 10 mg three times daily. Again, both drugs increased exercise capacity and reduced ST-segment depression at identical workloads, but there was no significant difference between the two groups. Both drugs were more effective at higher doses. All three compounds showed similar patterns of adverse effects, and tolerance did not develop with any agent during the study.

Beta.blockers There have been a number of studies comparing the effects of nicorandil and beta-blockers in angina. Hughes et al. [17] studied 37 patients with angiographically proven coronary artery disease and a positive exercise test in a randomized placebo-controlled parallel study. After a single-blind placebo phase, patients were randomized to receive either nicorandil 10 mg twice daily for 3 weeks followed by a 20 mg twice daily for 3 weeks, or atenolol 50 mg then 100 mg at the same intervals. Both agents caused significant and similar improvements in exercise time and time to onset of angina (Figure 3). Five patients reported head-

ache with nicorandil as opposed to one patient with atenolol. The predose peak exercise product (heart rate × systolic blood pressure) was reduced by atenolol but not by nicorandil. A double-blind study comparing metoprolol 100 mg twice daily with nicorandil 10 and 20 mg twice daily in 20 patients [18] again showed similar efficacy of both compounds, as did a further double-blind study of nicorandil in the same doses versus propranolol 40-80 mg thrice daily in 77 men with angina [19].

Calcium antagonists Guermonprez [20] compared nicorandil 20 mg twice daily with diltiazem 60 mg three times daily in a double-blind study over a 3-month period in 123 patients with a positive exercise test and either previous myocardial infarction or angiographically proven coronary artery disease. There was an equal improvement in work load and time to l-ram ST depression and to symptom onset. Patients reported similar decreases in angina attack rates for both compounds. Although more patients reported headache with nicorandil (21%) than with diltiazem (8%), there was no overall difference in total adverse effects (28.3% and 23.8%, respectively). A small study comparing nicorandil, propranolol, and low and high doses of diltiazem with placebo [21] again showed similar improvements in exercise duration and time to ischemia with all three agents.

Nifedipine has also been assessed with nicorandil in a double-blind study [22] that randomized 58 patients,

Overview of Clinical Efficacy of Nicorandit 233

Time (min.) 3

2 . 5 -

2

.5-

_

0.5

0 Pre-dose Post-dose

Atenolol

[ ] Nicorandil

Fig. 3. Comparison of the time to onset of angina in patients taking nicorandil or atenolol. (After Hughes et al. [17], with pe~mis - sion.)

after a 3-week prephase taking isosorbide 10 to 20 mg three times daily to t reatment with either nicorandil 10 mg twice daily for 4 weeks then 20 rag for 4 weeks, or to nifedipine 20 mg twice daily for 8 weeks. Both treatments significantly increased exercise duration and time to l-ram ST depression and symptom onset to a similar degree (Figure 4); however, nicorandil 20 mg produced greater improvement in exercise perfor~ mance, although this did not reach statistical signifi- cance because of the small size of the study. Thirteen patients experienced headache in the nicorandil group as compared with nine in the nifedipine group, but the patients taking nifedipine had a higher-incidence of vasodilator symptoms, such as flushing and ankle edema.

Data from these small trials seem to indicate that nicorandil 10 or 20 twice daily is an effective antianginal agent and that its effectiveness is comparable with the three major groups of existing antianginal drugs. It still remains unclear whether the addition of nicorandil to any or all of these compounds produces an additive beneficial effect. The effect of nicorandil in variant and unstable angina is less clearly docu- mented, but some studies have been performed.

U n s t a b l e A n g i n a

The paucity of existing" information on the role of nicorandil in unstable angina allows us little more than to speculate that the current large raulticenter British trial addressing this question may show it to be of value. That such hopes are not totally without founda-

tion may be seen from the studies showing beneficial hemodynamic effects of nicorandil over and above hi- trate treatment [3] and also from the small studies already in existence.

Kato et al. [23] randomized 75 patients with unstable angina to treatment with either intravenous nicorandil 2-6 mg/hr or intravenous isosorbide dinitrate 2-5 mg/hr for 3-9 hours in a double-blind study. Nico- randil was more effective in abolishing anginal attacks (75% of patients) than isosorbide (54% of patients), although these differences were not significant. Both drugs were effective in significantly reducing the number of anginal attacks from baseline. More interestingly, there is some evidence that nicorandil may have benefits in unstable angina refractory to current therapy. Araki et al. [24] studied eight patients with unstable angina unresponsive to oral therapy with isosorbide dinitrate 40-160 rag/day plus diltiazem 30-160 mg/day or nifedipine 80 rag/day. After the addition of nicorandil 5-10 mg four times a day, the number of anginal attacks fell from 12.6 to 1.05 per week, subsequent increasing to 6.23 per week after placebo was substituted for nicorandil in six patients. These results were not statistically analyzed.

Variant angina is thought to be caused by revers- ible nonocclusive spasm of the coronary artery. This can occur on the basis of an atherosclerotic plaque or in arteries that are at least angiographically normal. It is a condition with a high morbidity that is fre- quently difficult to treat.

In a single-blind noneomparative study [25] 32 patients were given nicorandil 5-10 mg four times a day for 3 days followed by the same period on placebo.


rain

2

0

-1

10mg 20mg 20mg 20mg

-2 4 8 -2 4 8 wks

• Exercise duration [ ] Anginal pain • lmm ST depression

Fig. 4. Comparison of the effects of nicorandil and nifedipine on exercise duration, time to angina and time to 1-mm ST depression in 58 patients. (After Ulvenstam et al. [22], with permission.)

Patients had all experienced three or more anginal attacks during the 2 days prior to the study. In 24 patients nicorandil completely abolished angina and reduced its frequency by more than 50% in a further four patients. The mean number of anginal attacks was 3.6 __ 0.4 prior to therapy, 0.7 _+ 0.2 during therapy, and 1.3 _+ 0.3 after withdrawal. In 17 patients continuous ECG monitoring throughout the three phases of the trial showed a significant reduction in the incidence of transient ST elevation from 8.4 _+ 2.7 per day to 0.4 _+ 0.2 per day during nicorandil therapy. After drug withdrawal the incidence rose to 1.9 _+ 0.7 a day.

Nicorandil has also been compared with nifedipine in 16 patients with angiographically confirmed coronary artery spasm and a history of chest pain at rest [26]. During two consecutive periods of 2 days patients received active drugs (30 mg nicorandil or 10 mg nifedipine orally) or placebo in a randomized or- der. One hour after drug/placebo intake, patients un- derwent an ergometrine provocation test. After placebo the tests were all positive with reproducible doses of ergometrine. After nicorandil the tests were negative in nine patients, compared with five negative tests after nifedipine. Overall both nicorandil and nifedipine were significantly effective when compared with placebo, although there was no significant difference between the two drugs.

Cardioprotection There is some in vitro evidence that nicorandil has a direct cardioprotective effect, independent of its hemodynamic effects, via its potassium channel activat- ing properties. The opening of ATP-sensitive potassium channels may be beneficial to the subsequent recovery of the heart following periods of ischemia followed by reperfusion, both in limiting infarct size following irreversible ischemic injury and in attenuat- ing myocardial "stunning" following briefer, revers- ible periods of ischemia.

In animal experiments [27] mimicking myocardial infarction by 120 minutes of coronary occlusion in adult male dogs, intravenous nicorandil given 10 minutes after the onset of occlusion produced a significant reduction in infarct size. Nicorandil treatment also re- sulted in enhanced recovery of regional systolic short- ening during reperfusion after shorter periods of occlusion (10-15 minutes), whereas similar levels of blood pressure reduction with sodium nitroprusside had no such effect. In a similar study [28], pretreat- ment with glibenclamide, a selective ATP-sensitive potassium channel antagonist, prevented nicorandil's acceleration of recovery without affecting the hemodynamic effects of nicorandil. These data suggest that the drug has a direct cardioprotective effect as a result of potassium-channel activation that is independent of its circulatory effects. In addition, there is

Overview of Clinical Efficacy of Nicorandil 235

evidence [27] that nicorandil appears to inhibit neutro- phil infiltration into damaged cardiac tissue. During reperfusion injury neutrophils infiltrate tissue, pro- ducing superoxide radicals. In vitro work suggests that nicorandil, along with other potassium-channel openers, but unlike nitroglycerin, produces a concert- tration-dependent inhibition of superoxide anion free radical production by canine and human neutrophils.

There is, however, little evidence for nicorandil as a cardioprotective agent in vivo at present. Nicorandil is a weak potassium-channel opener with lower po- tency than the exclusive potassium-channel opener, cromakalim [29], and it may be difficult to obtain adequate levels for this action by oral dosing. In one small study Orita et al. [30] showed improvements over con- trols in myocardial tissue blood flow, metabolism, and functional recovery in patients undergoing cardiac valve replacement in whom a nicorandil vasodilator- magnesium cardioplegic solution was infused prior to reperfusion.

Clearly an important potential role for a cardioprotective agent is use during coronary angioplasty. Some small studies have shown a benefit from nicorandil in this situation, although the possibility that this is a result, at least in part, of nicorandil's nitrate rather than its potassium-channel opening activity cannot be ignored. Nicorandil 4 mg intravenously significantly improved ischemic tolerance during angioplasty in 20 patients [31]. Saito et al. [32] compared the cardioprotective effects of a number of agents during coronary occlusion at angioplasty of proximal coronary stenoses in 40 patients. After the two 30-second occlusions the patients received either nitroglycerin 0.2 mg or verapamil 5 rag, or nicorandil 4 nag or an equivalent volume of saline. Five minutes after injection, a further occlusion was performed. The extent of ST-segment elevation was significantly less, and the delay until ST elevation was significantly longer with verapamil and nicorandil compared with nitrate or saline. Whereas verapamil and nitroglycerin produced hypotension and/or bradycardia in 30% and 20% of patients respectively, no adverse effects or hemodynamic changes were recorded with nicorandil. Clearly, however, these may not be pharmacologically equivalent doses.

Conclusions

Nicorandil is effective in the treatment of stable angina pectoris with comparable activity with existing antianginals. Its actions in variant and unstable angina may prove particularly useful, especially in cases currently refractory to treatment. In addition to this antianginal activity, the interesting effects of this compound on potassium channels of the ischemic myocardial cell justify further clinical work to determine the cardioprotective activity of nicorandil in both limiting infarct size and at tenuat ing myocardial stunning.

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potassium channel openers: clinical applications in ischemic heart disease—overview of clinical...

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