Nicorandil Versus Nitroglycerin for Symptomatic Relief of Angina in Patients With Slow Coronary Flow Phenomenon

Abstract

Objective:

Patients with the coronary slow flow phenomenon frequently experience angina episodes. The present study aimed to compare the efficacy of nicorandil versus nitroglycerin for alleviation of angina symptoms in slow flow patients.

Methods:

In a single-center, single-blind, parallel-design, comparator-controlled, randomized clinical trial (NCT02254252), 54 patients with slow flow and normal or near-normal coronary angiography who presented with frequent angina episodes were randomly assigned to 1-month treatment with nicorandil 10 mg, 2 times a day (n = 27) or sustained-release glyceryltrinitrate 6.4 mg 2 times a day (n =27). Frequency of angina episodes, pain intensity, and the Canadian Cardiovascular Society (CCS) grading of angina pectoris were assessed at baseline and after 1 month of treatment.

Results:

In all, 25 patients in the nicorandil arm and 24 patients in the nitroglycerin arm were analyzed. After 1 month, patients treated with nicorandil had fewer angina episodes (adjusted mean number of episodes per week, nicorandil versus nitroglycerin; 1.68 ± 0.15 vs 2.29 ± 0.15, P = .007, effect size = 14.6%). Patients also reported greater reductions in pain intensity with nicorandil versus nitroglycerin (adjusted mean of self-reported pain score; 3.03 ± 0.29 vs 3.89 ± 0.30, P = .046, effect size = 8.4%). A significantly higher proportion of patients in the nicorandil arm were categorized in CCS class I (76% vs 33.3%, P = .004) or class II (16.0% vs 45.8%, P = .032).

Conclusion:

In slow flow patients, nicorandil provides better symptomatic relief of angina than nitroglycerin.

Introduction

The phenomenon of coronary slow flow is qualitatively defined as delayed opacification of epicardial arteries in the absence of significant arterial narrowing and blockade. ¹ Once believed to be a benign angiographic finding with no clinical and prognostic implications, studies in the past 2 decades have transformed our understanding of this phenomenon. Coronary slow flow is now considered a distinct clinical entity arising from microvascular dysfunction with germane ramifications for the patient. ²

Patients with slow coronary flow are more likely to experience angina at rest, and the experienced episodes tend to be of pronounced intensity, often requiring emergency admission. ^2,3 In a case–control study, with a median follow-up of 21 months, 84% of patients with coronary slow flow phenomenon had recurring episodes of chest pain, 33% sought care in the emergency department, and 21% required re-admission. ² The pathophysiology of slow coronary flow remains elusive for the most part. Available studies suggest that endothelial dysfunction, particularly at the level of vessels with low diameter, plays a key role in this regard. ⁴ Based on observational studies, vasodilators that primarily affect large coronary arteries often fail to overturn the phenomenon of slow flow. In one of the earliest studies on patients with slow flow, intracoronary administration of nitroglycerin failed to normalize the flow, while dipyridamole accelerated dye run-off. ⁵ Furthermore, it has been shown that nitroglycerin might not be effective in salvaging angina symptoms in patients with angina and normal coronary angiography; in patients with slow flow, it might, paradoxically, lead to a worsening of ischemia due to a drop in aortic perfusion pressure. ^6,7

Therefore, it is perceivable that antiangina medications that exert vasodilatory effects in large coronary trunks as well as small dividing branches might be superior to nitroglycerin in the amelioration of angina symptoms. Nicorandil, a unique antiangina medication with dual actions, might prove beneficial in this regard. The nicotinamide derivative nicorandil exerts vasodilatory effects on both large and small arteries through nitrate-like properties and adenosine triphosphate-sensitive potassium channel opening, respectively. ⁸ Hypothetically, these features make nicorandil the antiangina medication of choice among the population of patients affected by the coronary slow flow phenomenon. To our knowledge, the possible role of nicorandil in the amelioration of stable angina symptoms in patients with coronary slow flow has not been investigated in a clinical trial setting. The present randomized clinical trial was thus designed to compare the short-term efficacy of nicorandil with nitroglycerin in a group of patients with coronary slow flow and normal or near-normal coronary angiography who presented with relapsing-remitting angina episodes.

Participants and Methods

Patients

Between March 2012 and March 2013, all patients with clinical diagnosis of stable angina who underwent scheduled coronary angiography in the Cath lab of Imam Reza Hospital (a university-affiliated hospital in Mashhad, Iran) were assessed for eligibility. Patients were deemed eligible if the following inclusion criteria were met: (1) on coronary angiographic studies, arterial narrowing did not exceed 50% in any of the 3 main coronary arteries and (2) delayed opacification in at least one of the main coronary arteries was documented. Coronary slow flow was defined as protracted Thrombolysis in Myocardial Infarction (TIMI) frame count. The TIMI frame count was determined quantitatively by incorporating the method described by Gibson et al ⁹ In brief, using a standard cineviewer, the number of cineframes between the first and last frames was calculated. The first frame was identified as the time when contrast media first appeared at the origin of an epicardial artery, touched both borders of its wall, and advanced in an anterograde manner. ⁹ The frame in which the dye opacified, a distal landmark branch was designated as the final frame. Due to its greater length, if left anterior descending artery was used for frame count determination, the resultant count was divided by 1.7, thus producing a final corrected TIMI frame count. ⁹ Poor coronary flow was defined as a corrected TIMI frame count exceeding 23 frames per second. Patients were excluded if they did not agree to participate or had comorbid cardiovascular conditions other than mild coronary atherosclerosis and coronary slow flow. Initially, 1726 patients were assessed for eligibility, of whom 59 patients met the inclusion criteria. One patient refused to partake in the study and was thus excluded. Additional diagnostic evaluations revealed heart failure in 3 patients and coronary artery ectasia in another, and they were also not included. The remaining 54 patients were randomly assigned to treatment arms. All angiographic studies were performed under local anesthesia by a single experienced cardiologist. Procedures dealing with humans were conducted in accordance with the ethical codes and standards laid down in the latest revision of the Helsinki declaration. Imam Reza Hospital Board of Ethics read and approved the study protocol. Prior to enrollment, written informed consent was obtained from all participants.

Trial Design and Interventions

This single-center, single-blind, parallel-group, non-placebo controlled, randomized clinical trial was initiated to compare the short-term effects of nicorandil versus nitroglycerin for angina relief in patients with mild coronary atherosclerosis and slow coronary flow. The protocol of the study is registered in ClinicalTrials.Gov (registration number NCT02254252).

Using simple randomization software in Microsoft Excel, numbers 1 to 55 were generated in a manner to be unrepeated and unsorted. With the random sequence available, numbers smaller than 28 were assigned to the nicorandil arm and numbers greater than 28 were assigned to the nitroglycerin arm. Patients in the nicorandil arm received standard treatment plus nicorandil (10 mg tablets, 2 times a day). Patients in the nitroglycerin arm were treated by the standard protocol plus sustained-release glyceryl trinitrate (6.4 mg tablets, 2 times a day). The standard treatment included an anti-platelet agent, a β-blocker, an angiotensin converting enzyme inhibitor, and a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor. Both nicorandil and nitroglycerin were white, round tablets of identical shape and were given to patients in prepackaged coded containers, thereby masking the identity of the administered medication.

Assessment

Patients were asked to take the medication in the prescribed frequency and quantity and return for a follow-up visit 1 month later. At baseline and at the follow-up visit, the following 3 main end points were evaluated:

Frequency of angina episodes: Patients were asked to determine, in the preceding week, how many times have they experienced an episode of typical angina?

Pain intensity in angina episodes: Patients were asked to determine the average intensity of chest pain experienced in angina episodes using a Likert-type scale, where 0 indicated ‘no pain’ and 10 indicated ‘worst pain imaginable’.

Canadian Cardiovascular Society (CCS) grading of angina pectoris: Based on patient’s description of angina episodes, angina severity was classified into one of CCS classes I (angina only with prolonged demanding physical activity) through IV (angina at rest).

At the follow-up visit, patients were questioned about adverse drug reactions and medication side effects, and unwanted reactions attributable to the prescribed anti-angina medications were recorded.

Statistical Analysis

All statistical analyses were done using the Statistical Package for the Social Sciences (SPSS) version 17.0 (SPSS Inc., Chicago, Illinois). Continuous variables are presented as mean ± standard deviation and categorical variables as proportions or ratios. Baseline continuous variables were compared across trial arms using the independent t test. The distribution of categorical variables between trial arms was compared using the Chi-square test or the Fisher exact test, where appropriate. End point variables: “frequency” and “intensity” of angina episodes were compared between the 2 arms using the analysis of covariance (ANCOVA) method. In each ANCOVA model, effect size was determined by partial η² and is expressed in percentages. The proportion of CCS classes across trial arms was compared using the Chi-square test. In all tests, a P value less than .05 was deemed necessary to reject the null hypothesis of indifference.

Results

Fifty-four patients with normal or near-normal coronary angiograms and coronary slow flow were allocated to either nicorandil (n = 27) or nitroglycerin (n = 27) arms of the trial. Two patients in the nicorandil arm and two in the nitroglycerin arm discontinued medication and were excluded. One patient in the nitroglycerin arm did not return for the follow-up visit. Therefore, 49 patients were included in the final analysis. Baseline clinical characteristics and coronary angiographic findings of the patients are presented in Table 1. The average age of participants was 54 years (ranging from 34 to 86 years) and was comparable between the trial arms. Females comprised 49.0% of the sample and the female-to-male ratio was similar between the 2 arms. The proportions of patients with hypertension, type 2 diabetes, and dyslipidemia were similar between the 2 groups. Based on coronary angiography findings, the degree of arterial narrowing in the 3 main epicardial arteries were not significantly different between the 2 arms (Table 1).

Table 1.

Baseline Characteristics of Patients Enrolled in the Randomized Clinical Trial.

	Nicorandil (n = 25)	Nitroglycerin (n = 24)	P Value
Age (years)	54.6 ± 11.1	53.7 ± 13.3	0.809
Sex (female/male)	11/14	13/11	0.572
Hypertension, n (%)	10 (40.0)	7 (29.2)	0.551
Diabetes, n (%)	4 (16.0)	3 (12.5)	1.000
Dyslipidemia, n (%)	5 (20.0)	5 (20.8)	1.000
Smoking status, n (%)	4 (16.0)	3 (12.5)	1.000
Coronary angiography findings
Coronary artery narrowing (%)
LAD	26.2 ± 11.1	23.5 ± 11.2	0.415
LCX	25.9 ± 6.8	26.2 ± 5.7	0.873
RCA	26.1 ± 7.6	22.4 ± 9.5	0.142

Abbreviations: LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

The comparative efficacy of nicorandil versus nitroglycerin on frequency and intensity of angina is demonstrated in Figure 1. Compared with nitroglycerin, nicorandil caused a greater decrease in the frequency of angina episodes (P = .007 and effect size = 14.6%). A greater decrease in the pain intensity of angina episodes was also observed with nicorandil (P = 0.046, effect size = 8.4%).

Figure 1.

Efficacy of nicorandil versus nitroglycerin for amelioration of angina frequency and intensity. Left panel, F = 7.863, P = .007, effect size = 14.6%. Right panel, F = 4.204, P = 0.046, effect size = 8.4%.

At baseline, 36% and 64% of patients in the nicorandil arm were in CCS classes II and III, respectively. In the nitroglycerin arm, 33.3% were initially categorized in the CCS class II, and angina in the remaining 16 (66.7%) patients was compatible with the CCS class III. Thus, at baseline, the distribution of CCS classes did not differ between groups (P = 1.000). After 1-month treatment, a downward change in CCS class was observed in 88.0% of the patients receiving nicorandil, compared with 66.7% of the patients receiving nitroglycerin (P = 0.095). In the follow-up visit, the distribution of CCS categories was significantly different between the 2 trial arms (Figure 2). A higher proportion of patients in the nicorandil arm were classified in the CCS class I category (76.0% vs 33.3%).

Figure 2.

Canadian Cardiovascular Society (CCS) grading of angina after 1 month in nicorandil versus nitroglycerin arm. After 1 month of treatment, a higher proportion of patients in the nicorandil arm were classified in CCS class I (P = .004), or class II (P = .032).

During the study period, no clinically significant adverse drug reactions were documented. Three patients in the nicorandil arm reported headaches. Gastrointestinal discomfort/dyspepsia was observed in another patient of this group.

Discussion

In the present study, we compared the efficacy of nicorandil with nitroglycerin in ameliorating angina symptoms in a group of patients with slow flow. Based on our observations, compared with nitroglycerin, nicorandil was significantly more effective in terms of reducing angina episode frequency and intensity. Moreover, patients receiving nicorandil were more likely to experience at least 1 level decrease in the CCS angina grade.

A number of studies to date have addressed the efficacy and safety of antiangina medications in patients with coronary slow flow. Beltrame et al, in a randomized, double-blind, placebo-controlled, cross-over study, delved into the possible utility of mibefradil, a T-type calcium channel blocker for symptomatic treatment of angina. ¹⁰ A total of 21 patients who experienced angina episodes at least 3 times in the preceding week were randomized to receive mibefradil or placebo. ¹⁰ Compared with those treated with placebo, mibefradil was significantly more effective in decreasing the number of episodes, duration of episodes, and also the need for rescue treatment with sublingual nitrates. ¹⁰ The authors argued that the efficacy of mibefradil might be ascribed to the selective blockade of T-type channels that are found in plenitude in coronary branches of low diameter. ¹⁰ In another 1-month randomized clinical trial, the effects of oral dipyridamole on slow coronary flow were examined. Twenty-five patients with symptoms of atypical angina were randomized to receive dipyridamole (75 mg 3 times a day) or placebo. ¹¹ Following 1 month of therapy, there was a complete disappearance of angina symptoms in 68% of patients, and the remaining 32% reported at least some degree of pain relief. ¹¹ It was suggested that since the phenomenon of slow coronary flow largely stems from the functional obstruction of microvessels due to endothelial dysfunction, dipyridamole, through primarily dilating coronary vessels of small diameter (< 200 µm), is able to relax flow resistance, thereby ameliorating angina symptoms in this group of patients. ¹¹ Promising results have also been obtained with lipid-lowering medications simvastatin, ¹² atorvastatin, ¹³ and also the β-blocker nebivolol. ¹⁴

In a proportion of patients with ST-segment elevation myocardial infarction, following reinstitution of blood flow in epicardial arteries, flow at the level of the microvasculature remains impeded, a phenomenon described as “no-reflow.” ¹⁵ Endothelial damage induced by the ischemic injury itself and the release of atherosclerotic debris have been proposed as the underlying pathophysiology. ¹⁶ Various vasodilators including adenosine, nicardipine, nitroprusside, verapamil, and nicorandil, when used in adjunct with percutaneous coronary intervention have been deemed effective in the prevention of no-reflow and curtailing the no-reflow zone. ^16,17 In a study of patients with acute myocardial infarction, Ito et al showed that administration of intravenous nicorandil in conjunction with coronary angioplasty, followed by oral nicorandil, results in a significant reduction of sizable no-reflow zone detected by contrast echocardiography. ¹⁸ Moreover, Toyama et al demonstrated that intracoronary injection of nicorandil in patients presenting with acute myocardial infarction and poor TIMI flow is associated with significant improvements in summed defect score and delta regional wall motion detected by single-photon emission computed tomography. ¹⁹ We complement the previous studies by demonstrating that nicorandil is also effective for the amelioration of angina frequency and intensity in patients with slow flow.

A number of limitations in the present study deserve mention. In the current study, we only looked at the comparative efficacy of nicorandil in the short term. Several previous studies in animals and humans have demonstrated that nicorandil might exert cardioprotective effects beyond immediate angina relief. ^{19 –21} A related clinical entity dubbed coronary “syndrome X” is described as the presence of typical angina despite normal coronary angiography. ⁷ Coronary slow flow phenomenon has been sometimes referred to as “coronary syndrome Y” to mark its distinction with syndrome X, since patients with the latter do not appear to enjoy the favorable prognosis associated with the former. ²² In a clinical study, patients with coronary slow flow were found to have significantly longer minimum corrected QT intervals. ²³ Saya et al reported a case of slow flow presenting with repeated transient episodes of ventricular tachyarrhythmias. ²⁴ Administration of dipyridamole in this patient successfully normalized the flow and resolved arrhythmia. ²⁴ The anti-arrhythmic properties of nicorandil have been well established. ^25,26 Consequently, prospective studies with longer durations of follow-up are paramount to ponder the potential long-term benefits of nicorandil on the progression of coronary atherosclerosis and clinical course of the disease in patients with slow flow.

The present clinical trial included a relatively small number of patients, and although we were able to demonstrate the superior efficacy of nicorandil versus nitroglycerin, the study might not have been powered enough to detect uncommon side effects associated with nicorandil use. Nicorandil use has been implicated in incident oral, anal, and penile ulcers, albeit rarely. ^{27 –29} In the present study, 3 patients taking nicorandil experienced transient headaches that were readily relieved by the use of over-the-counter analgesic medications. Headaches, the most frequent adverse effect reported with nicorandil use, appear to be dose related and therefore initiation of treatment with a lower dose and subsequent titration might be an appropriate strategy to decrease the incidence. ³⁰ Since patients with coronary slow flow are likely to benefit from long-term treatment with nicorandil, the safety profile of the medication deserves more thorough investigation in this group of patients.

Conclusion

In the present clinical trial, we demonstrate that nicorandil use is safe, and in comparison with nitroglycerin, results in a greater reduction of angina frequency and intensity in patients with coronary slow flow phenomenon. Further studies are needed to investigate the long-term clinical benefits of nicorandil for the management of ischemic heart disease in patients with coronary slow flow phenomenon.