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(Circulation. 2005;112:1284-1288.)
© 2005 American Heart Association, Inc.

Coronary Heart Disease

Impact of a Single Intravenous Administration of Nicorandil Before Reperfusion in Patients With ST-Segment–Elevation Myocardial Infarction

Hideki Ishii, MD; Satoshi Ichimiya, MD, PhD; Masaaki Kanashiro, MD, PhD; Tetsuya Amano, MD, PhD; Kenji Imai, MD, PhD; Toyoaki Murohara, MD, PhD; Tatsuaki Matsubara, MD, PhD

From the Department of Cardiology, Nagoya University Graduate of School of Medicine (H.I., T.A., K.J., T. Murohara); the Department of Cardiology, Yokkaichi Municipal Hospital, Yokkaichi, Mie (H.I., S.I., M.K.); and the Department of Internal Medicine, School of Dentistry, Aichi-Gakuin University (T. Matsubara), Nagoya, Japan.

Correspondence to Dr Hideki Ishii, Department of Cardiology, Nagoya University Graduate of School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. E-mail hkishii{at}med.nagoya-u.ac.jp

Received December 20, 2004; revision received May 5, 2005; accepted May 31, 2005.

	Abstract

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Background— Intravenous nicorandil, a hybrid compound of ATP-sensitive potassium channel opener and nitric oxide donor, has been reported to ameliorate early functional and clinical problems in patients with acute myocardial infarction. However, its effects on the late phase remain unclear.

Methods and Results— This follow-up study to 5 years of a randomized, double-blinded trial was conducted among 368 patients with first ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). They were randomly assigned to receive 12 mg of nicorandil or a placebo intravenously just before reperfusion. We analyzed incidence of cardiovascular death or rehospitalization for congestive heart failure after PCI as well as various aspects of epicardial flow and microvascular function. Mean follow-up was 2.4 years (SD, 1.4). A total of 12 (6.5%) patients receiving nicorandil and 30 (16.4%) receiving placebo had cardiovascular death or hospital admission for congestive heart failure (hazard ratio, 0.39; 95% CI, 0.20 to 0.76; P=0.0058). Postprocedural TIMI 3 flow was obtained in 89.7% of the nicorandil group and in 81.4% of the placebo (hazard ratio, 1.99; 95% CI, 1.09 to 3.65; P=0.025). Corrected TIMI frame count was furthermore lower in the nicorandil group (21.0±9.1 versus 25.1±14.1; P=0.0009). ST-segment resolution >50% was observed in 79.5% and 61.2% of the nicorandil and placebo groups, respectively (hazard ratio, 2.45; 95% CI, 1.54 to 3.90; P=0.0002).

Conclusions— The addition of intravenous nicorandil to PCI leads to beneficial clinical outcomes and prevents cardiovascular events of long duration and death in patients with ST-segment–elevation myocardial infarction.

Key Words: myocardial infarction • reperfusion • microcirculation • pharmacology

	Introduction

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Coronary reperfusion with thrombolysis and/or percutaneous coronary intervention (PCI) is performed for a wide range of patients with acute myocardial infarction (AMI). Early reperfusion of totally occluded coronary arteries reduces infarct size, cardiac mortality rates, and in-hospital events.^1,2 In combination with reperfusion therapy, pharmacological treatment can also attenuate myocardial dysfunction associated with AMI.^3,4 Recent clinical trials have shown that nicorandil, a hybrid of adenosine triphosphate–sensitive K channel opener and nitrates, exerts beneficial effects as an adjunctive therapy for patients with ischemic heart disease.^4–8 Experiments indicate that these effects are due to ischemic preconditioning,^9,10 which contributes to cardioprotection.^11–13 Intravenous nicorandil has been reported to ameliorate early functional and clinical problems in patients with AMI.^14,15 However, its effects on the later phase remain unclear, and no data are available on the efficacy of single intravenous injections of nicorandil before reperfusion for AMI cases.

The goal of the present study was to assess not only early but also chronic cardioprotective effects of single intravenous administrations of nicorandil before reperfusion for ST-segment–elevation myocardial infarction (STEMI) cases undergoing direct PCI.

	Methods

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Patients
Between November 1998 and October 2003, we performed a double-blinded, randomized clinical trial at the Department of Cardiology, Yokkaichi Municipal Hospital, the catchment area of which is in Yokkaichi city, near Nagoya and its outskirts in Mie prefecture; the total population of the area was 291 105 in 2000. Patients were eligible if they were age 30 years or older and admitted with STEMI. The diagnosis of STEMI was based on episodes of chest pain persisting at least 30 minutes but no longer than 24 hours and proving unresponsive to nitrates, ECG ST-segment elevation with at least 2 contiguous ECG leads, and >2-fold creatine kinase (CK) elevation above the maximum peak in the normal range. Exclusion criteria were age >80 years and left bundle-branch block on ECG. The physicians obtained written informed consent from each patient, and the study was approved by the hospital ethics committee.

Study Design
By the concealed envelope method, patients were randomly assigned into 2 groups: those who received intravenous nicorandil before reperfusion with PCI and those who received placebo. The total doses of 12 mg dissolved in 100 mL of 0.9% saline in the nicorandil group and 100 mL of 0.9% saline in the placebo group were administered by intravenous injection over a 20- to 30-minute period before the procedure. Other protocols were the same for the 2 groups. The physicians in the emergency room opened the envelope for the random assignment and administration of the drug. Cardiologists in charge who performed PCI and treated in the hospital were unaware of the random assignments. The solution of nicorandil was colorless and clear, and appearances were completely the same because the same vials of 0.9% saline were used in both groups. After arterial access was achieved, 3000 U of heparin was administered. If the infarct-related coronary artery was recognized, PCI was performed after adjunctive 7000 U heparin injections. The physicians, who were blinded to the treatment group assignment, determined the method and device for PCI. Intracoronary administration of 2.5 to 5 mg isosorbide dinitrate was used for all patients before the initial and the final angiograms to achieve maximal vasodilation. For all the patients, no angiographically residual stenosis was achieved, and there were also no deaths during PCI procedures.

The intravascular sheaths were removed 6 hours after PCI. With the exception of discontinuation for 1 hour before removing sheaths, patients were maintained on a 10 000- to 15 000-U/d dose of intravenous heparin for 48 to 60 hours. Aspirin (162 mg/d) was administered orally, and ticlopidine or cilostazol was applied when the stent was implanted. In the absence of contraindications, ACE inhibitors or angiotensin II receptor blockers (ARB) were administered.

The primary end point was cardiovascular death or unplanned admission to hospital for management of worsening congestive heart failure (CHF). A CHF admission was defined as admission to hospital necessitated by heart failure and primarily for its treatment with intravenous diuretics. Evidence of worsening CHF had to include at least one of the following items: increasing dyspnea on exercise, nocturnal dyspnea, orthopnea, and radiological signs of CHF. Secondary end points were the following immediately after reperfusion: (1) Thrombolysis In Myocardial Infarction (TIMI) trial grade after PCI; (2) reperfusion arrhythmias: ventricular tachycardia (a minimum of 5 consecutive beats of ventricular origin at a rate of >100 bpm) and ventricular fibrillation; (3) resolution of ST-segment elevation on ECG after PCI; (4) maximum serum CK; and (5) corrected TIMI frame count (cTFC) after PCI.

The first ECG was done immediately before coronary angiography, and the second was done 15 minutes after PCI. The magnitude of ST-segment elevation was measured 20 ms after the end of QRS complex. ST-segment elevation was calculated as the sum of ST-segment elevation >0.1 mV for leads I, aV_L, and V₁ to V₆ for anterior acute STEMI and leads II, III, aVf, and V₅ to V₆ for non–anterior acute STEMI. Samples for serum CK were obtained at admission and every 3 hours until 48 hours after PCI. From those measurements, we analyzed maximum CK level. The cTFC was measured as the number of cineframes required for contrast to first reach standardized distal coronary landmarks in the culprit artery.¹⁶ In this study, the filming speed was 30 frames per second. For a totally occluded vessel, a frame count of 100 was used. All measurements were performed by an experienced observer who was blinded to random assignment.

As the primary secondary end point, we analyzed the composite end point of all-cause mortality or all-cause admission.

Follow-up data were obtained from hospital charts and telephone interviews with the patients, with loss of 2 patients in the nicorandil group and 2 in the placebo group during the follow-up period.

Statistical Analysis
Univariate analysis of differences between the 2 groups was performed by the 2-tailed unpaired t test for continuous outcome variables and by ² or Fisher exact tests for discrete outcome variables. Differences in long-term cardiac event-free survival between the groups were examined with the Kaplan-Meier method and compared by using the log-rank test. We used Cox proportional hazards models to assess univariate and multivariable covariates associated with progression of all patients to the primary end point. Covariates assessed in univariate analyses were patient age at admission, body mass index, the incidence of diabetes mellitus, the incidence of hypertension, the incidence of hyperlipidemia, smoking status, Killip class at admission, and time to reperfusion from the onset. Any covariates that were significant on univariate analyses (P<0.25) were assessed by multivariable analyses. Risk reductions were calculated in the form of hazard ratios and 95% confidence intervals from Cox proportional hazards models. With reference to the STEMI site, subanalyses were performed. Patients with left main trunk lesion were included into the criteria of anterior wall AMI for these analyses. For final achievement of TIMI III grade, the incidence of freedom from reperfusion arrhythmias and the incidence of ST-segment resolution >50% after PCI in secondary end points, a logistical model was used. All analyses were based on the intention-to-treat principle. Differences were considered significant at the 5% level (P<0.05).

The study was designed to have approximately 80% power to detect a difference between groups in the time to occurrence of a primary outcome. Assumptions included use of a 2-tailed test, a 5% level of significance, and event rates of 12.5% in the nicorandil group and 25% in the placebo group. Our sample size calculation for this trial was based on the result of epidemiological studies on ischemic heart disease in Japan and of the trial between 1993 and 1997 in our institution that the 5-year rate of time to first event of the primary end point would be about 25%.

	Results

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We enrolled 368 consecutive patients; 185 were randomly allocated to nicorandil and 183 to placebo. Follow-up was concluded on January 31, 2004. The median duration of follow-up was 2.4 years (SD, 1.4). The baseline characteristics of the placebo and nicorandil groups are shown in Tables 1 and 2. There were no differences in age, sex, time to reperfusion from onset, incidence of coronary risk factors, blood pressure, heart rate, pulmonary capillary wedge pressure, serum CK level before PCI, culprit lesions, or quantitative angiographic data before and after PCI between the 2 groups, nor were there significant differences in the use of oral medications at discharge. ACE inhibitors or ARBs were administered for 83.2% of the nicorandil group and 80.9% of the placebo and ß-blockers for 11.3% and 13.1%, respectively. In all patients of the nicorandil group, no significant differences in vital signs, such as blood pressure or heart rate, were observed from before to after nicorandil administration.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Patient Characteristics

View this table: [in this window] [in a new window]   TABLE 2. Angiographic and ECG Findings

The main clinical outcome results are presented in Table 3. The end point defined as cardiovascular death or admission to hospital for CHF occurred in 12 (6.5%) patients receiving nicorandil and 30 (16.4%) receiving placebo (hazard ratio, 0.39; 95% CI, 0.20 to 0.76; P=0.0058) (Figure 1). A total of 6 (3.2%) patients in the nicorandil group and 20 (10.9%) in the placebo group had unplanned admission to a hospital for management of worsening CHF (hazard ratio, 0.29; 95% CI, 0.11 to 0.71; P=0.0072). There was no significant difference in the rate of cardiovascular death (3.2% versus 5.5%; hazard ratio, 0.59; 95% CI, 0.22 to 1.64; P=0.31). Even after adjusting for other risk factors at baseline, the nicorandil treatment effect on the risk of cardiovascular death or readmission to hospital for CHF remained significant and independent (P=0.0181). With reference to the STEMI site, we divided into 2 groups anterior wall STEMI and non–anterior wall STEMI. For the former, the 5-year rates for freedom from coronary heart disease death or readmission due to CHF was 92.0% in the nicorandil group and 78.0% in the placebo group (hazard ratio, 0.36; 95% CI, 0.14 to 0.92; P=0.033). With non–anterior wall AMI, the 5-year rates for freedom were 91.4% in the nicorandil group and 73.4% in the placebo group (hazard ratio, 0.43; 95% CI, 0.17 to 1.11; P=0.079).

View this table: [in this window] [in a new window]   TABLE 3. Primary and Components of the Composite End Point

View larger version (15K): [in this window] [in a new window]   Kaplan-Meier estimates for all patients: Coronary heart disease death or unplanned hospital admission for congestive heart failure.

The frequency of secondary end points in the acute phase was also significantly lower in the nicorandil group (Table 4). The hazard ratios were 1.99 (95% CI, 1.09 to 3.65; P=0.025) for final achievement of TIMI III grade, 1.85 (95% CI, 1.07 to 3.19; P=0.028) for freedom from reperfusion arrhythmias, and 2.45 (95% CI, 1.54 to 3.90; P=0.0002) for resolution of ST-segment elevation on ECG after PCI (>50% of initial value). Serum maximum CK levels that reflected infarct size were 3076±3051 IU/mL in the nicorandil group and 3818±3504 IU/mL in the placebo group (P=0.03). The cTFC was much lower in the nicorandil group (21.0±9.1 versus 25.1±14.1, P=0.0009).

View this table: [in this window] [in a new window]   TABLE 4. Secondary End Point

As to the composite end point of all-cause mortality or all-cause admission, there were 47 (25.4%) patients in the nicorandil group and 66 (36.1%) in the placebo group; however, it was not statistically significant (hazard ratio, 0.72; 95% CI, 0.49 to 1.04; P=0.08) (Table 3).

	Discussion

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The major finding of the present study is that a single intravenous administration of nicorandil before reperfusion ameliorated not only early but also later clinical events in patients with STEMI. In addition, acceleration of ST-segment resolution and improvement of epicardial flow were noted. Our protocol was quite simple, involving a single injection.

The most likely explanation for the salutary effects of intravenous nicorandil appears to be pharmacological prevention of slow flow. Nicorandil increases coronary blood flow, particularly to small vessels (<100 µm).¹⁷ A second possibility is that nicorandil has the same pharmacological effect as preconditioning influence. It has been shown that K-ATP channel openers, including nicorandil, prevent reperfusion injury and protect the heart against ischemic injury.^5,10,18 In the ischemic myocardium, K-ATP channels are activated by intracellular ATP depletion and outflow of potassium increased, shortening the duration of the action potential and reducing calcium inflow to myocytes.¹⁹ Inhibition and reduction of calcium inflow to myocytes may have cardioprotective effects on the ischemic heart, and K-ATP channel openers help this action.²⁰ In a recent study, mitochondrial K-ATP channels were further shown to be related to preconditioning as the end factor of many signal transduction systems, so that nicorandil might exert salutary effects through their activation.²¹ Through the collateral circulation, nicorandil could be delivered to areas at risk before PCI. In this point, intravenous administration had an advantage over intracoronary administration. Therefore, after the vessel was occluded, it was possible in risked areas that K-ATP channels were activated by nicorandil such as preconditioning effect. These possibilities might block progression of microvascular damage and inhibit reperfusion arrhythmias, resulting in better late phase outcomes.

It has been reported that incomplete ST-segment resolution after successful PCI for patients with AMI is associated with impaired myocardial reperfusion at the microcirculatory level and with further extension of myocardial damage.^22,23 Many studies have shown ST-resolution to be useful for prediction of clinical outcome with thrombolytic therapy and PCI for AMI.^23,24 Using the ECG is the simplest and cheapest option, and the most promising of the various parameters described is an index of the amount of ECG ST-segment elevation resolution. Our findings are of great significance in this context.

It is well known that the site of infarction itself influences clinical outcomes.^25,26 Gibbons et al²⁵ argued that the anticipated benefit from improved reperfusion therapy would be much greater and easier to detect in patients with an anterior AMI than in those with an inferior wall lesion. In the present study, we demonstrated that intravenous nicorandil was of borderline significance for non–anterior lesion STEMI. A possible explanation is that for patients with non–anterior STEMI, the prevention of ischemic mitral regurgitation followed by CHF could be the main reason, whereas for patients with anterior STEMI, reduction in the AMI site might be the main reason.

The dose of nicorandil in our study was 12 mg. Murayama et al²⁷ reported that intravenous administration of 8 mg for 2 minutes was useful in patients with acute coronary syndromes associated with impaired left ventricular systolic and/or diastolic function. Kato²⁸ reported intravenous administration of 4 to 12 mg nicorandil to be safe and have dose-dependent effects on coronary artery diameter and blood flow. Although the present study was performed with a relatively high dose to use a single injection, no side effects were observed in patients treated with 12 mg of nicorandil intravenously.

Limitations of the present trial need to be discussed. First, it remains unclear whether intravenous single injection followed by continuous intravenous injection might be superior to a single bolus injection. Earlier data suggested that slow flow or no reflow is likely to persist for several hours after coronary reperfusion.^29,30 To protect against this progression, continuous infusion of nicorandil might be most appropriate, although the protocol would then be more complex. Second, we have not assessed the most beneficial dose of nicorandil. Finally, this study consisted of only 368 patients and was done in a single center. Therefore, there was the possibility of selection bias and low statistical power.

In summary, the present study demonstrated that patients receiving nicorandil have markedly lowered major complications with significantly better outcomes. We used a system of one intravenous injection of 12 mg nicorandil to reduce costs and to establish a simple procedure that can be easily adopted by any institution. We conclude that intravenous nicorandil is a useful adjunctive therapy for patients with STEMI.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 112/9/1284    most recent CIRCULATIONAHA.104.530329v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ishii, H. Articles by Matsubara, T. Search for Related Content PubMed PubMed Citation Articles by Ishii, H. Articles by Matsubara, T. Related Collections Cardiovascular Pharmacology Catheter-based coronary and valvular interventions: other Acute myocardial infarction Related Article