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cceptedArticleThis article has been accepted for publication and undergone full peer review but hasnot been through the copyediting, typesetting, pagination and proofreading processwhich may lead to differences between this version and the Version of Record. Pleasecite this article as an 'Accepted Article', doi: 10.1111/1755-5922.12097Received Date : 18-Aug-2014Revised Date : 26-Sep-2014Accepted Date : 12-Oct-2014Article type : Original Research ArticleEffect of Nicorandil in patients with heart failure: a systematic review andmeta-analysisFujie Zhao, Sandip Chaugai, Peng Chen, Yan Wang, Dao Wen WangDepartments of Internal Medicine and Institute of Hypertension, TongjiHospital, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan 430030, P. R. of ChinaCorresponding Author:Dao Wen Wang, M.D., Ph.D.Departments of Internal MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyAcceptedArticle Wuhan 430030, People’s Republic of ChinaTel. (86-27)8366-2826 Fax (86-27)8366-2826Email address: dwwang@Running title: Nicorandil and therapy of heart failureABSTRACTBackground and Purpose: It is unclear whether nicorandil, a metabolic therapeutic drug, can be applied clinically to therapy of heart failure (HF). This meta-analysis evaluated therapeutic effects of nicorandil on HF patients. Experimental approach: We performed a systematic review andmeta-analysis of published studies evaluating effect of nicorandil on HF patients. Studies were stratified according to controlled versus uncontrolled designs and analyzed using random-effects meta-analysis models.Key Results: We identified total 20 studies with total 1222 patients. In 5 randomized controlled studies, nicorandil treatment resulted in reduction inall-cause mortality and hospitalization for cardiac causes (HR: 0.35, p<0.001), and improved cardiac pump function (SMD: 0.31, p=0.02). In 15 observational studies, nicorandil therapy increases cardiac pump function (SMD: 0.75,p<0.001), improves NYHA functional class (WMD: -1.33, p<0.001), decreases PCWP (WMD: -6.86mmHg, p<0.001), and pulmonary arterial pressure (SMD: -0.84, p<0.001).Conclusions & Implications: use of nicorandil in HF patients exerts substantial beneficial effects, suggesting that it may be an additional therapeutic agent for HF.AcceptedArticle INTRODUCTIONHeart Failure (HF) represents a raising health care concern in developed and developing countries, reaching epidemic proportions1. About 1% to 2% of adult population in developed countries suffers HF, with ≥ 10% prevalence among elderly (>70years)2. Heart failure is generally a chronic condition but can present acutely with pulmonary edema, cardiogenic shock or decompensation of CHF requiring emergency care. Vasodilators remain the conventional treatment for urgent care of patients with heart failure.Nicorandil, a nicotinamide derivative, is a recently developed vasodilator with potent coronary and peripheral vascular activity and has been used as a novel antianginal agent. It has a nitrate component and it is also a sarcolemmal ATP-sensitive potassium channels (K-ATP) opener. Nicorandil thus has a dual mechanism of vasodilation, which increases coronary blood flow and reduces preload and afterload, and has been shown to have antianginal efficacy similar to other traditional drugs. Besides, experimental studies have shown that nicorandil exerted cardioprotective effects through opening mitochondrial ATP-dependent potassium channels by reducing oxidative damage3,4, preserving ATPproduction4, preventing cytochrome c release4, modulating neutrophil properties5, enhancing the production of prostacyclin (PGI2)6, accelerating Na+ recovery7 and attenuating the mitochondrialCa2+overloadwith accompanying depolarization of the mitochondrial membrane8. On the other hand, opening of sarcolemmal ATP-dependent potassium channels may also show cardioprotective effects by abbreviating excitability such that calcium overload and energy consumption would beattenuated9.In addition, many other effects of nicorandil on cardiovascular system have been investigated, such as anti-inflammatory and anti-proliferative effects10, anti-apoptosis4,11-14, anti-ischemic and anti-infract15-17, anti-arrhythmic18-20,AcceptedArticle improving microvascular circulation21,22, protecting endothelial function13,23, especially protectingmitochondrialfunction4 and energy-modulatingfunction6,24,25. Cumulative evidences suggest that nicorandil has several beneficial effects on the myocardium and is promising for therapy of heart failure.Therefore, we hypothesized that nicorandil offers myocardial protection and is able to improve cardiac function and be used for therapy of heart failure. However there is still no large-scale, multicenter RCT on the effects of nicorandil in patients with heart failure, so this systematic review andmeta-analysis was performed to estimate the effects of nicorandil treatment on patients with heart failure.RESULTSStudy selection and characteristics. The flow of selecting studies for this systematic review and meta-analysis is shown in Figure 1. Briefly, of the initial 2907 hits, 113 articles were retrieved for detailed evaluation, and 20 articles including a total of 21 trials (Döring G. et al. study26included two different trials) were finally included in our systematic review, encompassing 1222 patients. In Akihiro Shirakabe27 and Takahisa Yamada28 studies, some patients were included in both the controlled and uncontrolled study analyses, but they were only included once in any given analysis, and so there was no overlap in patients included in our meta-analyses. Some studies27-34 either they were designed with an inappropriate control or only data about the nicorandil group could be extracted, though they were RCT, we still treated them as observational studies without a control group.Table 2 summarizes the design and methods of the included studies. There were 5 randomized controlled trials27,28,35-37 (n = 271) and 3 observationalAcceptedArticle study with a control group38-40 (n = 587) (i.e., controlled studies), and 12 observational studies without a control group26,29-34,41-45 (n = 391) (i.e., uncontrolled studies). Table 3 summarizes the baseline Characteristics of the Included Study Subjects. The risk of bias was low in the majority of studies, with a detailed assessment available in Table 1(1A and 1B).All-cause mortality and hospitalization for cardiac causes. In controlled studies, treatment with nicorandil was associated with a statistically significant 65% reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, 95% CI: 0.16 to 0.54, P<0.001; Figure 2) (3 trials, 663 patients included, with a mean follow-up of 1.6 years).The degree of heterogeneity in the treatment effect across all trials was low (I2: 47.2%) and non-significant (P = 0.128).Cardiac structure and function. In controlled studies, the results indicated that nicorandil therapy was superior to control therapy in terms of cardiac pump function improvement (SMD: 0.31, P = 0.02; Figure 3A.a).Additionally, nicorandil therapy tended to decrease pulmonary capillary wedge pressure (PCWP) (WMD: -3.23mm Hg, 95% CI:-8.18 to 1.72mm Hg, P=0.20; Figure3A.b),left ventricular diastolic diameter (LVDd) (WMD: -3.67 mm, p=0.12; Figure 3A.c), end diastolic volume (EDV) (WMD: -6.33ml, p=0.54; Figure3A.d), end systolic volume (ESV)(WMD: -9.28 ml, p=0.32; Figure 3A.e). Furthermore, echocardiography results indicated that nicorandil therapy significantly decreased the ratio of early transmitral diastolic velocity to early diastolic mitral annular tissue Doppler (E/Ea) (WMD: -4.64, 95% CI:-8.24 to-1.04, P=0.01; Figure 3A.f), increased deceleration time of early transmitral diastolic velocity (DcT)(WMD: 19.95 ms, 95% CI: 3.51 to 36.39 ms, P =0.02;AcceptedArticle Figure 3A.g) and tended to reduce early transmitral diastolic velocity (E)(WMD: -6.17cm/s, p = 0.16; Figure 3A.h)and increase early diastolic mitral annular measured by tissue Doppler (Ea)(WMD: 0.32 cm/s, p = 0.27; Figure 3A.i). This meant nicorandil therapy can improve left ventricular diastolic function.In uncontrolled studies, the results also indicated that nicorandil therapy was superior to control therapy in terms of cardiac pump function improvement (SMD: 0.75, p < 0.001; Figure 3B.a) and reducing PCWP (WMD: -6.86 mm Hg, 95% CI: -8.10 to-5.61 mm Hg, P <0.001; Figure 3B.b). Furthermore, nicorandil therapy was similarly found to reduce right atrial pressure (RAP) (WMD: -1.27 mm Hg, 95% CI:-2.38 to-0.16 mm Hg, P=0.03; Figure 3B.c).Functional capacity. In uncontrolled studies, nicorandil treatment significantly improved NYHA functional class (WMD: -1.33, 95% CI:-1.83to-0.83, p < 0.001; Figure 3C). The degree of heterogeneity in the treatment effect across all trials was modest (I2: 59.0%) but non-significant (P = 0.12).Blood pressure and heart rate. In controlled studies, nicorandil treatment resulted in significant changes in systolic blood pressure(SBP) (WMD: -5.87 mm Hg, 95% CI: -10.04 to -1.70 mm Hg; p = 0.006; Figure 3D.a), diastolic blood pressure(DBP)(WMD: -6.61 mm Hg, 95% CI: -11.38 to -1.84 mm Hg; p = 0.007; Figure 3D.b) and mean blood pressure(MBP)(WMD: -7.46 mm Hg, 95% CI: -11.78 to -3.14; p < 0.001; Figure 3D.c), whereas no significant differences were observed in heart rate (WMD: 0.74 beats/min, p = 0.77; Figure 3D.d).In uncontrolled studies, nicorandil treatment also resulted in significant changes in SBP (WMD: -7.96 mm Hg, 95% CI: -10.99 to -4.94 mm Hg; p < 0.001; Figure 3E.a), DBP(WMD: -2.36 mm Hg, 95% CI: -2.89 to -1.84 mm Hg;AcceptedArticle p < 0.001; Figure 3E.b), MBP(WMD: -7.92 mm Hg, 95% CI: -11.89 to -3.95; p < 0.001; Figure 3E.c), whereas no significant differences were observed in heart rate (WMD: 1.29 beats/min, p = 0.18; Figure 3E.d). Additional, nicorandil therapy also reduced pulmonary arterial pressure (SMD: -0.84, p < 0.001; Figure 3E.e) and peripheral resistance (SMD: -0.64, P =0.006; Figure 3E.f).Serum biomarkers. In controlled studies, nicorandil treatment tended to reduce serum biomarker for heart failure, B-type natriuretic peptide (BNP) (WMD: -111.46pg/ml; p = 0.43; Figure 3F.a).In uncontrolled studies, BNP level were down-regulated by nicorandil treatment(SMD: -1.09,P <0.001; Figure 3F.b). Matrix metalloproteinases (MMPs) (including MMP-2 and MMP-9) level were also down-regulated by nicorandil treatment(SMD: -1.18, P =0.04; Figure 3F.c).Myocardial microvascular circulation. The total defect score (TDS), evaluated by 123I-MIBG (Kasama S et al.) or by 99m Tc-MIBI (Fukushima Y et al.）, is known to represent a microvascular dysfunction. Nicorandil therapy significantly improved TDS (WMD: -6.81, 95% CI: -12.67 to -0.94, P = 0.02; Figure 3G).Sensitivity analyses. Sensitivity analyses were performed on all the variables included, but no significant results were found.DISCUSSIONWe have conducted the first systematic review and meta-analysis to evaluate the therapeutic effect of nicorandil on patients with HF. We found that use ofAcceptedArticle nicorandil in HF patients may exert markedly beneficial effects, not only in improving cardiac pump function, NYHA functional class, left ventricular diastolic function, myocardial microvascular circulation, but in reducingall-cause mortality and hospitalization for cardiac causes, pulmonary capillary wedge pressure, right atrial pressure, and systolic blood pressure, diastolic blood pressure, mean blood pressure, pulmonary arterial pressure, peripheral resistance, and reducing serum level of BNP and Matrix metalloproteinases, which are biomarker for heart failure, indicating that it may be an additional therapeutic agent for HF.Besides, as reported by Fukushima44, intravenous injection of nicorandil improves myocardial perfusion not only in the myocardial segments with coronary stenosis, but also in the myocardial segments without coronary stenosis. These results suggest that nicorandil might improve the myocardial microcirculation in both ischemic and non-ischemic heart failure.The reduction of preload and afterload was the effect of nicorandil as a vasodilator through nitrate-like and ATP-sensitive potassium-channel activating properties. In addition, it is noteworthy that nicorandil also exerts cardioprotective effects and energy-modulating function by reducing oxidative damage,3,4 preserving ATP production4 andprotectingmitochondrialfunction4. It seems plausible that the amelioration effects may finally translate into mechanical efficiency and contribute to the improvement of cardiac function, ameliorating clinical symptoms and long-term prognosis of patients with heart failure. Furthermore, it seems reasonable that the BNP level could bedown-regulated by nicorandil treatment. Considering that the BNP level is negatively related to the alteration of cardiac structure and function46, it seems reasonable to presume that nicorandil may play beneficial roles, not only in improvement of hemodynamics but also in cardiac remodeling.AcceptedArticleFurthermore, compared with nitroglycerin, nicorandil is associated with less hemodynamic tolerance and is safer.29-31 In addition, Further, recent studies found that nicorandil not only improves the cardiac function but also preserves kidney function and decreases mortality in acute heart failure patients with pre-existing renal dysfunction36,47,48. This may provide a unique niche to nicorandil in heart failure therapy.Study limitations. First, most of the included studies were observational in nature and thus may be affected by confounding by indication and/or selection bias. Second, there were differences in patients’ type of heart failure, differences in time to treatment success evaluation within the different studies, differences in nicorandil administration (dose and route) and differences in patients’ characteristics among included studies, all these factors might influenced the overall results of this systematic review and meta-analysis. However with the use of published aggregate data, we were unable to examine the effect of nicorandil in patient subgroups or do meta-regression analyses to evaluate these factors. Third, inclusion was restricted to published studies and may therefore be affected by publication bias. Fourth,twenty-seven years of clinical experience and medical therapy progress has been included into this analysis (Mitsuhiro Yokota, et al. 1987; Shu Kasama, et al. 2014), therefore significant changes in treatment strategy might have influenced the overall results of this meta-analysis. Finally, but importantly, lack of large-scale and long-term RCTs for evaluating the impact of nicorandil treatment on patients with heart failure might be a fetal flaw of thismeta-analysis.In conclusion, the use of nicorandil in HF patients can exert beneficial effects, not only in ameliorating clinical symptoms, hemodynamic effects, myocardial microvascular circulation and cardiac structure and function, but inAcceptedArticle reducing all-cause mortality and hospitalization for cardiac causes, indicating that it may be an additional therapeutic agent for HF. Additional well-designed, and long-term follow-up studies that include more diverse patient populations to further support the protective effects of nicorandil on cardiac function in patients with heart failure, especially in chronic heart failure, are needed.METHODSData sources and search strategy. We performed a systematic review and meta-analysis in accordance with the standards set forth by the PRISMA (Preferred Reporting Items for Systematic Reviews andMeta-Analyses)statement.49,50We searched PubMed, EMBASE, the Cochrane Collaboration database, Wiley online library and ISI Web of Science using the terms “nicorandil”, “K ATP channel openers”, “sigmart”, “SG-75”, “heart failure”, “cardiac dysfunction”, “cardiac insufficiency”, “cardiac inadequacy”, “cardiomyopathy”, “cardiovascular disease”, “clinical trials” and “patient analysis”. The search was not restricted to any language. In addition, we hand-searched references of retrieved articles and used PubMed’s related articles feature to identify studies not captured by our primary search strategy. We also try to get some articles or original data by author contact. The final search was run on January 25, 2014.Study selection. We included randomized controlled trials (RCTs), observational controlled studies and observational uncontrolled studies. Inclusion criteria were: 1) all the patients included were clearly diagnosed as having heart failure 2) follow-up rate of >85%. Reviews, animal studies, case reports, editorials, letters were excluded. Once full articles or abstracts were retrieved, studies that met the following criteria were further excluded: 1)AcceptedArticle irrelevant study design; 2) no access to either the full-text or abstracts for quality assessment and data extraction; 3) indeterminate title/abstract; 4) there was an overlap in patients with another study within the same analysis (in which case, the larger sample size of the 2 studies was selected). Thus, whereas some patients could possibly have been included in both the controlled and uncontrolled study analyses, they were only included once in any given analysis. Consequently, there was no overlap in patients included in our meta-analyses.Data extraction and quality assessment. Data was extracted in duplicate by 2 independent reviewers (Drs. Zhao and Chaugai). Disagreements were resolved by consensus. For controlled studies, mean value and standard deviation of the outcome measurements in each intervention group (nicorandil group and control group), and number of participants on whom the outcome was measured in each intervention group were extracted. For uncontrolled studies, mean value and standard deviation, and number of participants for a given measure before and after nicorandil treatment were extracted. If the outcome measurements or baseline measurements were not reported, they were calculated from the differences in changes frombaseline under the guidance of Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0.Todetermine the quality of the included studies, we used the Cochrane Collaboration Risk of Bias Tool (Table 1) for the 5 randomized control trials and the Newcastle-Ottawa scale for the observational studies. We set a follow-up rate of >85% as a limit to determine high risks of bias at follow-up for studies evaluated with the Newcastle-Ottawa scale in the outcome section of this scale (Table 2).Data synthesis and statistical analysis. For both controlled studies and uncontrolled studies the measurement data were pooled across studies andAcceptedArticle analyzed using random-effects meta-analysis models with inverse variance weighting. In case some variables were too few to do meta-analysis, we combined some variables together and used as one new variable. For example, we defined a new variable cardiac pump function meaning ejection fraction (EF) or cardiac index (CI) or cardiac output (CO). Similarly, variable pulmonary arterial pressure was used as a representation of mean pulmonary arterial pressure or pulmonary arterial systolic pressure (PASP), and a new variable peripheral resistance to represent total peripheral resistance (TPR) or systemic vascular resistance (SVR) or systemic vascular resistance index (SVRI). All these new variables were analyzed using standardized mean differences (SMD).We chose to pool the results of the studies based on the study design. Hence, the randomized controlled trials were pooled with the controlled cohort studies, and the uncontrolled observational studies were pooled together. Observational studies tend to overestimate treatment effects by confounding by indication.The magnitude of heterogeneity present was estimated using the I2statistic,an estimate of the proportion of the total observed variance that is attributed to between-study variance. To compare the effect of nicorandil based on pretreatment systolic blood pressure (SBP), we constructed a separatemeta-analysis stratified by systolic blood pressure using a random-effects generic inverse variance-weighting model to compare heterogeneity using the I2statistic.In the study by Minamiet al41, the only measure of variability reported was interquartile range. By including this study in the meta-analysis models, we are assuming a normal distribution of change in B-type natriuretic peptide (BNP).AcceptedArticle Besides, Tanaka et al. study42, Döring G. et al. study 226 and Thomas D. Giles. et al. study45were designed as parallel study, though they were used more than once in one meta-analysis, they were based on different population. That is to say, there was no overlap in patients included in our meta-analyses. Sensitivity analyses (exclusion of 1 study at a time) were performed to determine the stability of the overall treatment effects. All p values were2-tailed, and the statistical significance was set at 0.05. Throughout, values are presented as mean ± SD unless otherwise stated. All statistical analyses were performed by using RevMan 5.0 (The Cochrane Collaboration, Copenhagen, Denmark) and STATA software 12.0 (StataCorp, College Station, Texas).STUDYHIGHLIGHTSWhat is the current knowledge on the topic?With the progress of various treatment methods, heart failure is still a major potential threat to human health. Nicorandil, a recently developed vasodilator and metabolic therapeutic drug, has been used as a novel antianginal agent. But its cardioprotective effect on heart failure patients has not been well evaluated.What question this study addressed?We performed a systematic review and meta-analysis of published studies to evaluate the effect of nicorandil on HF patients.What this study adds to our knowledge?The use of nicorandil in HF patients exerts beneficial effects, including ameliorating clinical symptoms, improving left ventricular function, and reducing all-cause mortality and hospitalization for cardiac causes, indicating that it may be an additional therapeutic agent for HF.AcceptedArticle How this might change clinical pharmacology and therapeutics? Nicorandil may be an additional therapeutic agent for HF patients.ACKNOWLEDGMENTSThis work was supported by National Basic Research Programs (No.2012CB518004 and 2014CB541601). The authors thank Drs. Chaugai and Chen for data extraction and Statistical analysis. Many thanks to all those who helped us.CONFLICT OF INTERESTThe authors declared no conflict of interest.REFERENCE1 Fang, J., Mensah, G. A., Croft, J. B. & Keenan, N. L. Heart failure-related hospitalization in theU.S.1979 to 2004. J Am Coll Cardiol52. 428-434(2008).2 McMurray, J. J. et al. ESC Guidelines for the diagnosis and treatment of acute and chronicheart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and ChronicHeart Failure 2012 of the European Society of Cardiology. Developed in collaboration withthe Heart Failure Association (HFA) of the ESC. Eur Heart J33. 1787-1847(2012).3 Das, B. & Sarkar, C. Cardiomyocyte mitochondrial KATP channels participate in theantiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion inan intact anesthetized rabbit model. Pol J Pharmacol55. 771-786 (2003).4 Ozcan, C., Bienengraeber, M., Dzeja, P. P. & Terzic, A. 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