| BackgroundHeart protection means two implications, not only to "protect"(preservation), but also help to benefit for (favouritism or patronage). ACEI (angiotensin converting enzyme inhibitors) to provide a protective effect of impaired left ventricular function, is a manifestation of the heart protection. Heart Protection (cardioprotection) specifically refers to in some way, to prevent, delay and reduce myocardial injury, especially by means potentially fatal ischemic stress myocardial slow energy demand, and produce less toxic sugar leaven hydrolysates showed reduced myocardial injury. In the past two or three decades, it has been confirmed that provide strong heart protection against myocardial infarction complicated by ischemia-reperfusion injury.2011American Heart Association (American Heart Association, AHA)/American Heart Association Foundation (American College of Cardiology Foundation, ACCF) updated cardiovascular disease secondary prevention guidelines recommend aspirin (Aspirin) or clopidogrel p-blockers (β-Blocker) and the renin-angiotensin-aldosterone system blockers (ACEI, ARB, and aldosterone antagonists) and lipid-lowering drugs for secondary prevention program (class I evidence), the purpose relapse prevention, anti-sudden death, anti-left ventricular remodeling.Control of the existing mode of treatment for cardiovascular disease is still unsatisfactory, these drugs also have their own limitations, only solve narrow coronary intervention and coronary artery bypass grafting, but did not make the long-term benefit of patients.[4] Clinical research and development of new drugs for heart protection. In2012, based on the clinical practice of the unsatisfactory results, scholars:ischemic heart disease awareness should focus on obstructive coronary atherosclerosis center theory "to" myocardial ischemia center theory ". If myocardial ischemia as the main protection targets, obstructive coronary atherosclerosis is a common pathological factors, scholars can consider more potential induced myocardial ischemia factors, which developed more updated protection myocardial ischemic injury in strategy. Cardioprotective effects of adenosine triphosphate-sensitive potassium (KATP) channel opener this attention. Nicorandil clinical study more deeply the KATP channel opener.Nicorandil, a nicotinamide derivative, also known as smoke waves Ding has the nitrate part class nitrates characteristics, ATP-sensitive potassium channel agonist (ATP-sensitive potassium channel openers, KATP), a dual pharmacological mechanism with nitroglycerin or isosorbide esters, the drug has little effect on heart rate, blood pressure and other hemodynamic to produce clinical doses of antianginal little effect on cardiac contractility, and provide long-term protection of the heart. Now clinical oral formulations commonly used in the treatment of hypertension, stable angina pectoris, myocardial infarction (including PCI), cardiac arrhythmias, heart failure and other cardiovascular diseases, intravenous formulation for commonly used in intracoronary injection, with particular emphasis on its inducible ischemia preconditioning effect (transient ischemic preconditioning period caused ischemia reperfusion injury in a strong protective effect). Clinical application of nicorandil three Meta-analysis are:the role of nicorandil on the treatment of acute myocardial infarction (2009foreign language), system evaluation nicorandil beta blockers, long-acting nitrates drugs and calcium antagonists (Japanese)2010compared the efficacy and safety of stable angina, nicorandil prevention of coronary stenting no-reflow effect of systematic reviews (2010Chinese), nicorandil reperfusion in acute myocardial infarction efficacy Meta-analysis (2012, Chinese)Nicorandil (nicorandil) is a unique, ATP-sensitive potassium (KATP) channel the excited and class nitrates features dual pharmacological mechanism of drugs, and provide long-term protection of the heart. Drug against acute or chronic ischemic heart disease, congestive heart failure in patients with heart damage, with particular emphasis (ischaemic postconditioning, IPoC, that for a short pre-ischemic period caused ischemia-reperfusion injury induced ischemic preconditioning strong protective effect) effect.With the continuous development of the clinical research and the rise of evidence-based medicine, rational design rigorous systematic review (systematic review) and Meta-analysis (Meta-analysis) is regarded as the best way of evaluation and synthesis of a specific research question, while regarded as the highest level of clinical evidence. The Meta-analysis of a number of independent studies of the same problem is comprehensive quantitative statistical methods to increase statistical power and effect sizes estimated accuracy advantages. The Meta-analysis is not limited to synthesis of randomized controlled trials, more and more researchers began to quantitative combination of epidemiological studies, such as cohort studies and case-control studies, Meta-analysis.ObjectivesApplication of evidence-based medicine generic system evaluation methods, systematic evaluation of clinical research at home and abroad on the clinical application of nicorandil, to clarify the following question:(1) evaluation of traditional treatment programs based on the addition of nicorandil onall-cause mortality;(2) evaluation of nicorandil plus traditional treatment programs based on the clinical efficacy of chronic heart failure. Through the system evaluation methods aimed at understanding the nicorandil, whether on the basis of the existing standard treatment in patients with cardiovascular disease further benefits play a role in heart protection and improve the prognosis of patients with cardiovascular disease.Materials and methods[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]In accordance with the principle of evidence-based medicine, the system retrieves from the database to establish the initial to January2013, the Cochrane Controlled Trials Register database, PubMed, MEDLINE, EMBASE, Ovid, CBM, CNKI, Data resources. Search term:Chinese nicorandil "AND" heart "AND" end point "OR" death "OR" prognosis "; English" nicorandil "AND" heart "AND" death "OR" event "OR" end point "OR" mortality "OR" prognosis "; randomized controlled search terms" randomized controlled "OR" Clinical trial "OR" clinical study ". Initial results and then retrieved inclusion and exclusion criteria to filter. By two reviewers independently evaluated the quality of the included studies, extracted data and cross-checking, using Stata11.0software for all-cause mortality, Meta-analysis of revascularization and cardiovascular events. Effect sizes are HR, odds ratio (OR) and relative risk RR.Q test and I2test were used for heterogeneity. According to the test results using the corresponding effects model for effect size. Statistical homogeneity (P>0.1,12<50%) between studies, the use of a fixed effects model; Conversely, if P≤0, I2≥50%using a random effects model. Greater heterogeneity between studies (I2≥50%), further sensitivity analysis, meta-regression and subgroup analyzes, as far as possible to find the source of heterogeneity, and analysis of heterogeneous causes. Heterogeneity of the two groups is too large or can not find the data source, using the descriptive analysis. Meta-regression covariates screening, the level of significance defined as P<0.1.(Egger linear regression method) to assess publication bias funnel plot and quantitative tests, P>0.05prompt research the existence of the possibility of bias; such as P<0.05, is likely to prompt biased. Cardiovascular events is defined as the following conditions:cardiovascular death, sudden death (Sudden Death), acute coronary syndrome (including fatal or nonfatal acute myocardial infarction), chest pain or congestive heart failure readmission.[Nicorandil systematic reviews of chronic heart failure]In accordance with the principles of evidence-based medicine, the system retrieves from a database to establish initial to March2012cochrane Controlled Trials Register database, PubMed, MEDLINE, EMBASE, CBM, CNKI. Data resources. Search terms include:Chinese as the the nicorandil "," heart function; English is "the nicorandil" AND "heart failure" OR "cardiomyopathy" OR "heart the function OR" ventricular function; randomized controlled search term " randomized controlled "OR" clinical trial ". Initial results retrieved press the inclusion and exclusion criteria for screening. By two reviewers independently evaluate the quality of the included studies, data extraction and cross-checking. Main outcome measures: heart rate (HR), mean arterial blood pressure (MBP), pulmonary capillary wedge pressure (PCWP), RAP (right atrial pressure) SVR (systemic vascular resistance systemic vascular resistance), CI (Cardiac index cardiac index), left ventricular ejection fraction (LVEF), the type B natriuretic peptide (BNP),6-minute walk test (6MWT). Meta-analysis using Stata11.0Software. Meta-analysis using Stata11.0Software. Measurement data using the weighted mean difference (MD) as the effect size, the effect of volume,95%CI. First Q-test and I2test for heterogeneity between each incorporate research results. When statistical homogeneity (P>0.1,I2<50%) across studies, using the fixed effects model; Conversely, using a random effects model. Heterogeneity across studies is large (I2<50%), further sensitivity analysis and τ2(tau-squared) test. Two sets of heterogeneity is too large or can not find the data sources, using descriptive analysis. Test level of P<0.05was considered significant.[Nicorandil systematic reviews of acute heart failure]We searched databases of Cochrane Controlled Trials Register, PubMed, Ovid, Chinese Biomedical Literature Database (CBM), China Academic Journal Full-text Database (CNKI), and VIP database from inception through January,2013. Randomized controlled trials or observational studies were included if they compared the nicorandil group with a control group without receiving nicorandil treatment. Search term:"nicorandil" AND "acute" AND "heart failure" AND "patient" in Chinese;"nicorandil" AND "heart failure" AND the "acute" in English;study design was "randomized controlled trials.","random","control","observation","case-control studies, randomized controlled" OR "Clinical trial" OR "random" OR "control" OR "RCT" OR "observational study" OR "case-control ". Two investigators independently extracted study characteristics. RevMan software was used to analyze the data.Results[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]The study retrieved a total of225papers, according to the inclusion and exclusion criteria, the title, abstract, further and full-text reading, finally included17studies included patients with cardiovascular disease different types of patients with coronary artery disease, acute coronary syndrome (acute myocardial infarction and unstable angina) and stable angina, with or without a history of coronary intervention surgery and coronary artery bypass grafting. Nicorandil group on the basis of conventional therapy plus nicorandil, the control group was a control or placebo-controlled or nitrates were the control group without application of nicorandil treatment intervention group. The shortest observation period of2days, the longest observation period of five years. Quality of research evaluation,17studies were randomized controlled study, Six studies (Class A) complete description of the method of random distribution, double-blind operation, the method of allocation concealment and lost to follow-and intentional analysis; six studies (Class B) describes the method of random allocation, double-blind operation and follow-up with no reference to allocation concealment;5studies as(Class C), refer only to random, not specifically described randomly assigned, with or without blind Act and allocation concealment.(1) Meta-analysis of the effects on all-cause mortality results:①The hazard ratio included3studies, which are rigorous RCT study follow-up, the quality of the literature are Class A, with an average follow-up time for more than a year and a half, a meta-analysis results show that the Q test x2=3.97(df=2, P=0.137>0.1), I2=49.7%, Z=2.27(P=0.023<0.05), the combined effect of HR0.77(0.61-0.96), suggesting that long-term use of nicorandil can significantly reduce in patients with coronary heart disease, all-cause mortality. Sources of heterogeneity between studies consider the route of administration, into the patient population related to the different dosing regimens. But included only three studies, Meta results may be unstable.②If the number of deaths meta-analysis, can be included in the14studies included a total of6993cases of patients, the nicorandil group of3494cases,135cases of death, the mortality rate of3.86%;3499cases of the control group,166cases of death, the death rate4.74%. The odds ratio (OR) effect size, Q test x2=3.42(df=13), P=0.996,12=0.0%, no heterogeneity between studies. Z=1.77, to merge OR=0.818(0.655-1.022), P=0.077. Relative risk RR do effect size, Q test, x2=3.32(df=13), P=0.996, f=0.0%, no heterogeneity between studies. Z= 1.77, pooled RR value of0.826(0.6669-1.021),P=0.077. Taking into account the heterogeneity between studies, comprehensive consideration to be included in study different aspects of the route of administration, dosage, the follow-up period and the quality of the literature are prompted to use the nicorandil not significantly reduced all-cause mortality.(2) Revascularization events affect Meta-analysis of results:Five studies reported Revascularization. Into patients with a total of1030cases the nicorandil group of513cases,67cases of repeat revascularization in patients, the event rate was13.0%;517cases of the control group,70patients with repeat revascularization, the event rate was13.5%. Using the odds ratio (OR) effect size, Q test x2=5.96(df=4), P=0.202,12=32.9%, with moderate heterogeneity between studies. Z=0.02, to merge OR=1.006(0.576-1.755), P=0.985. Relative risk RR for the combined effect size, Q test x2=5.82,(df=4), P=0.213,11=31.2%, with moderate heterogeneity between studies. Z=0.05, the combined RR value of0.987(0.613-1.588), P=0.957. Due to the presence of heterogeneity, taking into account the different route of administration, the follow-up period and the quality of the literature included in the study, subgroup analysis, P values were greater than0.05, suggesting that use of nicorandil failed to significantly reduce repeat revascularization event occurs.(3) Impact on cardiovascular events Meta-analysis of results:①11studies included different types of patients with coronary heart disease, including acute coronary syndrome (acute myocardial infarction and unstable angina), and stable angina, with or without coronary intervention and coronary artery bypass grafting history. Nicorandil group on the basis of conventional therapy plus nicorandil, the control group was a control or placebo-controlled or nitrates were the control group without application of nicorandil treatment intervention group. The shortest observation period of2days, the longest observation period of five years. Quality of research evaluation,11studies were randomized controlled study, Six studies A complete description of a randomly assigned, double-blind operation, the method of allocation concealment and lost to follow-and intentional analysis;3studies as Class B, describes a method of randomly assigned, double-blind operation and follow-up with no reference to allocation concealment;2study as Class C, refer only to random, not specifically described randomly assigned, with or without blind Act and assigned hide. The proportion of males of each group and the proportion of patients with diabetes.②included in the11study patients with a total of7705cases the nicorandil group of3785cases,401cases of patients with cardiovascular events, the event rate of10.59%;3920cases of the control group, the occurrence of cardiovascular events in patients with539cases, the event rate was13.75%. The odds ratio (OR) effect size, Q test, x2=21.11(df=10), P=0.020, I2=52.6%, heterogeneity between studies>50%, using a random effects model analysis. Z=4.08, combined OR=0.441(0.297-0.653), P=0.000<0.001. The relative risk RR effect size, the Q test x2=18.81(df=10), P=0.043,I2=46.8%<50%, with moderate heterogeneity between studies, but can be applied to the fixed effect model analysis. Z=4.87, the combined RR value of0.744(0.660-0.838), P=0.000<0.001. Due to the presence of heterogeneity, taking into account included in the study in the different route of administration, the follow-up period, and the quality of the literature, and further sensitivity analysis, meta-regression and subgroup analysis, looking for sources of heterogeneity.(③by the sensitivity analysis, prompted the the IONA study is the main source of heterogeneity, it included10studies with other significantly different is the study of the large sample size. ④through the meta-regression results found that caused the main source of heterogeneity sample size (Adj R2=100%, P=0.003), countries (Adj R2=59.02%, P=0.071), diabetes patients in each study proportionate share (Adj R2=80.25%, P=0.026) were significant statistical significance (P values were greater than0.1). Mento Carlo replacement method test further the covariates corrected P value, the covariate "sample size" P=0.068, covariate "national" P value of0.439, covariate diabetes share of patients in each study Scale P value of0.329. Therefore, the proportion of patients with diabetes and nicorandil reduces cardiovascular events was a significant linear relationship between the relative risk RR value. Meta-regression diagram shows the following trend:the higher proportion of diabetic patients in the study, the lower the value of taking nicorandil and later cardiovascular events relative risk RR.⑤by a subgroup analysis stratified sample size, completely eliminate all heterogeneity (I2=0.0%). Greater than1000cases) large sample size (number of patients included in study1, the IONA study, the relative risk RR=0.845(0.739-0.967), P=0.014; Sample Size (included in the number of patients between100-1000cases) study6, the combined relative risk RR=0.479(0.353-0.651), P=0.000<0.001;4small sample sizes (included in the number of patients with less than100cases), combined relative risk RR value of0.387(0.223-0.671), P=0.001. Therefore, regardless of the sample size, prompt application of nicorandil can significantly reduce the risk of cardiovascular events.⑥Press the national stratified subgroup analysis, the elimination of part of the heterogeneity. South Korea2studies,I2=0.0%combined relative risk RR value of0.559(0.106-2.956), P=0.494; six studies in Japan, I2=0.0%, the merger relative risk RR=0.375(0.260-0.542), P=0.000<0.001;2study in the UK, I2=55.0%, the combined relative risk RR value of0.823(0.724-0.936), P=0.003; China one study, the combined relative risk RR=0.600(0.234-1.539), P=0.288. Research in Japan and the United Kingdom accounted for8of the11studies included, suggesting that application of nicorandil reducing the risk of cardiovascular events may be related to ethnic and regional relations.⑦subgroups stratified by the quality of the literature:the Jadad score assessed2studies quality level for the Class C,I2=0.0%, the combined relative risk RR value of0.581(0.242-1.393), P=0.224; Jadad score assessed3studies quality class B, I2=0.0%, the merger relative risk RR=0.381(0.216-0.670), P=0.001; the Jadad score evaluation of quality grade A six studies,I2=59.3%, the combined relative risk RR value of0.772(0.682-0.873), P=0.000<0.001. Therefore, the quality of class A and B show the application of nicorandil can significantly reduce the risk of cardiovascular events in patients with coronary heart disease, suggesting that the results of the Meta-analysis of high reliability.⑧according to the follow-up time stratified subgroup analysis,4studies of follow-up time were less than a month, I2=0.0%, the combined relative risk RR value of0.527(0.372-0.745), P=0.000<0.001;2studies of follow-up were six months, I2=0.0%, the merger relative risk RR was0.414(0.173-0.990), P=0.048;5studies with a minimum1-year study, I2=62.8%, combined relative risk RR=0.787(0.692-0.895), P=0.000<0.001. Prompt the length of time regardless of the application of nicorandil, were significantly reduced risk of cardiovascular events.⑨subgroup analysis stratified by administration nicorandil, a study implemented intracoronary injection of nicorandil, relative risk RR value of0.486(0.046-5.133), P=0.549;4researches simple oral nicorandil, I2=51.9%, the merger relative risk RR=0.800(0.706-0.907), P<0.001; four studies of simple intravenous application of nicorandil, I2=0.0%, combined relative risk RR value of0.384(0.233-0.629), P=0.000<0.001;2study adjourned to the first intravenous to oral medication, I2=0.0%, the combined relative risk RR was0.382(0.188-0.774), P=0.008. Tip different route of administration does not affect the nicorandil less the risk of cardiovascular events.⑩publication bias detection:distribution and asymmetry of the funnel plot of the11studies prompted research, the test of the Egger’s test P=0.002(-2.1755,-0.6881), suggests the presence of publication bias. Corrected by the trim and fill method, a meta-analysis results are consistent:the fixed effects model to calculate the combined effect of the amount of RR was0.749(0.664,0.845), Z=-4.718, P=0.000; random effects model to calculate the combined effect of the amount of RR value of0.525(0.387,0.712), Z=-4.140, P=0.000. Prompted the meta-analysis results are stable and reliable.[The Clinical Efficacy of Nicorandil in Chronic Heart Failure:Meta-analysis]Nine studies were included, a total of279patients. Meta-analysis results showed that:①and intravenous nitroglycerin, intravenous nicorandil24hours continuous application, which can cause the heart rate mildly increased faster (MD=1.272,95%of the CI value from0.385to2.160, P=0.005); PCWP significantly reduce (MD=-2.255,95the CI value of-4.236to-0.274, P=0.026); the SVR was significantly decreased (MD=-0.832,95the CI value of-1.304to-0.359, P=0.001). However, RAP, CI (Cardiac index cardiac index), compared to the MBP changes in the nitroglycerin group no difference.②single oral dose of40mg or60mg nicorandil tablets help reduce PCWP, SVR, and MBP.③on the basis of traditional treatment programs (including digitalis, diuretics, ACEI (ARB), BB, nitrates) plus oral nicorandil5mg, three times a day, short-term results and long-term sustained application of5-6months can be significantly improved LVEF (MD=1.712,95%of the CI value of0.658to2.767, P=0.001). Conclusion:The traditional treatment programs based on whether or not in combination with other vasodilators, nicorandil application by the oral route or intravenous routes, available in patients with ischemic cardiomyopathy (including6months after PCI) LVEF, PCWP, and SVR, dilated cardiomyopathy, valvular heart disease, hypertensive heart disease, such as congestive heart failure caused by chronic patients, access to good effect.[Nicorandil systematic reviews of acute heart failure]We identified32studies reporting nicorandil treatment in AHF,but only3of these studies met our criteria by reporting clinical efficacy of nicorandil in AHF.Two randomized controlled studies and one observational study were included with total of471cases enrolled.Nicorandil groups (n=113) were compared directly with controls (n=358) in3studies. Mean age of these patients were greater than65years, with blood pressure not less than90mmHg.Whether left ventricular ejection fraction was normal or reduced was ignorable. Those who have acute coronary syndrome with acute heart failure were exculed. nicorandil was continuous injection within30minutes for5days or continuously injected for48to72hours in3studies included. Changes of hemodynamics and cardiac function were reported. Result of meta-analysis showed that no significant difference was observed in the systolic blood pressure between nicorandil group and controls after intravenous nicorandil treatment48h to72h(Z=0.54,P=0.59). And it was indicated that indicators of AHF were improved after intravenous nicorandil treatment48h to72h in3included studies.One study showed that intravenous nicorandil treatment from the urgent phase of AHF may improve the prognosis.Conclusion[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]On the basis of the standard treatment plus nicorandil can significantly reduce the risk of cardiovascular events in patients with coronary heart disease, including cardiovascular death, fatal and non-fatal myocardial infarction admitted to hospital because of chest pain and heart failure attacks unplanned; may reduce the fulldue to the risk of mortality; did not significantly reduce repeat revascularization events. In reducing cardiovascular events in patients with coronary heart disease risk aspects, route of administration including oral, intravenous and intracoronary application of nicorandil; the application short time up to2days, as long as five years; application race and region are not limited.[Nicorandil systematic reviews of chronic heart failure]Traditional treatment programs based on whether or not in combination with other vasodilators, nicorandil application by the oral route or intravenous routes are available in patients with ischemic cardiomyopathy (including6months after PCI), expansion cardiomyopathy, valvular heart disease, hypertensive heart disease caused by chronic congestive heart failure in patients with LVEF, PCWP and SVR, to obtain a good effect.[Nicorandil systematic reviews of acute heart failure]Although limitations, the Meta-analysis results of this study suggested that blood pressure did not decreased significantly after intravenous nicorandil injection in the AHF the early stages.At the same time, the LVEF, LVD, CO, BNP and NT-pro-BNP were improved in patients with AHF, and possibly the event rate within six months could be reduced.Limitation[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]Nicorandil on large sample study of the prognosis of patients with coronary heart disease mainly the IONA, JCAD and Trend of OACIS of, which IONA randomized controlled trials, the JCAD and OACIS of non-randomized controlled study therefore not included in the meta-analysis. Has been included in the study except IONA, small sample volume, reducing the test performance of all-cause mortality; patients with coronary heart disease and diabetes should be concerned about the possibility of the application of nicorandil thereafter further benefit, and need more large, randomized, controlled study to prove its cardioprotective effects.[Nicorandil systematic reviews of chronic heart failure]Smaller study sample included in the clinical evaluation of the system volume, and the observation time of up to six months, unable to get a definitive conclusion with hard clinical endpoints such as mortality, these indicators is the evaluation of drug efficacy gold standard. Meanwhile, we also see that included in the study years earlier may nicorandil range of applications in patients with coronary heart disease. With the protective mechanism in the heart of the KATP research is expected to gradually carry out more in-depth, nicorandil various causes long-term follow-up study of chronic heart failure.[Nicorandil systematic reviews of acute heart failure]Our study has some limitations. Nicorandil for AHF clinical trials few existing research sample size, few randomized controlled trials, observational studies, may be related to the AHF is a high-risk acute. Less included in the study, relatively more confounding factors will have an impact on the test performance of the meta-analysis results. In addition, observation of the various studies focused on hemodynamic changes and cardiac function without improvement, rather than mortality hard endpoint. So the future still need to design rigorous randomized controlled studies or high-quality observational studies to prove its efficacy. |
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