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Nitrates for the prevention of cardiac morbidity and mortality in patients undergoing non-cardiac surgery.
Zhao, N, Xu, J, Singh, B, Yu, X, Wu, T, Huang, Y
The Cochrane database of systematic reviews. 2016;(8):CD010726
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Abstract
BACKGROUND Cardiac complications are not uncommon in patients undergoing non-cardiac surgery, especially in patients with coronary artery disease (CAD) or at high risk of CAD. Perioperative cardiac complications can lead to mortality and morbidity, as well as higher costs for patient care. Nitrates, which are among the most commonly used cardiovascular drugs, perform the function of decreasing cardiac preload while improving cardiac blood perfusion. Sometimes, nitrates are administered to patients undergoing non-cardiac surgery to reduce the incidence of cardiac complications, especially for patients with CAD. However, their effects on patients' relevant outcomes remain controversial. OBJECTIVES • To assess effects of nitrates as compared with other interventions or placebo in reducing cardiac risk (such as death caused by cardiac factors, angina pectoris, acute myocardial infarction, acute heart failure and cardiac arrhythmia) in patients undergoing non-cardiac surgery.• To identify the influence of different routes and dosages of nitrates on patient outcomes. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Chinese BioMedical Database until June 2014. We also searched relevant conference abstracts of important anaesthesiology or cardiology scientific meetings, the database of ongoing trials and Google Scholar.We reran the search in January 2016. We added three potential new studies of interest to the list of 'Studies awaiting classification' and will incorporate them into our formal review findings for the review update. SELECTION CRITERIA We included randomized controlled trials (RCTs) comparing nitrates versus no treatment, placebo or other pharmacological interventions in participants (15 years of age and older) undergoing non-cardiac surgery under any type of anaesthesia. DATA COLLECTION AND ANALYSIS We used standard methodological procedures as expected by Cochrane. Two review authors selected trials, extracted data from included studies and assessed risk of bias. We resolved differences by discussion and, when necessary, sought help and suggestions from a third review author. We used a random-effects model for data analysis. MAIN RESULTS We included 27 randomized controlled trials (RCTs) (8244 participants analysed). Investigators reported 12 different comparisons of three different nitrates (nitroglycerin, isosorbide dinitrate and nicorandil) versus no treatment, placebo or other pharmacological interventions. All participants were older than 15 years of age. More than half of the trials used general anaesthesia. Surgical procedures in most trials were at low to moderate risk for perioperative cardiac complications. Only two comparisons including three studies reported the primary outcome - all-cause mortality up to 30 days post operation. Researchers reported other morbidity outcomes and adverse events in a variable and heterogeneous way, resulting in limited available data for inclusion in the meta-analysis. We determined that the overall methodological quality of included studies was fair to low, in accordance with risk of bias in most domains.In summary, we found no difference in the primary outcome - all-cause mortality up to 30 days post operation - when nitroglycerin was compared with no treatment (one study, 60 participants, 0/30 vs 1/30; (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.01 to 7.87, very low-quality evidence based on GRADE criteria) or with placebo (two studies, 89 participants, 1/45 vs 0/44; RR 2.81, 95% CI 0.12 to 63.83, very low-quality evidence). Regarding our secondary outcomes, we noted no statistically significant differences in angina pectoris, acute myocardial infarction, acute heart failure, cardiac arrhythmia or cardiac arrest in any comparisons. In comparisons versus nitroglycerin, although more events of cardiac ischaemia were observed in participants receiving no treatment or placebo, we found no statistically significant differences in any comparisons, except the comparison of nicorandil versus placebo. One study revealed a potential dose-dependent protective effect of nicorandil for cardiac ischaemia.Adverse events were reported in a heterogeneous way among the comparisons. In general, more participants treated with nitrates had hypotension, tachycardia and headache, but investigators reported no statistically significant differences between groups in any comparisons. AUTHORS' CONCLUSIONS This systematic review suggests that nitroglycerin or isosorbide dinitrate is not associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery. Limited evidence suggests that nicorandil may reduce the risk of cardiac ischaemia in participants undergoing non-cardiac surgery. Additional studies are needed to consolidate the evidence.However, the data included in many of the analyses in this review are sparse - that is, adequate data are few - resulting in very low power to detect differences between nitrates and comparators. Thus, a more objective conclusion would state that available evidence is insufficient to show whether nitrates are associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery.Over the past decade, no high-quality studies have focused on association of cardiac mortality and morbidity with use of nitrates during non-cardiac surgery. This review underlines the need for well-designed trials in this field.
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Impacts of nicorandil on infarct myocardium in comparison with nitrate: assessed by cardiac magnetic resonance imaging.
Yamada, K, Isobe, S, Ishii, H, Yokouchi, K, Iwata, H, Sawada, K, Murohara, T
Heart and vessels. 2016;(9):1430-7
Abstract
In this pilot study, we compared the infarct and edema size in acute myocardial infarction (MI) patients treated by nicorandil with those treated by nitrate, using cardiac magnetic resonance (CMR) imaging. Fifty-two acute MI patients who underwent emergency percutaneous coronary intervention (PCI) were enrolled, and were assigned to receive nicorandil or nitrate at random just before reperfusion. For the assessment of infarct and edema areas, short-axis delayed enhancement (DE) and T2-weight (T2w) CMR images were acquired 6.1 ± 2.4 days after the onset of MI. A significant correlation was observed between the peak creatinine kinase (CK) level and the infarct size on DE CMR (r = 0.62, p < 0.05), as well as the edema size on T2w CMR (r = 0.70, p < 0.05) in patients treated by nicorandil (28 patients). A similar correlation was seen between the peak CK level and the infarct size on DE CMR (r = 0.84, p < 0.05), as well as the edema size on T2w CMR (r = 0.84, p < 0.05) in patients treated by nitrate (24 patients). The maximum CK level was significantly lower in patients treated by nicorandil rather than nitrate (1991 ± 1402, 2785 ± 2121 IU/L, respectively, p = 0.03). Both the edema size on T2w CMR and the infarct size on DE CMR were significantly smaller in patients treated by nicorandil rather than nitrate (17.7 ± 9.9, 21.9 ± 13.7 %; p = 0.03, 10.3 ± 6.0, 12.7 ± 6.9 %, p = 0.03, respectively). The presence and amount of microvascular obstruction were significantly smaller in patients treated by nicorandil rather than nitrate (39.2, 64.7 %; p = 0.03; 2.2 ± 1.3, 3.4 ± 1.5 cm(2); p = 0.02, respectively). Using CMR imaging, we demonstrated that the complementary use of intravenously and intracoronary administered nicorandil during PCI favorably acts more on the damaged myocardium after MI than nitrate. We need a further powered prospective study on the use of nicorandil.
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Is tongxinluo more effective than isosorbide dinitrate in treating angina pectoris? A systematic review and meta-analysis of randomized controlled trials.
Jia, Y, Bao, F, Huang, F, Leung, SW
Journal of alternative and complementary medicine (New York, N.Y.). 2011;(12):1109-17
Abstract
BACKGROUND Tongxinluo (TXL), consisting of 12 Chinese Materia Medica items catalogued in the Chinese Pharmacopoeia, is commercially available in China, South Korea, and Russia. Hundreds of randomized clinical trials (RCTs) on TXL in treating cardiovascular diseases were conducted and published in China. This study provides a comprehensive Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review with sensitivity and subgroup analyses to evaluate the evidence about whether TXL is more effective than isosorbide dinitrate (ISDN) in treating ischemic heart disease, particularly angina pectoris. METHODS RCTs published between 1996 and 2010 on TXL versus ISDN in treating angina pectoris for at least 4 weeks were retrieved from eight bibliographical databases (e.g., MEDLINE,(®) PubMed, Chinese National Knowledge Infrastructure, Cochrane Library, and WanFang Data). The quality of RCTs was assessed with the Jadad scale. Meta-analysis was performed to estimate the overall effects based on symptomatic and electrocardiographic (ECG) improvements. Subgroup analysis, sensitivity analysis, and meta-regression were conducted on the study characteristics of RCTs. RESULTS Twenty (20) RCTs with a total of 1936 participants were included after eligibility assessment. The Jadad score of all included studies was 2. The means of summary odds ratios (ORs) for comparing TXL and nitrates were 3.30 (95% confidence interval [CI] 2.37-4.58) by symptoms (n=20) and 2.38 (95% CI 1.846-3.09) by ECG (n=18). There was a significant correlation of ORs between symptoms and ECG (ρ=0.77 and p=0.00026). Subgroup analysis, sensitivity analysis, and meta-regression found no significant difference in overall effects among all study characteristics except the years of publication (p=0.0409). CONCLUSIONS The meta-analysis of 20 eligible RCTs demonstrates moderate evidence that TXL is more effective than ISDN for treating angina pectoris. This result warrants further RCTs of multicenters/countries, larger sample sizes, and higher quality.
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From hypertension to heart failure: role of nitric oxide-mediated endothelial dysfunction and emerging insights from myocardial contrast echocardiography.
Lapu-Bula, R, Ofili, E
The American journal of cardiology. 2007;(6B):7D-14D
Abstract
There is growing evidence that nitric oxide (NO)-mediated endothelial dysfunction occurs in hypertension and may represent the earliest stage of target organ damage, which ultimately leads to hypertensive heart disease and heart failure (HF). An understanding of how impaired myocardial microvascular function and flow reserve relate to early remodeling during the transition to HF in patients with hypertension may lead to new therapeutic insights. The hypertrophied heart, which is a feature of the adverse structural remodeling in hypertensive heart disease, may be accompanied by impaired coronary flow reserve (CFR). Reduced CFR could potentially cause subendocardial ischemia during conditions of high metabolic demand, such as uncontrolled hypertension and tachycardia. Such vulnerability of the subendocardium to abnormal perfusion or ischemia may accelerate the progression from compensated hypertrophy to HF. In this review, we discuss preliminary evidence that altered NO balance may contribute to cardiac hypertrophy-mediated myocardial ischemia. We also describe early results with myocardial contrast echocardiography in the postulated transition from compensated hypertrophy to cardiac failure. These data support further evaluation of NO mediators as potential targets for novel therapies in hypertensive heart disease.
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Responses to cardiovascular drugs during alcohol withdrawal.
Kähkönen, S
Alcohol and alcoholism (Oxford, Oxfordshire). 2006;(1):11-3
Abstract
AIM: To present findings on the kinetics and dynamics of cardiovascular drugs during alcohol withdrawal (AW), compared with that observed in remission. METHOD Studies were reviewed and summarized. RESULTS A single-dose study in alcoholic patients with propranolol, a beta-adrenergic antagonist, showed that the negative inotropic effect was decreased and the bradycardiac effect increased during AW as compared with during early remission. The hypotensive effect of isosorbid dinitrate, commonly used as a vasodilatator, was weaker at the onset of AW, being associated with the decreased bioavailability of the drug. Verapamil, which is a L-type Ca2+ channel antagonist, produced a bradycardiac effect at the onset of AW, but no effect was observed in early remission. The effect was probably due to changes in L-type Ca2+ channels because no differences in verapamil concentrations between AW and early remission were observed. CONCLUSION Taken together, AW modifies the dynamics and kinetics of cardiac drugs, which may have an impact on the treatment of alcoholic patients with cardiac diseases.
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[Clinical study on "sini" decoction on treating stenocardia for coronary heart disease].
Liang, Y
Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials. 2005;(8):737-9
Abstract
OBJECTIVE To observe clinical effect of "Sini" decoction on stenocardia for coronary heart disease. METHODS 65 cases of stenocardia for CHD with deficiency of yang or cold syndrome were randomly divided into" Sini" decoction therapeutic group and isosorbide dinitrate controll group. Drug effects of the two groups were compared by clinical symptoms, electrocardiogram (ECG), myocardial oxygen consumption and cardiac function. RESULTS "Sini" decoction had better effects on reducing myocardial oxygen consumption and improving cardiac function isosorbide dimitrate, and similar to improving clinical symptoms and ECG, decreasing frequency of stenocardia and dose of nitroglycerin on stenocardia for coronary heart disease. CONCLUSION "Sini" decoction can treat stenocardia for CHD with deficiency of yang or cold syndrome.
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[Effect of compound salvia injection on nitrate ester tolerance].
Wang, J, Wu, SD, Chen, SC, Yan, YF, Wu, CB, Xu, JB, Zheng, K
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2005;(1):25-9
Abstract
OBJECTIVE To investigate the effect and mechanism of Compound Salvia injection (CSI) on nitrate ester tolerance. METHODS Eighty-four patients with coronary heart disease (CHD) were randomly divided into three groups, Group A treated with isosorbide dinitrate (ISD, 15 mg, 4 times per day) alone, Group B with ISD plus CSI and Group C with ISD plus vitamin C. The therapeutic course for all groups was 10 days. The tolerance to nitrate ester and blood pressure were monitored. Before and after treatment, the color Doppler ultrasonic apparatus was used to detect the baseline value of humeral arterial internal diameters (D0), the humeral arterial dilatory response under compression [D1, that is, the flow-mediated vasodilation (FMD)] and the vasodilatory response after sucking of nitroglycerin (D2). And the blood levels of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS) mRNA expression were determined. The endothelial-dependent vasodilation (EDD) was expressed by (D1 - D0)/D0 x 100%, and the endothelial-independent vasodilation (EID) was expressed by (D2 - D0)/D0 x 100%. RESULTS (1) The occurrence rate of nitrate tolerance in Group B and C (28.57% and 35.7%) was lower than that in Group A (64.29%), but insignificant difference was found between the former two. (2) After treatment, blood pressure increased in Group A to the level of pre-treatment, that in Group C also increased but still lower than that of pre-treatment, while insignificant increase was observed in Group B, comparison between Group B and C showed significant difference (P < 0.05). (3) After treatment, EID lowered in Group A, EDD increased in Group B and C (P < 0.05), EDD and EID in Group B and C were higher than those in Group A (P < 0.05), and EDD was higher in Group B than in Group C (P < 0.05). (4) After treatment, ET-1 mRNA expression lowered in Group B, eNOS mRNA expression increased in Group B and C, with significant difference as compared with those before treatment and those in Group A (P < 0.05), and eNOS mRNA expression in Group C was lower than that in Group B (P < 0.05). CONCLUSION CSI could partially prevent the occurrence of tolerance to nitrate ester, with the effect better than vitamin C, the mechanism might be related with its regulation on eNOS, ET-1 mRNA expression and protection on vascular endothelial function.
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Nicorandil versus isosorbide dinitrate as adjunctive treatment to direct balloon angioplasty in acute myocardial infarction.
Ikeda, N, Yasu, T, Kubo, N, Hashimoto, S, Tsuruya, Y, Fujii, M, Kawakami, M, Saito, M
Heart (British Cardiac Society). 2004;(2):181-5
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Abstract
OBJECTIVE To compare the effects of nicorandil (a hybrid ATP sensitive potassium channel (K+(ATP) channel) opener/nitric oxide donor) with those of isosorbide dinitrate (ISDN) on myocardial microcirculation and cardiac function in patients with acute myocardial infarction (AMI) who had undergone reperfusion treatment by direct balloon angioplasty. DESIGN Double blind randomised study. PATIENTS 60 patients with AMI in Killip class I. INTERVENTIONS Patients were assigned into two treatment groups: a nicorandil group (n = 30) and an ISDN group (n = 30). Each drug was infused intravenously at 6 mg/h for 72 hours starting at admission and was administered directly to the treated coronary artery immediately after angioplasty. RESULTS Compared with ISDN, nicorandil more frequently caused recovery of ST segment elevation just after reperfusion (15 of 27 (55.5%) in the nicorandil group v 5 of 26 (19.2%) in the ISDN group, p = 0.006). The nicorandil group had higher values of averaged peak velocity 40 minutes after reperfusion (mean (SD) 24.8 (13.3) cm/s v 16.0 (11.1) cm/s, p = 0.045) and higher values of regional wall motion of the infarcted area three weeks after onset of AMI (-1.78 (1.11) v -2.50 (1.04) SD/chord, p = 0.046). CONCLUSIONS A combination of nicorandil drip infusion starting before reperfusion and intracoronary injection immediately after reperfusion is more effective than a similarly performed infusion of ISDN in preserving myocardial microcirculation in the reperfused AMI area. The nicorandil regimen resulted in better left ventricular regional wall motion.
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Lack of oxidative stress during sustained therapy with isosorbide dinitrate and pentaerythrityl tetranitrate in healthy humans: a randomized, double-blind crossover study.
Keimer, R, Stutzer, FK, Tsikas, D, Troost, R, Gutzki, FM, Frölich, JC
Journal of cardiovascular pharmacology. 2003;(2):284-92
Abstract
The mechanisms by which tolerance to organic nitrates develops are still poorly understood. Enhanced oxidative stress, i.e., increased free radical production following organic nitrate administration, has been recently suggested as a possible mechanism. A randomized, double-blind, crossover study assessed in 18 healthy young volunteers at baseline and 1 and 5 days after oral administration with therapeutically relevant doses of isosorbide dinitrate (ISDN, 30 mg TID) or pentaerythrityl tetranitrate (PETN, 80 mg TID) the effect on two index parameters of oxidative stress in vivo, i.e., urinary 8-iso-prostaglandin (PG)F2alpha and circulating 3-nitrotyrosine and their major urinary metabolites, 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha and 3-nitro-4-hydroxyphenylacetic acid. In addition, urinary cGMP and serum and urinary nitrate and nitrite were determined. All parameters were quantified by gas chromatography-mass spectrometry or gas chromatography-tandem mass spectrometry except for cGMP, which was analyzed by radioimmunoassay. Serum and urinary nitrite levels increased significantly following 5-day administration of ISDN and PETN. Neither urinary excretion of 8-iso-PGF2alpha and plasma 3-nitrotyrosine nor their respective metabolites changed significantly after ISDN or PETN administration. There were no significant differences between ISDN and PETN regarding these parameters. Urinary cGMP increased significantly only after ISDN. This study is compatible with a stimulation of cGMP by ISDN, but neither ISDN nor PETN enhances systemic oxidative stress in healthy volunteers.