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Effects of the Antianginal Drugs Ranolazine, Nicorandil, and Ivabradine on Coronary Microvascular Function in Patients With Nonobstructive Coronary Artery Disease: A Meta-analysis of Randomized Controlled Trials.
Zhu, H, Xu, X, Fang, X, Zheng, J, Zhao, Q, Chen, T, Huang, J
Clinical therapeutics. 2019;(10):2137-2152.e12
Abstract
PURPOSE The goal of this study was to investigate the effects of the antianginal drugs ranolazine, nicorandil, and ivabradine on coronary microvascular function. METHODS Electronic scientific databases were searched for randomized trials investigating the effects of antianginal drugs on coronary microvascular function. Primary outcomes were changes in the coronary flow reserve (CFR), index of microvascular resistance (IMR), and myocardial perfusion reserve index (MPRI). The secondary outcome was the Seattle Angina Questionnaire scores. The standardized mean difference or weighted mean difference (WMD) (95% CI) served as a summary statistic. FINDINGS The antianginal drugs ranolazine, nicorandil, and ivabradine did not increase the CFR compared with the control drugs (standardized mean difference, 0.39; 95% CI, -0.08 to 0.85; P = 0.10). Ranolazine did not increase the global MPRI compared with the control drugs (weighted mean difference [WMD], 0.11; 95% CI, -0.06 to 0.29; P = 0.21). However, in the subgroups with a baseline CFR <2.5 or a global MPRI <2, ranolazine increased the global MPRI (WMD, 0.19; 95% CI, 0.10 to 0.27; P < 0.0001). In addition, the subendocardial midventricular MPRI (mid-subendocardial MPRI) was improved after ranolazine treatment (WMD, 0.12; 95% CI, 0.03 to 0.20; P = 0.007). Moreover, nicorandil significantly reduced the IMR compared with the control drugs (WMD, -7.63; 95% CI, -11.82 to -3.44; P = 0.0004). In addition, ranolazine and ivabradine improved 3 of the 5 Seattle Angina Questionnaire scores. IMPLICATIONS Ranolazine improved the global MPRI in patients with definite coronary microvascular dysfunction and the mid-subendocardial MPRI with suspicious coronary microvascular dysfunction, and nicorandil reduced the IMR. In addition, ranolazine and ivabradine reduced angina. Moreover, it is possible that the IMR and mid-subendocardial MPRI are more sensitive than the CFR and global MPRI for evaluating coronary microvascular function.
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Nicorandil Versus Nitroglycerin for Symptomatic Relief of Angina in Patients With Slow Coronary Flow Phenomenon: A Randomized Clinical Trial.
Sani, HD, Eshraghi, A, Nezafati, MH, Vojdanparast, M, Shahri, B, Nezafati, P
Journal of cardiovascular pharmacology and therapeutics. 2015;(4):401-6
Abstract
OBJECTIVE Patients with the coronary slow flow phenomenon frequently experience angina episodes. The present study aimed to compare the efficacy of nicorandil versus nitroglycerin for alleviation of angina symptoms in slow flow patients. METHODS In a single-center, single-blind, parallel-design, comparator-controlled, randomized clinical trial (NCT02254252), 54 patients with slow flow and normal or near-normal coronary angiography who presented with frequent angina episodes were randomly assigned to 1-month treatment with nicorandil 10 mg, 2 times a day (n = 27) or sustained-release glyceryltrinitrate 6.4 mg 2 times a day (n =27). Frequency of angina episodes, pain intensity, and the Canadian Cardiovascular Society (CCS) grading of angina pectoris were assessed at baseline and after 1 month of treatment. RESULTS In all, 25 patients in the nicorandil arm and 24 patients in the nitroglycerin arm were analyzed. After 1 month, patients treated with nicorandil had fewer angina episodes (adjusted mean number of episodes per week, nicorandil versus nitroglycerin; 1.68 ± 0.15 vs 2.29 ± 0.15, P = .007, effect size = 14.6%). Patients also reported greater reductions in pain intensity with nicorandil versus nitroglycerin (adjusted mean of self-reported pain score; 3.03 ± 0.29 vs 3.89 ± 0.30, P = .046, effect size = 8.4%). A significantly higher proportion of patients in the nicorandil arm were categorized in CCS class I (76% vs 33.3%, P = .004) or class II (16.0% vs 45.8%, P = .032). CONCLUSION In slow flow patients, nicorandil provides better symptomatic relief of angina than nitroglycerin.
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The different association of epicardial fat with coronary plaque in patients with acute coronary syndrome and patients with stable angina pectoris: analysis using integrated backscatter intravascular ultrasound.
Harada, K, Harada, K, Uetani, T, Kataoka, T, Takeshita, M, Kunimura, A, Takayama, Y, Shinoda, N, Kato, B, Kato, M, et al
Atherosclerosis. 2014;(2):301-6
Abstract
OBJECTIVES We assessed the hypothesis that the epicardial fat is associated with coronary lipid plaque. BACKGROUND Epicardial fat volume (EFV) is increased in patients with acute coronary syndrome (ACS), and lipid-rich plaques have been associated with acute coronary events. METHODS We enrolled 112 individuals who underwent percutaneous coronary intervention (PCI) (66 with ACS; 46 with stable angina pectoris [SAP]) and classified plaque components using integrated backscatter intravascular ultrasound as calcified, fibrous, or lipid. Possible effects of PCI on plaque data were minimized by assessing 10-mm vessel lengths proximal to the culprit lesions. Total plaque volume and percentage volumes of individual plaque components were calculated. EFV and abdominal visceral fat area were measured using 64-slice computed tomography. RESULTS ACS patients had significantly higher EFV than did SAP patients (118 ± 44 vs.101 ± 41 mL, p = 0.019). In ACS patients, EFV was correlated with total plaque volume and percentage of lipid plaque (r = 0.27 and 0.31, respectively; p < 0.05). Moreover, an independent interaction between EFV and lipid-rich plaque (odds ratio, 1.04; 95% confidence interval, 1.00-1.07) were revealed. In contrast, in SAP patients, EFV was positively correlated with body mass index and abdominal visceral fat area but not with plaque characteristics. CONCLUSIONS EFV was associated with lipid-rich plaque in patients with ACS, whereas no correlation between EFV and coronary plaque profile was apparent in SAP patients. Epicardial fat may have a role in the development of lipid plaque, which contributes to the pathogenesis of ACS.
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Participants' experiences of care during a randomized controlled trial comparing a lay-facilitated angina management programme with usual care: a qualitative study using focus groups.
Nelson, P, Cox, H, Furze, G, Lewin, RJ, Morton, V, Norris, H, Patel, N, Elton, P, Carty, R
Journal of advanced nursing. 2013;(4):840-50
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Abstract
AIM: This paper is a report of a qualitative study conducted as part of a randomized controlled trial comparing a lay-facilitated angina management programme with usual care. Its aim was to explore participants' beliefs, experiences, and attitudes to the care they had received during the trial, particularly those who had received the angina management intervention. BACKGROUND Angina affects over 50 million people worldwide. Over half of these people have symptoms that restrict their daily life and would benefit from knowing how to manage their condition. DESIGN A nested qualitative study within a randomized controlled trial of lay-facilitated angina management. METHOD We conducted four participant focus groups during 2008; three were with people randomized to the intervention and one with those randomized to control. We recruited a total of 14 participants to the focus groups, 10 intervention, and 4 control. FINDINGS Although recruitment to the focus groups was relatively low by comparison to conventional standards, each generated lively discussions and a rich data set. Data analysis demonstrated both similarities and differences between control and intervention groups. Similarities included low levels of prior knowledge about angina, whereas differences included a perception among intervention participants that lifestyle changes were more easily facilitated with the help and support of a lay-worker. CONCLUSION Lay facilitation with the Angina Plan is perceived by the participants to be beneficial in supporting self-management. However, clinical expertise is still required to meet the more complex information and care needs of people with stable angina.
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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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Effects of treatment with once-daily nifedipine CR and twice-daily benidipine on prevention of symptomatic attacks in patients with coronary spastic angina pectoris-Adalat Trial vs Coniel in Tokyo against Coronary Spastic Angina (ATTACK CSA).
Oikawa, Y, Matsuno, S, Yajima, J, Nakamura, M, Ono, T, Ishiwata, S, Fujimoto, Y, Aizawa, T
Journal of cardiology. 2010;(2):238-47
Abstract
BACKGROUND We compared the efficacy of once-daily treatment with nifedipine CR 40 mg (NR) and twice-daily treatment with benidipine 4 mg (BD) in patients with coronary spastic angina (CSA) registered in 3 cardiovascular institutes in Tokyo. METHODS AND RESULTS CSA was diagnosed by an ischemic ST change during Holter ECG monitoring or drug-induced test. Thirty patients were randomly allocated to either NR or BD group. The number of symptomatic attacks and the total frequency of short-acting nitrates were examined based on the data in diaries written by patients. There were no significant differences in the baseline characteristics between the two groups. The median number (25-75% quartile) of attacks per week was significantly decreased in NR group, i.e., 1.0 (0.8-2.0) at baseline, 0.0 (0.0-1.0) after 4 weeks of treatment, and 0.0 (0.0-0.0) after 8 weeks of treatment (P=0.0093, P=0.0002, Wilcoxon's rank-sum test). No significant decrease was observed in BD, i.e. 1.0 (0.5-2.0) at baseline, 1.3 (0.0-3.0) after 4 weeks, and 0.0 (0.0-1.0) after 8 weeks. The number of attacks was fewer in NR than in BD group (P=0.074, P=0.015, U-test for difference). CONCLUSION Once-daily treatment with NR 40 mg was more effective than twice-daily treatment with BD in the prevention of CSA attacks.
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Which is first: left anterior descending artery anastomosis or right coronary artery anastomosis in off-pump coronary artery bypass grafting?
Yakut, N, Tulukoğlu, E, Emrecan, B, Bayrak, S, Yilik, L, Göktoğan, T, Gürbüz, A
The heart surgery forum. 2009;(5):E256-60
Abstract
OBJECTIVES The sequence of the distal anastomosis for revascularization in off-pump coronary artery bypass grafting (OPCABG) surgery is under debate. The hypothesis in this study was that an analysis of cardiac markers would reveal that anastomosing the left anterior descending coronary artery (LAD) before the right coronary artery (RCA) would decrease myocardial damage in OPCABG surgery for 2-vessel disease. METHODS Forty patients with stable angina who underwent OPCABG surgery and who had LAD and RCA lesions were randomized into 2 groups of 20 patients each. The LAD was revascularized first in group 1, and the RCA was revascularized first in group 2. Cardiac troponin I, creatine kinase (CK), and CK myocardial band (CK-MB) were measured in the 2 groups before surgery and at 8, 24, and 48 hours after surgery. RESULTS No mortality occurred in the 2 groups. The groups were similar with respect to sex, age, durations of anastomosis of the left internal thoracic artery to the LAD and of the saphenous vein graft to the RCA, and preoperative CK, CK-MB, and troponin I levels. Postoperative CK-MB levels were significantly higher in group 2 in the eighth and 24th postoperative hours than in group 1 (P = .009 and .041, respectively). Similarly, troponin I levels were significantly higher in group 2 in the eighth, 24th, and 48th hours than in group 1 (P = .003, .003, and .006, respectively). CONCLUSIONS Anastomosis to the LAD first in OPCABG surgery led to a slight reduction in myocardial enzyme release against the occlusion of the target vessels during anastomoses in patients with RCA and LAD stenoses.
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'Warm-up' phenomenon in diabetic patients with stable angina treated with diet or sulfonylureas.
Bilinska, M, Potocka, J, Korzeniowska-Kubacka, I, Piotrowicz, R
Coronary artery disease. 2007;(6):455-62
Abstract
BACKGROUND Classic sulfonyloureas (SUs) are known to attenuate ischaemic preconditioning. Gliclazide is an SU agent believed to be more protective. We assessed the effects of diet, glibenclamide, or gliclazide on the warm-up effect in type 2 diabetic patients with stable angina. METHODS The study group consisted of 64 men, aged 54+/-5 years: 17 patients without diabetes (G I) and 47 diabetic patients: 16 patients treated with glibenclamide (G II), 16 with gliclazide (G III) and 15 patients treated with diet (G IV). After the baseline positive exercise test (ET1), all patients reexercised after 30-min rest (ET2). We analysed exercise duration (ED, s), time to 1 mm ST depression (T-STD, s), max STD (mm), heart rate-systolic blood pressure product at 1 mm STD, or ischaemic threshold (mmHg/min x 100) and the total ischaemic time (s). RESULTS In G I, all analysed variables improved significantly during ET2 relative to ET1. Glibenclamide (G II) completely abolished the protective effect of exercise-induced ischaemia because only ED increased during ET2 (431 vs. 451, P<0.05). In G III, however, ED (486 vs. 537, P<0.001), T-STD (364 vs. 388, P<0.05) and max STD (2.5 vs. 2.0, P<0.05) improved significantly during ET2, whereas ischaemic threshold and total ischaemic time did not (PNS). In G IV, similar to G I, all variables improved significantly during ET2 relative to ET1. CONCLUSION Warm-up effect is preserved in diabetic patients with stable angina treated with diet, partially preserved in gliclazide-treated and abolished in glibenclamide-treated patients.
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Ivabradine: new drug. Best avoided in stable angina.
Prescrire international. 2007;(88):53-6
Abstract
(1) The first-line symptomatic treatment for stable angina is a betablocker such as atenolol. Some calcium channel blockers such as verapamil, and the potassium channel agonist amlodipine, are second-line alternatives. Long-acting nitrate derivatives have poorly documented efficacy but can be used as adjuvants or as third-line treatments. (2) Ivabradine is derived from verapamil but appears to have a different mechanism of action, mainly lowering the heart rate. It was approved for sale in Europe through the centralised procedure for second-line treatment of stable angina. (3) Clinical evaluation of ivabradine only includes randomised controlled trials versus two other anti-angina drugs: atenolol and amlodipine. Three double-blind randomised controlled trials lasting 3 to 4 months, based on surrogate exercise endpoints, failed to show that ivabradine was any more effective than atenolol or amlodipine, or even more effective than placebo in patients already treated with amlodipine. (4) In two one-year double-blind randomised controlled trials comparing ivabradine with atenolol or amlodipine in a total of 704 patients, ivabradine was no more effective than the comparators in preventing angina attacks. (5) In head-to-head comparisons, serious coronary events were significantly more frequent with ivabradine than with atenolol (3.8% versus 1.5%). Severe arrhythmias were also more frequent with ivabradine than with atenolol (1.3% versus 0.7%) or amlodipine (0.6% versus 0.2%). (6) Ivabradine provokes phosphenes (flashing lights, etc.) in about 17% of patients in the short term. Information is inadequate to assess possible risks of retinal toxicity in the long term. (7) Ivabradine is metabolised by cytochrome P450 isoenzyme CYP 3A4; there is therefore a potentially high risk of pharmacokinetic interactions. (8) In practice, for long-term preventive treatment of angina it is better to avoid ivabradine and to use better-documented treatments: preferably a betablocker, or, if a betablocker cannot be used, verapamil or amlodipine.
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Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial.
Ruzyllo, W, Tendera, M, Ford, I, Fox, KM
Drugs. 2007;(3):393-405
Abstract
BACKGROUND AND OBJECTIVE Current medical therapies for the symptoms of angina pectoris aim to improve oxygen supply and reduce oxygen demand in the myocardium. Not all patients respond to current antianginal monotherapy, or even combination therapy, and a new class of antianginal drug that complements existing therapies would be useful. This study was undertaken to compare the antianginal and anti-ischaemic effects of the novel heart-rate-lowering agent ivabradine and of the calcium channel antagonist amlodipine. PATIENTS AND METHODS Patients with a ≥3-month history of chronic, stable effort-induced angina were randomised to receive ivabradine 7.5mg (n = 400) or 10mg (n = 391) twice daily or amlodipine 10mg once daily (n = 404) for a 3-month, double-blind period. Bicycle exercise tolerance tests were performed at baseline and monthly intervals. The primary efficacy criterion was the change from baseline in total exercise duration after 3 months of treatment. Secondary efficacy criteria included changes in time to angina onset and time to 1mm ST-segment depression, rate-pressure product at trough drug activity, as well as short-acting nitrate use and anginal attack frequency (as recorded in patient diaries). RESULTS At 3 months, total exercise duration was improved by 27.6 +/- 91.7, 21.7 +/- 94.5 and 31.2 +/- 92.0 seconds with ivabradine 7.5 and 10mg and amlodipine, respectively, both ivabradine groups were comparable to amlodipine (p-value for noninferiority < 0.001). Similar results were observed for time to angina onset and time to 1mm ST-segment depression. Heart rate decreased significantly by 11-13 beats/min at rest and by 12-15 beats/min at peak of exercise with ivabradine but not amlodipine, and rate-pressure product decreased more with ivabradine than amlodipine (p-value vs amlodipine <0.001, at rest and at peak of exercise). Anginal attack frequency and short-acting nitrate use decreased substantially in all treatment groups with no significant difference between treatment groups. The most frequent adverse events were visual symptoms and sinus bradycardia with ivabradine (0.8% and 0.4% withdrawals, respectively) and peripheral oedema with amlodipine (1.5% withdrawals). CONCLUSIONS In patients with stable angina, ivabradine has comparable efficacy to amlodipine in improving exercise tolerance, a superior effect on the reduction of rate-pressure product (a surrogate marker of myocardial oxygen consumption) and similar safety.