[Outcome indicators in clinical trials on traditional Chinese medicine treatment of microvascular angina].

This study reviewed the current status of the use of outcome indicators in randomized controlled trial(RCT) on traditional Chinese medicine(TCM) treatment of microvascular angina(MVA) and analyzed the existing problems and possible solutions, aiming to provide a basis for the design of high-quality RCT and the establishment of core outcome sets for MVA. CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, Web of Science, and 2 clinical trial registries were searched for the RCT on TCM treatment of MVA according to pre-defined criteria. The Cochrane's risk of bias assessment tool was used to evaluate the methodological quality of the included RCT and the use of outcome indicators was summarized. A total of 69 RCTs were included, from which 100 outcome indicators were extracted, with the frequency of 430. The extracted outcome indicators belonged to 8 domains: response rate, symptoms and signs, physical and chemical examinations, TCM efficacy, safety, quality of life, economic evaluation, and long-term prognosis. The indicators of physical and chemical examinations were the most(70 indicators with the frequency of 211), followed by those of response rate(7 indicators with the frequency of 73) and symptoms and signs(7 indicators with the frequency of 54). The outcome indicators with higher frequency were adverse reactions, angina attack frequency, clinical efficacy, endothelin-1, total duration of treadmill exercise, and hypersensitive C-reactive protein. The RCT on TCM treatment of MVA had the following problems: irregular reporting of adverse reactions, diverse indicators with low frequency, lack of attention to the application of endpoint indicators, insufficient use of TCM differentiation and efficacy indicators, non-standard evaluation criteria and failure to reflect the basic characteristics of TCM. A unified MVA syndrome differentiation standard should be established, on the basis of which an MVA treatment efficacy evaluation system and core outcome indicator set that highlights the characteristics of TCM with patient-reported outcomes as the starting point should be established to improve the clinical research and research value.

Effect of Chinese medicine for promoting blood circulation on microvascular angina: A systematic review and meta-analysis.

BACKGROUND: Blood-activating drugs (BADs) are widely used to treat microvascular angina in China. This study aims to summarize relevant evidence from randomized controlled trials (RCTs) to assess the efficacy and safety of BADs in the treatment of microvascular angina. METHODS: We searched for relevant studies before June 2019 from seven databases. Twenty-four studies were included of 1903 patients with microvascular angina. All studies compared the use of traditional Chinese medicine for activating blood circulation (BADs) and Western medicine (WM) with the use of Western medicine alone. RESULTS: In all, 15 trials reported a significant effect of BADs on improving clinical symptoms compared with the control treatment (P < .00001), and 8 trials reported significant effects of BADs on reducing the frequency of angina pectoris attacks compared with Western medicine treatment (P < .00001). The pooled results also demonstrated that BADs provided a significant benefit in reducing the dosage of nitroglycerin required (P = .02), the maximum range of ST-segment depression (P = .003) and the descending degree of the ST-T segment of ECG (P = .0002); prolonging the total time of treadmill exercise (P < .00001) and the time of ST-segment depression of 1 mm (P = .002); enhancing the total effective rate of Traditional Chinese Medicine (TCM) syndromes (P < .00001); improving endothelial function (P < .00001); and reducing the levels of high-sensitivity C-reactive protein (hs-CRP) (P < .00001). BAD treatment showed no statistically significant effect on the levels of TNF-a (P = .8) or IL-6 (P = .13). No severe adverse events were reported. CONCLUSION: This meta-analysis shows that BADs are effective for the treatment of microvascular angina. Although concerns regarding selective bias and low methodological quality were raised, our findings suggest that BADs are beneficial for patients with microvascular angina and should be given priority for future clinical studies.

Index of microvascular resistance to assess the effect of rosuvastatin on microvascular function in women with chest pain and no obstructive coronary artery disease: A double-blind randomized study.

INTRODUCTION: Many women undergoing coronary angiography for chest pain have no or only minimal coronary artery disease (CAD). However, despite the lack of obstructive CAD, they still have an increased risk of major adverse cardiovascular events. Pleiotropic effects of statins may influence microvascular function, but if statins improve microvascular function in unselected chest pain patients is not well studied. This study assessed microvascular function by using the thermodilution-derived test "the index of microvascular resistance" (IMR) with the aim of determining the (i) IMR level in women with chest pain and non-obstructive CAD and if (ii) IMR is modified by high-dose statin treatment in these patients. Additional objectives were to identify the influence of statins on the health status as assessed with generic health questionnaires and on biomarkers of endothelial activation. MATERIALS AND METHODS: The study was a randomized, double-blind, single-center trial comparing 6 months of rosuvastatin treatment with placebo. In total, 66 women without obstructive CAD were included. Mean age was 52.7 years and 55.5 years in the placebo and rosuvastatin group, respectively. Microvascular function was assessed using the IMR, health status was assessed using the SF-36 and EQ-5D questionnaires, and biochemical values were assessed at baseline and 6 months later. RESULTS AND CONCLUSIONS: In the placebo group IMR was 14.6 (SD 5.7) at baseline and 14.4 (SD 6.5) at follow-up. In the rosuvastatin group IMR was 16.5 (SD 7.5) at baseline and 14.2 (SD 5.8) at follow-up. IMR did not differ significantly between the two study groups at follow-up controlled for preintervention values. C-reactive protein (CRP) was comparable between the groups at baseline, while at follow-up CRP was significantly lower in the rosuvastatin group compared to placebo [0.6 (±0.5) mg/L vs. 2.6 (±3.0) mg/L; p = 0.002]. Whereas rosuvastatin treatment for 6 months attenuated CRP levels, it did not improve microvascular function as assessed by IMR (Clinical Trials.gov NCT01582165, EUDRACT 2011-002630-39.3tcAZ).

Management of microvascular angina pectoris.

Microvascular angina (MVA) is defined as angina pectoris caused by abnormalities of small coronary arteries. In its most typical presentation, MVA is characterized by angina attacks mainly caused by effort, evidence of myocardial ischemia on non-invasive stress tests, but normal coronary arteries at angiography. Patients with stable MVA have excellent long-term prognoses, but often present with persistent and/or worsening of angina symptoms. Treatment of MVA is initially based on standard anti-ischemic drugs (beta-blockers, calcium antagonists, and nitrates), but control of symptoms is often insufficient. In these cases, several additional drugs, with different potential anti-ischemic effects, have been proposed, including ranolazine, ivabradine, angiotensin-converting enzyme (ACE) inhibitors, xanthine derivatives, nicorandil, statins, alpha-blockers and, in perimenopausal women, estrogens. In patients with 'refractory MVA', some further alternative therapies (e.g., spinal cord stimulation, pain-inhibiting substances such as imipramine, rehabilitation programs) have shown favorable results.

Traditional Chinese medicine syndrome patterns and qi-regulating, chest-relaxing and blood-activating therapy on cardiac syndrome X.

OBJECTIVE: To master the syndrome patterns characteristics and explore the effective therapy methods of Traditional Chinese Medicine (TCM) for cardiac syndrome X (CSX). METHODS: The TCM syndrome characteristics were mastered and the TCM intervention programs were determined by clinical investigations for TCM syndrome patterns characteristics of CSX patients. Then, the clinical efficacy studies on TCM intervention for CSX were carried out through randomized controlled trials. RESULTS: CSX is a clinical syndrome with the main manifestations of chest pain and chest stuffiness, and Qi stagnation, phlegm retention and blood stasis are the basic symptoms of CSX. As a result, the Qi-regulating, chest-relaxing and blood-activating therapy integrated with some Western Medicines was adopted for treatment. The effect of Qi-regulating, chest-relaxing and blood-activating therapy can reduce the frequency and degree of angina, improve the symptoms and exercise the tolerance of patients, inhibit the inflammatory response of vascular walls and protect the function of vascular endothelial cells, which is better than that of the simple and conventional Western Medicine alone. CONCLUSION: A good effect was achieved in the integration of Chinese and Western Medicines for CSX. The therapy is worthy to be applied further in clinical practice. On the other hand, more long-term and randomised controlled studies with large samples are still required to further determine the clinical efficacy and safety of the therapy.

Potential effectiveness of traditional Chinese medicine for cardiac syndrome X (CSX): a systematic review and meta-analysis.

BACKGROUND: Treatment of cardiac syndrome X with unknown pathological mechanism remains a big challenge for clinicians. Complementary and alternative medicine may bring a new choice for its management. The aim of this study is to evaluate the clinical effects of traditional Chinese medicine on cardiac syndrome X patients. METHODS: We systematically searched databases such as Cochrane CENTRAL, PubMed, EMBASE, CBM, Chinese National Knowledge Infrastructure (CNKI), WanFang and VIP, and handsearched relevant journals to identify randomized controlled trials. Following the steps of systematic review recommended by the Cochrane group, we assessed the quality of included studies, extracted valid data and undertook meta-analysis. RESULTS: Twenty one moderate-to low-quality randomized controlled trials involving 1143 patients were included. The results showed that traditional Chinese medicine could improve angina [OR=1.34, 95% CI: 1.2 to 1.50], electrocardiogram (ECG), endothelin-1 (ET-1) levels, prolong exercise duration in treadmill tests, and reduce angina frequency per week compared with routine treatment. No other side effect was reported except two cases of stomach pain. CONCLUSION: Compared with conventional treatment, traditional Chinese medicine shows the potential of optimizing symptomatic outcomes and improving ECG and exercise duration. The efficacy of TCM may find explanation in its pharmacological activity of adjusting the endothelial function. TCM, as a kind of alternative and complementary medicine, may provide another choice for CSX patients.

ω-3 fatty acid treatment in cardiac syndrome X: a double-blind, randomized, placebo-controlled clinical study.

OBJECTIVE: We conducted a clinical trial to examine the effect of ω-3 fatty acids in patients with cardiac syndrome X (CSX). We aimed to evaluate the potential impact of ω-3 fatty acids on endothelial function, oxidative stress, and symptom relief in the CSX. METHODS AND RESULTS: Eighteen patients with CSX were enrolled according to a double-blind, randomized, placebo-controlled design. Patients were randomized to ω-3 fatty acids (1440 mg/day, n=8) or placebo (n=10) for 4 months. We assessed plasma levels of malondialdehyde (MDA), endothelium-dependent vasodilatation [flow-mediated dilatation (FMD)], endothelium-independent vasodilatation [nitroglycerin-mediated dilatation (NMD)], and status of symptom [score with Seattle Angina Questionnaire (SAQ)] before and after the treatment. After 4 months, patients who were treated with ω-3 fatty acids showed significant increases in the FMD (from 47±48 to 104±23%, P<0.05) and NMD (from 51±53 to 93±35%, P<0.05) values, and significant decreases in the plasma MDA levels (4.4±0.86 to 3.35±0.33 µmol/l, P=0.012). SAQ scores were increased significantly in both groups (from 60±14 to 73±15%, P<0.05 placebo, from 67±10 to 81±9%, P<0.05 treatment group). NMD was correlated negatively with the plasma MDA levels. CONCLUSION: Four months of therapy with a moderate dose of ω-3 fatty acids improved the endothelial function and reduced oxidative stress in patients with CSX.

Persistent chest pain and no obstructive coronary artery disease.

Patients with persistent chest pain and no obstructive coronary artery disease are often labeled as having noncardiac pain and not offered further cardiologic testing or treatment. Diagnostic uncertainty for persistent chest pain is associated with adverse quality of life, morbidity, and health care costs. Two underdiagnosed cardiac causes for persistent chest pain include microvascular coronary disease and abnormal cardiac nociception. Microvascular coronary disease is associated with an increased risk of adverse cardiovascular events such as myocardial infarction, congestive heart failure, and sudden cardiac death, and treatment directed at improving endothelial function can improve outcomes. Abnormal cardiac nociception is also a cause for persistent chest pain caused by heightened coronary pain perception. Coronary reactivity testing allows for direct measurement of blood flow characteristics in response to vasoactive agents for the diagnoses of microvascular coronary disease and can be a useful tool to differentiate causes of chest pain. Coronary reactivity testing is an invasive method for assessing coronary vascular function, with current evidence suggesting that its associated risk is relatively low compared with the adverse prognosis associated with microvascular coronary dysfunction. Accurate diagnosis in patients with persistent chest pain and normal coronary arteries can be challenging and deserves adequate investigation in light of the associated morbidity, mortality, and health care costs.

[Effect of simvastatin on the reserve of heart function and endothelial function in X-syndrome].

OBJECTIVE: To determine the therapeutic effect of simvastatin combined with traditional medicine on patients with X-syndrome, and on the reserve of heart function and endothelial function. METHODS: Forty patients with X-syndrome were recruited from September 2006 to September 2007 and randomly divided into 2 groups (a simvastatin group and a control group). The control group received routine treatment including beta receptor blocker, calcium-channel blocker (CCB) and long active nitrate. The simvastatin group received simvastatin and the routine treatment. The clinical condition and exercise test (TET) were performed before and after the treatment.The levels of triglyeride (TG), total cholesterol (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C), endothelin-1 (ET-1) and nitric oxide (NO) were measured. RESULTS: The frequencies of chest pain in the simvastatin group were lower than those in the control group. The levels of ET-1, ET-1/NO, TG, TC, and LDL-C were significantly decreased in the simvastatin group as compared with the control group after the treatment. The levels of HDL-C and NO were significantly increased in the simvastatin group as compared with the control group after the treatment. The time in TET was significantly increased in the simvastatin group as compared with the control group. The frequencies of chest pain were positively related to the level of ET-1/NO and negatively related to the time in TET. CONCLUSION: Simvastatin is effective for patients with X-syndrome and may improve the endothelial function and the reserve of heart function.

Xuezhikang, an extract of cholestin, decreases plasma inflammatory markers and endothelin-1, improve exercise-induced ischemia and subjective feelings in patients with cardiac syndrome X.

Previous studies have demonstrated that Xuezhikang, an extract of cholestin, available from Chinese red yeast rice, could effectively modify lipid profile. The present study was undertaken to investigate whether Xuezhikang could modify endothelin-1 (ET-1), interleukin-6 (IL-6), high-sensitivity C-reactive protein (CRP) and exercise-induced ischemia in patients with cardiac syndrome X (CSX). Thirty-six patients with CSX were randomly assigned to 1200 mg/d of Xuezhikang or placebo group (n=18 respectively). Blood samples were drawn at day 0 and day 90 for measuring above parameters. The treadmill exercise tests and subjective feelings were also assessed at day 0 and day 90. The data showed that Xuezhikang therapy resulted in significant reductions in total cholesterol (TC, 19%), low-density lipoprotein cholesterol (LDL-C) (26%), and triglycerides (TG) compared with baseline (16%, p<0.01 respectively). The data also showed that Xuezhikang led significantly to reductions in median and log-CRP levels (38% and 44%, p<0.01 respectively), IL-6 (20%, p<0.01), and ET-1 (47%, p<0.01) compared with baseline. The exercise duration, and time to 1 mm ST-segment depression was significantly prolonged after Xuezhikang therapy (9% and 6%, p<0.05 respectively) accompanied by improvement of subjective feelings. Data suggested that the benefit of Xuezhikang resulted in significant modification vascular function by reduction of ET-1, inflammatory markers and LDL cholesterol, which may be clinically important for patients with CSX.

Electrical neuromodulation improves myocardial perfusion and ameliorates refractory angina pectoris in patients with syndrome X: fad or future?

At present, there is no reliable antianginal drug therapy for patients with cardiac syndrome X. Therefore, the effect of electrical neuromodulation on refractory angina pectoris and myocardial perfusion in cardiac syndrome X was assessed. Eight patients (aged 55+/-7 years) with heterogeneous myocardial perfusion and no esophageal abnormalities were included. The subjects were nonresponders to antianginal drug therapy. Angina pectoris attacks and myocardial perfusion dynamics were evaluated by positron emission tomography at baseline and following 4 weeks of (transcutaneous electrical nerve stimulation) TENS. Following TENS there was a reduction of angina pectoris episodes (baseline 20+/-3, TENS 3+/-1; p=0.012), and short acting nitroglycerin intake per week (baseline 10+/-3, TENS 2+/-1; p=0.008). The rate pressure product (mmHg min(-1)) during the cold pressor test (CPT) was reduced during TENS (baseline 12800+/-1200, TENS 11500+/-900; p=0.02). Following TENS, the perfusion reserve ratio between rest and dipyridamole flow increased (baseline 1.59+/-0.15, TENS 1.90+/-0.11 ml min(-1)x 100g; p=0.05). The coronary vascular resistance had a trend towards a reduction (baseline 0.96+/-0.04, TENS 0.85+/-0.06 mmHg min(-1)x 100 g/ml; p=0.06) during CPT. This observation may suggest that neurostimulation improves angina pectoris with a concomitant improvement of myocardial perfusion in cardiac syndrome X.

Antianginal and anti-ischemic effects of nisoldipine and ramipril in patients with syndrome X.

BACKGROUND: Syndrome X is defined as typical angina pectoris, positive treadmill exercise test, negative intravenous ergonovine test, and angiographically normal coronary arteries. HYPOTHESIS: In the present study, we investigated the anti-ischemic and antianginal effects of nisoldipine and ramipril in patients with syndrome X. METHODS: After 2 weeks of the first wash-out period, 18 patients (7 men, 11 women, age 46 +/- 10 years) were given nisoldipine (NIS) 5 mg twice daily for 4 weeks, and after 2 weeks of the second wash-out period, the same patients were given ramipril (RAM) 2.5 mg once daily for 4 weeks. A treadmill exercise test with modified Bruce protocol was performed at the end of each period. RESULTS: The time to angina in exercise (607 +/- 115 s-650 +/- 117 s, p = 0.006, vs. 630 +/- 114 s-660 +/- 123 s, p = 0.02), total exercise time (612 +/- 110 s-656 +/- 114 s, p = 0.0008, vs. 630 +/- 114 s-660 +/- 123 s, p = 0.02), and maximum MET value (11.09 +/- 2.08-11.86 +/- 2.04, p = 0.0016, vs. 11.42 +/- 2.09-12.2 +/- 2.26, p = 0.01) were increased significantly with both therapy modalities. The time to 1 mm ST-segment depression (123 +/- 93 s-220 +/- 172 s, p = 0.002) was increased significantly with NIS therapy. The time to ST-segment recovery (434 +/- 268 s-330 +/- 233 s, p = 0.016 vs. 443 +/- 289 s-370 +/- 278 s, p = 0.012), the frequency of anginal attacks per week (1.27 +/- 1.4-0 +/- 0.38, p = 0.005, vs. 1 +/- 1.32-0.33 +/- 0.59, p = 0.028), and the need for sublingual nitroglycerin (1.16 +/- 1.29-0.11 +/- 0.32, p = 0.005, vs. 0.94 +/- 1.16-0.27 +/- 0.57, p = 0.012) were decreased significantly with both drugs. CONCLUSION: We observed that 10 mg daily NIS and 2.5 mg daily RAM have similar anti-ischemic and antianginal effects in patients with syndrome X.

The effect of transcutaneous electrical nerve stimulation on coronary and systemic haemodynamics in syndrome X.

BACKGROUND: Neurostimulation techniques have been shown to be beneficial in patients with angina and syndrome X but the mechanism remains unclear. We examined the effect of transcutaneous electrical nerve stimulation (TENS) on coronary artery blood flow in a group of patients with syndrome X. METHODS: Coronary blood flows were measured in 11 patients with angiographically normal coronary arteries, positive results from exercise tests and angina (syndrome X) using intracoronary Doppler catheters combined with quantitative coronary angiography. RESULTS: The mean coronary flow velocity did not increase in any patient during TENS therapy; in fact, there was a fall from 5.2 +/- 2.8 to 4.3 +/- 1.9 cm/s (P = 0.02) and the coronary blood flow index fell from 47 +/- 22 to 38 +/- 16 cm/s per mm2 (P = 0.007). This was associated with a fall in the rate x pressure product from 0.92 +/- 0.22 to 0.83 +/- 0.18 mmHg/min (P = 0.038). The coronary vascular resistance rose from 2.4 +/- 1.1 to 3.0 +/- 1.6 mmHg/cm per s per mm2 (P = 0.041). There were no major changes in the epicardial coronary artery diameter during TENS and there was no significant effect on the response to the cold-pressor test. CONCLUSIONS: In this group of patients with syndrome X, TENS produced a small but significant fall in coronary artery blood flow associated with a reduction in the rate x pressure product. TENS had no significant effect on coronary vasomotion during sympathetic stimulation by the cold-pressor test. Thus, TENS is unlikely to have a direct effect on coronary artery vasomotion or haemodynamics in syndrome X but reduces the rate x pressure product and thus myocardial oxygen consumption.

[Insulin resistance and arterial hypertension]. / Insulinresistenz und arterielle Hypertonie.

Insulin resistance and reactive hyperinsulinemia occur not only in patients with obesity, impaired glucose tolerance or non-insulin-dependent (Type 2) diabetes mellitus, but also in many non-obese, non-diabetic individuals with essentiell hypertension and their normotensive, lean young offsprings. The common coexistance of a genetic predisposition for hypertension with insulin resistance helps to explain the frequent occurrence of hypertension as well as dyslipidemia, obesity and diabetes Type 2 in a given individual. In the pathogenesis of hypertension, inappropriate vasoconstriction and/or a structural vasculopathy appears to be an important and ultimate causative event. Several pressor mechanisms are discussed and a distinct sodium retention appears to be almost obligatory associated with diabetes mellitus, while essential and particularly obesity-associated hypertension involves predominantly a tendency for sympathetic activation. Acute hyperinsulinemia on one hand causes arterial vasodilation and on the other hand enhances renal sodium reabsorption and sympathetic activity. Chronically, hyperinsulinemia may promote cardiovascular muscle cell proliferation and atherogenesis. Insulin resistance affecting certain transmembrane cation transporters might lead to an elevation of intracellular cytosolic calcium levels thereby inducing inappropriate vasoconstriction. Nevertheless, whether insulin resistance and hyperinsulinemia contribute to the pathogenesis of hypertension per se is still unproven. Considering antihypertensive drugs, thiazide diuretics given in medium or high dosage as well as beta-blockers appear to promote insulin resistance, reactive hyperinsulinemia and dyslipidemia. Almost all calcium antagonists and the conventional sympthatolytics are metabolically neutral, while ACE-inhibitors and alpha 1-blockers tend to improve insulin resistance. In Type 2 diabetic patients, ACE-inhibitors exert in addition to their antihypertensive a potentially useful anti-diabetic effect. Nevertheless, the prognostic relevance of the metabolic side effects of antihypertensive drugs awaits further clarification.