Efficacy and safety of Shexiang Baoxin pill (MUSKARDIA) in patients with stable coronary artery disease: a multicenter, double-blind, placebo-controlled phase IV randomized clinical trial.

BACKGROUND: The Shexiang Baoxin Pill (MUSKARDIA) has been used for treating coronary artery disease (CAD) and angina for more than 30 years in China. Nevertheless, methodologically sound trials on the use of MUSKARDIA in CAD patients are scarce. The aim of the study is to determine the effects of MUSKARDIA as an add-on to optimal medical therapy (OMT) in patients with stable CAD. METHODS: A total of 2674 participants with stable CAD from 97 hospitals in China were randomized 1:1 to a MUSKARDIA or placebo group for 24 months. Both groups received OMT according to local tertiary hospital protocols. The primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary outcomes included all-cause mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina or heart failure, peripheral revascularization, angina stability and angina frequency. RESULTS: In all, 99.7% of the patients were treated with aspirin and 93.0% with statin. After 2 years of treatment, the occurrence of MACEs was reduced by 26.9% in the MUSKARDIA group (MUSKARDIA: 1.9% vs. placebo: 2.6%; odds ratio = 0.80; 95% confidence interval: 0.45-1.07; P  = 0.2869). Angina frequency was significantly reduced in the MUSKARDIA group at 18 months (P = 0.0362). Other secondary endpoints were similar between the two groups. The rates of adverse events were also similar between the two groups (MUSKARDIA: 17.7% vs. placebo: 17.4%, P = 0.8785). CONCLUSIONS: As an add-on to OMT, MUSKARDIA is safe and significantly reduces angina frequency in patients with stable CAD. Moreover, the use of MUSKARDIA is associated with a trend toward reduced MACEs in patients with stable CAD. The results suggest that MUSKARDIA can be used to manage patients with CAD. TRIAL REGISTRATION: chictr.org.cn, No. ChiCTR-TRC-12003513.

Protective Effects of Salvianolate on Myocardial Injury or Myocardial Infarction after Elective Percutaneous Coronary Intervention in NSTE-ACS Patients: A Randomized Placebo-Controlled Trial.

OBJECTIVE: To evaluate the protective effects of salvianolate on percutaneous coronary intervention (PCI) related myocardial injury or myocardial infarction after elective PCI in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients. METHODS: A total of 149 patients with NSTE-ACS who underwent elective PCI were enrolled. The patients were randomly allocated in a 1:1 ratio to the salvianolate group (74 cases) or the control group (75 cases). After exclusion criteria of coronary angiography, 60 patients with PCI therapy remained in the salvianolate group and 68 in the control group. The incidence and the severity of PCI related myocardial injury or myocardial infarction, in addition to major adverse cardiac events (MACEs) during 1 year follow-up after PCI were studied between the two groups. Multivariate logistic regression analysis was used to determine the independent factors for PCI related myocardial injury or myocardial infarction after elective PCI. RESULTS: Compared with the control group, salvianolate treatment reduced the incidence of PCI related severe myocardial injury or myocardial infarction (11.7% vs. 26.5%, P=0.035). The rate of MACEs or all-cause death within 1 month or 1 year after the procedure was not significantly different between the two groups. CONCLUSIONS: Periprocedural treatment with salvianolate reduces the incidence of PCI related severe myocardial injury or myocardial infarction, although it does not influence clinical prognosis. [Chinese clinical trial registry: ChiCTR1800016992].

The effects of simvastatin on angiogenesis: studied by an original model of atherosclerosis and acute myocardial infarction in rabbit.

Statins have shown pleiotropic effects, many of them independent of their impact on lipids. Angiogenesis can be beneficial in the acute myocardial infarction to improve circulation. However, it also can be harmful due to worsening of atherosclerosis. Here, we established a new minimal invasive rabbit model to study ischemic myocardium and atherosclerosis together to mimic clinical scenario. We demonstrated that simvastatin has the effect of pro-angiogenesis and further improve cardiac function in ischemic myocardium, as well as the effect of anti-angiogenesis to improve atherosclerosis in aorta vessels.

[Effects of shexiang baoxin pill on angiogenesis in atherosclerosis plaque and ischemic myocardium].

OBJECTIVE: To investigate the effects of Shexiang Baoxin Pill (SBP) in intervening atherosclerosis and myocardial infarction (AS-MI) in experimental animals, and inspect its influences on angiogenesis. METHODS: Twenty male New-Zealand rabbits were made into AS-MI model, and randomly divided into 2 groups equally. Group A was fed with high-fat diet for control; Group B was fed with high-fat diet but intervened with SBP. The cardiac function and the positive area of plaque were determined. The CD34 positive response intensity at infarcted marginal zone and aorta vessel wall, and the capillary density of myocardium were measured by immunohistochemical staining. In addition, the protein expressions of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) were detected by Western blot. RESULTS: Compared to Group A, the cardiac function was obviously improved (P<0.05) and the plaque positive area (%) was significantly decreased in Group B (45.82 +/- 3.68 vs 82.56 +/- 4.97, P<0.01). The CD34 positive response intensity and the capillary density as well as VEGF and VEGFR-2 expressions in infarcted marginal zone in Group A were higher than those in Group B (P<0.01); but these parameters at aorta vessel walls were lower in Group A than in Group B (P<0.01). CONCLUSION: SBP could advance the angiogenesis in the marginal zone of infarction, improve heart function, and embarrass angiogenesis in atherosclerotic plaque.

Effectiveness of open-label losartan/hydrochlorothiazide combination therapy in Asian patients with hypertension not controlled with ACE inhibitor or ARB monotherapy.

Antihypertensive efficacy and safety of losartan/hydrochlorothiazide (HCTZ) combinations have not been adequately studied in Asians. In this open-label, 12-week study in seven Asian areas, patients on monotherapy with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) but not at blood pressure (BP) goal (sitting diastolic BP (SiDBP) <90 mm Hg in non-diabetics and <80 mm Hg in diabetics) were switched to losartan 50 mg/HCTZ 12.5 mg. At 4 and 8 weeks, the therapy for patients not at goal BP was titrated to losartan 100 mg/HCTZ 12.5 mg and to losartan 100 mg/HCTZ 25 mg, respectively. Data analysis included 430 patients with mean (s.d.) age 53.0 (10.1) years and 51.9% of the female gender. After 8 weeks (primary end point; titration up to losartan 100 mg/HCTZ 12.5 mg), 73.5% (95% confidence interval (CI): 69.0-77.6) of patients reached BP goal; 63.4 and 78.1% of patients reached BP goal at 4 weeks (titration up to losartan 50 mg/HCTZ 12.5 mg) and at 12 weeks (titration up to losartan 100 mg/HCTZ 25 mg). The mean changes from baseline (95% CI) in sitting systolic BP and SiDBP at 8 weeks were -16.7 (-18.0 to -15.4) mm Hg and -12.1 (-12.9 to -11.4) mm Hg, respectively. Clinical and laboratory adverse experiences (AEs) were reported in 27.5 and 21.0% of patients, respectively. Nine patients were discontinued because of drug-related clinical AEs. Switching Asian patients currently not at BP goal with ARB or ACEI monotherapy to a losartan/HCTZ combination achieved BP goal in the majority of patients. Losartan/HCTZ combinations were generally well tolerated.

[Effects of rhodiola on expression of vascular endothelial cell growth factor and angiogenesis in aortic atherosclerotic plaque of rabbits].

OBJECTIVE: To investigate the effects of rhodiola on expression of vascular endothelial cell growth factor (VEGF) and angiogenesis in aortic atherosclerotic plaque of rabbits. METHODS: Thirty male New Zealand rabbits were randomly divided into 3 groups equally, i. e. the control group (A) fed with common diet and treated with distilled water, the high fat diet group (B) and the rhodiola group (C) fed with diet containing 1.5% cholesterol and treated respectively with distilled water and rhodiola (1 mL/kg per day), all the treatments were administered via gastrogavage once a day for 9 successive weeks. Level of blood lipids in various groups was determined and compared at the end of the experiment. Meanwhile, the tissue sample of aorta was taken for observation through HE and Sudan red staining, for detecting the CD34 positive response intensity by immunohistochemical staining and the VEGF expression by Real-time fluorescent quantitative PCR and Western blot. RESULTS: Determination of blood lipids showed that in Group C, TC was 42.01 +/- 1.99 mmol/L, TG 4.83 +/- 0.75 mmol/L and LDL-C 38.40 +/- 0.74 mmol/L, all lower than those in Group B (70.74 +/- 2.66 mmol/L, 8.75 +/- 0.78 mmol/L and 51.05 +/- 0.34 mmol/L, respectively), showing statistical difference between groups (P < 0.05). The intima/media tunica thickness ratio and the CD34 positive area of plaque in Group C were all lower than those in Group B (0.35 +/- 0.03 vs 0.43 +/- 0.03 and 29.12 +/- 2.56% vs 39.28 +/- 3.48%, P <0.05). Besides, the VEGF expression in atherosclerotic plaque was also lower in Group C than that in Group B. CONCLUSION: Rhodiola has the effects of inhibiting atherosclerosis formation, decreasing the VEGF expression and suppressing the angiogenesis in the plaque.

[Efficacy and safety of olmesartan medoxomil versus losartan potassium in Chinese patients with mild to moderate essential hypertension].

OBJECTIVE: To evaluate the efficacy and safety of olmesartan medoxomil compared with losartan potassium in patients with mild to moderate essential hypertension. METHOD: This is a randomized, double-blind, double-dummy, active-controlled, parallel, multi-center study. After a 2-week placebo run-in period, a total of 287 eligible subjects were randomized at 1:1 ratio to receive olmesartan medoxomil 20 mg or losartan potassium 50 mg, once daily for 8 weeks. The blood pressure was assessed after 4 weeks treatment. If the subject's seating diastolic blood pressure (SeDBP) was still >or=90 mm Hg, the dosage was doubled for another 4 weeks; for those subjects whose SeDBP was <90 mm Hg after 4-week treatment, the initial dosage remained unchanged and the treatment continued until completion of the study. RESULTS: (1) The mean trough reduction in SeDBP from baseline in olmesartan group was significantly greater than that in losartan group after 4 weeks (11.72 mm Hg vs 9.23 mm Hg, P=0.004) and 8 weeks treatment (12.94 mm Hg vs 11.01 mm Hg, P=0.035). (2) The number and percentage of responders in olmesartan group (81, 65.3%) were statistically higher than those (68, 52.7%) in losartan group (P=0.028) after 4 weeks treatment and were similar between the two groups after 8 weeks treatment (P>0.05). (3) Individual and overall trough/peak ratios of DBP and SBP in 24-hour ambulatory blood pressure monitoring were higher in olmesartan group than losartan group. The hypotensive effect of olmesartan was more durable than losartan at 24 hour interval. (4) The incidence of study drug-related adverse events (AEs) in olmesartan group (10.5%) was similar as that in losartan group (13.9%, P>0.05). Most of these AEs were mild and transient. CONCLUSION: This study shows that olmesartan medoxomil, at oral dose of 20 mg-40 mg once daily was effective and safe for hypertension treatment and the hypotensive effect was superior to losartan potassium (50 mg-100 mg once daily).

[Effects of antidepressant therapy in patients with suspected "angina pectoris" and negative coronary angiogram complicating comorbid depression].

OBJECTIVE: We observed the therapeutic effectiveness and safety of different antidepressants as well as the correlation between symptomatic improvement of depression and improvement of chest pain in patients with susceptible "angina pectoris" and negative coronary angiogram complicating comorbid depression. METHODS: In this double-blinded randomized study, a total of 123 eligible patients were allocated into three groups: (1) Group F: fluoxetine 20 mg QN (n = 41); (2) Group P: Placebo 1 tablet QN (n = 40); (3) Group F + O: fluoxetine 20 mg + olanzapine 2.5 mg QN for the former 2 weeks and only fluoxetine 20 mg QN for the latter 2 weeks (n = 42). The total therapy duration was 4 weeks. HAMD, HAMA and self-evaluation table of chest pain were obtained before therapy, at the end of 1 and 2 weeks after therapy. RESULTS: Baseline HAMD and HAMA scores and self-evaluation score of chest pain were similar among 3 groups and all scores were significantly improved post various therapies in the order of group F + O > group F > group P. The rate of score decrease were seen after 1 week treatment in group F + O and after 2 week treatment in group F. There was a significant positive correlation between the rates of self-evaluation chest pain score decrease and HAMD (r = 0.867, P < 0.001) and HAMA (r = 0.854, P < 0.001) score decreases after 4 weeks therapies (P < 0.05). During the whole course of treatment, no serious adverse reaction was found in all patients. CONCLUSION: In patients with suspected "angina pectoris" and negative coronary angiogram complicating comorbid depression, the antidepressants were safe and significantly improved the symptoms of depression and anxiety and chest pain. Low dose fluoxetine plus short term olanzapine regimen was superior to fluoxetine alone regimen in terms of stronger and quicker symptom improvement.

[Effect of rhodiola on expressions of Flt-1, KDR and Tie-2 in rats with ischemic myocardium].

OBJECTIVE: To investigate the effect of rhodiola on expression of vascular endothelial growth factors receptors (VEGFR) in myocardium of rats after myocardial infarction. METHODS: On the basis of successful establishment of myocardial infarction rat model, the experimental animals were divided into the model group, the rhodiola group, the positive control group and the sham-operated group, they were sacrificed after 6 weeks feeding. Their hearts were resected and embedded in paraffin to make sections with standard immunohistochemistry stain. Then the stained slices were analyzed in the IMS cell imagine analysis system using immunohistochemical quantitative analysis software. The field of vision of left ventricular myocardial tissue in three sites selected from the marginal area of infarction in each slice were determined, the mean value was then converted to positive area. Meanwhile, the mean optical density (OD) was calculated and the various expressions of VEGFR, i.e. Flt-1, KDR and angiopoietin receptor (Tie-2) were measured. RESULTS: The expressions of Flt-1 and Tie-2 in myocardial tissue were significantly increased in the rhodiola treated group after treatment, showing significant difference as compared with those in the positive control group and the model group (P < 0.05). The expression of KDR in myocardium after rhodiola intervention was higher than that in the sham-operated and nonintervened group (P < 0.05), but insignificantly different to that in the positive control group and model group. CONCLUSION: Rhodiola could improve angiogenesis to ameliorate myocardial ischemia by regulating the expression of Flt-1 and Tie-2 in ischemic myocardium.

[Effect of Zhenju Jiangya Tablet on the endothelial function of hyperlipidemic rabbits].

OBJECTIVE: To study the effect of Zhenju Jiangya Tablet (ZJ) on the injured endothelial cells and endothelium-dependent relaxation function of hyperlipidemia rabbits. METHODS: Male New Zealand rabbits were randomized into four groups: control group, hyperlipidemia group, ZJ group and sivastatin group. The endothelium-dependent relaxation function was evaluated by APV using intravascular Doppler, and the morphology of endothelial cells was detected by light microscopy and electron microscopy, and nitric oxide synthase was evaluated. RESULTS: ZJ reduced the lesions of hyperlipidemia vessels, and the APV after Ach injection of each group was (1.14+/-0.26), (1.74+/-0.59), (1.22+/-0.37) and (1.17+/-0.41) respectively. The eNOS of each group was (4.21+/-0.37), (1.43+/-0.88), (3.95+/-0.67) and (4.08+/-0.46) nmol x min(-1) x g(-1) respectively. CONCLUSION: ZJ can improve the abnormality of endothelial cells and endothelium-dependent relaxation function of hyperlipidemia.

[Effects of atenolol and diltiazem-SR on quality of life in the hypertensive patients].

OBJECTIVE: To compare the efficacy of atenolol and diltiazem-SR and the effects on the quality of life in hypertensive patients. METHODS: Seventy-three patients with mild to moderate hypertension (DBP 90 - 109 mmHg) were allocated randomly to be administered with atenolol 25 mg/d (group A, n=37) and diltiazem-SR 90 mg/d (group B, n=36) for eight weeks. The changes of heart rate, office blood pressure(OBP), ambulatory blood pressure(ABP) and the quality of life were compared before and after treatment. RESULTS: Heart rate, OBP and ABP decreased after treatment in both groups. The effective rate of blood pressure was 88.2% in group A and 93.8% in group B. Twenty four hour mean daytime and nighttime BP,daytime and nighttime BP loads declined in both groups (P<0.05 - 0.01). The quality of life was significantly increased in group B (P<0.05). Side effects were 21.6% in group A and 11.1% in group B, respectively (P>0.05). CONCLUSION: Atenolol and diltiazem-SR are more effective and tolerant in the treatment of the hypertension. Diltiazem improves the quality of life better than atenolol.

[Effect of salvianolate on migration of human vascular endothelial cells].

OBJECTIVE: To study the effect of salvianolate on the migration of endothelial cells induced by monocytes. METHODS: Transwell-boydom system was used to test the migration of endothelial cells induced by monocytes. Enzyme-linked immunosorbent assay (ELISA) and RT-polymerase chain reaction (RT-PCR) method were used to determine the effect of salvianolate on the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and their mRNA of monocytes. RESULTS: The migration of endothelial cells induced by monocytes was facilitated by salvianolate, compared with the control. After the monocytes were treated by salvianolate for 24 hours, the expression of mRNA of VEGF and bFGF was significantly up-regulated, and the expression of VEGF and bFGF was increased. CONCLUSION: The facilitation of salvianolate on the migration of endothelial cells induced by monocytes was observed. Salvianolate stimulates the expression of VEGF and bFGF and their mRNA of monocytes, and salvianolate may have the role of inducing migration of endothelial cells by working on these two factors.

[Changing trends of etiologic characteristics of cardiovascular diseases among inpatients in Shanghai: a retrospective observational study from 1948 to 1999].

OBJECTIVE: To investigate the trends in the change of etiologic types of cardiovascular disease among inpatients in Shanghai area from 1948 to 1999. METHODS: The retrospective estimate was based on the data survey in two major general hospitals of Shanghai. Descriptive statistics were provided for all patients meeting the inclusion criteria. Trend of percentage change was compared using linear regression. Diagnoses were categorized using the International Classification of Diseases, 9th Revision. RESULTS: (1) A total of 37 086 admissions with different etiologic types of heart diseases from 1948 to 1999 was reviewed. The percentage of heart diseases among the inpatients in medical wards was significantly increased during this period, being 9.89%, 15.69%, 20.91%, 23.54% and 24.24% (P < 0.05) for each decade respectively and reaching a peak in 1990s. (2) Patterns of different etiologic types of heart diseases changed markedly from 1948 to 1999. The percentage of coronary heart disease increased from 6.78% in 1940s to 39.19% in 1990s (P < 0.05), cardiac dysrhythmias from 0.63% to 18.84% (P < 0.05), cardiomyopathy from 0.05% to 5.01% (P < 0.05) and endocarditis from 0.02% to 0.69% (P < 0.05). The percentage of rheumatic heart disease decreased from 50.30% to 10.25% (P < 0.05). The percentage of hypertensive heart disease, myocarditis and congenital heart disease remained unchanged. (3) From 1948 to 1999 the overall in-hospital mortality of heart diseases in different decades decreased from 17.91%, 11.51%, 14.07%, 7.35% to 2.39% (P < 0.05). (4) Patients were slightly younger in 1950s (39.7 +/- 5.5) years than those in 1990s (60.1 +/- 12.7) years (P < 0.05). (5) The percentage of male patients increased (ranging from 50.7% in 1940s to 62.4% in 1990s, P < 0.05). CONCLUSIONS: Hospitalization patterns of heart diseases have changed dramatically in the second half of the last century in Shanghai. Coronary heart disease is the most frequent condition requiring hospitalization nowadays and the rates of many age-related heart diseases are increasing and this has been paralleled by a substantial increase of the rates in the community survey. More attention should be paid to these heart diseases in Shanghai and in this century.