Deng-feng Geng

Effect of cilostazol on the progression of carotid intima-media thickness: A meta-analysis of randomized controlled trials

BACKGROUND It has been well established that cilostazol has anti-proliferative effect against in-stent restenosis. However, it remains unclear whether cilostazol can prevent the progression of carotid atherosclerosis. METHODS AND RESULTS We performed a meta-analysis of all relevant randomized controlled trials (RCTs) to evaluate the effect of cilostazol on the progression of carotid intima-media thickness (IMT). Five RCTs with 698 patients [597 subjects with type 2 diabetes mellitus (T2DM)] were included in this study. Cilostazol was associated with a significant reduction in the progression of carotid IMT (WMD, -0.08mm, 95% CI -0.13, -0.04; P=0.00003). Subgroup analysis shows that cilostazol monotherapy or addition to dual antiplatelet therapy (aspirin and clopidogrel) was superior to placebo (WMD, -0.04mm, 95% CI -0.05, -0.03; P<0.00001), no antiplatelet medication (WMD, -0.12mm, 95% CI -0.21, -0.03; P=0.008), aspirin monotherapy (WMD, -0.06mm, 95% CI -0.12, 0.00; P=0.04) or dual antiplatelet therapy (WMD, -0.16mm, 95% CI -0.30, -0.02; P=0.03) in preventing the progression of carotid IMT. Cilostazol resulted in a significant decrease in total cholesterol (WMD -8.47mg/dl, 95% CI -14.18, -2.75; P=0.004) and LDL-C (WMD -8.25mg/dl, 95% CI -14.15, -2.36; P=0.006) and favorable trends in reducing triglyceride (WMD -15.83mg/dl, 95% CI -32.14, 0.48; P=0.06). CONCLUSION It suggests that cilostazol may have beneficial effects in preventing the progression of carotid atherosclerosis and improving pro-atherogenic lipid profile, especially in patients with T2DM. Whether the anti-atherosclerotic effect of cilostazol is independent of improving pro-atherogenic dyslipidemia is worth further investigation.

Effect of thiazolidinediones on in-stent restenosis in patients after coronary stenting: a meta-analysis of randomized controlled trials.

BACKGROUND Recent experimental studies have demonstrated that thiazolidinediones (TZDs) therapy inhibits proliferation and migration of vascular smooth muscle cells, accelerates endothelium reparation and attenuates neointimal hyperplasia. It implies that TZDs therapy may have beneficial effects on in-stent restenosis (ISR). Several small-sample clinical trials have evaluated the effect of TZDs therapy on ISR, however, the results were inconsistent across trials. METHODS AND RESULTS We performed a meta-analysis of all relevant randomized controlled trials to evaluate the effect of TZDs therapy on in-stent restenosis in patients undergoing coronary stenting. Eight trials involving 366 patients were included in this study. TZDs therapy was associated with a significant reduction in the risk of ISR in both diabetic (RR 0.37, 95% CI 0.23-0.59; P<0.0001) and non-diabetic patients (RR 0.16, 95% CI 0.05-0.45; P=0.0006). TZDs therapy was associated with a significant reduction in late lumen loss (WMD -0.54 mm, 95% CI -0.87 mm, -0.22 mm; P=0.001), percent diameter stenosis (WMD -15.7%, 95% CI -19.4%, -12.0%; P<0.00001), neointimal area/volume (SMD -0.76, 95% CI -1.13, -0.39; P<0.0001) and target lesion revascularization (RR 0.32, 95% CI 0.18-0.57; P=0.0001). CONCLUSIONS Our study suggests that TZDs therapy is an effective strategy in preventing ISR in both diabetic and non-diabetic patients undergoing coronary stenting. More studies, especially large multi-centre RCTs, are still warranted to further clarify the anti-restenotic effect of TZDs therapy.

Angiotensin receptor blockers for prevention of new-onset type 2 diabetes: a meta-analysis of 59,862 patients.

BACKGROUND Angiotensin receptor blockers (ARBs) have been linked to reduced risk of new-onset diabetes, but the evidence was insufficient. OBJECTIVE AND METHODS The aim of this study was to evaluate the effect of ARBs on the development of new-onset type 2 diabetes. Randomized controlled trials (RCTs) about ARBs and new-onset diabetes were identified by electronic and manual searches. RESULTS Eleven RCTs with 79,773 patients (59,862 non-diabetic patients at baseline) were included in this study. Compared with control group, incidence of new-onset diabetes was significantly reduced in ARBs group [OR 0.79, (0.74, 0.84)] and various categories of ARBs subgroup. ARBs were associated with significant reduction in the risk of new-onset diabetes compared with placebo [OR 0.83, (0.78, 0.89)], beta-blocker [OR 0.73, (0.62, 0.87)], calcium channel blocker [OR 0.76, (0.68, 0.85)] and non-ARB [OR 0.57, (0.36, 0.91)]. ARBs were associated with significant reduction in the risk of new-onset diabetes in patients with hypertension [OR 0.74, (0.68, 0.81)], heart failure [OR 0.70, (0.50, 0.96)], impaired glucose tolerance [OR 0.85, (0.78, 0.92)] or cardiocerebrovascular diseases [OR 0.84, (0.72, 0.97)]. Compared with control group, incidence of new-onset diabetes was significantly reduced in ARBs group, irrespective of achieved blood pressure level. ARBs were associated with a lower incidence of new-onset diabetes in Western population [OR 0.81, (0.76, 0.85)] and Japanese population [OR 0.61, (0.48, 0.79)]. CONCLUSION There is sufficient evidence that ARBs have beneficial effect in preventing new-onset type 2 diabetes. ARBs should be considered in patients with high risk of developing diabetes.

Effects of add-on lipid-modifying therapy on top of background statin treatment on major cardiovascular events: A meta-analysis of randomized controlled trials.

BACKGROUND In patients at high risk of atherosclerotic cardiovascular diseases (ASCVDs), residual cardiovascular risk persists despite the achievement of target LDL cholesterol levels with statin therapy. It is still unclear whether adding lipid-modifying agent to statin treatment can further improve clinical outcomes. METHODS Randomized controlled trials (RCTs) in terms of adding lipid-modifying agent to statin versus statin monotherapy in patients at high risk of ASCVD were identified by electronic and manual searches. Results were expressed as relative risk (RR) with 95% confidence intervals (CIs). RESULTS Eleven RCTs with 109,244 patients were included in this meta-analysis. Overall, the incidences of major adverse cardiovascular events (MACEs) were 9.70% in the statin combination groups and 9.92% in the statin monotherapy groups. No significant difference was observed in the risk of MACEs either in overall (RR 0.99, 95% CI 0.93-1.05, P=0.76) or subgroup analysis (CETP inhibitor: RR 1.07, 95% CI 0.93-1.23, P=0.37; niacin: RR 1.03, 95% CI 0.85-1.25, P=0.79; n-3 fatty acid: RR 0.98, 95% CI 0.88-1.09, P=0.70; fenofibrate: RR 0.93, 95% CI 0.80-1.09, P=0.38), with the exception of the statin/ezetimibe combination subgroup (RR 0.92, 95% CI 0.87-0.97, P=0.004). Adding lipid-modifying agent to statin significantly increased liver injury risk. Adding ezetimibe to statin did not alter side effect profile. CONCLUSION Adding niacin, CETP inhibitors, n-3 fatty acid or fibrates to statin therapy has all failed to achieve a clinical benefit. Adding ezetimibe to statin therapy further lowers LDL-cholesterol safely and translates into a clinical benefit in patients at high risk of ASCVD.

Long-term efficacy and safety of statin treatment beyond six years: A meta-analysis of randomized controlled trials with extended follow-up

Large-scale randomized controlled trials (RCTs) have well demonstrated the beneficial effects of cholesterol-lowering treatment with statins in patients at high risk of vascular disease. However, large statin RCTs were usually restricted to the typical 5-6 years. Moreover, non-cardiovascular events, especially the risk of cancer, probably failed to emerge within a restricted period of 6 years. The aim of this study was to evaluate the long-term efficacy and safety of statin treatment by performing a meta-analysis of statin RCTs with extended follow-up beyond 6 years. Six RCTs with post-trial follow-up were eligible for inclusion, involving 47,296 patients with total follow-up ranging from 6.7 to 14.7 years. During the post-trial period, all the surviving participants were advised to take a statin and the cholesterol level were almost identical between the original statin group and the original placebo group. Over the entire 6.7-14.7 years of follow-up, a significant reduction in the rates of all-cause mortality (relative risk 0.90, 95% confidence interval 0.85-0.96; P=0.0009), cardiovascular mortality (0.87, 0.81-0.93; P<0.0001) and major coronary events (0.79, 0.72-0.86; P<0.00001) was observed in favour of the original statin group. During 2-year post-trial period, further reduction in all-cause mortality (0.83, 0.74-0.93; P=0.001), cardiovascular mortality (0.81, 0.69-0.95; P=0.01) and major coronary events (0.77, 0.63-0.95; P=0.01) was observed among initially statin-treated patients. Over the entire follow-up period, statin treatment did not increase the incidence of cancers (0.99, 0.95-1.04; P=0.79), deaths from cancers (1.00, 0.93-1.07; P=0.98) and non-cardiovascular mortality (0.95, 0.90-1.00; P=0.07). In conclusion, statin treatment beyond 6 years is effective and safe in patients at high risk of vascular events. Moreover, earlier treatment with statin may not only preserve the initial benefit but also have further survival benefit for additional 2 years. Further studies are called for to explore the underlying mechanisms.

Cilostazol-Based Triple Antiplatelet Therapy Compared to Dual Antiplatelet Therapy in Patients with Coronary Stent Implantation: A Meta-Analysis of 5,821 Patients

Background: Uncertainties still remain in terms of what kinds of patients benefit most from cilostazol-based triple antiplatelet therapy (TAT) after coronary stenting. Methods: We performed a meta-analysis of all relevant randomized controlled trials (RCTs) to investigate the effect of TAT versus dual antiplatelet therapy (DAT) in terms of major adverse cardiovascular events (MACEs) in patients undergoing coronary stenting. Results: Fourteen RCTs with 5,821 patients were included in this study. TAT was associated with a significant reduction in the risk of MACEs compared to DAT [9.2 vs. 13.4%; odds ratio 0.59 (0.46, 0.76)] with consistent benefits among patients with diabetes, long lesions and small vessels. There were no significant between-group differences in the risk of cardiac death, myocardial infarction, stent thrombosis and bleeding events; however, the risk of target lesion revascularization was significantly lower in the TAT group. TAT resulted in borderline significant reduction in the risk of cardiovascular thrombotic events in unselected patients and significant decrease in patients with acute coronary syndrome [odds ratio 0.51 (0.27, 0.94)]. Conclusion: Under the treatment of standard DAT, the addition of cilostazol is an effective and relatively safe strategy in preventing MACEs after coronary stenting, especially for patients at high risk of restenosis or clinical events.

Local activation of cardiac stem cells for post-myocardial infarction cardiac repair

The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite continuous advancements in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. The emergence of stem cell transplantation approaches has recently represented promising alternatives to stimulate myocardial regeneration. Regarding their tissue‐specific properties, cardiac stem cells (CSCs) residing within the heart have advantages over other stem cell types to be the best cell source for cell transplantation. However, time‐consuming and costly procedures to expanse cells prior to cell transplantation and the reliability of cell culture and expansion may both be major obstacles in the clinical application of CSC‐based transplantation therapy after MI. The recognition that the adult heart possesses endogenous CSCs that can regenerate cardiomyocytes and vascular cells has raised the unique therapeutic strategy to reconstitute dead myocardium via activating these cells post‐MI. Several strategies, such as growth factors, mircoRNAs and drugs, may be implemented to potentiate endogenous CSCs to repair infarcted heart without cell transplantation. Most molecular and cellular mechanism involved in the process of CSC‐based endogenous regeneration after MI is far from understanding. This article reviews current knowledge opening up the possibilities of cardiac repair through CSCs activation in situ in the setting of MI.

Angiotensin II Receptor Blocker Attenuates Intrarenal Renin-Angiotensin-System and Podocyte Injury in Rats with Myocardial Infarction

The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI) are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs) provides renoprotective effects after MI by preventing augmented intrarenal renin-angiotensin-system (RAS)-induced podocyte injury. Sprague–Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16ink4a, decreased immunostaining for Wilms’ tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1) and decreased expressions of IGF-1 receptor (IGF-1R) protein and mRNA and phosphorylated(p)-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2’-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16ink4a-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway.

Effect of alpha-glucosidase inhibitors on the progression of carotid intima-media thickness: A meta-analysis of randomized controlled trials

BACKGROUND It remains unclear whether lowering postprandial glucose by alpha-glucosidase inhibitors (alpha-GIs) can prevent the progression of carotid intima-media thickness (IMT). METHODS AND RESULTS We performed a meta-analysis of all relevant randomized controlled trials (RCTs) to evaluate the effect of alpha-GIs on the progression of carotid IMT. Five RCTs with 411 patients were included in this study. Alpha-GIs therapy was associated with a significant reduction in the annual progression of carotid IMT (WMD, -0.06 mm/year, 95% CI -0.11, -0.01; P=0.02) and the progression in carotid IMT at the end of follow-up (WMD, -0.07 mm, 95% CI -0.12, -0.02; P=0.003). In subgroup analysis, alpha-GIs therapy was associated with a significant reduction in the annual progression of carotid IMT in patients with type 2 diabetes mellitus (T2DM) (WMD, -0.08 mm/year, 95% CI -0.10, -0.06; P<0.00001), and in the progression of carotid IMT in patients with impaired glucose tolerance (IGT) at the end of follow-up (WMD, -0.03 mm, 95% CI -0.05, -0.01; P=0.01). Alpha-GIs treatment was associated with significant increase in HDL-C (WMD 1.56 mg/dl, 95% CI 0.09, 3.03; P=0.04) and decrease in basal immunoreactive insulin as well as had favorable trends towards reducing HbA1c, triglyceride and diastolic blood pressure. CONCLUSION It suggests that alpha-GIs therapy may be an effective strategy in preventing the progression of carotid IMT in patients with IGT or T2DM. It partially contributes to the improvement in atherogenic metabolic parameters induced by alpha-GIs. More studies, especially large multi-centre RCTs, are still warranted to further clarify the anti-atherosclerotic effect of alpha-GIs.

Angiotensin converting enzyme inhibitors for prevention of new-onset type 2 diabetes mellitus: A meta-analysis of 72,128 patients

BACKGROUND Angiotensin converting enzyme inhibitors (ACEIs) have been linked to reduced risk of new-onset diabetes, but the evidence was insufficient. OBJECTIVE AND METHODS The aim of this study was to evaluate the effect of ACEIs on the development of new-onset type 2 diabetes. Randomized controlled trials (RCTs) about ACEIs and new-onset diabetes were identified by electronic and manual searches. RESULTS Nine RCTs with 92,404 patients (72,128 non-diabetic patients at baseline) were included in this study. Compared with control group, incidence of new-onset diabetes was significantly reduced in the ACEIs group [OR 0.80, (0.71, 0.91)], irrespective of achieved blood pressure levels at the follow-up. ACEIs therapy was associated with significant reduction in the risk of new-onset diabetes compared with beta-blockers/diuretics [OR 0.78, (0.65, 0.93)], placebo [OR 0.79, (0.64, 0.96)], or calcium channel blockers [OR 0.85, (0.73, 0.99)]. ACEIs treatment was associated with significant reduction in the risk of new-onset diabetes in patients with hypertension [OR 0.80, (0.68, 0.93)], coronary artery disease (CAD) or cardiovascular disease [OR 0.83, (0.68, 1.00)], or heart failure [OR 0.22, (0.10, 0.47)]. Among patients with impaired glucose tolerance or impaired fasting glucose, ramipril did not significantly reduce the incidence of diabetes [OR 0.91, (0.79, 1.05)], but significantly increased regression to normoglycemia. CONCLUSION ACEIs have beneficial effects in preventing new-onset diabetes. ACEIs provide additional benefits of lowering the risk of new-onset diabetes in patients with hypertension, CAD or other cardiovascular disease.