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BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs), phosphodiesterase 5 inhibitors (PDE-5Is), and soluble guanylate cyclase stimulator (sGCS), have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH. METHODS: Medline, the Cochrane Library, and other Internet sources were searched for randomized clinical trials exploring the efficacy of targeted drugs for patients with PAH. The primary effective end point of this network meta-analysis was a 6-minute walk distance (6MWD). RESULTS: Thirty-two eligible trials including 6,758 patients were identified. There was a statistically significant improvement in 6MWD, mean pulmonary arterial pressure, pulmonary vascular resistance, and clinical worsening events associated with each of the four targeted drugs compared with placebo. Combination therapy improved 6MWD by 20.94 m (95% confidence interval [CI]: 6.94, 34.94; P=0.003) vs prostanoids, and 16.94 m (95% CI: 4.41, 29.47; P=0.008) vs ERAs. PDE-5Is improved 6MWD by 17.28 m (95% CI: 1.91, 32.65; P=0.028) vs prostanoids, with a similar result with combination therapy. In addition, combination therapy reduced mean pulmonary artery pressure by 3.97 mmHg (95% CI: -6.06, -1.88; P<0.001) vs prostanoids, 8.24 mmHg (95% CI: -10.71, -5.76; P<0.001) vs ERAs, 3.38 mmHg (95% CI: -6.30, -0.47; P=0.023) vs PDE-5Is, and 3.94 mmHg (95% CI: -6.99, -0.88; P=0.012) vs sGCS. There were no significant differences in all-cause mortality and severe adverse events between prostanoids, ERAs, PDE-5Is, sGCS, combination therapy, and placebo. CONCLUSION: All targeted drugs for PAH are associated with improved clinical outcomes, especially combination therapy. However, all these drugs seem to show less favorable effects on survival in the short-term follow-up, suggesting further clinical trials are required.

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The optimal antithrombotic regimen remains controversial in patients taking oral anticoagulation (OAC) undergoing coronary stenting. This study sought to compare efficacy and safety outcomes of triple therapy (OAC, aspirin, and clopidogrel) vs dual therapy (clopidogrel with aspirin or OAC) in these patients. We hypothesize OAC plus clopidogrel could be the optimal regimen for patients with indications for OAC receiving stent implantation. Medline, the Cochrane Library, and other Internet sources were searched for clinical trials comparing the efficacy and safety of triple vs dual therapy for patients taking OAC after coronary stenting. Sixteen eligible trials including 9185 patients were identified. The risks of major adverse cardiac events (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 0.82-1.39, P = 0.65), all-cause mortality (OR: 0.98, 95% CI: 0.76-1.27, P = 0.89), myocardial infarction (OR: 1.01, 95% CI: 0.77-1.31, P = 0.97), and stent thrombosis (OR: 0.91, 95% CI: 0.49-1.69, P = 0.75) were similar between triple and dual therapy. Compared with dual therapy, triple therapy was associated with a reduced risk of ischemic stroke (OR: 0.57, 95% CI: 0.35-0.94, P = 0.03) but with higher major bleeding (OR: 1.52, 95% CI: 1.11-2.10, P = 0.01) and minor bleeding (OR: 1.59, 95% CI: 1.05-2.42, P = 0.03). Subgroup analysis indicated there were similar ischemic stroke and major bleeding outcomes between triple therapy and therapy with OAC plus clopidogrel. Treatment with OAC and clopidogrel was associated with similar efficacy and safety outcomes compared with triple therapy. Triple therapy could be replaced by OAC plus clopidogrel without any concern about additional risk of thrombotic events.

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AIMS: The present study sought to compare angiographic and clinical outcomes of a simple strategy versus a complex strategy in patients with coronary bifurcation lesions undergoing drug-eluting stent implantation. METHODS AND RESULTS: Medline, the Cochrane Library, and other internet sources were searched for randomised trials comparing simple strategy versus complex strategy for treating patients with bifurcation lesions. Nine eligible randomised trials including 2,569 patients were identified. The meta-analysis showed that cardiac death (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.40- 2.41, p=0.98) and stent thrombosis (OR: 0.64, 95% CI: 0.31-1.34, p=0.24) were similar in the simple and the complex strategy. Compared with the complex strategy, the simple strategy was associated with a reduced risk of either early or follow-up myocardial infarction (OR: 0.53, 95% CI: 0.36-0.79, p=0.002; OR: 0.60, 95% CI: 0.43-0.86, p=0.01, respectively). The overall risks of side branch restenosis (OR: 1.44, 95% CI: 0.73-2.87, p=0.30), target lesion (OR: 1.72, 95% CI: 0.95-3.12, p=0.07) and target vessel revascularisation (OR: 1.59, 95% CI: 0.94-2.69, p=0.09) were comparable between the two groups. In the true bifurcation, with large side branches, and DK-crush subgroups, there were higher rates of reintervention seen in the simple strategy than in the complex strategy. CONCLUSIONS: A complex strategy remains an optional treatment for patients with coronary bifurcation lesions without severe safety concerns. A complex strategy may be an optimal treatment for true bifurcation lesions with large side branches.

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Cardiac hypertrophy is a maladaptive change in response to pressure overload, and is also an important risk for developing heart failure. Berberine is known to have cardioprotective effects in patients with hypertension and in animal models of cardiac hypertrophy. In the current study, we observed that transverse aortic contraction (TAC) surgery induced a marked increase in heart size, the ratio of heart weight to body weight, cardiomyocyte apoptosis, myocardial fibrosis, and hypertrophic marker brain natriuretic peptide, all of which were effectively suppressed by berberine administration. In addition, berberine enhanced autophagy in hypertrophic hearts, which was accompanied by a decrease in heart size, cardiac apoptosis, and the attenuation of cardiac dysfunction. Furthermore, use of autophagy inhibitor 3-methyladenine (3-MA) blocked berberine-induced autophagy level, and abrogated the protection of berberine against heart hypertrophy, cardiac dysfunction, and apoptosis. Berberine ameliorated TAC-induced endoplasmic reticulum stress, which was also abolished by 3-MA. Moreover, berberine significantly inhibited the upstream signaling of autophagy, such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) phosphorylation. We conclude that berberine could attenuate left ventricular remodeling and cardiomyocyte apoptosis through an autophagy-dependent mechanism in a rat model of cardiac hypertrophy, which is, at least in part, associated with enhanced autophagy through inhibition of mTOR, p38 and ERK1/2 MAPK signaling pathways.

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