Apixaban and risk of myocardial infarction: meta-analysis of randomized controlled trials

The coagulation system contributes greatly to the evolution of myocardial infarction (MI). Anticoagulation may reduce the occurrence of MI as monotherapy or with con- comitant use of aspirin. Activated factor X antagonists (anti- Xa) and direct thrombin inhibitors have promising results in various indications in non-inferiority trials. However, results regarding their cardiovascular safety are heterogeneous. We systematically evaluated the risk of MI and mortality in patients receiving the new-generation oral anti-Xa agent apixaban. Electronic databases were searched to find pro- spective, randomized, controlled clinical trials (RCT) that evaluated the clinical impact of apixaban. Efficacy measures included frequency of MI, cardiovascular and overall mor- tality. Outcome parameters of RCTs were pooled with a ran- dom-effects model. Between January 2000 and December 2013, 12 RCTs comprising 54,054 patients were identified. Based on the pooled results, there was no increase in the risk of MI in patients treated with apixaban [odds ratio (OR) 0.90;95 % confidence interval (CI) 0.77–1.05; p = 0.17] com- pared to different controls. Cardiovascular and overall mor- tality with apixaban was comparable to the control groups (OR 0.88; 95 % CI 0.72–1.06; p = 0.18, OR 0.89; 95 % CI 0.77–1.03; p = 0.11, respectively). The pooled risk of major bleeding was lower in the apixaban treated groups (OR 0.84; 95 % CI 0.62–1.12; p = 0.23) however this reached signifi- cant level only in subgroup analysis of trials with anticoagu- lant regimes in the control (OR 0.66; 95 % CI 0.51–0.87; p = 0.003). In a broad spectrum of patients and compared to different controls apixaban treatment was not associated with an increase in MI or mortality

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

Pulmonary arterial hypertension (PH) is associated with high mortality due to right ventricular failure and hypoxia, therefore to understand the mechanism by which pulmonary vascular remodeling initiates these processes is very important. We used a well-characterized monocrotaline (MCT)-induced rat PH model, and analyzed lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, and phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-κB activation in order to elucidate the mechanisms by which sildenafil's protective effect in PH is exerted. Besides its protective effect on lung morphology, sildenafil suppressed multiple cytokines involved in neutrophil and mononuclear cells recruitment including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α/β, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1α, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, and MIP-3α. NF-κB activation and phosphorylation were also attenuated by sildenafil. Furthermore, sildenafil reduced extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation while enhanced activation of the cytoprotective Akt pathway in PH. These data suggest a beneficial effect of sildenafil on inflammatory and kinase signaling mechanisms that substantially contribute to its protective effects, and may have potential implications in designing future therapeutic strategies in the treatment of pulmonary hypertension

Clinical outcomes in patients treated for coronary in-stent restenosis with drug-eluting balloons: Impact of high platelet reactivity.

BACKGROUND: The impact of high platelet reactivity (HPR) on clinical outcomes after elective percutaneous coronary interventions (PCI) with drug-eluting balloons (DEB) due to in-stent restenosis (ISR) is unknown. OBJECTIVE: We sought to evaluate the prognostic importance of HPR together with conventional risk factors in patients treated with DEB. METHODS: Patients treated with DEB due to ISR were enrolled in a single-centre, prospective registry between October 2009 and March 2015. Only patients with recent myocardial infarction (MI) received prasugrel, others were treated with clopidogrel. HPR was defined as an ADP-test >46U with the Multiplate assay and no adjustments were done based on results. The primary endpoint of the study was a composite of cardiovascular mortality, MI, any revascularization or stroke during one-year follow-up. RESULTS: 194 stable angina patients were recruited of whom 90% were treated with clopidogrel. Clinical characteristics and procedural data were available for all patients; while platelet function testing was performed in 152 subjects of whom 32 (21%) had HPR. Patients with HPR had a higher risk for the primary endpoint (HR: 2.45; CI: 1.01-5.92; p = 0.03). The difference was primarily driven by a higher risk for revascularization and MI. According to the multivariate analysis, HPR remained a significant, independent predictor of the primary endpoint (HR: 2.88; CI: 1.02-8.14; p = 0.04), while total DEB length and statin treatment were other independent correlates of the primary outcome. CONCLUSION: HPR was found to be an independent predictor of repeat revascularization and MI among elective patients with ISR undergoing PCI with DEB

Baseline characteristics of the patient population.

<p>Baseline characteristics of the patient population.</p

Results of the platelet function test, frequency of high platelet reactivity and its relation to clinical endpoints.

<p><b>A:</b> A scatter plot of platelet reactivity with the Multiplate device in all patients. Values are presented as median {25% percentile, 75% percentile}, ADP reactivity presents as U. <b>B:</b> Percent of the platelet function tested cases with percent of HPR and no HPR patients in the total cohort based on the platelet reactivity values. <b>C:</b> Impact of platelet reactivity on MACE. <b>D:</b> Impact of platelet reactivity on MI. Values are presented as HR [95% CI]. *: asterisk marks hazard ratios from multivariate Cox regression analyses. ADP = adenosine diphosphate; AUC = area under the curve; HPR = high platelet reactivity; MACE = major adverse cardiovascular event; MI = myocardial infarction; HR = hazard ratio; CI = confidence interval.</p

Clinical and procedural predictors of MACE at one year.

<p>Clinical and procedural predictors of MACE at one year.</p

Event free survival of the patients based on the platelet reactivity during the follow up period.

<p><b>A:</b> Event free survival of the patients with and without HPR based on the consensus cut-off value. <b>B, C:</b> Event free survival of the patients based on the ROC curve analysis identified two potential cut-off values. Event rates at one year are shown for each group as Kaplan-Meier estimates. HPR = high platelet reactivity; ADP = adenosine diphosphate.</p

Clinical outcomes in the patient population and stratified according to the platelet reactivity.

<p>Clinical outcomes in the patient population and stratified according to the platelet reactivity.</p