Transcatheter or surgical aortic-valve replacement in intermediate-risk patients

BACKGROUND: Previous trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aorticvalve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients. METHODS: We randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort. RESULTS: The rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan–Meier event rates were 19.3% in the TAVR group and 21.1% in the surgery group (hazard ratio in the TAVR group, 0.89; 95% confidence interval [CI], 0.73 to 1.09; P=0.25). In the transfemoralaccess cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P=0.05), whereas in the transthoracic-access cohort, outcomes were similar in the two groups. TAVR resulted in larger aortic-valve areas than did surgery and also resulted in lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; surgery resulted in fewer major vascular complications and less paravalvular aortic regurgitation. CONCLUSIONS: In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313

Widespread Myocardial Delivery of Heart-Derived Stem Cells by Nonocclusive Triple-Vessel Intracoronary Infusion in Porcine Ischemic Cardiomyopathy: Superior Attenuation of Adverse Remodeling Documented by Magnetic Resonance Imaging and Histology.

Single-vessel, intracoronary infusion of stem cells under stop-flow conditions has proven safe but achieves only limited myocardial coverage. Continuous flow intracoronary delivery to one or more coronary vessels may achieve broader coverage for treating cardiomyopathy, but has not been investigated. Using nonocclusive coronary guiding catheters, we infused allogeneic cardiosphere-derived cells (CDCs) either in a single vessel or sequentially in all three coronary arteries in porcine ischemic cardiomyopathy and used magnetic resonance imaging (MRI) to assess structural and physiological outcomes. Vehicle-infused animals served as controls. Single-vessel stop-flow and continuous-flow intracoronary infusion revealed equivalent effects on scar size and function. Sequential infusion into each of the three major coronary vessels under stop-flow or continuous-flow conditions revealed equal efficacy, but less elevation of necrotic biomarkers with continuous-flow delivery. In addition, multi-vessel delivery resulted in enhanced global and regional tissue function compared to a triple-vessel placebo-treated group. The functional benefits after global cell infusion were accompanied histologically by minimal inflammatory cellular infiltration, attenuated regional fibrosis and enhanced vessel density in the heart. Sequential multi-vessel non-occlusive delivery of CDCs is safe and provides enhanced preservation of left ventricular function and structure. The current findings provide preclinical validation of the delivery method currently undergoing clinical testing in the Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial of CDCs in heart failure patients

Impact of right ventricle-pulmonary artery coupling on clinical outcomes in the PARTNER 3 trial

BACKGROUND Physiologic right ventricle–pulmonary artery (RV-PA) coupling may be impaired in patients with aortic stenosis (AS). OBJECTIVES This study aimed to assess the incidence and prognostic significance of impaired RV-PA coupling in low-risk patients with symptomatic severe AS undergoing transcatheter aortic valve replacement or surgical aortic valve replacement. METHODS RV-PA coupling was measured by transthoracic echocardiography as the ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP) in patients in the PARTNER (Placement of Aortic Transcatheter Valve) 3 trial. The primary endpoint was the composite of all-cause mortality, stroke, and rehospitalization at the 2-year follow-up. RESULTS Among 570 low-risk patients included in the analysis, RV-PA uncoupling was defined by a TAPSE/PASP ratio ≤ 0.55 mm/mm Hg. At baseline, 222 of 570 (38.9%) patients had RV-PA uncoupling. At 2 years, patients with baseline RV-PA uncoupling had an increased incidence of the primary endpoint (19.1% vs 9.9%, P = 0.002), all-cause mortality (5.9% vs 0.6%, P < 0.001), cardiovascular mortality (4.1% vs 0.6%, P = 0.003), and rehospitalization (13.5% vs 7.3%, P = 0.018). On multivariable analysis, baseline RV-PA uncoupling remained an independent predictor of the primary endpoint at 2 years (HR: 1.92; 95% CI: 1.04-3.57; P = 0.038). CONCLUSIONS In patients with symptomatic severe AS at low surgical risk undergoing transcatheter aortic valve replacement or surgical aortic valve replacement, baseline RV-PA uncoupling defined by TAPSE/PASP ≤ 0.55 mm Hg was associated with adverse clinical outcomes at 2 years, including all-cause mortality, cardiovascular mortality, and rehospitalization

Design and rationale of the XIENCE short DAPT clinical program: An assessment of the safety of 3-month and 1-month DAPT in patients at high bleeding risk undergoing PCI with an everolimus-eluting stent

Dual antiplatelet therapy (DAPT) is key for the prevention of recurrent ischemic events after percutaneous coronary intervention (PCI); however, it increases the risk of bleeding complications. While new generation drug-eluting stents have been shown superior to bare-metal stents after a short DAPT course, the optimal DAPT duration in patients at high bleeding risk (HBR) remains to be determined. TRIAL DESIGN: The XIENCE Short DAPT program consists of three prospective, single-arm studies (XIENCE 90, XIENCE 28 Global and XIENCE 28 USA) investigating 3- or 1-month DAPT durations in HBR patients undergoing PCI with the XIENCE stent. The XIENCE 90 study is being conducted in the US and enrolled 2047 subjects who discontinued DAPT at 3 months if they were free from myocardial infarction (MI), repeat coronary revascularization, stroke, or stent thrombosis. The XIENCE 28 program includes the USA study, enrolling 642 patients in US and Canada, and the Global study, enrolling 963 patients in Europe and Asia. In XIENCE 28, patients were to discontinue DAPT at 1 month post-PCI if event-free. The primary hypothesis for both XIENCE 90 and XIENCE 28 is that a short DAPT regimen will be non-inferior to a conventional DAPT duration with respect to the composite of all-cause death or MI. Patients enrolled in the prospective multicenter post-market XIENCE V USA study will be used as historical control group in a stratified propensity-adjusted analysis. CONCLUSIONS: The XIENCE Short DAPT Program will provide insights into the safety and efficacy of 2 abbreviated DAPT regimens of 3- and 1-month duration in a large cohort of HBR patients undergoing PCI with the XIENCE stent

Vessel density and cardiomyocyte hypertrophy.

<p><b>A</b>. Representative immunostaining sections with sma, isolectin B4 and DAPI, 1 month post treatment. <b>B</b>. Vessel density within the IZ (p = 0.05), <b>C</b>., the BZ and <b>D</b>., the RZ in the CDC-treated compared to placebo (Scale bar = 75μm). <b>E</b>. Representative sections immunostained with α-sa and WGA. <b>F., G</b>. Similar cardiomyocyte diameters in all three groups, both in the BZ and in the RZ. Scale bar = 50μm. Abbreviations: IZ, infarct zone; BZ, border zone; RZ, remote zone; sma, smooth muscle actin (red); isolectin B4 (green); DAPI, blue, 4',6-diamidino-2-phenylindole; asa, α-sarcomeric actinin; WGA, wheat germ agglutinin to define the cell borders. Error bars indicate SEM.</p

MRI results in triple-vessel protocol.

<p><b>A</b>. Representative baseline (upper row) and 1 month post-infusion (lower row) short-axis images in all three groups highlighting the decrease in the scar size and the scar thickness. Yellow arrowheads indicate the infarct zone borders. <b>B</b>. Ejection fraction (EF) decreased significantly in the placebo group compared to both CDC-treated groups (p = 0.1 placebo vs CDCs stop-flow and p = 0.05 placebo vs CDCs continuous-flow). <b>C., D., E</b>. Changes in end-systolic and end-diastolic volumes and in scar mass in the treated groups compared to placebo. <b>F</b>. Infarct wall thickening (p = 0.01 placebo vs CDCs stop-flow and p = 0.05 placebo vs CDCs continuous-flow) and <b>G</b>., infarct wall thickness (p = 0.1 placebo vs CDCs stop-flow and p<0.01 placebo vs CDCs continuous-flow) in the placebo compared to both treated groups. Error bars indicate SEM. * p<0.05, ** p<0.01</p

Multi-vessel study design and safety.

<p><b>A</b>. Timeline of the study. <b>B</b>., Allogeneic CDC isolation and manufacturing from 2 male donor hearts resulted in a master cell bank and bags of frozen CDCs. <b>C</b>. Effects of cryopreservation on CD105 and CD45 expression of CDCs. <b>D., E., F</b>. TIMI flow post-infusion in each vessel. <b>G., H</b>. TnI bump (7.4ng/ml) was observed at 24hrs in one animal after the stop-flow protocol. Error bars indicate SEM. Abbreviations: MI, myocardial infarction; CDCs, cardiosphere-derived cells; MRI, magnetic resonance imaging; LAD: left anterior descending artery.</p

Single-vessel Study.

<p><b>A</b>. Illustration of stop-flow protocol and <b>B</b>., the continuous-flow protocol. <b>C, D</b>. Box Plots showing serum [TnI] before infusion and 24hrs post infusion (p = ns; normal <0.05ng/ml). <b>E</b>. Short-axis contrast-enhanced images at baseline and 4 weeks after CDC or vehicle infusion showing <b>F</b>. significant changes of ejection fraction in placebo versus either treated group (p = 0.03 placebo vs CDCs stop-flow and p<0.01 placebo vs CDCs continuous-flow). <b>G</b>. Changes in end-systolic volume between baseline and 4 weeks post-infusion (p = 0.02 placebo vs CDCs stop-flow and p = 0.05 placebo vs CDCs continuous-flow), and <b>H</b>., in end-diastolic volume (p = 0.06 placebo vs CDCs stop-flow and p = 0.2 placebo vs CDCs continuous-flow). Changes in scar mass (<b>I</b>, p = 0.08 placebo vs CDCs stop-flow and p<0.01 placebo vs CDCs continuous-flow), <b>J</b>., infarct wall motion (p = 0.04 placebo vs CDCs stop-flow and p = 0.02 placebo vs CDCs continuous-flow) and <b>K</b>., infarct wall thickness between placebo and treated groups (p = ns). Error bars indicate SEM. * p<0.05, ** p<0.01</p

Structure-function correlations.

<p><b>A</b>. Representative 2,3,5-triphenyltetrazoliumchloride (TTC) sections covering the LV chamber from the apex to the base from all three groups tested. The blue arrowhead indicates the section level that corresponds to the MR images in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144523#pone.0144523.g003" target="_blank">3</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144523#pone.0144523.g004" target="_blank">4</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144523#pone.0144523.g005" target="_blank">5</a>. <b>B</b>. Correlation between the scar mass (g) evaluated separately by LGE images (JD) and by TTC staining (ET). <b>C</b>. Representative tagged CMR images with infarct zone (IZ) defined by the presence of enhancing myocardium, neighboring myocardium as border zone (BZ), and normal myocardium as remote zone (RZ) for the analysis of regional strain, highlighting the contractility differences among the groups. Blue arrowheads indicate the RV insertion and the location of the first segment of each map. <b>D., E., F</b>. Representative diagrams of the averaged strain included in the analysis (the more negative, the greater the contractility). <b>G</b>. Better contractility was observed in the CDC-treated group compared to the placebo. <b>H</b>. Trend towards better effect of CDC therapy on mid-ventricular wall synchrony assessed by CURE ratio. Error bars indicate SEM. * p<0.05, ** p<0.01</p