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Aims ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). In this study, we sought to evaluate the effect of anakinra, a recombinant interleukin-1 receptor antagonist, on the incidence of HF. Methods and results We performed a pooled analysis of three early phase randomized clinical trials. The endpoints included the composite of all-cause death and new-onset HF, and the composite of all-cause death and hospitalization for HF at 1-year follow-up. Safety events, including injection site reaction and serious infections, were also recorded. We analysed 139 patients with STEMI from three separate trials: VCUART (N = 10), VCUART2 (N = 30), and VCUART3 (N = 99). Of these, 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. Treatment with anakinra significantly reduced the incidence of all-cause death or new-onset HF (7 [8.2%] vs. 16 [29.1%], log-rank P = 0.002) and of all-cause death or HF hospitalization (0 [0] vs. 5 [9.1%], log-rank P = 0.007). Patients treated with anakinra had significantly higher injection site reactions (19 [22.6%] vs. 3 [5.5%], P = 0.016) without a significant difference in the incidence of serious infections (11 [13.1%] vs. 7 [12.7%], P = 0.435). Treatment with anakinra significantly reduced the area under the curve for high-sensitivity C-reactive protein between baseline and 14 days (75.48 [41.7–147.47] vs. 222.82 [117.22–399.28] mg day/L, P Conclusion IL-1 blockade with anakinra for 14 days in patients with STEMI reduces the incidence of new-onset HF or hospitalization for HF at 1 year following STEMI.

Background ST segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). We analyzed the effect of recombinant interleukin-1 receptor antagonist (anakinra) 100 mg subcutaneous injection given once or twice daily for 14 days on the occurrence of HF in a pooled analysis of 3 clinical trials. Methods Enrollment criteria and study procedures were the same across the three studies. High-sensitivity C-reactive protein (CRP) was measured at baseline, 72 hours, and 14 days to construct an area under the curve (AUC0–14). Clinical events up to 1 year were adjudicated by an independent committee blinded to treatment allocation. Data for anakinra once daily and anakinra twice daily were pooled into a single anakinra group. CRP data are presented as median and interquartile range to allow for deviation from Gaussian distribution and non-parametric tests were used to evaluate differences between groups. Kaplan-Meier survival analyses were conducted and the intervention groups were compared using a log-rank test. Results Between 2008 and 2017, 139 patients with STEMI were enrolled. 84 patients were randomized to anakinra and 55 patients were randomized to placebo. Anakinra significantly reduced the CRP AUC0–14 (76 [42–147] vs 222 [117–339] mg*day/L; P Conclusions Treatment with anakinra for 14 days following STEMI blunts the inflammatory response and appears to reduce the occurrence of HF events at 1 year. These results support the hypothesis that early and targeted modification of the inflammatory response in STEMI may be a viable strategy to improve patient outcomes. Adjudicated events at 1 year Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Heart Lung and Blood Institute (USA), American Heart Association (USA)

Background ST ‐segment–elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin‐1 blockade with anakinra significantly reduced the area under the curve for hsCRP (high sensitivity C‐reactive protein) levels during the first 14 days in patients with ST ‐segment–elevation myocardial infarction (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods and Results We conducted a randomized, placebo‐controlled, double‐blind, clinical trial in 99 patients with ST ‐segment–elevation myocardial infarction in which patients were assigned to 2 weeks treatment with anakinra once daily (N=33), anakinra twice daily (N=31), or placebo (N=35). hsCRP area under the curve was significantly lower in patients receiving anakinra versus placebo (median, 67 [interquartile range, 39–120] versus 214 [interquartile range, 131–394] mg·day/L; P P =0.21) or left ventricular ejection fraction (median, 3.9% [interquartile range, −1.6% to 10.2%] versus 2.7% [interquartile range, −1.8% to 9.3%]; P =0.61) at 12 months. The incidence of death or new‐onset heart failure or of death and hospitalization for heart failure was significantly lower with anakinra versus placebo (9.4% versus 25.7% [ P =0.046] and 0% versus 11.4% [ P =0.011], respectively), without difference between the anakinra arms. The incidence of serious infection was not different between anakinra and placebo groups (14% versus 14%; P =0.98). Injection site reactions occurred more frequently in patients receiving anakinra (22%) versus placebo (3%; P =0.016). Conclusions In patients presenting with ST ‐segment–elevation myocardial infarction, interleukin‐1 blockade with anakinra significantly reduces the systemic inflammatory response compared with placebo. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 01950299.

There is clear association between the intensity of the acute inflammatory response during acute myocardial infarction (AMI) and adverse prognosis after AMI. Interleukin‐1 (IL‐1) is a pro‐inflammatory cytokine released during AMI and involved in adverse remodeling and heart failure (HF). We describe a study to evaluate the safety and efficacy of IL‐1 blockade using an IL‐1 receptor antagonist (anakinra) during the acute phase of ST‐segment elevation myocardial infarction (STEMI). The Virginia Commonwealth University–Anakinra Remodeling Trial‐3 (VCU‐ART3; http://www.ClinicalTrials.gov NCT01950299) is a phase 2, multicenter, double‐blinded, randomized, placebo‐controlled clinical trial comparing anakinra 100 mg once or twice daily vs matching placebo (1:1:1) for 14 days in 99 patients with STEMI. Patients who present to the hospital with STEMI within 12 hours of symptom onset will be eligible for enrollment. Patients will be excluded for a history of HF (functional class III–IV), severe valvular disease, severe kidney disease (stage 4–5), active infection, recent use of immunosuppressive drugs, active malignancy, or chronic autoimmune/auto‐inflammatory diseases. We will measure the difference in the area under the curve for C‐reactive protein between admission and day 14, separately comparing each of the anakinra groups with the placebo group. The P value will be considered significant if

Evidence now indicates that inflammation contributes considerably to the initiation and progression of atherosclerosis and active inflammatory processes may trigger plaque rupture and enhance the risk of coronary thrombosis leading to a clinical ischemic event. Interest in characterizing inflammatory markers that predict clinical events have dominated clinical investigation. Such markers include C-reactive protein, Fibrinogen and a number of interleukins. Human macrophages avidly phagocytize cholesterol crystals. These cholesterol crystals induce a dose-dependent secretion of mature Interleukin 1-beta (IL-1β) from human monocytes and macrophages (an NLRP3 inflammasome-mediated pathway). Since IL-1β production leads to increased levels of IL-6 and C-reactive protein, this could be a mechanistic link between early deposition of cholesterol crystals within the vessel wall to the macrophage–monocyte interactions that initiate fatty streaks and promote local atherosclerotic progression. We have entered a time where a pure anti-inflammatory drug without significant effects on lipids or any other traditional cardiovascular risk factor decreased cardiovascular events. Patients with autoimmune diseases are at increase cardiovascular risk. In this review we describe the link between inflammation and atherosclerosis. Furthermore we explore the data regarding primary prevention, cardiac imaging for risk stratification and the implications of targeting inflammation in patients with autoimmune disease.

Permanent pacemaker (PPM) implantation remains common after transcatheter aortic valve implantation (TAVI). Invasive electrophysiology studies (EPSs) may reduce PPM implantation rates by identifying patients who do not require long-term pacing. At our institution, a new strategy in which patients with equivocal indications for pacing underwent EPSs to determine the need for PPM implantation was adopted. We compared baseline demographics, TAVI procedural details, and outcomes in patients without any conduction disturbance after TAVI, patients with new PPM implantation, and patients with EPS ± new PPM implantation. After exclusion for preexisting PPMs, of a total of 614 consecutive TAVI patients, 117 (19.1%) required new PPM implantation for unequivocal pacing indications, and 95 (15.5%) underwent EPSs. Of those patients who underwent EPSs, 28 (29.5%) required PPM implantation and 67 (70.5%) did not. The overall rate of new PPM implantation was higher for self-expanding versus balloon-expandable valves (34.0% vs 19.9%, p = 0.0011). PPM implantation increased intensive care and hospital length of stay compared with patients without any conduction disturbance (10.7 ± 8.3 vs 8.5 ± 6.4 days, p = 0.003). A negative EPS did not prolong length of stay. There were no significant differences in 30-day and 1-year mortality between groups. In conclusion, among TAVI patients with new-onset conduction disturbance, EPS is a safe strategy to identify those who require PPM implantation and those in whom PPMs can be avoided.

Patients at high bleeding risk (HBR) are at increased risk of bleeding following percutaneous coronary intervention (PCI) with drug-eluting stents (DES) due to the need for longer dual antiplatelet duration. We sought to evaluate the likelihood of receiving DES during PCI in HBR populations and to characterize DES utilization trends over time. Consecutive patients who underwent PCI from April 2003 to September 2015 were identified. HBR is defined as patients fulfilling 1 or more of the HBR criteria: age ≥75 years, anticoagulation use at discharge, history of stroke, cancer in previous 3 years, glucocorticoid use, hemoglobin (Hgb) 3 , or creatinine clearance (CCr)

Rationale: Virtually all mesenchymal stem cell (MSC) studies assume that therapeutic effects accrue from local myocardial effects of engrafted MSCs. Because few intravenously administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm. Objective: To test whether intravenously administered MSCs reduce left ventricular (LV) dysfunction both post–acute myocardial infarction and in ischemic cardiomyopathy and that these effects are caused, at least partly, by systemic anti-inflammatory activities. Methods and Results: Mice underwent 45 minutes of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O 2 , were administered intravenously. LV function was assessed by serial echocardiography, 2,3,5-triphenyltetrazolium chloride staining determined infarct size, and fluorescence-activated cell sorting assessed cell composition. Fluorescent and radiolabeled MSCs (1×10 6 ) were injected 24 hours post–myocardial infarction and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2×10 6 MSCs or saline intravenously 24 hours post–myocardial infarction (n=16 per group). At day 21, we harvested blood and spleens for fluorescence-activated cell sorting and hearts for 2,3,5-triphenyltetrazolium chloride staining. Adverse LV remodeling and deteriorating LV ejection fraction occurred in control mice with large infarcts (≥25% LV). Intravenous MSCs eliminated the progressive deterioration in LV end-diastolic volume and LV end-systolic volume. MSCs significantly decreased natural killer cells in the heart and spleen and neutrophils in the heart. Specific natural killer cell depletion 24 hours pre–acute myocardial infarction significantly improved infarct size, LV ejection fraction, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post–myocardial infarction were randomized to tail-vein injection of 2×10 6 MSCs, with injection repeated at week 3 (n=16) versus PBS control (n=16). MSCs significantly increased LV ejection fraction and decreased LV end-systolic volume. Conclusions: Intravenously administered MSCs for acute myocardial infarction attenuate the progressive deterioration in LV function and adverse remodeling in mice with large infarcts, and in ischemic cardiomyopathy, they improve LV function, effects apparently modulated in part by systemic anti-inflammatory activities.

With steady growth in the use of drug-eluting stents (DES), the indications for bare metal stents (BMS) have significantly changed over the last decade. This study aims to describe trends in the use of BMS and the evolution of the population receiving them over the past 10 years and determine patient characteristics associated with using BMS. Consecutive patients who underwent percutaneous coronary intervention (PCI) at the Washington Hospital Center from January 2005 through March 2015 were included. Baseline characteristics and inhospital outcomes of patients who underwent PCI with BMS versus DES were compared during 2 different time periods: from 2005 to 2010 and from 2011 to 2015. Multivariable analyses were performed for each period of time to determine independent variables associated with the choice of BMS rather than DES; 20,321 patients who underwent PCI were included in the present study. The mean age was 65.0 ± 12.5 years, 65.2% were men, and 30.4% were black. BMS use peaked in 2007 (47%) but has fallen steadily since; BMS accounted for only 10% of stents used in 2015. Presentation with acute coronary syndrome or cardiogenic shock was more common in patients receiving a BMS; this was reflected in higher rates of inhospital mortality and major bleeding among patients receiving BMS versus DES. Covariables independently associated with receiving a BMS common to both time periods included black race, Hispanic ethnicity, cardiogenic shock or acute coronary syndrome, oral anticoagulation, current smoking, increasing age, lower hematocrit, and history of chronic renal insufficiency. In conclusion, there has been a precipitous decline in the use of BMS over the last decade. Newer stent technology that promises shorter duration of dual antiplatelet therapy is likely to lead to the extinction of BMS over the next decade.

Right ventricular (RV) dysfunction was shown to be associated with adverse outcomes in a variety of cardiac patients and is considered a risk factor for adverse outcome according to the updated Valve Academic Research Consortium criteria.Our goal was to assess the impact of RV function at baseline on 1-year mortality among patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR).All patients with severe AS treated with TAVR from May 2007 to March 2015 at our center were included in the present study, and baseline and procedural characteristics were recorded for each patient. The patients were categorized according to RV function at baseline as assessed by current guidelines, and a comparison of mortality rates up to 1 year was performed.Among 650 patients, 606 had adequate echocardiogram quality and 146 (24%) had RV dysfunction. There were significant differences between the 2 groups, as patients with RV dysfunction were younger (81±9 vs 84±7 years, P=.01) and were more likely to be male (65% vs 42%, P.001). In addition, patients with RV dysfunction had higher rates of prior myocardial infarction (26% vs 16%, P=.02) and atrial fibrillation (51% vs 39%, P=.02). Echocardiographic parameters demonstrated higher rates of left ventricular ejection fraction40% (40% vs 18%, P.001), tricuspid regurgitation above moderate (16% vs 9%, P=.04), and higher pulmonary artery systolic pressure (50±17 vs 44±16 mm Hg, P.001) among patients with severe AS and RV dysfunction compared with patients with normal RV function. Despite the unfavorable cardiac function, patients with severe AS undergoing TAVR have similar functional class (P=.22) and mortality rates at 1year (27% vs 23%, log-rank P=.45).Patients with severe AS and RV dysfunction have similar 1-year mortality and functional class after TAVR to patients with normal RV function. The presence of RV dysfunction does not correlate with outcome in patients with severe AS.

Rationale: Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role. Objective: To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy. Methods and Results: This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ≤40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×10 6 cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98–66.97; P =0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70–9.74; P =0.02) and functional status scores (+5.65, 95% confidence interval −0.11 to 11.41; P =0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction. Conclusions: In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02467387.

Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response further promoting cardiac dysfunction and heart failure (HF). Pilot proof-of-concept studies with anakinra, recombinant Interleukin-1 (IL-1) receptor antagonist, have shown feasibility and safety of IL-1 blockade in patients with STEMI. In the current study we analyzed the effects of anakinra on left ventricular (LV) dimensions and function in patients with STEMI. Methods We enrolled patients with STEMI within 12 hours of presentation at 3 sites in the United States of America. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily alternated with placebo once daily every 12 hours, or placebo twice daily, for 14 days in a 1:1:1 ratio. A transthoracic echocardiogram was completed within 24 hours of admission and at 1 year follow up to measure LV end-diastolic and end-systolic volumes (LVEDV and LVESV, respectively), stroke volume (SV) and ejection fraction (LVEF). (ClinicalTrials NCT01950299) Results Paired echocardiography studies (follow up study obtained 362 days [336–375] after the baseline study) were available in 63 of the 99 patients (63%): 23 of 35 patients in the placebo group (66%) and 40 of the 64 patients in the anakinra group (62%, P>0.05 for missing studies between the 2 groups; P>0.05 for duration of follow up). Baseline LVEDV, LVESV, SV and LVEF was not significantly different comparing placebo and anakinra (all P>0.05). Patients treated with anakinra had a significant improvement in LVEF from 49.8% (41.8–60.0%) to 54.0% (46.0–58.4%, P=0.028) and SV from 43.6 ml (37.6–52.1 ml) to 48.7 ml (40.9–62.5 ml, P=0.008), whereas no significant changes occurred within the placebo group (LVEF: from 51.7% [40.1–56.0%] to 53.5% [43.4–59.4%], P=0.25; SV: from 47.7 ml [40.1–56.8 ml], to 53.0 ml [44.9–57.4 ml], P=0.81). The between-groups differences, however, were not statistically significant. No significant changes were noted in LVEDV and LVESV in either group. The interval changes in CRP between admission and 72 hours, expression of the acute inflammatory response, inversely correlated with the LVEF at follow up (R=-0.30, P=0.026), with higher levels of CRP corresponding to lower LVEF values Conclusions A significant improvement in cardiac systolic function was seen in patients treated with IL-1 receptor antagonist, anakinra, following STEMI, and not in patients with placebo. Further studies are however required to determine whether the benefits of IL-1 blockade in the prevention and treatment of HF are mediated by the effects on cardiac function. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply from Swedish Orphan Biovitrum

Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of recurrent ischemic events. Prior studies of IL-1 blockade have shown conflicting results regarding the risk of future events. Methods We enrolled patients with STEMI within 12 hours of presentation at 3 sites in the United States of America. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily (standard dose) alternated with placebo once daily every 12 hours, or placebo every 12 hours for 14 days in 1:1:1 ratio. Prespecified exploratory endpoints for recurrent ischemic events, adjudicated by an independent committee, evaluated the composite risk of subsequent acute myocardial infarction (AMI, World Health Organization classification Type 1), unstable angina, or urgent revascularization. Data are expressed as median and interquartile range or number and percentage. Cox regression analysis was used to generate unadjusted hazard ratios and confidence intervals. (ClinicalTrials.gov number, NCT01950299) Results Of 311 patients screened, 99 subjects (81% males, 58% Caucasians, 55 [49–62] years of age) were randomly assigned to anakinra twice daily (N=31), anakinra once daily (N=33) or placebo (N=35). The cohort included patients with hypertension (57%), tobacco use (55%), diabetes mellitus (30%), and prior diagnosis of coronary artery disease (21%) without statistically significant imbalances in the demographic characteristics between groups (all P>0.05). Discharge medications for the index STEMI admission, in addition to the study medication, included aspirin (100%), statins (100%), P2Y12 inhibitors (100%), beta-blockers (90%), and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (84%), without statistically significant imbalances between the 3 groups. Over the 1-year follow-up, recurrent ischemic events occurred in 5/35 (14.3%) patients treated with placebo and 6/64 (9.1%) patients treated with anakinra (hazard ratio = 0.68 [0.20–2.24], P=0.53). No differences were observed between high- and low-dose anakinra treatment groups. Conclusions A two week treatment with IL-1 receptor antagonist, anakinra, did not significantly decrease or increase recurrent ischemic events over the course of a 1-year follow-up in patients with STEMI. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply by Swedish Orphan Biovitrum

Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense inflammatory response that predicts an increased risk of death and heart failure (HF). In the current study we tested whether anakinra, a recombinant Interleukin-1 (IL-1) receptor antagonist, given once daily (standard dose) or twice daily reduced systemic inflammation in patients with STEMI. Methods We enrolled patients with STEMI within 12 hours of presentation at 3 sites. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily alternating with placebo once daily every 12 hours, or placebo twice daily, for 14 days in a 1:1:1 ratio. The primary efficacy outcome was the area under the curve for C-reactive protein levels (CRP-AUC) using a high-sensitivity assay at 14 days comparing anakinra (both arms) versus placebo followed by a comparison between each of the anakinra arms with placebo. Two pre-specified exploratory clinical efficacy endpoints, adjudicated by a blinded event committee, were assessed: a composite endpoint of all-cause death for any reason or incidence of HF (defined as new-onset HF requiring hospitalization or a new prescription of a loop diuretic, D+HF) and a composite endpoint of death and HF hospitalization (D+HHF) at 1 year. Data are expressed as median and interquartile range or number and percentage. Kaplan-Meyer survival curves were compared using Log-rank test (Mantel-Cox). (ClinicalTrials.gov number, NCT01950299) Results Of 311 patients screened, 99 subjects (80 [81%] males, 57 [58%] Caucasians, 55 [49–62] years of age) were randomly assigned to anakinra twice daily (N=31), anakinra once daily (N=33) or placebo (N=35). There were no significant imbalances in the demographic characteristics between groups (all P>0.05). The CRP-AUC was significantly lower in the anakinra group than in the placebo group (67 [39–120] versus 214 [131–394] mg/dl, P Conclusions Among patients with STEMI, IL-1 blockade significantly reduced the systemic inflammatory response compared with placebo, without any significant difference between standard or high dose regimens. Prespecified exploratory analyses on clinical endpoints demonstrate reduced incidence of HF and reduced HF hospitalizations, supporting the concept of beneficial effects with IL-1 blockade in patients with acute myocardial infarction. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply from Swedish Orphan Biovitrum

Patients with diabetes mellitus are prone to increased adverse outcomes after percutaneous coronary intervention, even with contemporary drug-eluting stents. Randomized controlled trials have demonstrated comparable clinical outcomes between an ultrathin bioresorbable-polymer sirolimus-eluting stent (BP-SES) and a thin-strut durable-polymer everolimus-eluting stent (DP-EES) that has specific labeling for patients with diabetes. We aimed to evaluate the safety and efficacy of the BP-SES in patients with diabetes mellitus. To determine the performance of the BP-SES in diabetic patients, patient-level data from the BIOFLOW II, IV, and V randomized controlled trials were pooled. The primary end point was target lesion failure (TLF), defined as the composite of cardiovascular death, target-vessel myocardial infarction, ischemia-driven target lesion revascularization, and definite or probable stent thrombosis, at 1 year. Among 1,553 BP-SES and 791 DP-EES patients, 757 diabetic patients were identified. Of the diabetic patients included in this analysis (494 BP-SES vs 263 DP-EES), the proportion of insulin- and noninsulin-treated patients was similar between groups. The 1-year TLF rate in the diabetic population was 6.3% in the BP-SES group and 8.7% in the DP-EES group (hazard ratio 0.82, 95% confidence interval 0.047 to 1.43, p = 0.493). There were no significant differences, based on stent type or diabetes treatment regimen, in TLF hazards. In a patient-level pooled analysis of the diabetic population from randomized trials, 1-year clinical safety and efficacy outcomes were similar in patients treated with ultrathin BP-SES and thin-strut DP-EES.

Background/purpose Numerous GPIs are available for PCI. Although they were tested in randomized controlled trials, a comparison between the different GPI strategies is lacking. Thus, we performed a Bayesian network meta-analysis to compare different glycoprotein IIb/IIIa inhibitor (GPI) strategies with heparin and bivalirudin for percutaneous coronary intervention (PCI). Methods MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov were searched by two independent reviewers for randomized controlled trials comparing high-dose bolus tirofiban, abciximab, eptifibatide, heparin with provisional glycoprotein IIb/IIIa inhibitors, and bivalirudin with provisional GPI that reported clinical outcomes. Mixed treatment comparison model generation was performed to directly and indirectly compare between different anticoagulation strategies for all-cause mortality, myocardial infarction, major adverse cardiovascular events, major bleeding, minor bleeding, need for transfusion, and thrombocytopenia. Results A total of 41 randomized controlled trials with 38,645 patients were included in the analysis, among which 2654 were randomized to high-dose bolus tirofiban, 6752 to abciximab, 1669 to eptifibatide, 16,500 to heparin, and 11,070 to bivalirudin. Mean age was 64±11years, 75% were male, 91% were treated with stenting, 71% with clopidogrel, and 74% for acute coronary syndrome. High-dose bolus tirofiban was associated with a significant reduction in all-cause mortality compared with heparin (OR 0.57 [credible intervals 0.37, 0.9]) and eptifibatide (OR 0.44 [credible intervals 0.19, 1.0]). GPI regimens had less myocardial infarction and major adverse cardiovascular events but greater bleeding compared with heparin and bivalirudin. There was no difference among the GPI therapies for other outcomes, including myocardial infarction, major adverse cardiovascular events, and major bleeding. Conclusions Our network meta-analysis of 38,645 patients demonstrated that GPI regimens were associated with a reduction in recurrent myocardial infarction or major adverse cardiovascular events for PCI, while bivalirudin was associated with the lowest risk of bleeding.

Objective Comparison of transradial versus transfemoral access for complex percutaneous coronary intervention (PCI) with regard to both complications and long-term outcomes. Background Radial access has been shown to confer superior results in patients undergoing PCI, especially in patients with acute coronary syndromes. However, radial access has limitations of sheath and device size, which may increase procedure time and result in inferior outcomes. Methods Patients undergoing PCI for complex lesions, defined as type C according the ACC/AHA classification system, were included in this study. Propensity matching was performed to adjust for differences in baseline characteristics. Transradial patients were then compared to transfemoral patients in regard to procedural, in-hospital, and 6-month outcomes. Results Among 2142 patients with 2591 lesions treated, 1876 had femoral access and 267 had radial access. Radial access patients were more likely to be male (75% vs. 66%, P = 0.003) and less likely to present with acute myocardial infarction (27% vs. 42%, P

Purpose To report a case of a thrombosed GORE® VIABAHN® endoprosthesis stent-graft in the femoral artery (SFA) and popliteal artery managed using the pulse-spray technique and complicated by compartment syndrome of the lower leg of the affected limb. Case Report A 61-year-old woman with three Viabahn stent grafts relining seven bare-metal stents in her right SFA and popliteal artery visited our hospital with complaint of recurrent lifestyle-limiting claudication of right leg. Angiography and intravascular ultrasound showed complete intra-stent obstruction by thrombus from the proximal right SFA to the proximal popliteal artery. Catheter-directed thrombolysis using pulse-spray technique followed by mechanical thrombectomy was performed. Despite successful recanalization, unfortunately, compartment syndrome developed on her right leg on the following day and fasciotomy was performed. Conclusion The larger thrombus burden in Viabahn stent-grafts and its unique physicochemical properties increases the risk for distal embolic complications and potential poor clinical outcomes.

Although metallic coronary stents significantly reduce angina pectoris compared with optimal medical therapy, angina after percutaneous coronary intervention (PCI) remains frequent. We, therefore, sought to compare the incidence of any angina during the 1 year after PCI among the spectrum of commercially available metallic stents. Metallic stent type was classified as bare metal stent, Cypher, Taxus Express, Xience V, Promus Element, and Resolute. The primary end point was patient-reported angina within 1 year of PCI. Multivariable logistic regression was performed to assess the independent association of stent type with any angina at 1 year. Overall, 8,804 patients were queried in regard to angina symptoms; 32.3% experienced angina at some point in the first year after PCI. Major adverse cardiovascular events, a composite of all-cause mortality, target vessel revascularization, and Q-wave myocardial infarction, increased with angina severity: 6.8% for patients without angina, 10.0% for patients with class 1 or 2 angina, and 19.7% for patients with class 3 or 4 angina (p0.001 for trend). After multivariable adjustment, there was no significant association between stent type and angina at 1 year after PCI. Baseline Canadian Cardiovascular Society class 3 or 4 angina, history of coronary artery bypass grafting, and history of PCI were associated with a higher likelihood of angina at 1 year; increasing age, male gender, presentation with acute coronary syndrome, and higher stented length were associated with less angina. In conclusion, metallic stent type is not associated with the occurrence of angina at up to 1 year after PCI.

Background New oral anticoagulants (NOAC) and the Watchman device represent an alternative to warfarin for stroke prophylaxis in atrial fibrillation (AF) patients. However, no studies compare these new treatments. We performed a network meta-analysis to indirectly compare Watchman and NOACs among AF patients. Methods We performed a MEDLINE search for studies comparing warfarin with NOACs (dabigatran, rivaroxaban, apixaban and edoxaban) or Watchman in AF patients with reported clinical outcomes. Mixed treatment comparison model generation was performed to directly and indirectly compare NOACs, warfarin and Watchman. Results 14 studies with 246,005 patients were included in the analysis, among which 124,823 were treated with warfarin, 120,450 were treated with NOACs and 732 had Watchman implanted. Mean age was 72±9years, 53% were male, and mean CHADS2 score was 2.1±1.6. Both NOACs and Watchman were superior to warfarin in hemorrhagic stroke prevention (OR=0.46 [0.30–0.82] and OR=0.21 [0.05–0.99], respectively). NOACs significantly reduced total stroke (OR=0.78 [0.58–0.96]) and major bleeding (OR=0.78 [0.65–0.91]) compared with warfarin. Indirect comparison between NOAC and Watchman revealed no significant differences in outcomes, though there was a trend toward higher rates of ischemic stroke with Watchman compared with NOAC (OR 2.60 [0.60–13.96]) with the opposite findings with hemorrhagic stroke (OR=0.44 [0.09–2.14]). Conclusions NOAC therapy was superior to warfarin for multiple outcomes while Watchman reduced hemorrhagic stroke. Further studies are needed to assess Watchman versus NOAC to optimize therapy for stroke prevention in AF patients.

Objective We evaluate the prevalence of complications and failure rates between the most commonly used “active” anchoring vascular closure device (VCD), AngioSeal™ and the “passive” anchoring VCD, Mynx™, in all-comers undergoing percutaneous coronary intervention (PCI). Methods A total of 4,074 patients between 2008 and 2014, representing an era when both devices were available, were included. Thirty-two percent were acute coronary syndromes (37% STEMI). VCD choice was at the operator's discretion and included AngioSeal (n = 2,910) or Mynx (1,164). Cardiogenic shock or patients receiving intra-aortic balloon pumps were excluded. Safety was assessed by vascular complications defined as either vascular injury (perforation, dissection, acute limb ischemia, arteriovenous fistula, pseudoaneurysm with thrombin injection, or surgical repair) or access-site bleed (hemoglobin droP >3 g/dL requiring transfusion, retroperitoneal bleed, or hematoma >5 cm, or the composite of both. Efficacy was evaluated by device failure and defined as inability to achieve immediate hemostasis or use of additional hemostatic mechanisms. Outcomes at 30-days were evaluated. Results Groups (AngioSeal vs Mynx) were fairly balanced with regards to bleeding risk factors of gender (male, 65% vs 66%), body mass index (30 ± 6 vs 30 ± 7), heart failure class III/IV (5% vs 6%), chronic kidney disease (15% vs 17%), use of glycoprotein IIb/IIIa inhibitor (5% vs 4%), or bivalirudin (86% vs 88%), all P >0.5. The AngioSeal group was slightly younger (64 ± 12 vs 65 ± 12, P

Objectives The aim of this study was to determine the risk of scaffold thrombosis (ST) after percutaneous coronary intervention (PCI) with placement of an ABSORB bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) by conducting a systematic review and meta-analysis. Background PCI with BVS placement holds great potential, but concern has recently been raised regarding the risk of ST. Methods MEDLINE/PubMed, Cochrane CENTRAL, and meeting abstracts were searched for all studies that included outcomes data for patients after PCI with BVS placement. For studies comparing BVSs with drug-eluting stents (DES), pooled estimates of outcomes, presented as odds ratios (ORs) with 95% confidence intervals (CIs), were generated with random-effects models. Results Our analysis included 10,510 patients (8,351 with a BVS and 2,159 with DES) with a follow-up of 6.4 ± 5.1 months and 60 ± 11 years of age; 78% were male, 36% had stable angina, and 59% had acute coronary syndrome (ACS). Among patients with a BVS, cardiovascular death occurred in 0.6%, myocardial infarction (MI) in 2.1%, target lesion revascularization in 2.0%, and definite/probable ST in 1.2% of patients. Of BVS patients, 0.27% had acute ST and 0.57% had subacute ST. Meta-analysis demonstrated that patients who received a BVS were at a higher risk of MI (OR: 2.06, 95% CI: 1.31 to 3.22, p = 0.002) and definite/probable ST (OR: 2.06, 95% CI: 1.07 to 3.98, p = 0.03) compared with patients who received DES, whereas there was a trend toward decreased all-cause mortality with a BVS (OR: 0.40, 95% CI: 0.15 to 1.06, p = 0.06). Conclusions Patients undergoing PCI with a BVS had increased definite/probable ST and MI during follow-up compared with DES. Further studies with long-term follow-up are needed to assess the risk of ST with a BVS.

Stem cell therapy as a treatment option for acute myocardial infarction or heart failure caused by ischemic or nonischemic cardiomyopathy has focused on direct cardiac delivery of stem cells to facilitate cardiac engraftment. Once engrafted, it was believed that these cells would either transdifferentiate into new functioning myocytes or stimulate the expansion of resident myocardial stem cells. However, a sea change in thinking about cell therapy in cardiovascular disease has occurred as mounting evidence indicates that (1) inflammation is a major mechanism contributing to the progressive myocardial dysfunction seen in patients post-acute myocardial infarction and in patients with cardiomyopathy, and (2) systemic paracrine-mediated anti-inflammatory effects of stem cells can drive beneficial cardiac effects in these diseases. These concepts lead to a potentially transformative strategy that intravenous delivery of stem cells, through systemic anti-inflammatory mechanisms, improves myocardial function and thereby obviates the need for invasive methods of stem cell delivery. Until recently, the prevailing view of the mechanism responsible for any potential benefit of stem cells in patients with acute myocardial infarction (AMI) or with heart failure (HF) caused by ischemic or nonischemic cardiomyopathy (ICM/NICM) was that benefit derived from local effects—once engrafted in damaged myocardium, the stem cells either transdifferentiate into functional myocardium, stimulate resident myocardial stem cells to expand, and repopulate the heart with functioning myocytes or secrete substances leading to myocardial healing. This mechanistic perspective implied that the greater the number of engrafted cells in the myocardium, the greater the cardiac benefit. Because few intravenously administered stem cells engraft in injured myocardium, invasive strategies providing direct delivery of stem cells to the heart were uniformly adopted. This necessarily involved either catheter-based delivery (intracoronary or transendocardial injection) or surgical delivery (direct intramyocardial injection). A transformative concept relating to stem cell treatment of patients with AMI or ICM/NICM has recently …

Stem cell therapeutics, as other therapeutic strategies, must surmount multiple requirements before reaching the phase of clinical trials. These requirements can be onerous in terms of time and funding and could, thereby, lead to abandonment of many promising therapeutics. One of these requirements is the perceived necessity of conducting large animal efficacy studies—especially pig studies—prior to initiating a clinical trial. The value of such a strategy, despite acceptance by experts, has never been demonstrated scientifically, raising the question of whether bias rather than evidence hampers the development of new therapeutic strategies. Of the questions facing investigators involved in developing new treatment strategies, one is common across disease disciplines and therapeutic approaches: What animal models should be used to determine whether the likelihood a therapeutic will be clinically successful is high enough to justify spending years of effort and tens, or even hundreds, of millions of dollars in clinical trials? A particularly vexing extension of this question is whether it is necessary to test efficacy in a large animal model prior to clinical trial launch. The purpose of this Viewpoint is to challenge the prevailing view, epitomized by the following quote: “Translational studies in large animal models (usually pigs) are rare because they are expensive, complex, time-consuming, technically demanding, slow, and usually not suitable for mechanistic investigations; nevertheless, because they are conducted in settings closer to the human situation than those found in rodent models, these studies are essential to justify the risks and costs of clinical trials.”1 This quote reflects current unofficial dogma that once efficacy of an intervention is established in mouse or other rodent models, efficacy needs confirmation in a large animal model—the most popular one being the pig.1–3 This is not a trivial conclusion because adequately powered pig studies are expensive from both …

Aims In the drug-eluting stent (DES) era, patients with acute coronary syndrome (ACS) had a higher risk of early stent thrombosis compared with stable patients. The present study aimed to evaluate whether the same is true for the bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, CA, USA). Methods and results We assessed the relationship between the incidence of definite/probable scaffold thrombosis (ScT) (overall ScT and early ScT) and ACS percentage with the latest publications, including the most recent large randomised controlled trials. Out of a total study population of 13,708 devices in 45 trials, overall ScT was observed in 185 devices (1.35%) at a weighted mean follow-up period of 9.4 months, while early ScT was reported in 125 devices (0.97%) out of 12,896 devices in 44 trials. Meta-regression analysis demonstrated no significant correlation between overall/early ScT and the percentage of patients with ACS (overall ScT: R2=0.030, p=0.255; early ScT: R2=0.067, p=0.090). Conclusions ACS appeared to have little impact on the incidence of ScT after the implantation of BVS. Further clinical study is warranted to investigate the predictors of ScT using multivariate analysis with sufficient statistical power.

Aims The present study aimed to investigate whether the Magmaris resorbable magnesium scaffold (RMS) has platelet-repelling properties by comparing its acute thrombogenicity with an equivalent stainless steel stent in an arteriovenous shunt model. Methods and results An ex vivo porcine carotid jugular arteriovenous shunt was established and connected to Sylgard tubing containing the Magmaris RMS with sirolimus-eluting PLLA coating and an equivalent 316L stainless steel stent with sirolimus-eluting PLLA coating. Six shunts (two shunt runs per pig) were run comparing the two scaffolds (n=9) in alternating order. Nested generalised linear mixed models were employed to compare variables between scaffold groups. Confocal fluorescent microscopy containing CD61/CD42b demonstrated that the 316L equivalent stent had significantly greater platelet coverage of the total scaffold compared with Magmaris (5.8% vs. 2.8%, adjusted rate ratio 2.21 [1.41, 3.47], p=0.012). Scanning electron microscopy demonstrated significantly greater thrombus deposition on the 316L equivalent stent as a percentage of the total scaffold compared with Magmaris (8.0% vs. 5.3%, p=0.009). Magmaris also had significantly less CD14 positive monocyte deposition and a trend towards less PM-1 positive neutrophil compared with the 316L equivalent stent. Conclusions Magmaris has less thrombogenicity and inflammatory cell deposition compared with the equivalent 316L stainless steel (in geometry and design) stent in a porcine arteriovenous shunt model. These data suggest that resorbable magnesium scaffolds may have inherent properties that reduce adhesion of platelets and inflammatory cells.

The aim of this network meta-analysis is to assess the impact of strut thickness on clinical outcomes in patients who underwent percutaneous coronary intervention. We searched Medline/PubMed and performed a Bayesian network meta-analysis to compare outcomes of patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) of different strut thicknesses (ultrathin 60 to 80 μm; thin 81 to 100 μm; intermediate 101 to 120 μm; thick ≥120 μm). Studies comparing DES with similar strut thickness, bare metal stents, and fully bioresorbable scaffolds were excluded. Odds ratios with credible intervals (OR [CrIs]) were generated with random-effects models to compare outcomes. Our primary end point was stent thrombosis (ST). We identified 69 RCTs including 80,885 patients (ultrathin group = 10,219; thin group = 36,575; intermediate group = 11,399; thick group = 22,692). Mean age was 64 ± 11 years and 75% were male gender. When compared with thick-strut DES, ultrathin struts had significant less ST and myocardial infarction (OR 0.43 [CrI 0.27 to 0.68]; and OR 0.73 [CrI 0.62 to 0.92], respectively). Sensitivity analysis including only studies with permanent polymer DES gave similar results. Improvement in DES technology with thinner struts is associated with significant reduction in ST and myocardial infarction compared with thicker struts.

Current guidelines recommend that percutaneous coronary intervention (PCI) should be restricted to the culprit vessel in ST elevation myocardial infarction (STEMI) patients with multi-vessel disease (MVD) and without cardiogenic shock. However, newer data suggests that performing complete revascularization (CR) in MVD patients may lead to better outcomes compared to intervention in the culprit vessel only. The aim of this meta-analysis is to examine the available data to determine if CR (using either angio- or fractional flow reserve guidance—FFR) following primary PCI in STEMI patients without cardiogenic shock impacts clinical outcomes. Meta-analysis was performed by conducting a literature search of PubMed from January 2004 to July 2017. Pooled estimates of outcomes, presented as odds ratios (OR) [95% confidence intervals], were generated using random-effect models. A total of 9 studies (3317 patients) were included. CR showed a significant MACE reduction (OR 0.49, 95% CI 0.36–0.66, p

Background We have recently found that 3 repeated doses (12×106 each) of c‐kitPOS cardiac progenitor cells (CPCs) were markedly more effective than a single dose of 12×106 cells in alleviating postinfarction left ventricular dysfunction and remodeling. However, since the single‐dose group received only one third of the total number of CPCs given to the multiple‐dose group, it is unknown whether the superior therapeutic efficacy was caused by repeated treatments per se or by administration of a higher total number of CPCs. This issue has major clinical implications because multiple cell injections in patients pose significant challenges, which would be obviated by using 1 large injection. Accordingly, we determined whether the beneficial effects of 3 repeated CPC doses can be recapitulated by 1 large dose containing the same total number of cells. Methods and Results Rats with a 30‐day‐old myocardial infarction received 3 echo‐guided intraventricular infusions, 35 days apart, of vehicle‐vehicle‐vehicle, 36×106 CPCs‐vehicle‐vehicle, or 3 equal doses of 12×106 CPCs. Infusion of a single, large dose of CPCs (36×106 cells) produced an initial improvement in left ventricular function, but no further improvement was observed after the second and third infusions (both vehicle). In contrast, each of the 3 doses of CPCs (12×106) caused a progressive improvement in left ventricular function, the cumulative magnitude of which was greater than with a single dose. Unlike the single dose, repeated doses reduced collagen content and immune cell infiltration. Conclusions Three repeated doses of CPCs are superior to 1 dose even though the total number of cells infused is the same, possibly because of greater antifibrotic and anti‐inflammatory actions.

Over the past 1.5 decades, numerous stem cell trials have been performed in patients with cardiovascular disease. Although encouraging outcome signals have been reported, these have been small, leading to uncertainty as to whether they will translate into significantly improved outcomes. A reassessment of the rationale for the use of stem cells in cardiovascular disease is therefore timely. Such a rationale should include analyses of why previous trials have not produced significant benefit and address whether mechanisms contributing to disease progression might benefit from known activities of stem cells. The present paper provides such a reassessment, focusing on patients with left ventricular systolic dysfunction, either nonischemic or ischemic. We conclude that many mechanisms contributing to progressive left ventricular dysfunction are matched by stem cell activities that could attenuate the myocardial effect of such mechanisms. This suggests that stem cell strategies may improve patient outcomes and justifies further testing.

Objectives We sought to identify if baseline characteristic differences in patients who receive a 23 mm vs. 26 mm valve impact clinical outcomes. Background Transcatheter aortic valve replacement (TAVR) is currently an approved therapy for patients with severe aortic stenosis who are considered inoperable or are at high risk. Methods We retrospectively examined baseline characteristics and outcomes of patients receiving a 23 mm (n = 132) vs. 26 mm valve (n = 81) via the transfemoral approach. Results Gender (P 0.99, minor bleed 19.0 vs. 22.0%, P = 0.67 and life threatening bleed 7.0 vs. 5.0%, P = 0.77). In-hospital death (6.0 vs. 5.0%, P >0.99), 30-day all-cause death (7.6 vs. 6.2%, P = 0.69), and all-cause death at 1 year (17.4 vs. 25.9%, P = 0.13) were also similar between groups. Gender, valve size, previous coronary bypass surgery and atrial fibrillation were not independently associated with mortality; however, on multivariate analysis STS score was (HR 1.11; 95% CI 1.02–1.19; P = 0.01). Conclusion Patients undergoing TAVR with 23 and 26 mm valves have similar clinical outcomes despite significant differences in baseline characteristics. © 2015 Wiley Periodicals, Inc.

Introduction Accuracy of intracoronary imaging to discriminate functionally significant coronary stenosis according to vessel diameter remains to be defined. Methods PubMed, Scopus, and Google Scholar were systematically searched for studies assessing diagnostic accuracy (area under the receiver operating characteristic curve [AUC], the primary end point) and sensitivity and specificity (the secondary end points) of minimal luminal area (MLA) or of minimal luminal diameter (MLD) derived from intravascular ultrasound (IVUS) or optical coherence tomography (OCT) to detect functionally significant stenosis as determined with fractional flow reserve (FFR). Results Fifteen studies were included, 2 with 110 patients analyzing only left main (LM), 5 with 224 patients and 306 lesions using OCT, and 9 with 1532 patients and 1681 lesions with IVUS. Median MLA for the OCT studies was 1.96 mm 2 (1.85-1.98 mm 2 ), 2.9 mm 2 (2.7-3.1 mm 2 ) for MLA of all lesions assessed with IVUS, 2.8 mm 2 (2.7-2.9 mm 2 ) for lesions with an angiographic diameter >3 mm, 2.4 mm 2 (2.4-2.5 mm 2 ) for lesions 2 (5.1-5.6 mm 2 ) for LM lesions. For OCT-MLA, AUC was 0.80 (0.74-0.86), with a sensitivity of 0.81 (0.74-0.87) and specificity of 0.77 (0.71-0.83), whereas OCT-MLD had an AUC of 0.85 (0.79-0.91), sensitivity of 0.74 (0.69-0.78), and specificity of 0.70 (0.68-0.73). For IVUS-MLA, AUC was 0.78 (0.75-0.81) for all lesions, 0.78 (0.73-0.84) for vessels with a diameter >3 mm, and 0.79 (0.70-0.89) for those with a diameter Conclusion Intravascular ultrasound and OCT had modest diagnostic accuracy for identification hemodynamically significant lesions, also with specific cutoff for different diameters. Invasive imaging for assessment of LM severity demonstrated excellent correlation with FFR. What is already known about this subject? Fractional flow reserve represents the criterion standard to evaluate the prognostic value of coronary stenosis, whereas its relationship with IVUS and OCT remains to be assessed. What does this study add? Despite improvement, IVUS and OCT do not predict functional stenosis, even with dedicated cutoff, apart from LM disease. How might this impact on clinical practice? The recent guidelines of myocardial revascularization have stressed the crucial role of FFR before performing percutaneous coronary intervention on LM, whereas intravascular imaging is often exploited to drive revascularization. The present analysis stresses the point that LM percutaneous coronary intervention may be driven only by intravascular imaging, given the high accuracy for significant ischemic lesions, whereas for other vessels, these 2 techniques mirror 2 different aspects.

Studies have linked on-treatment platelet reactivity (PR) to adverse clinical outcomes. Because new P2Y 12 inhibitors (prasugrel and ticagrelor) have been predominantly tested against clopidogrel, data on pharmacodynamic comparisons between these 2 drugs are scarce. We compared ticagrelor with prasugrel in a network meta-analysis. PubMed, Cochrane, and EMBASE were searched for studies assessing PR in patients with coronary artery disease treated with ticagrelor or prasugrel. All studies using prasugrel and/or ticagrelor providing platelet function measurement data using VerifyNow P2Y12 reaction units (PRUs), platelet reactivity index (PRI) vasodilator-stimulated phosphoprotein phosphorylation, or maximal platelet aggregation (MPA) by light transmission aggregometry were considered eligible. Mixed treatment comparison models directly compared ticagrelor and prasugrel and indirectly compared them using clopidogrel as a comparator with data presented as mean difference (95% confidence interval). Data were extracted from 29 studies, including 5,395 patients. Compared with clopidogrel 75 mg, both prasugrel 10 mg and ticagrelor 90 mg twice daily were associated with lower PRU (mean difference −117 [−134.1, −100.5] and −159.7 [−182.6, −136.6], respectively), a lower PRI (−24.2 [−28.2, −20.3] and −33.6 [−39.9, −27.6], respectively), and lower MPA (−11.8 [−17, −6.3] and −20.7 [−28.5, −12.8], respectively). Similar results were obtained with clopidogrel 150 mg. Ticagrelor 90 mg twice daily was associated with lower PRU (−42.5 [−62.9, −21.9]), lower PRI (−9.3 [−15.6, −3.5]), and lower MPA (−8.9 [−16.4, −1.2]) compared with prasugrel 10 mg. In conclusion, our meta-analysis suggests that ticagrelor achieved significantly lower on-treatment PR compared with prasugrel, with both being superior to clopidogrel standard or high dose.

Baseline anemia is associated with transfusions and increased risk of mortality in patients who underwent cardiac surgery and percutaneous coronary intervention. The impact of blood transfusions in anemic patients who underwent transcatheter aortic valve implantation (TAVI) remains unclear. All patients who underwent transfemoral TAVI at our institution were retrospectively included. We determined the effect of blood transfusions on short- and long-term mortality and its interaction with baseline hemoglobin levels and bleeding complications. Additionally, we evaluated baseline hemoglobin effect on mortality. A total of 332 patients were included. All patients (99%) except 2 (1%) met the definition for anemia. Of the 332 patients, 124 (37%) received a blood transfusion and 208 (63%) did not. Blood transfusions were associated with increased in-hospital (p

Chest pain or other symptoms concerning for acute coronary syndrome continues to remain a major reason for presentation to the emergency department. However, there is significant heterogeneity in the spectrum of risk severity of these patients. The electrocardiogram (ECG) remains a critically valuable tool in the physician's arsenal to diagnose patients and help with risk stratification. There are multiple high-risk ECG findings that are suggestive of adverse outcome and may benefit from rapid transfer for coronary angiography. This article reviews specific high-risk ECG patterns that may represent acute myocardial infarction or identify impending acute myocardial infarction that benefit from early diagnostic coronary angiography.

Background Recent studies suggest the Orsiro sirolimus-eluting stent (O-SES), which has ultrathin struts with a biodegradable sirolimus-eluting polymer coating, performed better than contemporary drug-eluting stents (DES). We performed a meta-analysis to compare clinical outcomes for all randomized controlled trials (RCTs) of O-SES vs contemporary DES. Methods/materials PubMed, Cochrane CENTRAL, and meeting abstracts were searched for all RCTs comparing O-SES with contemporary DES. Pooled estimates of longest available clinical outcomes at a minimum of one-year follow-up, presented as odds ratios (OR) [95% confidence intervals], were generated with random-effect models. Results We included 8 RCTs with a total of 11,176 patients (5444 O-SES and 5732 contemporary DES [3537 EES, 1295 ZES, and 1264 BP-BES) with a mean age of 65 ± 11, 74% were male, 40% underwent PCI for stable angina, and 56% for ACS. We assessed outcomes comparing O-SES vs. everolimus-eluting stents, vs. permanent-polymer DES, and vs. all DES including biodegradable-polymer DES. Orsiro performed comparably in all categories with a trend toward a reduction in myocardial infarction (0.83 [0.68, 1.02], p = 0.07) and stent thrombosis (0.75 [0.54, 1.04], p = 0.08). Conclusion Overall, the Orsiro SES had similar clinical outcomes to contemporary DES with a trend toward reduction in myocardial infarction and stent thrombosis.

Background— A comparison in acute thrombogenicity between the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold and the Absorb bioresorbable vascular scaffold has not been performed. This study assessed acute thrombogenicity of Magmaris compared with Absorb and the Orsiro hybrid drug-eluting stent in a porcine arteriovenous shunt model. Methods and Results— An ex vivo porcine carotid jugular arteriovenous shunt was established and connected to SYLGARD tubing containing the Magmaris, Absorb, and Orsiro scaffolds/stents and allowed to run in the shunt for a maximum of 1 hour. Twelve shunts (2 shunt runs per pig) were run comparing the 3 scaffolds in alternating order. Nested generalized linear mixed models were used to compare variables between scaffold groups while adjusting for variability between shunt runs. Confocal fluorescent microscopy costaining CD61/CD42b demonstrated that both Magmaris (3.0%) and Orsiro (4.6%) had less platelet coverage of the total scaffold compared with Absorb (21.8%). Scanning electron microscopy demonstrated significantly less thrombus deposition to Magmaris as a percentage of the total scaffold compared with Absorb (5.0% versus 16.1%, P =0.02). Magmaris had significantly less PM-1–positive neutrophil and CD14-positive monocyte adherence compared with both Orsiro and Absorb. Orsiro had significantly less monocyte deposition compared with Absorb. Conclusions— Despite a similar scaffold strut thickness, the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold was significantly less thrombogenic compared with the Absorb bioresorbable vascular scaffold in an ex vivo porcine arteriovenous shunt model. Further studies are needed to determine whether the reduced thrombogenicity of Magmaris will result in reductions in major cardiovascular events.

The use of optical coherence tomography (OCT) in PCI guidance is limited perhaps by the lack of adequately powered studies which compare its efficacy and outcomes to the other more popular imaging modalities. We therefore performed a meta-analysis to compare clinical outcomes following OCT-guided PCI with the other imaging modalities in two separate comparisons. We abstracted data from randomized control trials and observational comparative studies focusing on OCT versus either angiography- or IVUS-guided PCI outcomes identified following a systematic search (April 2006 and May 2017). This meta-analysis included a total of 2781 patients; OCT-guidance versus Angiography guidance (n = 1753) and OCT-guidance versus IVUS-guidance (n = 1028). Pooled estimates of outcomes, presented as odds ratios (OR) [95% confidence intervals], were generated with random-effect models. OCT guidance showed lower rates of MACE (OR 0.70 [0.49, 1.00] p = 0.05) and cardiac deaths (OR 0.40 [0.18, 0.90] p = 0.03) compared to Angiography-guidance alone but no statistical significant results for myocardial infarction (OR 0.70 [0.42, 1.16] p = 0.17), stent thrombosis (OR 1.17 [0.40, 3.43] p = 0.77) and target lesion revascularizations (OR 1.07 [0.48, 2.38] p = 0.86).No statistical significance was observed in the OCT versus IVUS comparison; MACE (OR 0.89 [0.46, 1.73] p = 0.73), cardiac deaths (OR 0.56 [0.12, 2.70] p = 0.47), MI (OR 0.56 [0.12, 2.70] p = 0.47), ST (OR 0.43 [0.06, 2.95] p = 0.39), and TLR(OR 0.99 [0.45, 2.18] p = 0.99). OCT-guided PCI in comparison with angiography-guided was associated with reduction in adverse events for the composite of cardiac deaths, myocardial infarction and repeat revascularizations. There was no statistically significant difference in clinical outcomes observed in the comparison between OCT- and IVUS-guidance.

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

HF patients with signs and symptoms of worsening heart failure (HF), despite optimal medical therapy, have a poor prognosis. The pathways contributing to HF are multiple, probably accounting, in part, for current treatment approaches not being more effective. Stem cells, particularly mesenchymal stem cells (MSCs), have a broad range of activities, making them particularly interesting candidates for a new HF therapeutic. This review presents an overview of the studies examining the efficacy of stem cell studies administered to HF patients, focusing mainly on MSCs. It examines the issues surrounding autologous vs. allogenic stem cells, the results of different routes of administration, and implications deriving from the belief that for stem cells to be effective, they must engraft in the myocardium and exert local effects. Since intravenous administration of stem cells leads to sparse cardiac engraftment, stem cell delivery strategies have uniformly involved catheter-based delivery systems. This becomes problematic in a disease that will almost certainly require delivery of the therapeutic throughout the course of the disease. Importantly, it appears that a critical contributing cause of the progressive cardiac dysfunction experienced by HF patients is the existence of a persistent inflammatory response. Since MSCs exert potent anti-inflammatory effects through paracrine mechanisms, it is possible that intravenous delivery of MSCs may be therapeutically effective. If this concept is valid, it could lead to a transformational change in stem cell delivery strategies.

Background— Clinical presentation of bare metal stent in-stent restenosis (ISR) in patients undergoing target lesion revascularization is well characterized and negatively affects on outcomes, whereas the presentation and outcomes of first- and second-generation drug-eluting stents (DESs) remains under-reported. Methods and Results— The study included 909 patients (1077 ISR lesions) distributed as follows: bare metal stent (n=388), first-generation DES (n=425), and second-generation DES (n=96), categorized into acute coronary syndrome (ACS) or non-ACS presentation mode at the time of first target lesion revascularization. ACS was further classified as myocardial infarction (MI) and unstable angina. For bare metal stent, first-generation DES and second-generation DES, ACS was the clinical presentation in 67.8%, 71.0%, and 66.7% of patients, respectively ( P =0.470), whereas MI occurred in 10.6%, 10.1%, and 5.2% of patients, respectively ( P =0.273). The correlates for MI as ISR presentation were current smokers (odds ratio, 3.02; 95% confidence interval [CI], 1.78–5.13; P P P =0.060). ACS presentations had an independent effect on major adverse cardiac events (death, MI, and re-target lesion revascularization) at 6 months (MI versus non-ACS: adjusted hazard ratio, 4.06; 95% CI, 1.84–8.94; P P =0.046). Conclusions— ISR clinical presentation is similar irrespective of stent type. MI as ISR presentation seems to be associated with patient and not device-related factors. ACS as ISR presentation has an independent effect on major adverse cardiac events, suggesting that ISR remains a hazard and should be minimized.

Patients with a history of heart disease are at increased risk for future cardiovascular events, including myocardial infarction (MI), stroke, and death resulting from cardiovascular disease. Although coronary artery disease remains the leading cause of mortality worldwide, advancements in medical therapy, particularly antithrombotic agents, have improved patient outcomes.1–4 Although the trend for MI and death after acute coronary syndrome (ACS) over the past 20 years has declined,5,6 such medical advancements are still met with discouraging rates of death and MI after revascularization.7 To this end, it is the recommendation of the American College of Cardiology and American Heart Association that all ACS patients, regardless of whether percutaneous coronary intervention was performed, be treated with dual antiplatelet therapy (DAPT) for 1 year ( Class IA ).8 Such recommendations are based largely on results from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, which assessed aspirin versus DAPT with aspirin and clopidogrel for the reduction of ischemic end points in patients presenting with non–ST-segment–elevation ACS who did not receive percutaneous coronary intervention.9 Seeing a need for further risk reduction in long-term management of patients with established atherothrombotic risk, the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P)–Thrombolysis in Myocardial Infarction (TIMI) 50 was conducted. The study drug, vorapaxar (Zontivity, Merck, NJ), is an antagonist of the platelet protease-activated receptor (PAR-1) and inhibits thrombin-induced platelet aggregation.10,11 Vorapaxar was shown to have a significant benefit for the reduction of cardiovascular death and ischemic complications in addition to secondary prevention.12 Vorapaxar was also tested in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial as part of adjunct therapy in the non–ST-segment–elevation ACS population.13 In this population, however, …