Endovascular Ultrasound Renal Denervation to Treat Hypertension: The RADIANCE II Randomized Clinical Trial.

Importance: Two initial sham-controlled trials demonstrated that ultrasound renal denervation decreases blood pressure (BP) in patients with mild to moderate hypertension and hypertension that is resistant to treatment. Objective: To study the efficacy and safety of ultrasound renal denervation without the confounding influence of antihypertensive medications in patients with hypertension. Design, Setting, and Participants: Sham-controlled, randomized clinical trial with patients and outcome assessors blinded to treatment assignment that was conducted between January 14, 2019, and March 25, 2022, at 37 centers in the US and 24 centers in Europe, with randomization stratified by center. Patients aged 18 years to 75 years with hypertension (seated office systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg despite taking up to 2 antihypertensive medications) were eligible if they had an ambulatory SBP/DBP of 135/85 mm Hg or greater and an SBP/DBP less than 170/105 mm Hg after a 4-week washout of their medications. Patients with an estimated glomerular filtration rate of 40 mL/min/1.73 m2 or greater and with suitable renal artery anatomy were randomized 2:1 to undergo ultrasound renal denervation or a sham procedure. Patients were to abstain from antihypertensive medications until the 2-month follow-up unless prespecified BP criteria were exceeded and were associated with clinical symptoms. Interventions: Ultrasound renal denervation vs a sham procedure. Main Outcomes and Measures: The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months. The primary safety composite outcome of major adverse events included death, kidney failure, and major embolic, vascular, cardiovascular, cerebrovascular, and hypertensive events at 30 days and renal artery stenosis greater than 70% detected at 6 months. The secondary outcomes included mean change in 24-hour ambulatory SBP, home SBP, office SBP, and all DBP parameters at 2 months. Results: Among 1038 eligible patients, 150 were randomized to ultrasound renal denervation and 74 to a sham procedure (mean age, 55 years [SD, 9.3 years]; 28.6% female; and 16.1% self-identified as Black or African American). The reduction in daytime ambulatory SBP was greater with ultrasound renal denervation (mean, -7.9 mm Hg [SD, 11.6 mm Hg]) vs the sham procedure (mean, -1.8 mm Hg [SD, 9.5 mm Hg]) (baseline-adjusted between-group difference, -6.3 mm Hg [95% CI, -9.3 to -3.2 mm Hg], P < .001), with a consistent effect of ultrasound renal denervation throughout the 24-hour circadian cycle. Among 7 secondary BP outcomes, 6 were significantly improved with ultrasound renal denervation vs the sham procedure. No major adverse events were reported in either group. Conclusions and Relevance: In patients with hypertension, ultrasound renal denervation reduced daytime ambulatory SBP at 2 months in the absence of antihypertensive medications vs a sham procedure without postprocedural major adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT03614260.

Prevalence of diagnostically-discrepant Clostridioides difficile clinical specimens: insights from longitudinal surveillance.

Background: Clostridioides difficile Infection (CDI) is a healthcare-associated diarrheal disease prevalent worldwide. A common diagnostic algorithm relies on a two-step protocol that employs stool enzyme immunoassays (EIAs) to detect the pathogen, and its toxins, respectively. Active CDI is deemed less likely when the Toxin EIA result is negative, even if the pathogen-specific EIA is positive for C. difficile. We recently reported, however, that low-toxin-producing C. difficile strains recovered from Toxin-negative ('discrepant') clinical stool specimens can be fully pathogenic, and cause lethality in a rodent CDI model. To document frequency of discrepant CDI specimens, and evaluate C. difficile strain diversity, we performed longitudinal surveillance at a Southern Arizona tertiary-care hospital. Methods: Diarrheic stool specimens from patients with clinical suspicion of CDI were obtained over an eight-year period (2015-2022) from all inpatient and outpatient Units of a > 600-bed Medical Center in Southern Arizona. Clinical laboratory EIA testing identified C. difficile-containing specimens, and classified them as Toxin-positive or Toxin-negative. C. difficile isolates recovered from the stool specimens were DNA fingerprinted using an international phylogenetic lineage assignment system ("ribotyping"). For select isolates, toxin abundance in stationary phase supernatants of pure cultures was quantified via EIA. Results: Of 8,910 diarrheic specimens that underwent diagnostic testing, 1733 (19.4%) harbored C. difficile. Our major findings were that: (1) C. difficile prevalence and phylogenetic diversity was stable over the 8-year period; (2) toxigenic C. difficile was recovered from 69% of clinically Tox-neg ('discrepant') specimens; (3) the six most prevalent USA ribotypes were recovered in significant proportions (>60%) from Tox-neg specimens; and (4) toxin-producing C. difficile recovered from discrepant specimens produced less toxin than strains of the same ribotype isolated from non-discrepant specimens. Conclusion: Our study highlights the dominance of Toxin EIA-negative CDI specimens in a clinical setting and the high frequency of known virulent ribotypes in these specimens. Therefore, a careful reevaluation of the clinical relevance of diagnostically-discrepant specimens particularly in the context of missed CDI diagnoses and C. difficile persistence, is warranted.

Oligofructose improves small intestinal lipid-sensing mechanisms via alterations to the small intestinal microbiota.

BACKGROUND: Upper small intestinal dietary lipids activate a gut-brain axis regulating energy homeostasis. The prebiotic, oligofructose (OFS) improves body weight and adiposity during metabolic dysregulation but the exact mechanisms remain unknown. This study examines whether alterations to the small intestinal microbiota following OFS treatment improve small intestinal lipid-sensing to regulate food intake in high fat (HF)-fed rats. RESULTS: In rats fed a HF diet for 4 weeks, OFS supplementation decreased food intake and meal size within 2 days, and reduced body weight and adiposity after 6 weeks. Acute (3 day) OFS treatment restored small intestinal lipid-induced satiation during HF-feeding, and was associated with increased small intestinal CD36 expression, portal GLP-1 levels and hindbrain neuronal activation following a small intestinal lipid infusion. Transplant of the small intestinal microbiota from acute OFS treated donors into HF-fed rats also restored lipid-sensing mechanisms to lower food intake. 16S rRNA gene sequencing revealed that both long and short-term OFS altered the small intestinal microbiota, increasing Bifidobacterium relative abundance. Small intestinal administration of Bifidobacterium pseudolongum to HF-fed rats improved small intestinal lipid-sensing to decrease food intake. CONCLUSION: OFS supplementation rapidly modulates the small intestinal gut microbiota, which mediates improvements in small intestinal lipid sensing mechanisms that control food intake to improve energy homeostasis. Video Abstract.

Clinical and economic outcomes of liberal versus selective drug-eluting stent use: insights from temporal analysis of the multicenter Evaluation of Drug Eluting Stents and Ischemic Events (EVENT) registry.

BACKGROUND: Although the benefits of drug-eluting stents (DES) for reducing restenosis after percutaneous coronary intervention are well established, the impact of alternative rates of DES use on population-level outcomes is unknown. METHODS AND RESULTS: We used data from the Evaluation of Drug Eluting Stents and Ischemic Events (EVENT) registry to examine the clinical impact and cost-effectiveness of varying DES use rates in routine care. Between 2004 and 2007, 10,144 patients undergoing percutaneous coronary intervention were enrolled in the EVENT registry at 55 US centers. Clinical outcomes and cardiovascular-specific costs were assessed prospectively over 1 year of follow-up. Use of DES decreased from 92 in 2004 to 2006 (liberal use era; n=7587) to 68 in 2007 (selective use era; n=2557; P<0.001). One-year rates of death or myocardial infarction were similar in both eras. Over this time period, the incidence of target lesion revascularization increased from 4.1 to 5.1, an absolute increase of 1.0 (95 confidence interval, 0.1 to 1.9; P=0.03), whereas total cardiovascular costs per patient decreased by $401 (95 confidence interval, 131 to 671; P=0.004). The risk-adjusted incremental cost-effectiveness ratio for the liberal versus selective DES era was $16,000 per target lesion revascularization event avoided, $27,000 per repeat revascularization avoided, and $433 000 per quality-adjusted life-year gained. CONCLUSIONS: In this prospective registry, a temporal reduction in DES use was associated with a small increase in target lesion revascularization and a modest reduction in total cardiovascular costs. These findings suggest that although clinical outcomes are marginally better with unrestricted DES use, this approach represents a relatively inefficient use of healthcare resources relative to several common benchmarks for cost-effective care.

Mode of death after contemporary percutaneous coronary intervention: a report from the Evaluation of Drug Eluting Stents and Ischemic Events registry.

BACKGROUND: When selecting clinical trial end points, some investigators prefer cardiovascular death (CVD) while others believe that all-cause mortality is more relevant. However, the relative contribution of CVD to 1-year mortality after contemporary percutaneous coronary intervention (PCI) is not known. METHODS: We evaluated the mode of death (MOD) in EVENT, a prospective PCI registry at 55 US hospitals. Vital status was assessed at 6 and 12 months as part of the study protocol, and MOD was independently reviewed in blinded fashion. RESULTS: Between 2004 and 2007, EVENT enrolled 10,144 patients of whom 295 (2.9%) died within the first year: 51 (17%) ≤30 days; and 244 (83%) between 31 and 365 days after index PCI. Overall, CVD accounted for 42% of deaths, and no clear cause could be identified in a substantial subgroup (25% of deaths). Among patients who died ≤30 days, the MOD was more likely to be CVD (odds ratio 3.96, 95% CI 2.08-7.55), whereas the incidence of CVD and non-CVD was similar after 30 days. Findings were similar after a series of sensitivity analyses including reassignment of unknown MOD to the CVD category, using multiple imputation modeling, or when evaluating MOD in prespecified subgroups of patients with diabetes, acute coronary syndromes, or left ventricular dysfunction. CONCLUSIONS: Among unselected PCI patients, 1-year mortality is approximately 3%, and CVD is confirmed in <50% of all deaths. Regardless of analytic approach, CVD is the primary contributor to overall mortality during the first 30 days after PCI, whereas rates of CVD and non-CVD are remarkably similar after the first month after PCI.

Patellar button wear patterns in well-functioning total knee arthroplasty retrievals.

One of the common reasons for early revision or poor outcome in total knee arthroplasty is due to patellar maltracking, loosening, or pain. The analysis of how the patellofemoral mechanism operates and wears in vivo has not been a focus of many retrieval studies. This paper describes the wear pattern observed on patellar buttons from well-functioning TKA specimens that were harvested as part of a donor program. The attempt was to describe the variations in wear patterns to see if any commonalities existed that may predict a well-functioning patellofemoral mechanism after TKA.

Phylogenomic analysis of Clostridioides difficile ribotype 106 strains reveals novel genetic islands and emergent phenotypes.

Clostridioides difficile infection (CDI) is a major healthcare-associated diarrheal disease. Consistent with trends across the United States, C. difficile RT106 was the second-most prevalent molecular type in our surveillance in Arizona from 2015 to 2018. A representative RT106 strain displayed robust virulence and 100% lethality in the hamster model of acute CDI. We identified a unique 46 KB genomic island (GI1) in all RT106 strains sequenced to date, including those in public databases. GI1 was not found in its entirety in any other C. difficile clade, or indeed, in any other microbial genome; however, smaller segments were detected in Enterococcus faecium strains. Molecular clock analyses suggested that GI1 was horizontally acquired and sequentially assembled over time. GI1 encodes homologs of VanZ and a SrtB-anchored collagen-binding adhesin, and correspondingly, all tested RT106 strains had increased teicoplanin resistance, and a majority displayed collagen-dependent biofilm formation. Two additional genomic islands (GI2 and GI3) were also present in a subset of RT106 strains. All three islands are predicted to encode mobile genetic elements as well as virulence factors. Emergent phenotypes associated with these genetic islands may have contributed to the relatively rapid expansion of RT106 in US healthcare and community settings.

Evaluation of coronary artery calcium screening strategies focused on risk categories: the Dallas Heart Study.

BACKGROUND: A strategy using coronary artery calcium (CAC) screening to refine coronary heart disease risk assessment in moderately high risk (MHR) subjects (10-year risk 10%-20%) has been suggested. The potential impact of this strategy is unknown. METHODS: Coronary artery calcium screening strategies focused on MHR subjects were modeled in 2,610 subjects aged 30 to 65 years undergoing Framingham risk scoring and CAC assessment in the Dallas Heart Study. The proportions of subjects eligible for imaging and reclassified from MHR to high risk (HR) (10-year risk >20%) based upon CAC scores were determined. RESULTS: Only 1.0% of women and 15.4% of men were at MHR by Framingham risk scoring and thus eligible for imaging, and <0.1% and 1.1% respectively, changed from MHR to HR using a CAC threshold > or = 400. Coronary artery calcium imaging targeting MHR subjects was also relatively inefficient (>100 women, 14.3 men scanned per subject reclassified). Restricting to an older age range (45-65 years) or expanding the MHR group to 6% to 20% risk had virtually no impact on risk assessment in women. In a secondary analysis, a proposed imaging strategy targeting promotion of subjects from lower risk to MHR was more efficient and had greater yield than current recommendations targeting promotion from MHR to HR. CONCLUSIONS: Coronary artery calcium screening strategies focused on MHR subjects will have a negligible impact on risk assessment in women and a modest impact in men. Further studies are needed to optimize the use of CAC screening as an adjunct to coronary heart disease risk assessment, especially for women and those at seemingly lower risk.

Independent associations between metabolic syndrome, diabetes mellitus and atherosclerosis: observations from the Dallas Heart Study.

Diabetes mellitus (DM) has been termed a "coronary disease equivalent", yet data suggest that only those DM subjects with metabolic syndrome (MetS) are at increased coronary risk. Using data from the Dallas Heart Study, a large, probability-based population study, we assessed the individual and joint associations between MetS, DM and atherosclerosis, defined as coronary artery calcium (CAC) detected by electron-beam computerised tomography (EBCT) and abdominal aortic plaque (AAP) detected by magnetic resonance imaging. Among 2,735 participants, the median age was 44 years; 1,863 (68%) were non-white; 1,509 (55%) were women; 697 (25.5%) had MetS without DM; 53 (1.9%) had DM without MetS; and 246 (9.0%) had both DM and MetS. The prevalence of CAC increased from those with neither MetS nor DM (16.6%) to MetS only (24.0%) to DM only (30.2%) to both MetS and DM (44.7%) (ptrend <0.0001). The prevalence of CAC was higher in those with both DM and MetS versus either alone (p<0.0001). After adjustment, MetS and DM were each independently associated with CAC (odds ratio [OR] 1.4, 95% confidence intervals [CI] 1.1-1.8; OR 1.8, 95% CI 1.3-2.5, respectively). Compared with the group without DM or MetS, those with both MetS and DM had the most CAC (adjusted OR 2.3; 95% CI 1.6-3.2). All analyses of AAP yielded qualitatively similar results. In conclusion, both MetS and DM are independently associated with an increased prevalence of atherosclerosis, with the highest observed prevalence in subjects with both DM and MetS.

An Engineered Synthetic Biologic Protects Against Clostridium difficile Infection.

Morbidity and mortality attributed to Clostridium difficile infection (CDI) have increased over the past 20 years. Currently, antibiotics are the only US FDA-approved treatment for primary C. difficile infection, and these are, ironically, associated with disease relapse and the threat of burgeoning drug resistance. We previously showed that non-toxin virulence factors play key roles in CDI, and that colonization factors are critical for disease. Specifically, a C. difficile adhesin, Surface Layer Protein A (SlpA) is a major contributor to host cell attachment. In this work, we engineered Syn-LAB 2.0 and Syn-LAB 2.1, two synthetic biologic agents derived from lactic acid bacteria, to stably and constitutively express a host-cell binding fragment of the C. difficile adhesin SlpA on their cell-surface. Both agents harbor conditional suicide plasmids expressing a codon-optimized chimera of the lactic acid bacterium's cell-wall anchoring surface-protein domain, fused to the conserved, highly adherent, host-cell-binding domain of C. difficile SlpA. Both agents also incorporate engineered biocontrol, obviating the need for any antibiotic selection. Syn-LAB 2.0 and Syn-LAB 2.1 possess positive biophysical and in vivo properties compared with their parental antecedents in that they robustly and constitutively display the SlpA chimera on their cell surface, potentiate human intestinal epithelial barrier function in vitro, are safe, tolerable and palatable to Golden Syrian hamsters and neonatal piglets at high daily doses, and are detectable in animal feces within 24 h of dosing, confirming robust colonization. In combination, the engineered strains also delay (in fixed doses) or prevent (when continuously administered) death of infected hamsters upon challenge with high doses of virulent C. difficile. Finally, fixed-dose Syn-LAB ameliorates diarrhea in a non-lethal model of neonatal piglet enteritis. Taken together, our findings suggest that the two synthetic biologics may be effectively employed as non-antibiotic interventions for CDI.

Endothelial progenitor cell mobilization after percutaneous coronary intervention.

BACKGROUND: In animal models, circulating endothelial progenitor cells (EPC) have been shown to participate in repair of damaged or degenerating vascular surfaces. In humans, reduced EPC counts correlate with cardiovascular risk and disease outcome; yet it has been difficult to establish that EPC are in fact mobilized in response to vascular injury as a physiologic response. We therefore studied early (<12h) mobilization of EPCs into the peripheral circulation after a defined vascular manipulation, percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) and non-ACS patients. METHODS AND RESULTS: CD34/CD31 positive EPC colony forming units (EPC-CFU) were quantified by a blinded observer in peripheral blood samples from eight control patients with angiographically normal coronary arteries, and in 30 patients with coronary artery lesions before and 12h after PCI. All patients (n=38) had one or more CV risk factors. Ten patients presented with acute coronary syndrome (PCI(ACS)), and the rest (n=20) underwent elective PCI (PCI(Elect)). Despite the presence of an acute coronary syndrome, patients in the PCI(ACS) group did not present with increased EPC-CFU compared with either the PCI(Elect) or control groups (P>0.05). In addition, EPC-CFU (colonies/ml blood) increased significantly in the PCI(Elect) group after stent placement (11.8+1.6 before versus 16.5+1.9 after, P=0.0009), while in contrast, PCI did not stimulate EPC mobilization in patients in the PCI(ACS) group (9.6+3.2 before versus 6.5+1.8, P=0.20). We found a higher presenting vascular endothelial growth factor (VEGF) level in the PCI(Elect) group compared to PCI(ACS) (78.7+25.2 versus 15.3+7.9 pg/ml blood, P=0.02). However, VEGF levels increased after PCI only in the PCI(ACS) group (15.3+7.9 to 133.3+27.5 pg/ml, P=0.003) and not in the PCI(Elect) group (78.7+25.2 to 79.7+12.2 pg/ml, P=0.97). CONCLUSION: Our findings suggest that focal coronary endothelial injury as a result of PCI triggers early mobilization of EPC into the peripheral circulation in patients presenting for an elective PCI, without a corresponding rise in VEGF levels. In contrast, patients with an acute coronary syndrome fail to respond to PCI with early EPC mobilization despite a significant rise in VEGF. The results of the present study may suggest a novel mechanism for early EPC augmentation after PCI.

Repeat revascularization after contemporary percutaneous coronary intervention: an evaluation of staged, target lesion, and other unplanned revascularization procedures during the first year.

BACKGROUND: Although drug-eluting stents and intensive secondary prevention have contributed to improved outcomes after percutaneous coronary intervention (PCI), repeat revascularization remains relatively common in contemporary practice. We used data from the multicenter Evaluation of Drug-Eluting Stents and Ischemic Events registry to evaluate the relative frequency and timing of staged revascularization, target lesion revascularization (TLR), and other nontarget revascularization during the first year after contemporary PCI. METHODS AND RESULTS: Patients with staged revascularization, TLR, and other unplanned procedures (elsewhere in the target vessel or in other coronary arteries) were evaluated in time-dependent models using Kaplan-Meier life-table estimation. Predictors of TLR and unplanned revascularization at nontarget sites were identified using logistic regression. Between July 2004 to June 2007, 10 144 patients undergoing PCI were enrolled at 55 US hospitals, of whom 86% were treated with at least 1 drug-eluting stent. Twelve percent required repeat revascularization within the first year (3% staged; 9% unplanned). More than 75% of staged revascularizations were performed <30 days after index PCI, although there was significant variation in this practice across hospitals (range, 0%-54%). TLR occurred in 4.5% of patients, with higher hazard rates between 2 to 9 months after PCI, whereas the risk of unplanned non-TLR (4.4% cumulative incidence) was constant over time. CONCLUSIONS: Among unselected patients undergoing PCI in the drug-eluting stent era, the incidence of repeat revascularization at 1 year is ≈12%. Among unplanned procedures, only half are performed for TLR. To achieve further improvements in PCI outcomes, future efforts should concentrate as much on identifying ischemia-producing lesions and intensifying secondary prevention therapies as on the prevention of restenosis.

Hand-held plasma isolation device for point-of-care testing.

The ability to analyze a whole blood sample retrieved from a patient is a critical tool used for diagnosing many diseases and conditions. Real-time blood analyzers are already widely used in point-of-care diagnoses and treatment. Being able to analyze plasma that has been isolated from its whole blood source is another important diagnostic tool that has not yet been applied to point-of-care applications. Advancing plasma separation techniques to the extent that they can be integrated into a point-of-care device could expedite certain diagnostic decisions and treatments, increase the number and quality of diagnostic tests that can be administered point-of-care, and ultimately improve patient outcomes. The hand-held plasma isolation device (HHPID) utilizes a unique array of parallel fiber glass filters within a specialized housing to produce a plasma sample from a small quantity of whole blood. This can be done at a patient's bedside without a power supply. This would negate the need to send blood samples away to a laboratory to be centrifuged; a change that could save precious hours or minutes in critical care situations. Initial testing has suggested that the quality and composition of outputted plasma from the HHPID are comparable to plasma retrieved by centrifuging. The HHPID could serve as a companion device for current real-time blood analyzers, which can be enhanced to accept either a whole blood or a plasma sample depending on the blood parameter of interest.

In-hospital outcomes and cost comparison of femoropopliteal reopening strategies.

PURPOSE: Atherectomy has emerged as an alternative to percutaneous transluminal angioplasty (PTA) for endovascular reopening. Despite increasing use of atherectomy (and higher cost of atherectomy catheters compared with balloon catheters), few studies have compared outcomes and costs with other reopening strategies. METHODS: We performed a retrospective cohort study involving all patients undergoing isolated femoropopliteal PTA (n=69) or atherectomy (n=92) at our institution from 1/2005 to 4/2006. The choice of reopening strategy was left to the treating physician, and no patients with relative contraindications to stent placement (specifically common femoral artery lesions) were included. Device and supply costs were calculated using the hospital resource-based accounting system, and other costs were calculated using the hospital micro-cost accounting system. Professional fees were calculated from the Medicare Fee Schedule. RESULTS: Baseline characteristics were generally well matched. There were no significant differences in complications (vascular complications, urgent repeat reopening, death, myocardial infarction, or stroke) between groups (PTA 8.7% vs. atherectomy 5.4%, P=.53). PTA required more balloons (2.0±0.8 vs. 0.7±1.0, P<.001) and stents (1.5±0.8 vs. 0.2±0.5, P<.001), but fewer atherectomy catheters (0.0±0.0 vs. 1.2±0.4, P<.001). Neither procedural supply costs (PTA $3137±1459 vs. atherectomy $3338±1505, P=.20) nor total costs differed between PTA and atherectomy patients ($10,945±4521 vs. $10,783±3857, P=.42). CONCLUSIONS: Initial outcomes and costs are comparable for femoropopliteal PTA and atherectomy. The choice of reopening strategy should therefore be based on operator experience and anatomic suitability. Further studies are required to determine whether there are differences in long-term outcomes or costs between these approaches.

Comparison of bleeding complications using arterial closure device versus manual compression by propensity matching in patients undergoing percutaneous coronary intervention.

Arterial closure devices (ACDs) provide immediate hemostasis, improve comfort, and allow early ambulation after percutaneous coronary intervention (PCI). The aim of this study was to evaluate ACD utilization and post-PCI major bleeding in an unselected cohort. Patients receiving ACDs were propensity matched to those with manual compression to evaluate a primary end point of National Cardiovascular Data Registry (NCDR) major bleeding and a secondary end point of major bleeding stratified by previously developed NCDR bleeding risk categories. Bleeding events that required transfusion, prolonged hospital stays, and/or decreases in hemoglobin ≥3.0 g/dl were included. Length of stay, defined as days after PCI until discharge, was also evaluated. Secondary analysis of bleeding and complication rates between ACD types (suture vs collagen plug) was performed. Five thousand four hundred twenty-one patients underwent PCI, and 2,324 patients (43%) were included in the final propensity matching: 1,162 with ACDs and 1,162 manual compression patients. Major bleeding was reduced in ACD patients compared to those with manual compression (2.4% vs 5.2%, p <0.001), and NCDR high-risk patients receiving ACDs had the greatest reduction in major bleeds (3.1% vs 10.3%, p <0.001). Length of stay (1.9 ± 1.9 vs 2.3 ± 5.3 days, p = 0.007) and pseudoaneurysms (0.3% vs 1.1%, p = 0.028) were decreased in ACD patients. Suture-based devices revealed a lower composite event rate than collagen-plug ACDs (1.4% vs 3.4%, p = 0.048). In conclusion, ACD use is associated with reductions in NCDR major bleeding, length of stay, and pseudoaneurysms in PCI patients.

Tissue characterisation of atherosclerotic plaque in the left main: an in vivo intravascular ultrasound radiofrequency data analysis.

AIMS: To characterise plaque phenotypes in the left main stem (LMS) and the proximal left anterior descending (LAD) coronary artery using virtual histology assisted intravascular ultrasound (VH-IVUS). METHODS AND RESULTS: Patients with IVUS pullbacks including no less than the proximal 30 mm of the LAD and through the ostium of the left main were identified from a global IVUS registry. Plaque composition and phenotype frequency in the LMS and five consecutive non-overlapping 6 mm segments in the LAD were studied, resulting in six analysed segments per patient. There were 74 patients (72% male, mean age 65 years). The median LMS length was 5.4 mm (IQR 2.8-8.7 mm). The percent of fibrofatty plaque was greater in the LMS compared to the proximal LAD segments (27.9% [20.0-39.2] vs. 17.3% [12.2-23.1], p<0.001). Dense calcium and necrotic core content was less prevalent in the LMS compared to the LAD segments (2.5% [0.9-4.7] vs. 7.9% [4.1-12.3], p<0.001; and 8.0% [3.7-11.8] vs. 14% [9.2-17.9], p<0.001). The frequency of thin cap fibroatheroma (TCFA) was higher in the LAD compared with LMS (0% vs. 16.9% [4.9-34.5], p<0.001). Within the LAD, TCFA was most frequently observed in the second 6 mm segment, 12 mm from the ostium. CONCLUSIONS: TCFA was present more frequently in the proximal LAD than LMS, supporting the notion that plaque rupture occurs in non-uniform locations throughout the coronary tree and preferentially spares the LMS.

Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies.

We assessed the cardiovascular safety of liraglutide, a glucagon-like peptide-1 receptor agonist, using existing clinical data. Patient-level results from all completed phase 2 and 3 studies from the liraglutide clinical development programme were pooled to determine rates of major adverse cardiovascular events (MACE): cardiovascular death, myocardial infarction, stroke. MACE were identified by querying the study database using Medical Dictionary for Regulatory Activities (MedDRA) terms combined with serious adverse events recorded by study investigators. Broad, narrow, and custom groups of MedDRA queries were used. Candidate events from each query were independently adjudicated post hoc. In 15 studies (6638 patients; 4257 liraglutide treated), there were 114 patients with MACE identified using the broad MedDRA query. Of these, 44 were classified as serious adverse events and 39 were adjudicated as MACE. The incidence ratio for adjudicated broad/serious MACE associated with liraglutide was 0.73 (95% CI 0.38-1.41) versus all comparator drugs (metformin, glimepiride, rosiglitazone, insulin glargine, placebo), within cardiovascular safety limits defined by the United States Food & Drug Administration for diabetes therapies under current investigation.

Prognostic implications of creatine kinase-MB elevation after percutaneous coronary intervention: results from the Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) registry.

BACKGROUND: Creatine kinase-MB (CK-MB) elevation after percutaneous coronary intervention (PCI) has been associated with increased risk for mortality. Although most studies have defined periprocedural myocardial infarction (pMI) as an elevation in CK-MB >3× upper limit of normal (ULN), use of different CK-MB assays and variation in site-specific definitions of the ULN may limit the value of such relative thresholds. METHODS AND RESULTS: We used data from the multicenter Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) registry to examine the impact of variations in site-specific thresholds for CK-MB elevation on the incidence of pMI as well as the relationship between absolute peak levels of CK-MB after PCI and 1-year mortality. The study cohort consisted of 6347 patients who underwent nonemergent PCI and had normal CK-MB at baseline. Across the 59 study centers, the ULN for CK-MB ranged from 2.6 to 10.4 ng/mL (median, 5.0 ng/mL), and there was an inverse relationship between the site-specific ULN and the incidence of pMI (defined as CK-MB elevation >3× ULN). Although any postprocedure elevation of CK-MB was associated with an adverse prognosis, in categorical analyses, only CK-MB ≥50 ng/mL was independently associated with increased 1-year mortality (hazard ratio, 4.71; 95% confidence interval, 2.42 to 9.13; P<0.001). Spline analysis using peak CK-MB as a continuous variable suggested a graded, nonlinear relationship with 1-year mortality, with an inflection point at ≈30 ng/mL. CONCLUSIONS: Among unselected patients undergoing PCI, there is a graded relationship between CK-MB elevation after PCI and 1-year mortality that is particularly strong for large CK-MB elevations (>30 to 50 ng/mL). Future studies that include pMI as a clinical end point should consider using a core laboratory to assess CK-MB (to ensure consistency) and raising the threshold for defining pMI above current levels (to enhance clinical relevance).

Predicting restenosis of drug-eluting stents placed in real-world clinical practice: derivation and validation of a risk model from the EVENT registry.

BACKGROUND: Prediction of restenosis after percutaneous coronary intervention (PCI) remains challenging, and existing risk assessment algorithms were developed before the widespread adoption of drug-eluting stents (DES). METHODS AND RESULTS: We used data from the EVENT registry to develop a risk model for predicting target lesion revascularization (TLR) in 8829 unselected patients undergoing DES implantation between 2004 and 2007. Using a split-sample validation technique, predictors of TLR at 1 year were identified from two thirds of the subjects (derivation cohort) using multiple logistic regression. Integer point values were created for each predictor, and the summed risk score (range, 0 to 10) was applied to the remaining sample (validation cohort). At 1 year, TLR occurred in 4.2% of patients, and after excluding stent thrombosis and early mechanical complications, the incidence of late TLR (more likely representing restenosis-related TLR) was 3.6%. Predictors of TLR were age <60, prior PCI, unprotected left main PCI, saphenous vein graft PCI, minimum stent diameter < or =2.5 mm, and total stent length > or =40 mm. Comparison of observed versus predicted rates of TLR according to risk score demonstrated good model fit in the validation set. There was more than a 3-fold difference in TLR rates between the lowest risk category (score=0; TLR rate, 2.2%) and the highest risk category (score > or =5; TLR rate, 7.5%). CONCLUSIONS: The overall incidence of TLR remains low among unselected patients receiving DES in routine clinical practice. A simple risk model incorporating 6 readily available clinical and angiographic variables helps identify individuals at extremely low (<2%) and modestly increased (>7%) risk of TLR after DES implantation.