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Background The interaction between thrombosis and inflammation appears central to COVID-19-associated coagulopathy and likely contributes to poor outcomes. Tissue factor is a driver of disordered coagulation and inflammatory signaling in viral infections and is important for viral replication; therefore, tissue factor may be an important therapeutic target in COVID-19. Study Design ASPEN-COVID-19 (NCT04655586) is a randomized, prospective open-label blinded endpoint (PROBE), active comparator Phase 2b trial to evaluate the safety and efficacy of recombinant Nematode Anticoagulant Protein c2 (rNAPc2), a potent tissue factor inhibitor, in patients hospitalized with COVID-19 with elevated D-dimer levels. This report describes the design of the Phase 2b dose ranging and proof of concept study. Participants are randomly assigned, in a 1:1:2 ratio, to lower or higher dose rNAPc2 by subcutaneous injection on days 1, 3, and 5 or to heparin according to local standard of care; randomization is stratified by baseline D-dimer level (at 2X upper limit of normal). The primary efficacy endpoint for Phase 2b is proportional change in D-dimer concentration from baseline to Day 8 or day of discharge, whichever is earlier. The primary safety endpoint is major or non-major clinically relevant bleeding through Day 8. Phase 2b enrollment began in December 2020 and is projected to complete ∼160 participants by Q4 2021. Conclusions ASPEN-COVID-19 will provide important data on a novel therapeutic approach that may improve outcomes in hospitalized COVID-19 patients beyond available anticoagulants by targeting tissue factor, with potential effects on not only thrombosis but also inflammation and viral propagation.

Objective Acute coronary syndrome (ACS) trials typically use a composite primary outcome (myocardial infarction [MI], stroke, or cardiovascular death), but differential patient characteristics, timing, and consequences associated with individual component end points as first events have not been well studied. We compared patient characteristics and prognostic significance associated with first cardiovascular events in the post-ACS setting for initially stabilized patients. Methods We combined patient-level data from 4 trials of post-ACS antithrombotic therapies (PLATO, APPRAISE-2, TRACER, and TRILOGY ACS) to characterize the timing of and characteristics associated with first cardiovascular events (MI, stroke, or cardiovascular death). Landmark analysis at 7 days after index ACS presentation was used to focus on spontaneous, postdischarge events that were not confounded by in-hospital procedural complications. Using a competing risk framework, we tested for differential associations between prespecified covariates and the occurrence of nonfatal stroke vs MI as the first event, and we examined subsequent events after the first nonfatal event. Results Among 46,694 patients with a median follow-up of 358 (25th, 75th percentiles 262, 486) days, a first ischemic event occurred in 4,307 patients (9.2%) as follows: MI in 5.8% (n = 2,690), stroke in 1.0% (n = 477), and cardiovascular death in 2.4% (n = 1,140). Older age, prior stroke/transient ischemic attack, prior atrial fibrillation, and higher diastolic blood pressure were associated with a significantly greater risk of stroke vs MI, whereas prior percutaneous coronary intervention was associated with a greater risk of MI vs stroke. Second events occurred in 32% of those with a first nonfatal stroke at a median of 13 (3, 59) days after the first event and in 32% of those with a first nonfatal MI at a median of 35 (5, 137) days after the first event. The most common second event was a recurrent MI among those with MI as the first event and cardiovascular death among those with stroke as the first event. Conclusions Approximately 9% of patients experienced a first cardiovascular event in the post-ACS setting during a median follow-up of 1 year. Although the profile and prognostic implications of stroke vs MI as the first nonfatal event differ substantially, approximately one-third of these patients experienced a second event, typically soon after the first event. These findings have implications for improving post-ACS care and influencing the design of future cardiovascular trials.

Background In the SAFE-PCI for Women trial, patient preference for radial access for future procedures was greater than for femoral access. We sought to assess whether radial or femoral access impacts formal measures of quality-of-life (QOL) among women undergoing cardiac catheterization. Methods We assessed QOL using European quality of life–5 dimensions (EQ-5D) and EQ visual analog scale (EQ-VAS) scores among 304 women randomized to radial or femoral arteriotomy in the SAFE-PCI for Women trial at sites with QOL substudy approval. Patient surveys were administered at baseline, hospital discharge, and 30 days (for percutaneous coronary intervention patients). Results Women randomized to both treatments had similar EQ-5D index and EQ-VAS scores at baseline, hospital discharge, and 30-day follow-up. After adjustment for baseline scores, there was no effect of assigned treatment on EQ-5D (discharge 0.004; 95% CI −0.03 to 0.04; 30 days −0.03; 95% CI −0.09 to 0.02) or EQ-VAS (discharge −1.31; 95% CI −4.74 to 2.12; 30 days −2.10; 95% CI −8.92 to 4.71) scores. At discharge, 60.5% versus 63.5% ( P = .60) of patients in radial and femoral groups were free from access site pain; at 30 days, rates were 85.7% versus 77.6% ( P = .30), respectively. Patient preference for the same access strategy for repeat procedures was greater in the radial versus femoral group (77.2% vs 26.8%; P Conclusions Using established QOL instruments, we did not measure any difference in QOL or functional status according to access site strategy in women undergoing cardiac catheterization, yet patient preference for the radial approach was significantly greater. Other factors influencing patient choice for radial access should be investigated.

Background Older patients with atrial fibrillation (AF) and coronary artery disease (CAD) face high risk of stroke and bleeding with antithrombotic therapy. Balancing safe and effective use of aspirin, clopidogrel, and warfarin in this population is important. Methods From the Duke Databank for Cardiovascular Disease, we identified patients with AF ≥65 years old with angiographically confirmed CAD from 2000 to 2010. Antithrombotic use was described across age and Congestive heart failure, Hypertension, Age >75 years, Diabetes, prior Stroke/transient ischemic attack (CHADS 2 ) stroke risk and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding scores. Death and the composite of death, myocardial infarction, and stroke by antithrombotic strategy were reported. Results Of 2,122 patients ≥65 years old with AF and CAD, 477 (22.5%) were ≥80 years old; 1,133 (53.4%) had acute coronary syndromes. Overall rates of aspirin, clopidogrel, and warfarin use were 83.4%, 34.6%, and 38.9%, respectively. Compared with patients 65 to 79 years old, more patients ≥80 years old were at high stroke risk (CHADS 2 ≥2, 84.7% vs 57.8%) and high bleeding risk (ATRIA 5-10, 55.8% vs 23.3%). Warfarin use in both age groups increased with higher CHADS 2 scores and decreased with higher ATRIA scores. Of patients ≥80 years old with CHADS 2 ≥2, 150 (38.2%) received warfarin. Antithrombotic strategy was not associated with improved 1-year adjusted outcomes. Conclusions Among older patients with AF and CAD, overall warfarin use was low. Patients ≥80 years old at highest stroke risk received warfarin in similar proportions to the overall cohort. Further investigation into optimizing antithrombotic strategies in this population is warranted.

Background The contemporary need for repeat revascularization in older patients after percutaneous coronary intervention (PCI) has not been well studied. Understanding repeat revascularization risk in this population may inform treatment decisions. Methods We analyzed patients ≥65 years old undergoing native-vessel PCI of de novo lesions from 2005 to 2009 discharged alive using linked CathPCI Registry and Medicare data. Repeat PCIs within 1 year of index procedure were identified by claims data and linked back to CathPCI Registry to identify target vessel revascularization (TVR). Surgical revascularization and PCIs not back linked to CathPCI Registry were excluded from main analyses but included in sensitivity analyses. Independent predictors of TVR after drug-eluting stent (DES) or bare-metal stent (BMS) implantation were identified by multivariable logistic regression. Results Among 343,173 PCI procedures, DES was used in 76.5% (n = 262,496). One-year TVR ranged from 3.3% (overall) to 7.1% (sensitivity analysis). Precatheterization and additional procedure-related TVR risk models were developed in BMS (c-indices 0.54, 0.60) and DES (c-indices 0.57, 0.60) populations. Models were well calibrated and performed similarly in important patient subgroups (female, diabetic, and older [≥75 years]). The use of DES reduced predicted TVR rates in high-risk older patients by 35.5% relative to BMS (from 6.2% to 4.0%). Among low-risk patients, the number needed to treat with DES to prevent 1 TVR was 63-112; among high-risk patients, this dropped to 28-46. Conclusions In contemporary clinical practice, native-vessel TVR among older patients occurs infrequently. Our prediction model identifies patients at low versus high TVR risk and may inform clinical decision making.

Background New percutaneous coronary intervention (PCI) device technologies are often rapidly adopted into clinical practice, yet few studies have examined the overall impact of these new technologies on patient outcomes in community practice. Methods In hopes of determining temporal trends in PCI outcomes, we used data from the Centers for Medicare & Medicaid Service's Chronic Condition Warehouse (n = 3,250,836) by comparing patient characteristics and rates of 3-year major adverse cardiac events (MACE) across the balloon angioplasty (POBA) era (01/1991-09/1995), the bare metal stent (BMS) era (02/1998-04/2003), and the drug-eluting stent (DES) era (05/2004-10/2006). The adjusted association between era and outcomes was determined with Cox proportional hazards modeling (POBA era as reference). Results Compared with the POBA era, patients undergoing PCI were significantly older and had more medical comorbidities, and the risk for 3-year MACE was significantly lower during the BMS and DES eras (BMS vs. POBA adjusted HR [95% CI]: 0.930 [0.926–0.935]; DES vs. BMS: 0.831 [0.827–0.835]). Compared with males, the adjusted risk for 3-year MACE among females was lower during the POBA era, but slightly higher during the BMS and DES eras. Across all three eras, patients ≥75 years of age had higher adjusted risk for MACE compared with younger patients, and the risk for revascularization was lower for both females and older patients. Conclusions Despite its application in older and sicker Medicare beneficiaries, there has been a significant decrease in post-PCI MACE over time. The risk for death or myocardial infarction is higher among females and older patients compared with males and younger patients; therefore, future studies should focus on improving clinical outcomes in these high-risk subgroups.

Women are at higher risk than men for bleeding and vascular complications after percutaneous coronary intervention (PCI). Compared with femoral access, radial access reduces these complications but may be more challenging in women because of higher rates of radial artery spasm, tortuosity, and occlusion as well as lower rates of procedure success. Whether the safety advantages of radial versus femoral access in women undergoing PCI are outweighed by reduced effectiveness has not been studied. The Study of Access site For Enhancement of PCI for Women is a prospective, randomized clinical trial comparing radial with femoral arterial access in women undergoing PCI. In conjunction with the US Food and Drug Administration‧s Critical Path Cardiac Safety Research Consortium, this study embeds the randomized clinical trial into the existing infrastructure of the National Cardiovascular Data Registry™ CathPCI Registry™ through the National Institute of Health‧s National Cardiovascular Research Infrastructure. The primary efficacy end point is a composite of bleeding (Bleeding Academic Research Consortium types 2, 3, or 5) or vascular complication requiring intervention occurring at 72 hours after PCI or by hospital discharge. The primary feasibility end point is procedure success. Secondary end points include procedure duration, contrast volume, radiation dose, quality of life, and a composite of 30-day death, vascular complication, or unplanned revascularization.

Percutaneous coronary intervention (PCI) is an integral part of the treatment of coronary artery disease. The most common complication of PCI, bleeding, typically occurs at the vascular access site and is associated with short-term and long-term morbidity and mortality. Periprocedural bleeding also represents the primary safety concern of concomitant antithrombotic therapies essential for PCI success. Use of radial access for PCI reduces procedural bleeding and hence may change the risk profile and net clinical benefit of these drugs. This new drug-device safety interaction creates opportunities to advance the safe and effective use of antithrombotic agents during PCI. In June 2010 and March 2011, leaders from government, academia, professional societies, device manufacturing, and pharmaceutical industries convened for 2 think tank meetings. Titled TREAT I and II, these forums examined approaches to improve the overall safety of PCI by optimizing strategies for antithrombotic drug use and radial artery access. This article summarizes the content and proceedings of these sessions.