Standardized Definitions for Cardiogenic Shock Research and Mechanical Circulatory Support Devices: Scientific Expert Panel From the Shock Academic Research Consortium (SHARC).

The Shock Academic Research Consortium is a multi-stakeholder group, including representatives from the US Food and Drug Administration and other government agencies, industry, and payers, convened to develop pragmatic consensus definitions useful for the evaluation of clinical trials enrolling patients with cardiogenic shock, including trials evaluating mechanical circulatory support devices. Several in-person and virtual meetings were convened between 2020 and 2022 to discuss the need for developing the standardized definitions required for evaluation of mechanical circulatory support devices in clinical trials for cardiogenic shock patients. The expert panel identified key concepts and topics by performing literature reviews, including previous clinical trials, while recognizing current challenges and the need to advance evidence-based practice and statistical analysis to support future clinical trials. For each category, a lead (primary) author was assigned to perform a literature search and draft a proposed definition, which was presented to the subgroup. These definitions were further modified after feedback from the expert panel meetings until a consensus was reached. This manuscript summarizes the expert panel recommendations focused on outcome definitions, including efficacy and safety.

Defining Strategies of Modulation of Antiplatelet Therapy in Patients With Coronary Artery Disease: A Consensus Document from the Academic Research Consortium.

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.

Ticagrelor with or without aspirin following percutaneous coronary intervention in high-risk patients with concomitant peripheral artery disease: A subgroup analysis of the TWILIGHT randomized clinical trial.

BACKGROUND: The optimal antiplatelet regimen after percutaneous coronary intervention (PCI) in patients with peripheral artery disease (PAD) is still debated. This analysis aimed to compare the effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients with PAD undergoing PCI. METHODS: In the TWILIGHT trial, patients at high ischemic or bleeding risk that underwent PCI were randomized after 3 months of dual antiplatelet therapy (DAPT) to aspirin or matching placebo in addition to open-label ticagrelor for 12 additional months. In this post-hoc analysis, patient cohorts were examined according to the presence or absence of PAD. The primary endpoint was Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding. The key secondary endpoint was a composite of all-cause death, myocardial infarction (MI), or stroke. Endpoints were assessed at 12 months after randomization. RESULTS: Among 7,119 patients, 489 (7%) had PAD and were older, more likely to have comorbidities, and multivessel disease. PAD patients had more bleeding or ischemic complications than no-PAD patients. Ticagrelor monotherapy compared to ticagrelor plus aspirin was associated with less BARC 2, 3, or 5 bleeding in PAD (4.6% vs 8.7%; HR 0.52; 95%CI 0.25-1.07) and no-PAD patients (4.0% vs 7.0%; HR 0.56; 95%CI 0.45-0.69; interaction P-value .830) and a similar risk of death, MI, or stroke in these 2 groups (interaction P-value .446). CONCLUSIONS: Despite their higher ischemic and bleeding risk, patients with PAD undergoing PCI derived a consistent benefit from ticagrelor monotherapy after 3 months of DAPT in terms of bleeding reduction without any relevant increase in ischemic events. CLINICAL TRIAL REGISTRY INFORMATION:: https://www. CLINICALTRIALS: gov/study/NCT02270242.

Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium.

The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.

Sex-stratified differences in early antithrombotic treatment response in patients presenting with ST-segment elevation myocardial infarction.

BACKGROUND: The mechanisms underlying the increased risk of bleeding that female patients with ST-segment Elevation Myocardial Infarction (STEMI) exhibit, remains unclear. The present report assessed sex-related differences in response to pre-hospital dual antiplatelet therapy (DAPT) initiation in patients with STEMI. METHODS: The COMPARE CRUSH trial randomized patients presenting with STEMI to receive a pre-hospital loading dose of crushed or integral prasugrel tablets in the ambulance. In this substudy, we compared platelet reactivity levels and the occurrence of high platelet reactivity (HPR; defined as platelet reactivity ≥208) between sexes at 4 prespecified time points after DAPT initiation, and evaluated post-PCI bleeding between groups. RESULTS: Out of 633 STEMI patients, 147 (23%) were female. Females compared with males presented with significantly higher levels of platelet reactivity and higher HPR rates at baseline (232 [IQR, 209-256] vs 195 [IQR, 171-220], P < .01, and 76% vs 41%, OR 4.58 [95%CI, 2.52-8.32], P < .01, respectively). Moreover, female sex was identified as the sole independent predictor of HPR at baseline (OR 5.67 [95%CI, 2.56-12.53], P < .01). Following DAPT initiation, levels of platelet reactivity and the incidence of HPR were similar between sexes. Post-PCI bleeding occurred more frequently in females compared with males (10% vs 2%, OR 6.02 [95%CI, 2.61-11.87], P < .01). Female sex was an independent predictor of post-PCI bleeding (OR 3.25 [95%CI, 1.09-9.72], P = .04). CONCLUSIONS: In this contemporary STEMI cohort, female STEMI patients remain at risk of bleeding complications after primary PCI. However, this is not explained by sex-specific differences in the pharmacodynamic response to pre-hospital DAPT initiation.

Consensus minimum core data elements adapted to peripheral vascular intervention in the drug-eluting era: Consensus report from the Registry Assessment of Peripheral Interventional Devices (RAPID) Pathways "LEAN" working group.

Registry Assessment of Peripheral Interventional Devices (RAPID) initiated the Pathways Program to provide a transparent, collaborative forum in which to pursue insights into multiple unresolved questions on benefit-risk of paclitaxel-coated devices, including understanding the basis of the mortality signal, without a demonstrable potential biological mechanism, and whether the late mortality signal could be artifact intrinsic to multiple independent prospective randomized data sources that did not prespecify death as a long-term end point. In response to the directive, the LEAN-Case Report Form working group focused on enhancements to the RAPID Phase I Minimum Core Data set through the addition of key clinical modifiers that would be more strongly linked to longer-term mortality outcomes after peripheral arterial disease intervention in the drug-eluting device era, with the goal to have future mortality signals more accurately examined.

Definitions and Clinical Trial Design Principles for Coronary Artery Chronic Total Occlusion Therapies: CTO-ARC Consensus Recommendations.

Over the past 2 decades, chronic total occlusion (CTO) percutaneous coronary intervention has developed into its own subspecialty of interventional cardiology. Dedicated terminology, techniques, devices, courses, and training programs have enabled progressive advancements. However, only a few randomized trials have been performed to evaluate the safety and efficacy of CTO percutaneous coronary intervention. Moreover, several published observational studies have shown conflicting data. Part of the paucity of clinical data stems from the fact that prior studies have been suboptimally designed and performed. The absence of standardized end points and the discrepancy in definitions also prevent consistency and uniform interpretability of reported results in CTO intervention. To standardize the field, we therefore assembled a broad consortium comprising academicians, practicing physicians, researchers, medical society representatives, and regulators (US Food and Drug Administration) to develop methods, end points, biomarkers, parameters, data, materials, processes, procedures, evaluations, tools, and techniques for CTO interventions. This article summarizes the effort and is organized into 3 sections: key elements and procedural definitions, end point definitions, and clinical trial design principles. The Chronic Total Occlusion Academic Research Consortium is a first step toward improved comparability and interpretability of study results, supplying an increasingly growing body of CTO percutaneous coronary intervention evidence.

Ticagrelor with or without Aspirin in High-Risk Patients after PCI.

BACKGROUND: Monotherapy with a P2Y12 inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI). METHODS: In a double-blind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant bleeding among patients who were at high risk for bleeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We also evaluated the composite end point of death from any cause, nonfatal myocardial infarction, or nonfatal stroke, using a noninferiority hypothesis with an absolute margin of 1.6 percentage points. RESULTS: We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus placebo and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval [CI], 0.45 to 0.68; P<0.001). The difference in risk between the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving ticagrelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (difference, -0.06 percentage points; 95% CI, -0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority). CONCLUSIONS: Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke. (Funded by AstraZeneca; TWILIGHT ClinicalTrials.gov number, NCT02270242.).

Randomized evaluation of vessel preparation with orbital atherectomy prior to drug-eluting stent implantation in severely calcified coronary artery lesions: Design and rationale of the ECLIPSE trial.

BACKGROUND: Severe coronary artery calcification has been associated with stent underexpansion, procedural complications, and increased rates of early and late adverse clinical events in patients undergoing percutaneous coronary intervention. To date, no lesion preparation strategy has been shown to definitively improve outcomes of percutaneous coronary intervention for calcified coronary artery lesions. STUDY DESIGN AND OBJECTIVES: ECLIPSE (NCT03108456) is a prospective, randomized, multicenter trial designed to evaluate two different vessel preparation strategies in severely calcified coronary artery lesions. The routine use of the Diamondback 360 Coronary Orbital Atherectomy System is compared with conventional balloon angioplasty prior to drug-eluting stent implantation. The trial aims to enroll approximately 2000 subjects with a primary clinical endpoint of target vessel failure, defined as the composite of cardiac death, target vessel-related myocardial infarction, or ischemia-driven target vessel revascularization assessed at 1 year. The co-primary endpoint is the acute post-procedural in-stent minimal cross-sectional area as assessed by optical coherence tomography in a 500-subject cohort. Enrollment is anticipated to complete in 2022 with total clinical follow-up planned for 2 years. CONCLUSIONS: ECLIPSE is a large-scale, prospective randomized trial powered to demonstrate whether a vessel preparation strategy of routine orbital atherectomy system is superior to conventional balloon angioplasty prior to implantation of drug-eluting stents in severely calcified coronary artery lesions.

Pre-hospital treatment with crushed versus integral tablets of prasugrel in patients presenting with ST-Segment Elevation Myocardial Infarction-1-year follow-up results of the COMPARE CRUSH trial.

The present research letter reports the 1-year clinical outcomes of the randomized COMPARE CRUSH trial, which allocated STEMI patients at first medical contact in the ambulance to receive either crushed or integral tablets of prasugrel loading dose. This trial aimed to investigate whether early enhanced antiplatelet effect constituted by the crushed potent oral P2Y12 inhibitor prasugrel could lead to improved early myocardial reperfusion and clinical outcomes.

Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HBR.

AIMS: Patients at high bleeding risk (HBR) represent a prevalent subgroup among those undergoing percutaneous coronary intervention (PCI). Early aspirin discontinuation after a short course of dual antiplatelet therapy (DAPT) has emerged as a bleeding avoidance strategy. The aim of this study was to assess the effects of ticagrelor monotherapy after 3-month DAPT in a contemporary HBR population. METHODS AND RESULTS: This prespecified analysis of the TWILIGHT trial evaluated the treatment effects of early aspirin withdrawal followed by ticagrelor monotherapy in HBR patients undergoing PCI with drug-eluting stents. After 3 months of ticagrelor plus aspirin, event-free patients were randomized to 12 months of aspirin or placebo in addition to ticagrelor. A total of 1064 (17.2%) met the Academic Research Consortium definition for HBR. Ticagrelor monotherapy reduced the incidence of the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding compared with ticagrelor plus aspirin in HBR (6.3% vs. 11.4%; hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.35-0.82) and non-HBR patients (3.5% vs. 5.9%; HR 0.59, 95% CI 0.46-0.77) with similar relative (Pinteraction = 0.67) but a trend towards greater absolute risk reduction in the former [-5.1% vs. -2.3%; difference in absolute risk differences (ARDs) -2.8%, 95% CI -6.4% to 0.8%, P = 0.130]. A similar pattern was observed for more severe BARC 3 or 5 bleeding with a larger absolute risk reduction in HBR patients (-3.5% vs. -0.5%; difference in ARDs -3.0%, 95% CI -5.2% to -0.8%, P = 0.008). There was no significant difference in the key secondary endpoint of death, myocardial infarction, or stroke between treatment arms, irrespective of HBR status. CONCLUSIONS: Among HBR patients undergoing PCI who completed 3-month DAPT without experiencing major adverse events, aspirin discontinuation followed by ticagrelor monotherapy significantly reduced bleeding without increasing ischaemic events, compared with ticagrelor plus aspirin. The absolute risk reduction in major bleeding was larger in HBR than non-HBR patients.

Ticagrelor monotherapy in patients with chronic kidney disease undergoing percutaneous coronary intervention: TWILIGHT-CKD.

AIMS: The aim of this study was to assess the impact of chronic kidney disease (CKD) on the safety and efficacy of ticagrelor monotherapy among patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: In this prespecified subanalysis of the TWILIGHT trial, we evaluated the treatment effects of ticagrelor with or without aspirin according to renal function. The trial enrolled patients undergoing drug-eluting stent implantation who fulfilled at least one clinical and one angiographic high-risk criterion. Chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, was a clinical study entry criterion. Following a 3-month period of ticagrelor plus aspirin, event-free patients were randomly assigned to aspirin or placebo on top of ticagrelor for an additional 12 months. Of the 6835 patients randomized and with available eGFR at baseline, 1111 (16.3%) had CKD. Ticagrelor plus placebo reduced the primary endpoint of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding as compared with ticagrelor plus aspirin in both patients with [4.6% vs. 9.0%; hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.80] and without (4.0% vs. 6.7%; HR 0.59, 95% CI 0.47-0.75; Pinteraction = 0.508) CKD, but the absolute risk reduction was greater in the former group. Rates of death, myocardial infarction, or stroke were not significantly different between the two randomized groups irrespective of the presence (7.9% vs. 5.7%; HR 1.40, 95% CI 0.88-2.22) or absence of (3.2% vs. 3.6%; HR 0.90, 95% CI 0.68-1.20; Pinteraction = 0.111) CKD. CONCLUSION: Among CKD patients undergoing PCI, ticagrelor monotherapy reduced the risk of bleeding without a significant increase in ischaemic events as compared with ticagrelor plus aspirin.

Effect of Prehospital Crushed Prasugrel Tablets in Patients With ST-Segment-Elevation Myocardial Infarction Planned for Primary Percutaneous Coronary Intervention: The Randomized COMPARE CRUSH Trial.

BACKGROUND: Early treatment with a potent oral platelet P2Y12 inhibitor is recommended in patients presenting with ST-segment-elevation myocardial infarction scheduled to undergo primary percutaneous coronary intervention (pPCI). The impact on coronary reperfusion of crushed P2Y12 inhibitor tablets, which lead to more prompt and potent platelet inhibition, is unknown. METHODS: We conducted a randomized controlled, multicenter trial in the Netherlands, enrolling patients with ST-segment-elevation myocardial infarction scheduled to undergo pPCI. Patients were randomly allocated to receive in the ambulance, before transfer, a 60-mg loading dose of prasugrel either as crushed or integral tablets. The independent primary end points were thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at initial coronary angiography, and complete (≥70%) ST-segment resolution 1 hour after pPCI. The safety end points were TIMI major and Bleeding Academic Research Consortium ≥3 bleedings. Secondary end points included platelet reactivity and ischemic outcomes. RESULTS: A total of 727 patients were assigned to either crushed or integral tablets of prasugrel loading dose. The median time from study treatment to wire-crossing during pPCI was 57 (47-70) minutes. The primary end point TIMI 3 flow in the infarct-related artery before pPCI occurred in 31.0% in the crushed group versus 32.7% in the integral group (odds ratio, 0.92 [95% CI, 0.65-1.30], P=0.64). Complete ST-segment resolution 1 hour after pPCI was present in 59.9% in the crushed group versus 57.3% in the integral group (odds ratio, 1.11 [95% CI, 0.78-1.58], P=0.55). Platelet reactivity at the beginning of pPCI, measured as P2Y12 reactivity unit, differed significantly between groups (crushed, 192 [132-245] versus integral, 227 [184-254], P≤0.01). TIMI major and Bleeding Academic Research Consortium ≥3 bleeding occurred in 0% in the crushed group versus 0.8% in the integral group, and in 0.3% in the crushed group versus 1.1% in the integral group, respectively. There were no differences observed between groups regarding ischemic events at 30 days. CONCLUSIONS: Prehospital administration of crushed prasugrel tablets does not improve TIMI 3 flow in the infarct-related artery before pPCI or complete ST-segment resolution 1 h after pPCI in patients presenting with ST-segment-elevation myocardial infarction scheduled for pPCI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03296540.

Long-Term Safety and Efficacy of Durable Polymer Cobalt-Chromium Everolimus-Eluting Stents in Patients at High Bleeding Risk: A Patient-Level Stratified Analysis From Four Postapproval Studies.

BACKGROUND: Long-term outcomes in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention with a drug-eluting stent are unclear. Therefore, we aimed to evaluate long-term adverse events in HBR patients undergoing percutaneous coronary intervention with cobalt-chromium everolimus-eluting stent implantation. METHODS: We analyzed stratified data from 4 all-comers postapproval registries. Patients with at least 1 of the following criteria were categorized as HBR: age ≥75 years, history of major bleeding (MB), history of stroke, chronic oral anticoagulant use, chronic kidney disease, anemia, or thrombocytopenia. Additionally, in a separate analysis, patients were categorized according to the recently published Academic Research Consortium HBR criteria. The Kaplan-Meier method was used for time-to-event analyses. Coronary thrombotic events (CTE) included myocardial infarction or definite/probable stent thrombosis. MB was defined according to the TIMI (Thrombolysis in Myocardial Infarction) or GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) scales. Impact of CTE and MB on subsequent risk of mortality was assessed using multivariable Cox regression with MB and CTE included as time-updated covariates. RESULTS: Of the total 10 502 patients included, 3507 (33%) were identified as HBR. Compared with non-HBR patients, those at HBR had more comorbidities, higher lesion complexity, and a higher risk of 4-year mortality (Hazard Ratio [HR] 4.38 [95% CI, 3.76-5.11]). Results were qualitatively similar when using Academic Research Consortium criteria to define HBR. Risk of mortality was increased after CTE (HR 5.02 [95% CI, 3.93-6.41]), as well as after MB (HR 4.92 [95% CI, 3.82-6.35]). Of note, this effect was consistent across the spectrum of bleeding risk (P-interaction test 0.97 and 0.06, respectively). CONCLUSIONS: Compared with the non-HBR population, HBR patients experienced worse 4-year outcomes after percutaneous coronary intervention with cobalt-chromium everolimus-eluting stent. Both CTE and MB had a significant impact on subsequent risk of mortality irrespective of bleeding risk.

Important considerations for trials for peripheral arterial disease: Lessons learned from the paclitaxel mortality signal: A report on behalf of the registry assessment for peripheral interventional Devices (RAPID) Paclitaxel Pathways Program.

The Registry Assessment of Peripheral Devices (RAPID) convened a multidisciplinary group of stakeholders including clinicians, academicians, regulators and industry representatives to conduct an in-depth review of limitations associated with the data available to assess the paclitaxel mortality signal. Available studies were evaluated to identify strengths and limitations in the study design and data quality, which were translated to lessons learned to help guide the design, execution, and analyses of future studies. We suggest numerous actionable responses, such as the development and use of harmonized data points and outcomes in a consensus lean case report form. We advocate for reduction in missing data and efficient means for accrual of larger sample sizes in Peripheral arterial disease studies or use of supplemental datasets. Efforts to share lessons learned and working collaboratively to address such issues may improve future data in this device area and ultimately benefit patients. Condensed Abstract: Data sources evaluating paclitaxel-coated devices were evaluated to identify strengths and limitations in the study design and data quality, which were translated to lessons learned to help guide the design, execution, and analyses of future studies. We suggest numerous actionable responses, which we believe may improve future data in this device area and ultimately benefit patients.

Registry Assessment of Peripheral Interventional Devices objective performance goals for superficial femoral and popliteal artery peripheral vascular interventions.

BACKGROUND: The Superficial Femoral Artery-Popliteal EvidencE Development Study Group developed contemporary objective performance goals (OPGs) for peripheral vascular interventions (PVI) for superficial femoral artery (SFA)-popliteal artery disease using the Registry Assessment of Peripheral Interventional Devices. METHODS: The Society for Vascular Surgery Vascular Quality Initiative PVI registry from January 2010 to October 2016 was used to develop OPGs based on SFA-popliteal procedures (n = 21,377) for intermittent claudication and critical limb ischemia (CLI). OPGs included 1-year rates for target lesion revascularization (TLR), major amputation, and 1 and 4-year survival rates. OPGs were calculated for the SFA and popliteal arteries and stratified by four treatments: angioplasty alone (percutaneous transluminal angioplasty [PTA]), self-expanding stenting, atherectomy, and any treatment type. Outcomes were illustrated by unadjusted Kaplan-Meier analyses. RESULTS: Cohorts included PTA (n = 7505), stenting (n = 9217), atherectomy (n = 2510) and any treatment (n = 21,377). The mean age was 69 years, 58% were male, 79% were White, and 52% had CLI. The freedom from TLR OPGs at 1 year in the SFA were 80.3% (PTA), 83.2% (stenting), 83.9% (atherectomy), and 81.9% (any treatments). The freedom from TLR OPGs at 1 year in the popliteal were 81.3% (PTA), 81.3% (stenting), 80.2% (atherectomy), and 81.1% (any treatments). The freedom from major amputation OPGs at 1 year after SFA PVI were 93.4% (PTA), 95.7% (stenting), 95.1% (atherectomy), and 94.8% (any treatments). The freedom from major amputation OPG at 1 year after popliteal PVI were 90.5% (PTA), 93.7% (stenting), 91.8% (atherectomy), and 91.8%, (any treatments). The 4-year survival OPGs after SFA PVI were 76% (PTA), 80% (stenting), 82% (atherectomy), and 79% (any treatments), and for the popliteal artery were 72% (PTA), 77% (stenting), 82% (atherectomy), and 75% (any treatment). On a multivariable analysis, which included patient-level, leg-level, and lesion-level covariates, CLI was the single independent factor associated with increased TLR, amputation, and mortality. CONCLUSIONS: The Superficial Femoral Artery-Popliteal EvidencE Development OPGs define a new, contemporary benchmark for SFA-popliteal interventions using a large subset of real-world evidence to inform more efficient peripheral device clinical trial designs to support regulatory and clinical decision-making. It is appropriate to discuss proposals intended for regulatory approval with the US Food and Drug Administration to refine the OPG to match the specific trial population. The OPGs may be updated using coordinated registry networks to assess long-term real-world device performance.

Comparative influence of bleeding and ischemic risk factors on diabetic patients undergoing percutaneous coronary intervention with everolimus-eluting stents.

OBJECTIVE: To investigate the impact of ischemic and bleeding risk factors on long-term clinical outcomes of patients with diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI) with everolimus-eluting stents. BACKGROUND: Second-generation drug-eluting stents have substantially improved outcomes after PCI in the general population; however, DM patients continue to experience high rates of ischemic and bleeding complications. METHODS: DM patients from the pooled XIENCE V registry were divided into high or low bleeding and ischemic risk groups (HBR, LBR, HIR, and LIR) based on established bleeding (age ≥ 75 years; chronic kidney disease; anemia; prior stroke; oral anticoagulation; thrombocytopenia; prior major bleeding) and ischemic (acute coronary syndrome; prior myocardial infarction [MI]; ≥3 stents implanted; ≥3 vessels treated; ≥3 lesions treated; stent length > 60 mm; bifurcation treated with ≥2 stents; chronic total occlusion) risk factors. The primary outcomes were major adverse cardiac events (MACE; cardiac death, MI, or stent thrombosis) and major bleeding at 4-year follow-up. RESULTS: A total of 3,704 DM patients were divided into four groups (21.5% LBR/LIR; 39.0% LBR/HIR; 15.6% HBR/LIR; 23.9% HBR/HIR). Compared with LBR/LIR patients, those at HBR/HIR and HBR/LIR had a significantly higher risk of MACE (HR (95% CI) 2.7 (1.9-3.9) and 2.2 (1.5-3.2), respectively) and major bleeding (2.7 (1.6-4.8) and 2.6 (1.4-4.7), respectively), while LBR/HIR patients did not. CONCLUSIONS: Among DM patients undergoing PCI, presence of bleeding risk factors was associated with a higher risk of both ischemic and bleeding events, whereas commonly used features of ischemic risk did not impact long-term clinical outcomes.

Impact of renal function in high bleeding risk patients undergoing percutaneous coronary intervention: a patient-level stratified analysis from four post-approval studies.

Data on ischemic and bleeding outcomes after percutaneous coronary intervention (PCI) in high bleeding risk (HBR) patients with chronic kidney disease (CKD) are scarce. We aimed to evaluate the association between CKD and ischemic and bleeding outcomes in HBR patients who underwent PCI. Among 10,502 patients in the four post-approval registries evaluating patients undergoing PCI, 2,300 patients presented with at least one major or two minor ARC-HBR criteria. CKD was defined as eGFR < 60 mL/min/1.73 m2. These HBR patients were divided into 3 groups: eGFR < 30 mL/min/1.73 m2 defined as severe CKD (N = 221), eGFR 30- < 60 mL/min/1.73 m2 defined as moderate CKD (N = 970), eGFR ≥ 60 mL/min/1.73 m2 defined as no CKD (N = 1,109). The primary endpoint was the composite of cardiac death, myocardial infarction, or stent thrombosis, and the safety endpoint was major bleeding up to 4-year follow-up. HBR patients with CKD were more often female and had higher rates of comorbidities compared to those without CKD. Reduced renal function was associated with higher rates of the primary endpoint (severe CKD vs. moderate CKD vs. no CKD: 30.2% vs. 12.5% vs. 9.1%, P < 0.01) as well as major bleeding (10.3% vs. 8.9% vs. 6.4%, P = 0.03). After adjustment, severe CKD and moderate CKD in HBR patients remained independent predictors for the primary endpoint (HR [95%CI] 2.84 [1.94-4.16], P < 0.01, 1.48 [1.10-2.00], P < 0.01) compared to those with no CKD. However, decreased renal function was no longer significantly associated with major bleeding after adjustment. In conclusions, in HBR patients undergoing PCI, CKD has an important impact on major ischemic events after PCI.

Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS.

AIMS: The aim of this study was to determine the effect of ticagrelor monotherapy on clinically relevant bleeding and major ischaemic events in relation to clinical presentation with and without non-ST elevation acute coronary syndromes (NSTE-ACS) among patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS AND RESULTS: We conducted a pre-specified subgroup analysis of The Ticagrelor With Aspirin or Alone in High Risk Patients After Coronary Intervention (TWILIGHT) trial, which enrolled 9006 patients with high-risk features undergoing PCI with DES. After 3 months of dual antiplatelet therapy (DAPT) with ticagrelor plus aspirin, 7119 adherent and event-free patients were randomized in a double-blind manner to ticagrelor plus placebo versus ticagrelor plus aspirin for 12 months. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding while the composite of all-cause death, myocardial infarction (MI), or stroke was the key secondary outcome. Among patients with NSTE-ACS (n = 4614), ticagrelor monotherapy reduced BARC 2, 3, or 5 bleeding by 53% [3.6% vs. 7.6%; hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.36-0.61; P < 0.001) and in stable patients (n = 2503) by 24% (4.8% vs. 6.2%; HR 0.76; 95% CI 0.54-1.06; P = 0.11; nominal Pint = 0.03). Rates of all-cause death, MI, or stroke among those with (4.3% vs. 4.4%; HR 0.97; 95% CI 0.74-1.28; P = 0.84) and without (3.1% vs. 3.2%; HR 0.96; 95% CI 0.61-1.49; P = 0.85) NSTE-ACS were similar between treatment arms irrespective of clinical presentation (Pint = 0.96). CONCLUSION: Among patients with or without NSTE-ACS who have completed an initial 3-month course of DAPT following PCI with DES, ticagrelor monotherapy reduced clinically meaningful bleeding events without increasing ischaemic risk as compared with ticagrelor plus aspirin. The benefits of ticagrelor monotherapy with respect to bleeding events were more pronounced in patients with NSTE-ACS. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02270242.

Defining High Bleeding Risk in Patients Undergoing Percutaneous Coronary Intervention.

Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention-related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018. These meetings were organized by the Cardiovascular European Research Center on behalf of the ARC-HBR group and included representatives of the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, as well as observers from the pharmaceutical and medical device industries. A consensus definition of patients at high bleeding risk was developed that was based on review of the available evidence. The definition is intended to provide consistency in defining this population for clinical trials and to complement clinical decision-making and regulatory review. The proposed ARC-HBR consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention.