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Background The EXCEL trial reported similar five-year rates of the primary composite outcome of death, myocardial infarction (MI), or stroke after percutaneous coronary intervention (PCI) compared with coronary artery bypass grafting (CABG) for treatment of obstructive left main coronary artery disease (LMCAD). Aims We sought to determine whether these outcomes remained consistent regardless of geography of enrolment. Methods We performed a pre-specified subgroup analysis based on regional enrolment. Results Among 1,905 patients randomised to PCI (n=948) or CABG (n=957), 1,075 (56.4%) were recruited at 52 European Union (EU) centres, and 752 (39.5%) were recruited at 67 North American (NA) centres. EU versus NA patients varied according to numerous baseline demographics, anatomy, pharmacotherapy and procedural characteristics. Nonetheless, the relative rates of the primary endpoint after PCI versus CABG were consistent across EU versus NA centres at 30 days and 5 years. However, NA participants had substantially higher late rates of ischaemia-driven revascularisation (IDR) after PCI, driven predominantly by the need for greater target vessel and lesion revascularisation. This culminated in a significant difference in the relative risk of the secondary composite outcome of death, MI, stroke, or IDR at 5 years (pinteraction=0.02). Conclusions In the EXCEL trial, the relative risks for the 30-day and five-year primary composite outcome of death, MI or stroke after PCI versus CABG were consistent irrespective of geography. However, five-year rates of IDR after PCI were significantly higher in NA centres, a finding the Heart Team and patients should consider when making treatment decisions. ClinicalTrials.gov identifier: NCT01205776.

BACKGROUND: Compared with everolimus-eluting metallic stents, the Absorb bioresorbable scaffold (BRS) results in increased rates of myocardial infarction (MI) and scaffold thrombosis (ST) during its three-year bioresorption phase. It is unknown whether prolonged dual antiplatelet therapy (DAPT) duration might decrease the risk of ischaemic events. AIMS: We sought to evaluate the impact of DAPT duration on ischaemic and bleeding outcomes following BRS implantation. METHODS: We conducted an individual patient data pooled analysis from four ABSORB randomised trials and one prospective ABSORB registry. Study endpoints were MI, ST, bleeding, and death up to three-year follow-up. Propensity score-adjusted Cox regression analysis was used to account for baseline differences related to DAPT duration. RESULTS: The five ABSORB studies included 2,973 patients. DAPT use was 91.7%, 53.2%, and 48.0% at 1, 2, and 3 years, respectively. DAPT use within the first year after BRS implantation was associated with markedly lower risks of MI (adjusted hazard ratio [aHR] 0.17, 95% CI: 0.10-0.32; p

Background In the COAPT trial, transcatheter mitral valve repair with the MitraClip plus maximally tolerated guideline-directed medical therapy (GDMT) improved clinical outcomes compared with GDMT alone in symptomatic patients with heart failure (HF) and 3+ or 4+ secondary mitral regurgitation (SMR) due to left ventricular (LV) dysfunction. Aims In this COAPT substudy, we sought to evaluate two-year outcomes in HF patients with reduced LV ejection fraction (HFrEF; LVEF ≤40%) versus preserved LVEF (HFpEF; LVEF >40%) and in those with severe (LVEF ≤30%) versus moderate (LVEF >30%) LV dysfunction. Methods The principal effectiveness outcome was the two-year rate of death from any cause or HF hospitalisations (HFH). Subgroup analysis with interaction testing was performed according to baseline LVEF; 472 patients (82.1%) had HFrEF (mean LVEF 28.0%±6.2%; range 12% to 40%) and 103 (17.9%) had HFpEF (mean LVEF 46.6%±4.9%; range 41% to 65%), while 292 (50.7%) had severely depressed LVEF (LVEF ≤30%; mean LVEF 23.9%±3.8%) and 283 (49.3%) had moderately depressed LVEF (LVEF >30%; mean LVEF 39.0%±6.8%). Results The two-year rate of death or HFH was 56.7% in patients with HFrEF and 53.4% with HFpEF (HR 1.16, 95% CI: 0.86-1.57, p=0.32). MitraClip reduced the two-year rate of death or HFH in patients with HFrEF (HR 0.50, 95% CI: 0.39-0.65) and HFpEF (HR 0.60, 95% CI: 0.35-1.05), pint=0.55. MitraClip was consistently effective in reducing the individual endpoints of mortality and HFH, improving MR severity, quality of life, and six-minute walk distance in patients with HFrEF, HFpEF, LVEF ≤30%, and LVEF >30%. Conclusions In the COAPT trial, among patients with HF and 3+ or 4+ SMR who remained symptomatic despite maximally tolerated GDMT, the MitraClip was consistently effective in improving survival and health status in patients with severe and moderate LV dysfunction and those with preserved LVEF.

Background: There is a paucity of data regarding the effect of inhibition of the renin-angiotensin system on outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). We sought to examine long-term outcomes of patients with left main coronary disease (LMCAD) randomized to PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents or CABG according to treatment at discharge with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in the large-scale, multicenter, randomized EXCEL trial. Methods: EXCEL randomized 1905 patients with LMCAD of low and intermediate anatomical complexity (visually-assessed SYNTAX score ≤32) to PCI (n = 948) versus CABG (n = 957). Patients were categorized according to whether they were treated with ACEI/ARB at discharge; their outcomes from discharge to 5 years were examined using multivariable logistic regression with an offset for follow-up time. Results: Among 1775 patients discharged alive with known ACEI/ARB treatment status, 896 (50.5%) were treated with one of these agents. Among those treated with ACEI/ARB, the 5-year rate of all-cause death was similar after PCI or CABG (10.7% versus 9.8% respectively, adjOR, 0.94; 95% CI, 0.56-1.57) in contrast to patients not treated with ACEI/ARB (15.0% versus 7.8%, respectively, adjOR, 2.20; 95% CI, 1.32-3.67) (Pinteraction = 0.02). Significant interactions between treatment arm (PCI versus CABG) and ACEI/ARB treatment status were also found for cardiovascular death (Pinteraction = 0.03), ischemia-driven revascularization (Pinteraction = 0.03), target vessel revascularization (Pinteraction = 0.007) and target vessel failure (Pinteraction = 0.0009). Conclusion: In the EXCEL trial, the postdischarge rates of death and revascularization after 5 years were similar after PCI and CABG in patients with LMCAD treated with ACEI/ARB at discharge. In contrast, event rates were higher after PCI versus CABG in those not so treated.

Background: A consensus on preferred treatment for patients with EGFR-mutated (EGFRm) advanced or metastatic non-small-cell lung cancer (a/mNSCLC) who have progressed on osimertinib and platinum-based chemotherapy (PBC) has yet to be established. The study objectives were to describe patient characteristics and treatment patterns in this context and assess corresponding clinical outcomes in the US real-world setting. Methods: This study was a retrospective analysis of data sourced from Flatiron’s de-identified database, which included electronic health records and curated cancer data from approximately 280 US cancer clinics (~800 US sites of care). The index line of therapy (LOT) was defined as initiation of a new treatment regimen after osimertinib and PBC. Adults were eligible for inclusion if they: 1) were diagnosed with a/mNSCLC on or after January 1, 2011; 2) had evidence of an activating EGFR mutation (exon 19 or L858R); 3) initiated a new LOT between November 13, 2015, and June 30, 2021, after treatment with osimertinib and PBC. Treatment regimens in the index LOT were summarized, and real-world overall survival (rwOS, defined as the time from initiation of index LOT to death) and real-world progression-free survival (rwPFS, defined as the time from initiation of index LOT to disease progression or death) were assessed. Results: Among 273 study patients included, the majority were ≥65 years (57%), female (67%), Caucasian (65%; Asian, 17%; Black or African American, 6%), with no history of smoking (58%), performance status 0-1 (82%), and >2 prior LOT (64%). Median follow-up duration was 7.3 months. Index treatment regimens were classified as tyrosine kinase inhibitor (TKI) monotherapy (15%) or TKI in combination with non-immuno-oncologic agents (12%), non-platinum-based chemotherapy (23%), immuno-oncologic monotherapy (17%) or combination therapy (15%), PBC (12%), a regimen containing a clinical study drug (4%), or other NSCLC therapy (1%). Deaths occurred in 203 patients (74%) during follow-up; median rwOS was 8.6 months (95% confidence interval [CI], 7.4-9.8). Real-world progression occurred in 235 patients (86%); median rwPFS was 3.3 months (95% CI, 2.8-4.4). Conclusions: For patients with EGFRm a/mNSCLC, third-generation EGFR TKIs such as osimertinib can provide disease control, however progression is common. After disease progression, chemotherapy is often the next treatment of choice. Results of this real-world study show that treatment patterns after EGFR TKI and PBC are highly variable and suggest poor clinical outcomes, highlighting the need for more efficacious treatments among patients with previously treated a/mNSCLC. Citation Format: Jyoti D. Patel, Jie Meng, Sudarshan Phani, Aaron Crowley, Summera Zhou, Maribel Salas, Yoko Tanaka, Hoa Le, Jeffrey Anderson, Karen L. Reckamp. Clinical characteristics, real-world treatment patterns, and clinical outcomes among patients with previously treated metastatic or unresectable EGFR-mutated non-small cell lung cancer in the United States. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6754.

Background Whether the time of day of primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation myocardial infarction (STEMI) is associated with infarct size, microvascular obstruction (MVO), and prognosis is uncertain. We compared infarct size assessed by cardiac MRI (CMR) and clinical outcomes in STEMI patients according to the pPCI time of day from a large, individual patient-data pooled database. Methods We pooled patient-level data from five randomized pPCI trials in which infarct size was measured within 1 month by CMR. Patients were categorized according to the pPCI time of day. Results Among 1519 patients with STEMI, 794 (52.2%) underwent pPCI between 8:00 h and 15:59 h, 431 (28.4%) between 16:00 h and 23:59 h, and 294 (19.4%) between 24:00 h and 7:59 h. Infarct size was assessed in 1331 patients at a median of 3.0 days (interquartile range 2.0-5.0) after pPCI. Compared with patients who underwent PCI between 8:00 h and 15:59 h, infarct size was not significantly different for patients undergoing PCI from 16:00 h to 23:59 h [adjusted difference -0.7%, 95% confidence interval (CI) -3.1 to 1.7%, P = 0.46] or 24:00 h to 7:59 h (adjusted difference 0.9%, 95% CI -1.2 to 3.1%, P = 0.29). The time of day of pPCI was also unrelated to MVO and the 1-year risks of death or heart failure hospitalization. Conclusion In this large-scale, individual patient data pooled analysis, no association was found between the time of day of pPCI and infarct size, MVO, or prognosis after STEMI.

BACKGROUND: Acute coronary syndromes most commonly arise from thrombosis of lipid-rich coronary atheromas that have large plaque burden despite angiographically appearing mild.OBJECTIVES: We sought to examine the outcomes of percutaneous coronary intervention (PCI) of non-flow-limiting vulnerable plaques.METHODS: Three-vessel imaging was performed with a combination intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) catheter after successful PCI of all flow-limiting coronary lesions in 898 patients presenting with myocardial infarction (MI). Patients with an angiographically non-obstructive stenosis not intended for PCI but with IVUS plaque burden ≥65% were randomized to treatment of the lesion with a bioresorbable vascular scaffold (BVS) plus guideline-directed medical therapy (GDMT) vs. GDMT alone. The primary powered effectiveness endpoint was the IVUS-derived minimum lumen area (MLA) at protocol-driven 25-month follow-up. The primary (non-powered) safety endpoint was randomized target lesion failure (TLF; cardiac death, target vessel-related MI or clinically-driven target lesion revascularization) at 24 months. The secondary (non-powered) clinical effectiveness endpoint was randomized lesion-related major adverse cardiac events (MACE; cardiac death, MI, unstable angina, or progressive angina) at latest follow-up.RESULTS: A total of 182 patients were randomized (93 BVS, 89 GDMT alone) at 15 centers. The median angiographic diameter stenosis of the randomized lesions was 41.6%; by NIRS-IVUS median plaque burden was 73.7%, median MLA was 2.9 mm2, and median maximum lipid plaque content was 33.4%. Angiographic follow-up at 25 months was completed in 167 patients (91.8%), and median clinical follow-up was 4.1 years. The follow-up MLA in BVS-treated lesions was 6.9±2.6 mm2 compared with 3.0±1.0 mm2 in GDMT alone-treated lesions (least square means difference 3.9 mm2, 95% CI 3.3-4.5, PCONCLUSIONS: PCI of angiographically mild lesions with large plaque burden was safe, substantially enlarged the follow-up MLA and was associated with favorable long-term clinical outcomes, warranting the performance of an adequately powered randomized trial.

The win ratio was introduced in 2012 as a new method for examining composite endpoints and has since been widely adopted in cardiovascular (CV) trials. Improving upon conventional methods for analysing composite endpoints, the win ratio accounts for relative priorities of the components and allows the components to be different types of outcomes. For example, the win ratio can combine the time to death with the number of occurrences of a non-fatal outcome such as CV-related hospitalizations (CVHs) in a single hierarchical composite endpoint. The win ratio can provide greater statistical power to detect and quantify a treatment difference by using all available information contained in the component outcomes. The win ratio can also incorporate quantitative outcomes such as exercise tests or quality-of-life scores. There is a need for more practical guidance on how best to design trials using the win ratio approach. This manuscript provides an overview of the principles behind the win ratio and provides insights into how to implement the win ratio in CV trial design and reporting, including how to determine trial size.

Background Transcatheter mitral valve repair with the MitraClip results in marked clinical improvement in some but not all patients with secondary mitral regurgitation (MR) and heart failure (HF). Objectives This study sought to evaluate the clinical predictors of a major response to treatment in the COAPT trial. Methods Patients with HF and severe MR who were symptomatic on maximally tolerated guideline-directed medical therapy (GDMT) were randomly assigned to MitraClip plus GDMT or GDMT alone. Super-responders were defined as those alive without HF hospitalization and with ≥20-point improvement in the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score at 12 months. Responders were defined as those alive without HF hospitalization and with a 5 to Results Among 614 enrolled patients, 41 (6.7%) had missing KCCQ-OS data and could not be classified. At 12 months, there were 79 super-responders (27.2%), 55 responders (19.0%), and 156 nonresponders (53.8%) in the MitraClip arm compared with 29 super-responders (10.2%), 46 responders (16.3%), and 208 nonresponders (73.5%) in the GDMT-alone arm (overall p Conclusions Baseline predictors of clinical super-responders in patients with HF and severe secondary MR in the COAPT trial were lower serum creatinine, KCCQ-OS score and MitraClip treatment. Improved MR severity and reduced right ventricular systolic pressure at 30 days are associated with a long-term favorable clinical response after transcatheter mitral valve repair. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079 )

Aims Heart failure (HF) hospitalization prior to transcatheter aortic valve replacement (TAVR) is associated with increased post-procedural mortality. We sought to assess the association between recent (≤6 months) HF hospitalization and long-term adverse outcomes in patients with symptomatic, severe aortic stenosis, undergoing TAVR in the PARTNER 2 trial and registries. Methods and results Intermediate to high or even prohibitive risk patients who underwent TAVR in the PARTNER 2 trial and registries were included in the analysis. Clinical outcomes at 30 days and 2 years were compared between patients according to whether they were recently hospitalized for HF, using Kaplan-Meier event rates and study-stratified multivariable Cox proportional hazards regression models. A sensitivity analysis was conducted using propensity score matching. Of 3988 patients (99.8%) with available information on recent HF hospitalization, 1622 patients (40.7%) were hospitalized for HF symptoms during the 6 months prior to TAVR. After multivariable adjustments, recent HF hospitalization was associated with increased all-cause mortality at 30 days [adjusted hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.07-2.48, P = 0.02] and 2 years (adjusted HR 1.30, 95% CI 1.13-1.49, P = 0.0003), which was driven by increased cardiovascular mortality. Infective endocarditis rate at 2 years was also higher in patients with recent HF hospitalization (adjusted HR 2.35, 95% CI 1.38-4.01, P = 0.002). These results remained consistent when propensity score matching was used. Conclusion In a large cohort of patients with severe symptomatic aortic stenosis from the PARTNER 2 trial and registries, all-cause and cardiovascular mortality as well as infective endocarditis rates at 2 years were higher in patients with recent HF hospitalization.

Objectives The aim of this study was to examine the association between body mass index (BMI), infarct size (IS) and clinical outcomes. Background The association between obesity, IS, and prognosis in patients undergoing primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction is incompletely understood. Methods An individual patient-data pooled analysis was performed from 6 randomized trials of patients undergoing pPCI for ST-segment elevation myocardial infarction in which IS (percentage left ventricular mass) was assessed within 1 month (median 4 days) after randomization using either cardiac magnetic resonance (5 studies) or 99mTc sestamibi single-photon emission computed tomography (1 study). Patients were classified as normal weight (BMI Results Among 2,238 patients undergoing pPCI, 644 (29%) were normal weight, 1,008 (45%) were overweight, and 586 (26%) were obese. BMI was not significantly associated with IS, microvascular obstruction, or left ventricular ejection fraction in adjusted or unadjusted analysis. BMI was also not associated with the 1-year composite risk for death or heart failure hospitalization (adjusted hazard ratio: 1.21 [95% confidence interval: 0.74 to 1.71] for overweight vs. normal [p = 0.59]; adjusted hazard ratio: 1.21 [95% confidence interval 0.74 to 1.97] for obese vs. normal [p = 0.45]) or for death or heart failure hospitalization separately. Results were consistent when BMI was modeled as a continuous variable. Conclusions In this individual patient-data pooled analysis of 2,238 patients undergoing pPCI for ST-segment elevation myocardial infarction, BMI was not associated with IS, microvascular obstruction, left ventricular ejection fraction, or 1-year rates of death or heart failure hospitalization.

Background: Valve-in-valve (VIV) treatment with transcatheter aortic valve replacement (TAVR) is a viable option for patients with failing aortic bioprosthetic valves. Optimal management of those with concomitant mitral regurgitation (MR) remains undetermined. Therefore, we sought to assess the implications of concomitant MR in patients undergoing VIV-TAVR. Methods and Results: The PARTNER 2 VIV registry enrolled patients with degenerated surgical aortic bioprosthesis at high risk for reoperation. Patients with core-laboratory echocardiographic assessment of MR were analyzed; severe MR was excluded. We compared patients with ≤mild MR versus moderate MR and assessed changes in MR severity and clinical outcomes. A total of 339 patients (89 initial registry, 250 continued access) underwent VIV procedures; mean age 79.0 ± 10.2 years, mean Society of Thoracic Surgeon score 8.9 ± 4.5%. At baseline, 228/339 (67.3%) had ≤mild MR and 111/339 (32.7%) had moderate MR. In paired analysis, there was significant improvement in ≥moderate MR from baseline to 30 days (32.6% vs. 14.5%, p

Elderly patients may have increased platelet reactivity and adverse events after percutaneous coronary intervention. Whether age is an independent predictor of worse outcomes after accounting for platelet reactivity is unknown. We sought to determine the relation between age and platelet reactivity on 2-year outcomes after percutaneous coronary intervention with drug-eluting stents (DES). ADAPT-DES was a prospective observational registry comprising 8,582 DES-treated patients. Patients were categorized with an age cutoff of 75 years. On-clopidogrel platelet reactivity was evaluated with VerifyNow P2Y12 testing. Multivariable Cox proportional hazards regression models were used to describe the relation between increasing age and 2-year clinical outcomes. Patients ≥75 old were more likely to be women and had more cardiovascular risk factors and more extensive coronary artery disease than younger patients. Residual platelet reactivity on-clopidogrel increased slightly with age (adjusted r = 0.05, p0.0001). Age ≥75 years was associated with greater all-cause mortality (adjusted HR 1.64, 95% CI 1.25 to 2.15, p0.001), myocardial infarction (adjusted HR 1.33, 95% CI 1.01 to 1.74, p = 0.04) and clinically relevant bleeding (adjusted HR 1.33, 95% CI 1.10 to 1.61 p = 0.003). In contrast, the risk of stent thrombosis was independent of age (adjusted HR 0.83, 95% CI 0.46 to 1.52, and p = 0.55). Considered as a continuous variable, age was directly related to clinically relevant bleeding, cardiac and all-cause mortality, was inversely related to stent thrombosis, and was not related to myocardial infarction. There was no significant interaction between age and on-treatment platelet reactivity for the risk of 2-year clinical outcomes. In conclusion, increasing age had a stronger association with the risk of death and bleeding than of thrombotic events. Despite being associated with older age, higher residual platelet reactivity did not modify the adjusted relative risks of ischemic and bleeding events associated with age.

Background Autopsy studies suggest that implanting stents in lipid-rich plaque (LRP) may be associated with adverse outcomes. Objectives The purpose of this study was to evaluate the association between LRP detected by near-infrared spectroscopy (NIRS) and clinical outcomes in patients with coronary artery disease treated with contemporary drug-eluting stents. Methods In this prospective, multicenter registry, NIRS was performed in patients undergoing coronary angiography and possible percutaneous coronary intervention (PCI). Lipid core burden index (LCBI) was calculated as the fraction of pixels with the probability of LRP >0.6 within a region of interest. MaxLCBI4mm was defined as the maximum LCBI within any 4-mm-long segment. Major adverse cardiac events (MACE) included cardiac death, myocardial infarction, definite or probable stent thrombosis, or unplanned revascularization or rehospitalization for progressive angina or unstable angina. Events were subcategorized as culprit (treated) lesion–related, nonculprit (untreated) lesion–related, or indeterminate. Results Among 1,999 patients who were enrolled in the COLOR (Chemometric Observations of Lipid Core Plaques of Interest in Native Coronary Arteries Registry), PCI was performed in 1,621 patients and MACE occurred in 18.0% of patients, of which 8.3% were culprit lesion–related, 10.7% were nonculprit lesion–related, and 3.1% were indeterminate during 2-year follow-up. Complications from NIRS imaging occurred in 9 patients (0.45%), which resulted in 1 peri-procedural myocardial infarction and 1 emergent coronary bypass. Pre-PCI NIRS imaging was obtained in 1,189 patients, and the 2-year rate of culprit lesion–related MACE was not significantly associated with maxLCBI4mm (hazard ratio of maxLCBI4mm per 100: 1.06; 95% confidence interval: 0.96 to 1.17; p = 0.28) after adjusting clinical and procedural factors. Conclusions Following PCI with contemporary drug-eluting stents, stent implantation in NIRS-defined LRPs was not associated with increased periprocedural or late adverse outcomes compared with those without significant lipid.

Aim: To evaluate the impact of left ventricular ejection fraction (LVEF) on 3-year outcomes in patients with left main coronary artery disease (LMCAD) undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in the EXCEL trial. Methods and results: The EXCEL trial randomized patients with LMCAD to PCI with everolimus-eluting stents (n = 948) or CABG (n = 957). Among 1804 patients with known baseline LVEF, 74 (4.1%) had LVEF

The prognostic impact of resting heart rate (RHR) following revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with left main coronary artery disease (LMCAD) is unknown. We aimed to assess the effect of RHR at discharge on 3-year cardiovascular outcomes following PCI and CABG for LMCAD. In the EXCEL trial, 1,905 patients with LMCAD were randomized to PCI with everolimus-eluting stents versus CABG. RHR was measured at discharge following the index hospitalization. The principal outcome measure was the composite endpoint of death, myocardial infarction (MI) or stroke at 3 years. Among 1,303 patients in sinus rhythm with available ECGs, the median (IQR) discharge RHR was 72 (62to 81) bpm. Median discharge RHR was higher after CABG versus PCI (78 [IQR 70 to 86] versus 65 [IQR 59 to 74] bpm, p0.0001). At 3 years, 107 patients (8.2%) had a primary composite endpoint event including 61 patients (4.7%) who died. By multivariable analysis, discharge RHR assessed as a continuous variable (per 5 bpm) was an independent predictor at 3 years of the primary composite endpoint of death, MI, or stroke (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.06 to 1.25, p = 0.0006); the secondary composite endpoint of death, MI, stroke, or ischemia-driven revascularization at 3 years (HR 1.12, 95% CI 1.05 to 1.19, p = 0.0007); all-cause mortality (HR 1.18, 95% CI 1.07 to 1.31, p = 0.002); and cardiovascular death (HR 1.16, 95% CI 1.00 to 1.33, p = 0.046). No significant interactions were present between RHR and treatment with PCI versus CABG for the primary (p

BACKGROUND: Moderate or worse paravalvular regurgitation (PVR) post transcatheter aortic valve replacement (TAVR) is associated with increased mortality. The mechanisms by which this occurs are not fully understood. AIMS: The aim of this study was to determine the mechanism by which PVR leads to worse outcomes. METHODS: A total of 1,974 intermediate-risk patients who received TAVR in the PARTNER 2 trial and registries were grouped by PVR severity. Clinical and echocardiographic outcomes were compared. RESULTS: Overall 1,176 (60%) patients had none/trace, 680 (34%) had mild, and 118 (6%) had ≥moderate PVR. At two years, ≥moderate PVR patients had increased risks of all-cause (HR 2.33 [1.41-3.85], p-value=0.001) and cardiovascular death (HR 3.30 [1.74-6.28], p-value

Background: Circadian rhythms may influence myocardial tolerance to ischemia-reperfusion phenomena occurring during cardiac procedures. While conflicting results exist on the effect of time-of-day on surgical aortic valve replacement (SAVR), afternoon procedures could be associated with a reduced risk of death, rehospitalization or periprocedural myocardial infarction, compared with morning procedures. We examined the impact of procedure time-of-day on outcomes after transcatheter aortic valve replacement (TAVR) or SAVR. Methods: We analyzed patients at intermediate- or high-surgical risk who underwent elective TAVR (n=4457) or SAVR (n=1129) in the PARTNER (Placement of Aortic Transcatheter Valve) 1 and 2 trials and registries according to time-of-day (morning versus afternoon) using the Kaplan-Meier event rates and multivariable Cox proportional hazards regression models. Sensitivity analysis was conducted using 1:1 propensity-score matching. The primary end point was all-cause death or rehospitalization at 2 years. Results: At 2 years, no difference was observed between patients operated in the morning versus the afternoon within the SAVR (32.3% versus 30.6%, adjusted hazard ratio, 1.08 [95% CI, 0.82–1.41], P =0.58) and TAVR cohorts (35.7% versus 35.4%, adjusted hazard ratio, 1.01 [95% CI, 0.89–1.14], P =0.86) with regards to the primary end point. Rates of periprocedural myocardial infarction were low and similar between morning and afternoon in SAVR (1.6% versus 1.0%, P =0.51) and TAVR (0.4% versus 0.4%, P =0.86), as were all other clinical end points. Similar results were observed in propensity-score matched analysis. Conclusions: Procedure time-of-day was not associated with clinical outcomes after TAVR or SAVR. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00530894, NCT01314313, NCT03222141, and NCT03222128.

Background Transcatheter aortic valve replacement (TAVR) for degenerated surgical bioprosthetic aortic valves is associated with favorable early outcomes. However, little is known about the durability and longer-term outcomes associated with this therapy. Objectives The aim of this study was to examine late outcomes after valve-in-valve TAVR. Methods Patients with symptomatic degeneration of surgical aortic bioprostheses at high risk (≥50% major morbidity or mortality) for reoperative surgery were prospectively enrolled in the multicenter PARTNER (Placement of Aortic Transcatheter Valves) 2 valve-in-valve and continued access registries. Three-year clinical and echocardiographic follow-up was obtained. Results Valve-in-valve procedures were performed in 365 patients. The mean age was 78.9 ± 10.2 years, and the mean Society of Thoracic Surgeons score was 9.1 ± 4.7%. At 3 years, the overall Kaplan-Meier estimate of all-cause mortality was 32.7%. Aortic valve re-replacement was required in 1.9%. Mean transaortic gradient was 35.0 mm Hg at baseline, decreasing to 17.8 mm Hg at 30-day follow-up and 16.6 mm Hg at 3-year follow-up. Baseline effective orifice area was 0.93 cm2, increasing to 1.13 and 1.15 cm2 at 30 days and 3 years, respectively. Moderate to severe aortic regurgitation was reduced from 45.1% at pre-TAVR baseline to 2.5% at 3 years. Importantly, moderate or severe mitral and tricuspid regurgitation also decreased (33.7% vs. 8.6% [p Conclusions At 3-year follow-up, TAVR for bioprosthetic aortic valve failure was associated with favorable survival, sustained improved hemodynamic status, and excellent functional and quality-of-life outcomes. (The PARTNER II Trial: Placement of Aortic Transcatheter Valves II - PARTNER II - Nested Registry 3/Valve-in-Valve [PII NR3/ViV]; NCT03225001)

Aims Transcatheter aortic valve replacement (TAVR) is now an established therapy for intermediate-risk surgical candidates with symptomatic, severe aortic stenosis. The clinical impact of new-onset left bundle branch block (LBBB) after TAVR remains controversial and has not been studied in intermediate-risk patients. We therefore sought to analyse outcomes associated with new LBBB in a large cohort of intermediate-risk patients treated with TAVR. Methods and results A total of 2043 patients underwent TAVR in the PARTNER II trial and S3 intermediate-risk registry and survived to hospital discharge. Patients were excluded from the current analysis due to baseline conduction disturbances, pre-existing permanent pacemaker (PPM), and new PPM during the index hospitalization. Clinical outcomes at 2 years were compared between patients with and without persistent, new-onset LBBB at hospital discharge, and multivariable analysis was performed to identify predictors of mortality. Among 1179 intermediate-risk patients, new-onset LBBB at discharge occurred in 179 patients (15.2%). Patients with new LBBB were similar to those without except for more frequent diabetes and more frequent treatment with SAPIEN 3 vs. SAPIEN XT. At 2 years, new LBBB was associated with increased rates of all-cause mortality (19.3% vs. 10.8%, P = 0.002), cardiovascular mortality (16.2% vs. 6.5%, P Conclusions In a large cohort of intermediate-risk patients from the PARTNER II trial and registry, persistent, new-onset LBBB occurred in 15.2% of patients without baseline conduction disturbances or pacemaker. New LBBB was associated with adverse clinical outcomes at 2 years, including all-cause and cardiovascular mortality, rehospitalization, new pacemaker implantation, and worsened left ventricular systolic function. Clinical Trial Registration ClinicalTrials.gov #NCT01314313 and NCT03222128.

Combining patient-level data from clinical trials can connect rare phenomena with clinical endpoints, but statistical techniques applied to a single trial may become problematical when trials are p...

The prognostic impact of high-sensitivity C-reactive protein (CRP) levels in patients with left main coronary artery disease (LMCAD) treated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) is unknown. We sought to determine the effect of elevated baseline CRP levels on the 3-year outcomes after LMCAD revascularization and to examine whether CRP influenced the relative outcomes of PCI versus CABG.In the EXCEL trial, patients with LMCAD and Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) scores ≤32 were randomized to PCI versus CABG. The primary composite outcome of death, myocardial infarction (MI), or stroke was analyzed according to baseline CRP levels.Among 999 patients with available CRP levels, median CRP was 3.10 mg/L (interquartile range 1.12-6.40 mg/L). The rate of the primary composite end point of death, MI, or stroke at 3 years steadily increased with greater baseline CRP levels. The adjusted relationship between the 3-year composite rate of death, MI, or stroke and baseline CRP modeled as a continuous log-transformed variable demonstrated steadily increasing event rates with greater CRP levels (adjusted hazard ratio, 1.26, 95% CI 1.10-1.44, P = .0008). Similarly, patients with CRP ≥10 mg/L had a 3-fold higher risk of the 3-year primary end point compared to patients with lower CRP levels (adjusted hazard ratio 2.92, 95% CI 1.88-4.54, P.0001). The association between an elevated CRP level and the adjusted 3-year risk of the primary composite end point did not differ according to revascularization strategy (PIn patients with LMCAD undergoing revascularization, elevated baseline CRP levels were strongly associated with subsequent death, MI, and stroke at 3 years, irrespective of the mode of revascularization. Further studies are warranted to determine whether anti-inflammatory therapies may improve the prognosis of high-risk patients with LMCAD following revascularization.

Background Near-infrared spectroscopy (NIRS) and intravascular ultrasound are promising imaging modalities to identify non-obstructive plaques likely to cause coronary-related events. We aimed to assess whether combined NIRS and intravascular ultrasound can identify high-risk plaques and patients that are at risk for future major adverse cardiac events (MACEs). Methods PROSPECT II is an investigator-sponsored, multicentre, prospective natural history study done at 14 university hospitals and two community hospitals in Denmark, Norway, and Sweden. We recruited patients of any age with recent (within past 4 weeks) myocardial infarction. After treatment of all flow-limiting coronary lesions, three-vessel imaging was done with a combined NIRS and intravascular ultrasound catheter. Untreated lesions (also known as non-culprit lesions) were identified by intravascular ultrasound and their lipid content was assessed by NIRS. The primary outcome was the covariate-adjusted rate of MACEs (the composite of cardiac death, myocardial infarction, unstable angina, or progressive angina) arising from untreated non-culprit lesions during follow-up. The relations between plaques with high lipid content, large plaque burden, and small lumen areas and patient-level and lesion-level events were determined. This trial is registered with ClinicalTrials.gov, NCT02171065. Findings Between June 10, 2014, and Dec 20, 2017, 3629 non-culprit lesions were characterised in 898 patients (153 [17 women, 745 [83 men; median age 63 [IQR 55-70] years). Median follow-up was 3.7 (IQR 3.0-4.4) years. Adverse events within 4 years occurred in 112 (13.2 951.0-15.6) of 898 patients, with 66 (8.0 95.2-10.0) arising from 78 untreated non-culprit lesions (mean baseline angiographic diameter stenosis 46.9[SD 15.9]). Highly lipidic lesions (851 [24 of 3500 lesions, present in 520 [59 of 884 patients) were an independent predictor of patient-level non-culprit lesion-related MACEs (adjusted odds ratio 2.27, 95.25-4.13) and nonculprit lesion-specific MACEs (7.83, 4.12-14.89). Large plaque burden (787 [22 of 3629 lesions, present in 530 [59 of 898 patients) was also an independent predictor of non-culprit lesion-related MACEs. Lesions with both large plaque burden by intravascular ultrasound and large lipid-rich cores by NIRS had a 4-year non-culprit lesion-related MACE rate of 7.095.0-10.0). Patients in whom one or more such lesions were identified had a 4-year non-culprit lesion-related MACE rate of 13.295.4-17.6). Interpretation Combined NIRS and intravascular ultrasound detects angiographically non-obstructive lesions with a high lipid content and large plaque burden that are at increased risk for future adverse cardiac outcomes. Copyright (C) 2021 Elsevier Ltd. All rights reserved. BackgroundNear-infrared spectroscopy (NIRS) and intravascular ultrasound are promising imaging modalities to identify non-obstructive plaques likely to cause coronary-related events. We aimed to assess whether combined NIRS and intravascular ultrasound can identify high-risk plaques and patients that are at risk for future major adverse cardiac events (MACEs).MethodsPROSPECT II is an investigator-sponsored, multicentre, prospective natural history study done at 14 university hospitals and two community hospitals in Denmark, Norway, and Sweden. We recruited patients of any age with recent (within past 4 weeks) myocardial infarction. After treatment of all flow-limiting coronary lesions, three-vessel imaging was done with a combined NIRS and intravascular ultrasound catheter. Untreated lesions (also known as non-culprit lesions) were identified by intravascular ultrasound and their lipid content was assessed by NIRS. The primary outcome was the covariate-adjusted rate of MACEs (the composite of cardiac death, myocardial infarction, unstable angina, or progressive angina) arising from untreated non-culprit lesions during follow-up. The relations between plaques with high lipid content, large plaque burden, and small lumen areas and patient-level and lesion-level events were determined. This trial is registered with ClinicalTrials.gov, NCT02171065.FindingsBetween June 10, 2014, and Dec 20, 2017, 3629 non-culprit lesions were characterised in 898 patients (153 [17%] women, 745 [83%] men; median age 63 [IQR 55–70] years). Median follow-up was 3·7 (IQR 3·0–4·4) years. Adverse events within 4 years occurred in 112 (13·2%, 95% CI 11·0–15·6) of 898 patients, with 66 (8·0%, 95% CI 6·2–10·0) arising from 78 untreated non-culprit lesions (mean baseline angiographic diameter stenosis 46·9% [SD 15·9]). Highly lipidic lesions (851 [24%] of 3500 lesions, present in 520 [59%] of 884 patients) were an independent predictor of patient-level non-culprit lesion-related MACEs (adjusted odds ratio 2·27, 95% CI 1·25–4·13) and non-culprit lesion-specific MACEs (7·83, 4·12–14·89). Large plaque burden (787 [22%] of 3629 lesions, present in 530 [59%] of 898 patients) was also an independent predictor of non-culprit lesion-related MACEs. Lesions with both large plaque burden by intravascular ultrasound and large lipid-rich cores by NIRS had a 4-year non-culprit lesion-related MACE rate of 7·0% (95% CI 4·0–10·0). Patients in whom one or more such lesions were identified had a 4-year non-culprit lesion-related MACE rate of 13·2% (95% CI 9·4–17·6).InterpretationCombined NIRS and intravascular ultrasound detects angiographically non-obstructive lesions with a high lipid content and large plaque burden that are at increased risk for future adverse cardiac outcomes.FundingAbbott Vascular, Infraredx, and The Medicines Company.

INTRODUCTION The optimal choice of oral P2Y 12 receptor inhibitors has the potential to significantly influence outcomes. We seek to compare the safety and efficacy of the three most commonly used oral P2Y 12 receptor inhibitors (clopidogrel, prasugrel, and ticagrelor) in acute coronary syndromes (ACS) via a comprehensive systematic review and network meta-analysis. EVIDENCE ACQUISITION In line with the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, we performed a comprehensive search for RCTs which compared cardiovascular and hemorrhagic outcomes after use of at least two of the distinct oral P2Y 12 receptor inhibitors (i.e. clopidogrel, prasugrel, and ticagrelor). A search strategy has been designed to systematically search multiple databases, including MEDLINE with PubMed interface, The Cochrane Central Register of Controlled Trials, and Embase. In addition, key inclusion criteria will be trial size of at least 100 patients and at least 1 month of follow-up time. Several prespecified subgroups will be explored, including Asian patients, patients presenting with ST-elevation myocardial infarction, patients of advanced age, and others. EVIDENCE SYNTHESIS Exploratory frequentist pairwise meta-analyses will be based primarily on a random-effects method, relying on relative risks (RR) for short-term outcomes and incidence rate ratios (IRR) for long-term outcomes. Inferential frequentist network meta-analysis will be based primarily on a random-effects method, relying on RR and IRR as specified above. Results will be reported as point summary of effect, 95% CI, and P values for effect, and graphically represented using forest plots. CONCLUSIONS An international collaborative network meta-analysis has begun to comprehensively analyze the safety and efficacy of prasugrel, ticagrelor and clopidogrel, each on a background of aspirin, for management of patients with ACS. It is our hope that the rigor and breadth of the undertaking described herein will provide novel insights that will inform optimal patient care for patients with ACS treated conservatively, or undergoing revascularization.

Importance Among those with aortic stenosis, natriuretic peptide levels can provide risk stratification, predict symptom onset, and aid decisions regarding the timing of valve replacement. Less is known about the prognostic significance and potential clinical utility of natriuretic peptide levels measured after valve replacement. Objective To determine the associations of elevated B-type natriuretic peptide (BNP) levels after transcatheter aortic valve replacement (TAVR) and change in BNP levels between follow-up time points with risk of subsequent clinical outcomes. Design, Setting, and Participants In this cohort study, patients with severe symptomatic aortic stenosis at intermediate, high, or prohibitive surgical risk for aortic valve replacement who underwent TAVR from the PARTNER IIA cohort, PARTNER IIB cohort, SAPIEN 3 intermediate-risk registry, and SAPIEN 3 high-risk registry were included. B-type natriuretic peptide levels were obtained at baseline and discharge as well as 30 days and 1 year after TAVR. For each measurement, a BNP ratio was calculated using measured BNP level divided by the upper limit of normal for the assay used. Outcomes were evaluated in landmark analyses out to 2 years. Data were collected from April 2011 to January 2019. Main Outcomes and Measures All-cause death, cardiovascular death, rehospitalization, and the combined end point of cardiovascular death or rehospitalization. Results Among 3391 included patients, 1969 (58.1%) were male, and the mean (SD) age was 82 (7.5) years. Most patients had a BNP ratio greater than 1 at each follow-up time point, including 2820 of 3256 (86.6%) at baseline, 2652 of 2995 (88.5%) at discharge, 1779 of 2209 (80.5%) at 30 days, and 1799 of 2391 (75.2%) at 1 year. After adjustment, every 1-point increase in BNP ratio at 30 days (approximately equivalent to an increase of 100 pg/mL in BNP) was associated with an increased hazard of all-cause death (adjusted hazard ratio [aHR], 1.11; 95% CI, 1.07-1.15), cardiovascular death (aHR, 1.16; 95% CI, 1.11-1.21), and rehospitalization (aHR, 1.08; 95% CI, 1.03-1.14) between 30 days and 2 years. Among those with a BNP ratio of 2 or more at discharge, after adjustment, every 1-point decrease in BNP ratio between discharge and 30 days was associated with a decreased hazard of all-cause death (aHR, 0.92; 95% CI, 0.88-0.96) between 30 days and 2 years. Conclusions and Relevance Elevated BNP levels after TAVR was independently associated with increased subsequent mortality and rehospitalizations. Further studies to determine how best to mitigate this risk are warranted.

BACKGROUND While slow gait speed is known to be associated with poor outcomes in patients at high surgical risk who undergo transcatheter aortic valve replacement (TAVR), the prognostic significance of slow gait speed in intermediate risk TAVR patients is poorly understood. OBJECTIVES We assessed the association between baseline 6-min walk test (6MWT) performance and both 2-year mortality and health status in intermediate risk patients undergoing TAVR as a part of the PARTNER II/S3i studies. METHODS The association of baseline 6MWT with mortality over 2-years after TAVR was examined using Cox regression; both unadjusted and adjusted for age, left ventricular ejection fraction, coronary artery disease, pulmonary disease, renal insufficiency, and STS score. Patients were divided into four groups according to baseline 6MWT: unable to walk and in three equal tertiles of slow, medium, and fast walkers. Among surviving patients, improvement in 6MWT and quality of life were compared. RESULTS Among 2,037 intermediate risk TAVR patients (mean age 81.7 years, STS score 5.6%), 8.2% were unable to walk. Baseline 6MWT was associated with all-cause mortality over 2 years (Hazard ratio (HR) 0.87 per 50 m, 95% confidence interval [CI] 0.83 to 0.92, p

Transcatheter mitral valve repair with the MitraClip results in marked clinical improvement in some but not all patients with secondary mitral regurgitation (MR) and heart failure (HF).This study sought to evaluate the clinical predictors of a major response to treatment in the COAPT trial.Patients with HF and severe MR who were symptomatic on maximally tolerated guideline-directed medical therapy (GDMT) were randomly assigned to MitraClip plus GDMT or GDMT alone. Super-responders were defined as those alive without HF hospitalization and with ≥20-point improvement in the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score at 12 months. Responders were defined as those alive without HF hospitalization and with a 5 to 20-point KCCQ-OS improvement at 12 months. Nonresponders were those who either died, were hospitalized for HF, or had 5-point improvement in KCCQ-OS at 12 months.Among 614 enrolled patients, 41 (6.7%) had missing KCCQ-OS data and could not be classified. At 12 months, there were 79 super-responders (27.2%), 55 responders (19.0%), and 156 nonresponders (53.8%) in the MitraClip arm compared with 29 super-responders (10.2%), 46 responders (16.3%), and 208 nonresponders (73.5%) in the GDMT-alone arm (overall p 0.0001). Independent baseline predictors of clinical responder status were lower serum creatinine and KCCQ-OS scores and treatment assignment to MitraClip. MR grade and estimated right ventricular systolic pressure at 30 days were improved to a greater degree in super-responders and responders but not in nonresponders.Baseline predictors of clinical super-responders in patients with HF and severe secondary MR in the COAPT trial were lower serum creatinine, KCCQ-OS score and MitraClip treatment. Improved MR severity and reduced right ventricular systolic pressure at 30 days are associated with a long-term favorable clinical response after transcatheter mitral valve repair. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079).

Cigarette smoking is a well-known risk factor for coronary artery disease (CAD). However, the impact of smoking on outcomes after coronary revascularization, especially in patients with left main CAD (LMCAD) is less well understood. The EXCEL trial randomized 1,905 patients with LMCAD and visually assessed low or intermediate anatomical complexity (SYNTAX score ≤32) to PCI with everolimus-eluting stents or CABG. Patients were categorized according to smoking status (current, former, or never), and their outcomes at 5 years were compared by logistic regression with follow-up time included as a log-transformed offset variable. The primary endpoint was a composite of death, myocardial infarction, or stroke. Among 1893 patients with known smoking status at baseline, 416 (22%) were current smokers and 774 (41%) were former smokers. The crude rates of the primary endpoint were 19.5% for never smokers, 20.5% for former smokers (p = 0.61 vs never smokers), and 23.1% for smokers (p = 0.15 vs never smokers). Compared with never smokers, the adjusted risk of the primary endpoint was higher for current smokers (adjOR 1.82, 95% confidence interval [CI] 1.126 to 2.63; p = 0.001), but not for former smokers (adjOR 1.00, 95% CI 0.75 to 1.33, p = 0.10). The relative efficacy of PCI versus CABG for the 5-year primary endpoint was similar irrespective of smoking status (Pinteraction = 0.22). In conclusion, current smokers in the EXCEL trial had a higher adjusted 5-year risk of the primary composite endpoint of death, myocardial infarction, or stroke than never smokers, whereas former smokers were not at increased risk. Active smoking was a risk factor after LMCAD revascularization irrespective of revascularization method.

The aim of this study was to assess race-based differences in patients undergoing percutaneous coronary intervention from a large pooled database of randomized controlled trials.Data on race-based outcomes after percutaneous coronary intervention are limited, deriving mainly from registries and single-center studies.Baseline characteristics and outcomes at 30 days, 1 year, and 5 years were assessed across different races, from an individual patient data pooled analysis from 10 randomized trials. Endpoints of interest included death, myocardial infarction, and major adverse cardiac events (defined as cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization). Multivariate Cox proportional hazards regression was performed to assess associations between race and outcomes, controlling for differences in 12 baseline covariates.Among 22,638 patients, 20,585 (90.9%) were white, 918 (4.1%) were black, 404 (1.8%) were Asian, and 473 (2.1%) were Hispanic. Baseline and angiographic characteristics differed among groups. Five-year major adverse cardiac event rates were 18.8% in white patients (reference group), compared with 23.9% in black patients (p = 0.0009), 11.2% in Asian patients (p = 0.0007), and 21.5% in Hispanic patients (p = 0.07). Multivariate analysis demonstrated an independent association between black race and 5-year risk for major adverse cardiac events (hazard ratio: 1.28; 95% confidence interval: 1.05 to 1.57; p = 0.01).In the present large-scale individual patient data pooled analysis, comorbidities were significantly more frequent in minority-group patients than in white patients enrolled in coronary stent randomized controlled trials. After accounting for these differences, black race was an independent predictor of worse outcomes, whereas Hispanic ethnicity and Asian race were not. Further research examining race-based outcomes after percutaneous coronary intervention is warranted to understand these differences.

Background Individual randomized controlled trials (RCTs) of periprocedural anticoagulation with bivalirudin versus heparin during percutaneous coronary intervention (PCI) have reported conflicting results. Study-level meta-analyses lack granularity to adjust for confounders, explore heterogeneity, or identify subgroups that may particularly benefit or be harmed. Objective To overcome these limitations, we sought to develop an individual patient-data pooled database of RCTs comparing bivalirudin versus heparin. Methods We conducted a systematic review to identify RCTs in which ≥1,000 patients with acute myocardial infarction (AMI) undergoing PCI were randomized to bivalirudin versus heparin. Results From 738 identified studies, 8 RCTs met the prespecified criteria. The principal investigators of each study agreed to provide patient-level data. The data were pooled and checked for accuracy against trial publications, with discrepancies addressed by consulting with the trialists. Consensus-based definitions were created to resolve differing antithrombotic, procedural, and outcome definitions. The project required 3.5 years to complete, and the final database includes 27,409 patients (13,346 randomized to bivalirudin and 14,063 randomized to heparin). Conclusion We have created a large individual patient database of bivalirudin versus heparin RCTs in patients with AMI undergoing PCI. This endeavor may help identify the optimal periprocedural anticoagulation regimen for patient groups with different relative risks of adverse ischemic versus bleeding events, including those with ST-segment and non-ST-segment elevation MI, radial versus femoral access, use of a prolonged bivalirudin infusion or glycoprotein inhibitors, and others. Adherence to standardized techniques and rigorous validation processes should increase confidence in the accuracy and robustness of the results.

Background: Elevated resting heart rate (RHR) is associated with adverse cardiovascular outcomes in patients with untreated aortic valve stenosis (AS). However, the impact of RHR following transcatheter (TAVR) or surgical aortic valve replacement (SAVR) on cardiovascular outcomes is unknown. We therefore sought to determine the effect of RHR at 30 days after aortic valve replacement (AVR) on 2-year outcomes in patients with severe symptomatic AS. Methods: The study population consists of 3170 patients from the PARTNER 2 Trial and its embedded registries who underwent TAVR or SAVR for severe AS, and had available 12-lead electrocardiograms demonstrating sinus rhythm at 30 days post-procedure. Outcomes at 2 years were analyzed according to 30-day RHR modeled as a continuous variable and in groups (RHR ≥75 bpm and RHR Results: By multivariable analysis, RHR ≥75 bpm at 30 days after AVR was an independent predictor of the composite endpoint of all-cause death, rehospitalization or stroke (hazard ratio [HR] 1.26, 95% confidence interval [CI], 1.05–1.52, p = 0.015) and rehospitalization (HR 1.42, 95% CI, 1.12–1.79, p = 0.004). Similarly, RHR modeled as a continuous variable (per 5 bpm) remained an independent predictor of all-cause death, rehospitalization or stroke (adjusted HR 1.07, 95% CI, 1.03–1.11, p = 0.0007), and rehospitalization (adjusted HR 1.09, 95% CI, 1.04–1.14, p = 0.0003) at 2 years. Conclusions: In patients with severe AS treated with TAVR or SAVR, resting heart rate at 30 days post-procedure was an independent predictor of the composite endpoint of all-cause death, rehospitalization or any stroke, and of rehospitalization at 2 years.

OBJECTIVES We aimed to evaluate the safety and efficacy of the dedicated Tryton side branch (SB) stent for the treatment of true bifurcations involving large SBs. BACKGROUND Bifurcation lesions are associated with lower procedural success and a higher risk of adverse cardiac events. Provisional stenting (PS) is currently the default approach for the treatment of bifurcation lesions. The Tryton stent is a dedicated bifurcation stent system for the treatment of true bifurcation lesions. METHODS We performed an individual-patient-data pooled post-hoc analysis of the Tryton Pivotal randomized controlled trial and post-approval Confirmatory Study. Only patients with true bifurcations involving a SB ≥ 2.25 mm in diameter were included. The primary endpoint was non-inferiority of Tryton compared with PS for target vessel failure (TVF) at 1 year. RESULTS Of the 411 patients meeting the criteria for enrolment, 287 patients were treated with the Tryton stent and 124 with PS. Procedural success was higher in the Tryton group (95.4 versus 82.3%, P < 0.0001). TVF at 1 year was 8.1% in the Tryton group and 9.7% in the PS group, meeting the pre-specified criteria for non-inferiority established for the randomized controlled trail (pnon-inferiority = 0.02). At 9-month angiographic follow-up, SB diameter stenosis was significantly lower in the Tryton group (29.3 ± 21.9 versus 41.1 ± 17.5, P = 0.0008) and in-segment binary restenosis (diameter stenosis ≥ 50%) was higher in the PS group (19.0 versus 34.2%, respectively, P = 0.052). CONCLUSIONS In patients with true bifurcations involving a large SB, treatment with the Tryton SD Stent was clinically non-inferior to PS and showed favorable angiographic outcomes.

Objectives The aim of this study was to further evaluate clinical outcomes in patients with and without PCS. Background Prior cardiac surgery (PCS) is associated with increased surgical risk and post-operative complications following surgical aortic valve replacement (SAVR), but whether this risk is similar in transcatheter aortic valve replacement (TAVR) is unclear. Methods In the PARTNER 2A (Placement of Aortic Transcatheter Valve) trial, 2,032 patients with severe aortic stenosis at intermediate surgical risk were randomized to TAVR with the SAPIEN XT valve or SAVR. Adverse clinical outcomes at 30 days and 2 years were compared using Kaplan-Meier event rates and multivariate Cox proportional hazards regression models. The primary endpoint of the PARTNER 2 trial was all-cause death and disabling stroke. Results Five hundred nine patients (25.1%) had PCS, mostly (98.2%) coronary artery bypass grafting. There were no significant differences between TAVR and SAVR in patients with or without PCS in the rates of the primary endpoint at 30 days or 2 years. Nevertheless, an interaction was observed between PCS and treatment arm; whereas no-PCS patients treated with TAVR had higher rates of 30-day major vascular complications than patients treated with SAVR (adjusted hazard ratio: 2.66; 95% confidence interval: 1.68 to 4.22), the opposite was true for patients with PCS (adjusted hazard ratio: 0.27; 95% confidence interval: 0.11 to 0.66) (pinteraction Conclusions In the PARTNER 2A trial of intermediate-risk patients with severe aortic stenosis undergoing SAVR versus TAVR, the relative risk for 2-year adverse clinical outcomes was similar between TAVR and SAVR in patients with or without PCS.

Background: Patients with severe aortic stenosis (AS) at intermediate surgical risk, treated with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) have simi...

AIMS: Randomised controlled trials have reported instantaneous wave-free ratio (iFR) to be non-inferior to fractional flow reserve (FFR) for major adverse cardiovascular events at one year; however, iFR is limited by sensitive landmarking of the pressure waveform, and the assumption that maximal flow and minimal resistance occur during a fixed period of diastole. We sought to validate the resting full-cycle ratio (RFR), a novel non-hyperaemic index of coronary stenosis severity based on unbiased identification of the lowest distal coronary pressure to aortic pressure ratio (Pd/Pa), independent of the ECG, landmark identification, and timing within the cardiac cycle.METHODS AND RESULTS: VALIDATE-RFR was a retrospective study designed to derive and validate the RFR. The primary endpoint was the agreement between RFR and iFR. RFR was retrospectively determined in 651 waveforms in which iFR was measured using a proprietary Philips/Volcano wire. RFR was highly correlated to iFR (R2=0.99, pCONCLUSIONS: RFR is diagnostically equivalent to iFR but unbiased in its ability to detect the lowest Pd/Pa during the full cardiac cycle, potentially unmasking physiologically significant coronary stenoses that would be missed by assessment dedicated to specific segments of the cardiac cycle.

BACKGROUND Peripheral arterial disease (PAD) is one of the most common manifestations of atherosclerotic disease worldwide. Peripheral arterial calcification reduces acute success and long-term patency of endovascular therapy for PAD. Several calcium modification devices are available for use in peripheral interventions. Outcomes after peripheral intravascular lithotripsy (IVL), a novel approach using pulsatile sonic waves to treat luminal and medial calcium in patients with PAD, have not been extensively characterized. Therefore, we sought to perform an individual patient-level data (IPD) pooled analysis of available studies to evaluate the efficacy and safety of IVL in the treatment of PAD. METHODS AND RESULTS We pooled IPD, including baseline and procedural variables, from five prospective studies which assessed IVL in the treatment of patients with extensive peripheral artery calcification. Final postprocedural percent diameter stenosis (%DS) and procedural angiographic complications were assessed by independent core laboratory. Efficacy endpoints were analyzed using linear mixed effects models and safety endpoints were tabulated overall and by vascular bed. Among 336 patients who underwent endovascular revascularization with use of IVL, there was a significant reduction between pre-procedural and final %DS of 55.1% (95% confidence interval 53.3-57.0%, p

Background: The feasibility of intravascular lithotripsy (IVL) for modification of severe coronary artery calcification (CAC) was demonstrated in the Disrupt CAD I study (Disrupt Coronary Artery Disease). We next sought to confirm the safety and effectiveness of IVL for these lesions. Methods: The Disrupt CAD II study was a prospective multicenter, single-arm post-approval study conducted at 15 hospitals in 9 countries. Patients with severe CAC with a clinical indication for revascularization underwent vessel preparation for stent implantation with IVL. The primary end point was in-hospital major adverse cardiac events (cardiac death, myocardial infarction, or target vessel revascularization). An optical coherence tomography substudy was performed to evaluate the mechanism of action of IVL, quantifying CAC characteristics and calcium plaque fracture. Independent core laboratories adjudicated angiography and optical coherence tomography, and an independent clinical events committee adjudicated major adverse cardiac events. Results: Between May 2018 and March 2019, 120 patients were enrolled. Severe CAC was present in 94.2% of lesions. Successful delivery and use of the IVL catheter was achieved in all patients. The post-IVL angiographic acute luminal gain was 0.83±0.47 mm, and residual stenosis was 32.7±10.4%, which further decreased to 7.8±7.1% after drug-eluting stent implantation. The primary end point occurred in 5.8% of patients, consisting of 7 non–Q-wave myocardial infarctions. There was no procedural abrupt closure, slow or no reflow, or perforations. In 47 patients with post-percutaneous coronary intervention optical coherence tomography, calcium fracture was identified in 78.7% of lesions with 3.4±2.6 fractures per lesion, measuring 5.5±5.0 mm in length. Conclusions: In patients with severe CAC who require coronary revascularization, IVL was safely performed with high procedural success and minimal complications and resulted in substantial calcific plaque fracture in most lesions. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03328949.

Objectives The aim of this study was to assess the implications of concomitant tricuspid regurgitation (TR) in patients undergoing valve-in-valve (VIV) transcatheter aortic valve replacement. Background Patients undergoing VIV transcatheter aortic valve replacement with concomitant TR may have worse outcomes, and optimal management remains undetermined. Methods The multicenter PARTNER 2 (Placement of Aortic Transcatheter Valves) VIV trial enrolled patients with symptomatic degenerated surgical aortic bioprostheses who were at high risk for reoperation. Outcomes were assessed between patients with mild or no TR versus moderate or severe TR. Results A total of 237 patients underwent VIV procedures (mean age 78.7 ± 10.8 years, mean Society of Thoracic Surgeons score 9.1 ± 4.8%). In this cohort, 162 patients (68.4%) had mild or no TR, and 75 patients (31.6%) had moderate or severe TR. Although there was no difference in New York Heart Association functional class III or IV symptomatic status (89.3% vs. 91.4%; p = 0.62) or moderate or severe right ventricular dysfunction (9.4% vs. 16.9%; p = 0.11), patients with moderate or severe TR were more likely to be at high surgical risk, with a Society of Thoracic Surgeons score of >8 (62.7% vs 46.9%; p = 0.02). There was no difference in a composite endpoint of death and rehospitalization between moderate or severe TR and mild or no TR, either at 30 days (10.7% vs. 9.9%; p = 0.85) or at 1-year follow-up (24.1% vs. 23.2%; p = 0.80). There was a significant reduction in overall moderate or severe TR from baseline at 30 days (31.1% vs. 21.1%; p = 0.002), which was sustained at 1-year follow-up (38.0% vs. 22.8%; p = 0.004). Conclusions Despite higher predicted surgical risk, the presence of TR was not a predictor of long-term outcomes. Importantly, there was significant reduction in TR severity at both short- and long-term follow-up. In selected patients undergoing VIV transcatheter aortic valve replacement, it may be appropriate to conservatively manage concomitant TR.

Background QRS fragmentation (fQRS) is believed to reflect myocardial scar formation in patients with coronary disease. Whether early formation of fQRS in patients with ST-segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) is correlated with infarct size and prognosis is unknown. We assessed the prognostic value of fQRS at 60min post-PCI and its correlation with infarct size in patients with anterior STEMI managed with primary PCI. Methods The INFUSE-AMI trial enrolled 452 patients with anterior STEMI undergoing primary PCI. Electrocardiograms (ECGs) were performed at baseline and 60min post-PCI. Infarct size was evaluated using cardiac magnetic resonance imaging at 30days post-PCI. Target vessel failure (TVF) was defined as the composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target vessel revascularization. Study groups were defined as patients with versus without fQRS at 60min post-PCI. Results Out of 421 patients with ECG data 60min post-PCI, 68 patients (16.2%) had fQRS. Patients with versus without fQRS had similar baseline characteristics and infarct size (16.9%±8.7% vs. 16.1%±10.5%, p=0.62), but patients with fQRS had higher adjusted risk of 1-year TVF (adjusted HR 2.27, 95% CI 1.06–4.89, p=0.036) and a trend toward a higher risk of the composite cardiac death or target vessel myocardial infarction (9.0% vs. 4.1%, p=0.08) at 1year. Conclusion fQRS in patients with STEMI is associated with TVF but does not correlate with infarct size.

Objectives The purpose of this study was to identify sex-specific outcomes of intermediate risk patients undergoing transcatheter aortic valve replacement with the SAPIEN 3 valve. Background A survival difference has been observed in women as compared with men in inoperable and high-risk patients receiving early-generation balloon-expandable valves for transcatheter aortic valve replacement (TAVR). Whether a sex-specific outcome difference persists with newer-generation valves and in lower-risk patients is unknown. Methods The PARTNER (Placement of Aortic Transcatheter Valves) II S3 trial included high-risk (HR) (Society of Thoracic Surgeons risk score >8% or heart team determination) and intermediate-risk (IR) (Society of Thoracic Surgeons risk score 4% to 8% or heart team determination) patients with severe symptomatic aortic stenosis who were treated with TAVR with the SAPIEN 3 valve. Patient characteristics and clinical outcomes at 30 days and 1 year were compared by sex. Results Between October 2013 and December 2014, 1,661 patients were enrolled: 583 were HR (338 men, 245 women) and 1,078 were IR (666 men, 412 women). In both cohorts, women were more likely than men to be frail (22% vs. 13%; p Conclusions The study found no apparent sex-specific differences in survival or stroke in this trial of TAVR. This may reflect the changing demographic of patients enrolled, use of newer-generation valves with more sizes available, and more accurate valve sizing techniques.

Background In patients with severe aortic regurgitation (AR), the left ventricular ejection fraction (LVEF) and left ventricle (LV) size are crucial for determining clinical prognosis and timing of valve intervention. In clinical practice, LV internal diameters obtained at end-diastole are used to assess the degree of LV dilatation. Whether quantification of LV volumes would provide more robust information as compared to LV linear dimensions is unknown. Methods We retrospectively analyzed preoperative and postoperative transthoracic echocardiograms of patients who underwent aortic valve replacement (AVR) for severe AR. Indexed linear LV end-diastolic and end-systolic diameters along with indexed LV end-diastolic and end-systolic volumes were obtained as per current guidelines. Post-AVR LV reverse remodeling, defined as ≥10% reduction in measures of LV volumes (Teichholz and Simpson's methods), was determined. Positive and negative agreement was calculated between the volume- and diameter-based LV reverse remodeling. Results Sixty-two consecutive patients were included. Nine patients (17%) without LV reverse remodeling based on Teichholz were reclassified as having LV reverse remodeling based on Simpson (positive agreement 0.846 [95% CI 0.772, 0.921], negative agreement 0.200 [95% CI -0.350, 0.435]). Left ventricle (LV) reverse remodeling assessed by the Teichholz method was underestimated by a mean of 31 mL/m2 (β = -0.65 [95% CI -1.06 to -0.24], P = .003) compared to Simpson method. Conclusion Compared to the volume-based method, diameter-based LV measurement incorrectly identified LV reverse remodeling post-AVR in 17% of patients with severe AR. Left ventricle (LV) volume may be a better measure to assess LV remodeling post-AVR than LV diameter-based measurements.

Background: The determinants and significance of early (30-day) heart failure symptoms after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI) remain unclear. We investigated the clinical and imaging correlates of early post-discharge heart failure in patients with STEMI, and evaluated its impact on clinical outcomes. Methods: Patients from the INFUSE-AMI trial were categorized according to New York Heart Association (NYHA) functional classification at their 30-day visit (NYHA class ≥2 versus 1). Independent correlates of NYHA class ≥2 were determined by multivariable logistic regression. A landmark analysis beyond 30 days was performed to assess the impact of 30-day NYHA class ≥2 on 1-year risk of death or hospitalization for heart failure. Results: Among 402 patients enrolled in the INFUSE-AMI trial with data on NYHA class at 30 days, 76 (18.9%) had NYHA class ≥2. Independent correlates of 30-day NYHA class ≥2 were age, Killip class ≥2 at presentation, heart rate at presentation, intraprocedural no-reflow, and 30-day infarct size (% total ventricular mass). After adjustment for infarct size, patients with NYHA class ≥2 remained at higher risk of death or hospitalization for heart failure at 1-year follow-up compared to those in NYHA class 1 (11.8% vs. 2.8%, adjusted hazard ratio 3.78, 95% confidence interval 1.16–12.22, P=0.03). Conclusions: Clinical, procedural, and imaging variables predict the development of clinical heart failure after primary percutaneous coronary intervention in patients with STEMI. Early post-discharge heart failure symptoms identify a high-risk patient cohort for subsequent heart failure hospitalization and death, independent of infarct size. Trial Registration: ClinicalTrials.gov ; NCT00976521

Objectives This study sought to determine if indexed effective orifice area (EOAi), using left ventricular outflow tract measured from computed tomography (EOAiCT), reclassified prosthesis–patient mismatch (PPM) compared with conventional echocardiogram-defined measurements (EOAiTTE). Background PPM does not predict mortality following transcatheter aortic valve replacement (TAVR). However, it is unknown if the EOAiCT of the left ventricular outflow tract improves risk stratification. Methods A total of 765 TAVR patients from the PARTNER II (Placement of Aortic Transcatheter Valves II) trial S3i cohort were evaluated. EOAi was calculated using the continuity equation, and the left ventricular outflow tract area was derived from baseline computed tomography. Traditional echocardiographic categories defined PPM: absent (>0.85 cm2/m2), moderate (≥0.65 and ≤0.85 cm2/m2), or severe (≤0.65 cm2/m2). Correlation of EOAiCT and EOAiTTE to 1-year outcomes was performed. Results The incidence of PPM was 24% with EOACT compared with 45% with EOAiTTE. Only 6% of PPM was graded severe by EOAiCT compared with 9% by EOAiTTE. EOAiTTE, but not EOAiCT, defined PPM showed association with reduced left ventricular mass regression (p = 0.03 vs. p = 0.52). There was no association between PPM and death or rehospitalization at 1 year with either modality. EOACT was associated with minor stroke at 1 year (log-rank p = 0.04), and EOAiTTE with stroke/transient ischemic attack (log-rank p = 0.030). Furthermore, when subjects with mild or greater paravalvular regurgitation were excluded, the presence of PPM did not show association with any outcome. Conclusions EOAiCT downgrades frequency and severity of PPM in patients after TAVR, and was not associated with mortality 1 year after TAVR. EOAiTTE, but not EOAiCT, was associated with less left ventricular mass regression.