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Background: The CoreValve U.S. Pivotal High Risk Trial was the first randomized trial to show superior 1-year mortality of transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (SAVR) among high operative mortality-risk patients., Objectives: The authors sought to compare TAVR to SAVR for mid-term 5-year outcomes of safety, performance, and durability., Methods: Surgical high-risk patients were randomized (1:1) to TAVR with the self-expanding bioprosthesis or SAVR. VARC-1 (Valve Academic Research Consortium I) definitions were applied. Severe hemodynamic structural valve deterioration was defined as a mean gradient ≥40 mm Hg or a change in gradient ≥20 mm Hg or new severe aortic regurgitation. Five-year follow-up was planned., Results: A total of 797 patients were randomized at 45 U.S. centers, of whom 750 underwent an attempted implant (TAVR = 391, SAVR = 359). The overall mean age was 83 years, and the STS score was 7.4%. All-cause mortality rates at 5 years were 55.3% for TAVR and 55.4% for SAVR. Subgroup analysis showed no differences in mortality. Major stroke rates were 12.3% for TAVR and 13.2% for SAVR. Mean aortic valve gradients were 7.1 ± 3.6 mm Hg for TAVR and 10.9 ± 5.7 mm Hg for SAVR. No clinically significant valve thrombosis was observed. Freedom from severe SVD was 99.2% for TAVR and 98.3% for SAVR (p = 0.32), and freedom from valve reintervention was 97.0% for TAVR and 98.9% for SAVR (p = 0.04). A permanent pacemaker was implanted in 33.0% of TAVR and 19.8% of SAVR patients at 5 years., Conclusions: This study shows similar mid-term survival and stroke rates in high-risk patients following TAVR or SAVR. Severe structural valve deterioration and valve reinterventions were uncommon. (Safety and Efficacy Study of the Medtronic CoreValve ® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Few studies have examined the impact of novel indices of comorbidity, frailty, and disability on outcomes after transcatheter aortic valve replacement (TAVR)., Objectives: This study analyzed patients from the Medtronic CoreValve U.S. Pivotal Trial program to develop a simple scoring system that incorporates standard and novel predictor variables., Methods: A multidisciplinary heart team used objective criteria, such as The Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM), and subjective criteria to assess patients' eligibility for TAVR. The analysis included 3,687 patients randomly divided (2:1) into a derivation cohort (n = 2,482) and a validation cohort (n = 1,205). The study evaluated predictors of all-cause death, which were used to calculate a risk score for each patient., Results: The overall mortality rate was 5.8% at 30 days and 22.8% at 1 year. Home oxygen use, assisted living, albumin levels <3.3 g/dl, and age >85 years predicted death at 30 days. Home oxygen use, albumin levels <3.3 g/dl, falls in the past 6 months, STS PROM score >7%, and severe (≥5) Charlson comorbidity score predicted death at 1 year. A simple scoring system created on the basis of these multivariable predictors effectively stratified risk at 30 days and 1 year into low-risk, moderate-risk, and high-risk subsets. This score showed a 3-fold difference in mortality rates for the low-risk and high-risk subsets at 30 days (3.6% and 10.9%, respectively) and 1 year (12.3% and 36.6%, respectively). The 1-year mortality model was more stable than the 30-day model (C-statistics: 0.79 vs. 0.75)., Conclusions: A simple score dominated by novel predictors of outcome effectively stratified early and late mortality rates in extreme-risk and high-risk patients and may assist in selecting appropriate candidates for TAVR. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In patients with severe aortic stenosis at increased risk for surgery, self-expanding transcatheter aortic valve replacement (TAVR) is associated with improved 2-year survival compared with surgery., Objectives: This study sought to determine whether this clinical benefit was sustained over time., Methods: Patients with severe aortic stenosis deemed at increased risk for surgery by a multidisciplinary heart team were randomized 1:1 to TAVR or open surgical valve replacement (SAVR). Three-year clinical and echocardiographic outcomes were obtained in those patients with an attempted procedure., Results: A total of 797 patients underwent randomization at 45 U.S. centers; 750 patients underwent an attempted procedure. Three-year all-cause mortality or stroke was significantly lower in TAVR patients (37.3% vs. 46.7% in SAVR; p = 0.006). Adverse clinical outcome components were also reduced in TAVR patients compared with SAVR patients, including all-cause mortality (32.9% vs. 39.1%, respectively; p = 0.068), all stroke (12.6% vs. 19.0%, respectively; p = 0.034), and major adverse cardiovascular or cerebrovascular events (40.2% vs. 47.9%, respectively; p = 0.025). At 3 years aortic valve hemodynamics were better with TAVR patients (mean aortic valve gradient 7.62 ± 3.57 mm Hg vs. 11.40 ± 6.81 mm Hg in SAVR; p < 0.001), although moderate or severe residual aortic regurgitation was higher in TAVR patients (6.8% vs. 0.0% in SAVR; p < 0.001). There was no clinical evidence of valve thrombosis in either group., Conclusions: Patients with severe aortic stenosis at increased risk for surgery had improved 3-year clinical outcomes after TAVR compared with surgery. Aortic valve hemodynamics were more favorable in TAVR patients without differences in structural valve deterioration. (Safety and Efficacy Study of the Medtronic CoreValve(®) System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In EVEREST II (Endovascular Valve Edge-to-Edge Repair Study), treatment of mitral regurgitation (MR) with a novel percutaneous device showed superior safety compared with surgery, but less effective reduction in MR at 1 year., Objectives: This study sought to evaluate the final 5-year clinical outcomes and durability of percutaneous mitral valve (MV) repair with the MitraClip device compared with conventional MV surgery., Methods: Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the device or conventional MV surgery in a 2:1 ratio (178:80). Patients prospectively consented to 5 years of follow-up., Results: At 5 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the as-treated population was 44.2% versus 64.3% in the percutaneous repair and surgical groups, respectively (p = 0.01). The difference was driven by increased rates of 3+ to 4+ MR (12.3% vs. 1.8%; p = 0.02) and surgery (27.9% vs. 8.9%; p = 0.003) with percutaneous repair. After percutaneous repair, 78% of surgeries occurred within the first 6 months. Beyond 6 months, rates of surgery and moderate-to-severe MR were comparable between groups. Five-year mortality rates were 20.8% and 26.8% (p = 0.4) for percutaneous repair and surgery, respectively. In multivariable analysis, treatment strategy was not associated with survival., Conclusions: Patients treated with percutaneous repair more commonly required surgery for residual MR during the first year after treatment, but between 1- and 5-year follow-up, comparably low rates of surgery for MV dysfunction with either percutaneous or surgical therapy endorse the durability of MR reduction with both repair techniques. (EVEREST II Pivotal Study High Risk Registry; NCT00209274)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The U.S. pivotal trial for the self-expanding valve found that among patients with severe aortic stenosis at increased risk for surgery, the 1-year survival rate was 4.9 percentage points higher in patients treated with a self-expanding transcatheter aortic valve bioprosthesis than in those treated with a surgical bioprosthesis., Objectives: Longer-term clinical outcomes were examined to confirm if this mortality benefit is sustained., Methods: Patients with severe aortic stenosis who were at increased surgical risk were recruited. Eligible patients were randomly assigned in a 1:1 ratio to transcatheter aortic valve replacement with the self-expanding transcatheter valve (transcatheter aortic valve replacement [TAVR] group) or to aortic valve replacement with a surgical bioprosthesis (surgical group). The 2-year clinical and echocardiographic outcomes were evaluated in these patients., Results: A total of 797 patients underwent randomization at 45 centers in the United States. The rate of 2-year all-cause mortality was significantly lower in the TAVR group (22.2%) than in the surgical group (28.6%; log-rank test p < 0.05) in the as-treated cohort, with an absolute reduction in risk of 6.5 percentage points. Similar results were found in the intention-to-treat cohort (log-rank test p < 0.05). The rate of 2-year death or major stroke was significantly lower in the TAVR group (24.2%) than in the surgical group (32.5%; log-rank test p = 0.01)., Conclusions: In patients with severe aortic stenosis who are at increased surgical risk, the higher rate of survival with a self-expanding TAVR compared with surgery was sustained at 2 years. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI)., Background: Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support., Methods: We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points., Results: Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling., Conclusions: Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).

Objectives: The aim was to compare safety and effectiveness of the CoStar drug-eluting stent (DES) (Conor MedSystems, Menlo Park, California) with those of the Taxus DES (Boston Scientific, Maple Grove, Minnesota) in de novo single- and multivessel percutaneous coronary intervention (PCI)., Background: Paclitaxel elution from a stent coated with biostable polymer (Taxus) reduces restenosis after PCI. The CoStar DES is a novel stent with laser-cut reservoirs containing bioresorbable polymer loaded to elute 10 microg paclitaxel/30 days., Methods: Patients undergoing PCI for a single target lesion per vessel in up to 3 native epicardial vessels were randomly assigned 3:2 to CoStar or Taxus. Primary end point was 8-month major adverse cardiac events (MACE), defined as adjudicated death, myocardial infarction (MI), or clinically driven target vessel revascularization (TVR). Protocol-specified 9-month angiographic follow-up included 457 vessels in 286 patients., Results: Of the 1,700 patients enrolled, 1,675 (98.5%) were evaluable (CoStar = 989; Taxus = 686), including 1,330 (79%) single-vessel and 345 (21%) multivessel PCI. The MACE rate at 8 months was 11.0% for CoStar versus 6.9% for Taxus (p < 0.005), including adjudicated death (0.5% vs. 0.7%, respectively), MI (3.4% vs. 2.4%, respectively), and TVR (8.1% vs. 4.3%, respectively). Per-vessel 9-month in-segment late loss was 0.49 mm with CoStar and 0.18 mm with Taxus (p < 0.0001). Findings were consistent across pre-specified subgroups., Conclusions: The CoStar DES is not noninferior to the Taxus DES based on per-patient clinical and per-vessel angiographic analyses. The relative benefit of Taxus is primarily attributable to reduction in TVR. Follow-up to 9 months showed no apparent difference in death, MI, or stent thrombosis rates.

Objectives: This study sought to compare aggregate medical care costs for patients undergoing percutaneous coronary intervention with paclitaxel-eluting stents (PES) and bare-metal stents (BMS) and to formally evaluate the incremental cost effectiveness of PES for patients undergoing single-vessel percutaneous coronary intervention., Background: Although the cost effectiveness of SES has been studied in both clinical trials and decision-analytic models, few data exist on the cost effectiveness of alternative drug-eluting stent (DES) designs. In addition, no clinical trials have specifically examined the cost effectiveness of DES among patients managed without mandatory angiographic follow-up., Methods: We performed a prospective economic evaluation among 1,314 patients undergoing percutaneous coronary revascularization randomized to either PES (N = 662) or BMS (N = 652) in the TAXUS-IV trial. Clinical outcomes, resource use, and costs (from a societal perspective) were assessed prospectively for all patients over a 1-year follow-up period. Cost effectiveness was defined as the incremental cost per target vessel revascularization (TVR) event avoided and was analyzed separately among cohorts assigned to mandatory angiographic follow-up (n = 732) or clinical follow-up alone (n = 582)., Results: The PES reduced TVR by 12.2 events per 100 patients treated, resulting in a 1-year cost difference of 572 dollars per patient with incremental cost-effectiveness ratios of 4,678 dollars per TVR avoided and 47,798 dollars/quality-adjusted life year (QALY) gained. Among patients assigned to clinical follow-up alone, the net 1-year cost difference was 97 dollars per patient with cost-effectiveness ratios of 760 dollars per TVR event avoided and $5,105/QALY gained., Conclusions: In the TAXUS-IV trial, treatment with PES led to substantial reductions in the need for repeat revascularization while increasing 1-year costs only modestly. The cost-effectiveness ratio for PES in the study population compares reasonably with that for other treatments that reduce coronary restenosis, including alternative drug-eluting stent platforms.

Objectives: We sought to determine the safety and efficacy of polymer-regulated site-specific delivery of paclitaxel in patients with diabetes mellitus undergoing stent implantation., Background: Percutaneous coronary intervention in patients with diabetes is associated with high rates of restenosis and repeat revascularization due to excessive neointimal proliferation, a process that may be blunted with the site-specific delivery of paclitaxel., Methods: In the TAXUS-IV trial, 1,314 patients were prospectively randomized to the slow rate-release polymer-based paclitaxel-eluting TAXUS stent or the bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). Medically treated diabetes was present in 318 patients (24%), 105 of whom required insulin., Results: Among patients with diabetes, the TAXUS stent, compared to the bare-metal stent, reduced the rate of 9-month binary angiographic restenosis by 81% (6.4% vs. 34.5%, p < 0.0001), and reduced the 12-month rates of target lesion revascularization by 65% (7.4% vs. 20.9%, p = 0.0008), target vessel revascularization by 53% (11.3% vs. 24%, p < 0.004), and composite major adverse cardiac events by 44% (15.6% vs. 27.7%, p = 0.01). The one-year rates of cardiac death (1.9% vs. 2.5%), myocardial infarction (3.2% vs. 6.4%), and subacute thrombosis (0.6% vs. 1.2%) were comparable between the paclitaxel-eluting and control stents, respectively. In the insulin-requiring subgroup, the TAXUS stent reduced angiographic restenosis by 82% (7.7% vs. 42.9%, p = 0.0065), and reduced the one-year rate of target lesion revascularization by 68% (6.2% vs. 19.4%, p = 0.07), a relative reduction similar to patients without diabetes., Conclusions: The site-specific delivery of paclitaxel after coronary stent implantation is highly effective in reducing clinical and angiographic restenosis in patients with diabetes mellitus.

Objectives: The aim of this study was to discern a target range of anticoagulation for enoxaparin during percutaneous coronary intervention (PCI) as measured by the Rapidpoint ENOX (Pharmanetics Inc., Morrisville, North Carolina), a new point-of-care test., Background: In the U.S., enoxaparin has been used in only a small proportion of PCI procedures, partly because a rapid enoxaparin-specific assay was unavailable., Methods: We analyzed data from 445 enrolled patients receiving subcutaneous or intravenous enoxaparin in a prospective, multicenter study. Serial anticoagulation measurements and clinical outcomes were recorded., Results: The in-hospital composite occurrence of death, myocardial infarction, and urgent target vessel revascularization was 5.4%, and Thrombolysis In Myocardial Infarction (TIMI) major bleeding, minor bleeding, and any reported bleeding occurred in 0.2%, 1.3%, and 7.9% of patients, respectively. No significant association between procedural ENOX times and ischemic events was observed (p = 0.222), although the event rate was 4.0% among those with ENOX times between 250 to 450 s versus 7.2% for those outside this range (p = 0.134). Increasing ENOX time at sheath removal was correlated with any bleeding (p = 0.010) with a 1% increase for every approximately 30-s rise., Conclusions: Ischemic events were infrequent, and the rate appeared lowest in the mid-range of ENOX times. Bleeding events increased with increasing ENOX times. These observations, combined with a suggested procedural anti-Xa level of 0.8 to 1.8 IU/ml, translate into a recommended ENOX time range of 250 to 450 s for PCI and <200 to 250 s for sheath removal.

Objectives: The purpose of this study was to evaluate the safety, feasibility, optimal deployment technique and 1-year clinical outcome for the Advanced Cardiovascular Systems (ACS) MultiLink stent., Background: Optimal stent deployment assessed by quantitative coronary angiography and intravascular ultrasound (IVUS) is associated with improved clinical outcome., Methods: Forty-nine consecutive patients with a discrete stenosis in a native coronary artery 3 to 4 mm in diameter were treated with the new, balloon-expandable ACS MultiLink stent. Stent expansion was assessed in all patients using quantitative coronary angiography and serial IVUS imaging after 8-, 12- and 16-atm inflations. Clinical follow-up was obtained at 30 days and 1 year., Results: All 49 patients had successful placement of a MultiLink stent without death, emergency coronary artery bypass graft surgery or Q wave myocardial infarction. After placement of the MultiLink stent, the minimal lumen diameter increased from 1.24 to 2.98 mm (p < 0.001), and diameter stenosis decreased from 61% to 7% (p = 0.001). Minimal lumen cross-sectional area by IVUS increased progressively after 8, 12 and 16 atm (5.6 to 6.8 to 7.4 mm2, respectively, p < 0.001). However, only 64% of stents achieved a lumen/reference area ratio > or = 70%. No adverse clinical events occurred by 30 days, and by 1 year only one patient (2.0%) required revascularization of the stented artery., Conclusions: Treatment of stenoses in native coronary arteries with the MultiLink stent is associated with a high success rate and a low incidence of adverse events by 1 year, despite the fact that the majority of stents did not meet IVUS-defined criteria for "optimal stenting" derived from first-generation devices.

Objectives: The purpose of the study was to describe the configuration, and investigate the mechanisms, of QRS changes occurring during percutaneous transluminal coronary angioplasty (PTCA)., Background: QRS changes during PTCA have been attributed to both a passive ST segment shift and conduction disturbances (peri-ischemic block). The direct relation between ST segment shift and QRS changes, however, has not been established, and the definition of conduction disturbances remains to be clarified., Methods: Twelve-lead electrocardiograms (ECGs) were recorded before PTCA, at the end of 2 min of PTCA and after return to baseline values in 29 patients (left anterior descending coronary artery [LAD] in 13 patients, right coronary artery [RCA] in 14 and left circumflex coronary artery in 2). Electrocardiographic complexes before and during PTCA were superimposed to determine the amplitudes of initial, terminal and total QRS deflection; the relations of QRS changes to baseline (TP segment) and ST segment shift; and the duration of QRS and corrected QT intervals. RESULTS. 1) The direction of the initial QRS deflection was unchanged, but changes of its amplitude occurred. 2) Terminal QRS deflection changed in all patients with a ST segment shift > 17% of the R amplitude, and the correlation between the decrease in the S amplitude and ST segment shift was significant (r = 0.9, p < 0.01) in patients with LAD PTCA. Correlation between changes in total QRS amplitude and ST segment shift in patients with RCA PTCA was weaker (r = 0.54, p = 0.056). 3) Transient conduction disturbance manifested by QRS widening in selected leads occurred in 2 of 29 patients. CONCLUSIONS. 1) Changes in terminal QRS deflection during PTCA are proportional to the magnitude of the ST segment shift. 2) Conduction disturbances manifested by increased QRS duration occurred infrequently. We suggest that the term peri-ischemic block be applied only to changes in QRS configuration associated with QRS widening.

Objectives: This study sought to determine the long-term outcome of adult patients undergoing percutaneous balloon aortic valvuloplasty., Background: Percutaneous balloon aortic valvuloplasty has been offered as an alternative to aortic valve replacement for selected patients with valvular aortic stenosis. Although balloon aortic valvuloplasty produces an immediate reduction in the transvalvular aortic gradient, a high incidence of restenosis frequently leads to recurrent symptoms. Therefore, it is unclear whether balloon aortic valvuloplasty impacts on the long-term outcome of these patients., Methods: Clinical, hemodynamic and echocardiographic data were collected at baseline in 165 patients undergoing balloon aortic valvuloplasty and examined for their ability to predict long-term outcome., Results: The median duration follow-up was 3.9 years (range 1 to 6). Ninety-nine percent follow-up was achieved. During this 6-year period, 152 patients (93%) died or underwent aortic valve replacement, and 99 (60%) died of cardiac-related causes. The probability of event-free survival (freedom from death, aortic valve replacement or repeat balloon aortic valvuloplasty) 1, 2 and 3 years after valvuloplasty was 40%, 19% and 6%, respectively. In contrast, the probability of survival 3 years after balloon aortic valvuloplasty in a subset of 42 patients who underwent subsequent aortic valve replacement was 84%. Survival after aortic valvuloplasty was poor regardless of the presenting symptom, but patients with New York Heart Association functional class IV congestive heart failure had events earliest. Univariable predictors of decreased event-free survival were younger age, advanced congestive heart failure symptoms, lower ejection fraction, elevated left ventricular end-diastolic pressure, presence of coronary artery disease and increased left ventricular internal diastolic diameter. Stepwise multivariable logistic regression analysis found that only younger age and a lower left ventricular ejection fraction contributed independent adverse prognostic information (chi-square 14.89, p = 0.0006)., Conclusions: Long-term event-free and actuarial survival after balloon aortic valvuloplasty is dismal and resembles the natural history of untreated aortic stenosis. Aortic valve replacement may be performed in selected subjects with good results. However, the prognosis for the remainder of patients who are not candidates for aortic valve replacement is particularly poor.

The utility of ergonovine testing for coronary artery spasm was assessed in 3,447 patients with angiographically insignificant (less than 50% diameter stenosis) or no coronary artery disease. No patients clinically had Prinzmetal's variant angina. Overall, 4% had a positive ergonovine test result, defined by spasm causing greater than or equal to 75% focal stenosis. Complications related to ergonovine use occurred in 11 patients (0.03%). In a training sample of 1,136 patients (studied between 1980 and 1984), two independent predictors of spasm were found by using multivariate analysis: the amount of visible coronary artery disease on the coronary angiogram (p less than 0.0001) and a smoking history (p = 0.001). A model to predict spasm based on these variables was validated in a test group of 2,311 patients who received ergonovine from 1985 to 1989. This model allowed the identification of a subset of 400 patients in the validation sample who had a 10% positive test rate compared with a 2% positive test rate in the remaining patients. These results should permit clinicians who use provocative testing in the catheterization laboratory to reserve testing for the subset of this group of patients most likely to have abnormal findings.