Steven J. Yakubov

Transcatheter aortic-valve replacement with a self-expanding prosthesis.

BACKGROUND We compared transcatheter aortic-valve replacement (TAVR), using a self-expanding transcatheter aortic-valve bioprosthesis, with surgical aortic-valve replacement in patients with severe aortic stenosis and an increased risk of death during surgery. METHODS We recruited patients with severe aortic stenosis who were at increased surgical risk as determined by the heart team at each study center. Risk assessment included the Society of Thoracic Surgeons Predictor Risk of Mortality estimate and consideration of other key risk factors. Eligible patients were randomly assigned in a 1:1 ratio to TAVR with the self-expanding transcatheter valve (TAVR group) or to surgical aortic-valve replacement (surgical group). The primary end point was the rate of death from any cause at 1 year, evaluated with the use of both noninferiority and superiority testing. RESULTS A total of 795 patients underwent randomization at 45 centers in the United States. In the as-treated analysis, the rate of death from any cause at 1 year was significantly lower in the TAVR group than in the surgical group (14.2% vs. 19.1%), with an absolute reduction in risk of 4.9 percentage points (upper boundary of the 95% confidence interval, -0.4; P<0.001 for noninferiority; P = 0.04 for superiority). The results were similar in the intention-to-treat analysis. In a hierarchical testing procedure, TAVR was noninferior with respect to echocardiographic indexes of valve stenosis, functional status, and quality of life. Exploratory analyses suggested a reduction in the rate of major adverse cardiovascular and cerebrovascular events and no increase in the risk of stroke. CONCLUSIONS In patients with severe aortic stenosis who are at increased surgical risk, TAVR with a self-expanding transcatheter aortic-valve bioprosthesis was associated with a significantly higher rate of survival at 1 year than surgical aortic-valve replacement. (Funded by Medtronic; U.S. CoreValve High Risk Study ClinicalTrials.gov number, NCT01240902.).

Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization.

BACKGROUND In the setting of percutaneous coronary revascularization, agents in the class known as platelet glycoprotein IIb/IIIa inhibitors have significantly reduced the incidence of death or nonfatal myocardial infarction at 30 days. We assessed whether there are differences in safety or efficacy between two such inhibitors, tirofiban and abciximab. METHODS Using a double-blind, double-dummy design at 149 hospitals in 18 countries, we randomly assigned patients to receive either tirofiban or abciximab before undergoing percutaneous coronary revascularization with the intent to perform stenting. The primary end point was a composite of death, nonfatal myocardial infarction, or urgent target-vessel revascularization at 30 days. The trial was designed and statistically powered to demonstrate the noninferiority of tirofiban as compared with abciximab. RESULTS The primary end point occurred more frequently among the 2398 patients in the tirofiban group than among the 2411 patients in the abciximab group (7.6 percent vs. 6.0 percent; hazard ratio, 1.26; one-sided 95 percent confidence interval of 1.51, demonstrating lack of equivalence, and two-sided 95 percent confidence interval of 1.01 to 1.57, demonstrating the superiority of abciximab over tirofiban; P=0.038). The magnitude and the direction of the effect were similar for each component of the composite end point (hazard ratio for death, 1.21; hazard ratio for myocardial infarction, 1.27; and hazard ratio for urgent target-vessel revascularization, 1.26), and the difference in the incidence of myocardial infarction between the tirofiban group and the abciximab group was significant (6.9 percent and 5.4 percent, respectively; P=0.04). The relative benefit of abciximab was consistent regardless of age, sex, the presence or absence of diabetes, or the presence or absence of pretreatment with clopidogrel. There were no significant differences in the rates of major bleeding complications or transfusions, but tirofiban was associated with a lower rate of minor bleeding episodes and thrombocytopenia. CONCLUSIONS Although the trial was intended to assess the noninferiority of tirofiban as compared with abciximab, the findings demonstrated that tirofiban offered less protection from major ischemic events than did abciximab.

Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery

OBJECTIVES This study sought to evaluate the safety and efficacy of the CoreValve transcatheter heart valve (THV) for the treatment of severe aortic stenosis in patients at extreme risk for surgery. BACKGROUND Untreated severe aortic stenosis is a progressive disease with a poor prognosis. Transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis is a potentially effective therapy. METHODS We performed a prospective, multicenter, nonrandomized investigation evaluating the safety and efficacy of self-expanding TAVR in patients with symptomatic severe aortic stenosis with prohibitive risks for surgery. The primary endpoint was a composite of all-cause mortality or major stroke at 12 months, which was compared with a pre-specified objective performance goal (OPG). RESULTS A total of 41 sites in the United States recruited 506 patients, of whom 489 underwent attempted treatment with the CoreValve THV. The rate of all-cause mortality or major stroke at 12 months was 26.0% (upper 2-sided 95% confidence bound: 29.9%) versus 43.0% with the OPG (p < 0.0001). Individual 30-day and 12-month events included all-cause mortality (8.4% and 24.3%, respectively) and major stroke (2.3% and 4.3%, respectively). Procedural events at 30 days included life-threatening/disabling bleeding (12.7%), major vascular complications (8.2%), and need for permanent pacemaker placement (21.6%). The frequency of moderate or severe paravalvular aortic regurgitation was lower 12 months after self-expanding TAVR (4.2%) than at discharge (10.7%; p = 0.004 for paired analysis). CONCLUSIONS TAVR with a self-expanding bioprosthesis was safe and effective in patients with symptomatic severe aortic stenosis at prohibitive risk for surgical valve replacement. (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).

Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients

Background Although transcatheter aortic‐valve replacement (TAVR) is an accepted alternative to surgery in patients with severe aortic stenosis who are at high surgical risk, less is known about comparative outcomes among patients with aortic stenosis who are at intermediate surgical risk. Methods We evaluated the clinical outcomes in intermediate‐risk patients with severe, symptomatic aortic stenosis in a randomized trial comparing TAVR (performed with the use of a self‐expanding prosthesis) with surgical aortic‐valve replacement. The primary end point was a composite of death from any cause or disabling stroke at 24 months in patients undergoing attempted aortic‐valve replacement. We used Bayesian analytical methods (with a margin of 0.07) to evaluate the noninferiority of TAVR as compared with surgical valve replacement. Results A total of 1746 patients underwent randomization at 87 centers. Of these patients, 1660 underwent an attempted TAVR or surgical procedure. The mean (±SD) age of the patients was 79.8±6.2 years, and all were at intermediate risk for surgery (Society of Thoracic Surgeons Predicted Risk of Mortality, 4.5±1.6%). At 24 months, the estimated incidence of the primary end point was 12.6% in the TAVR group and 14.0% in the surgery group (95% credible interval [Bayesian analysis] for difference, ‐5.2 to 2.3%; posterior probability of noninferiority, >0.999). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVR had higher rates of residual aortic regurgitation and need for pacemaker implantation. TAVR resulted in lower mean gradients and larger aortic‐valve areas than surgery. Structural valve deterioration at 24 months did not occur in either group. Conclusions TAVR was a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. (Funded by Medtronic; SURTAVI ClinicalTrials.gov number, NCT01586910.)

Combined Accelerated Tissue-Plasminogen Activator and Platelet Glycoprotein IIb/IIIa Integrin Receptor Blockade With Integrilin in Acute Myocardial Infarction Results of a Randomized, Placebo-Controlled, Dose-Ranging Trial

BACKGROUND Platelet activation and aggregation may be key components of thrombolytic failure to restore and maintain perfusion in acute myocardial infarction. We performed a placebo-controlled, dose-ranging trial of Integrilin, a potent inhibitor of platelet aggregation, with heparin, aspirin, and accelerated alteplase. METHODS AND RESULTS We assigned 132 patients in a 2:1 ratio to receive a bolus and continuous infusion of one of six Integrilin doses or placebo. Another 48 patients were randomized in a 3:1, double-blind fashion to receive the highest Integrilin dose from the first phase or placebo. All patients received accelerated alteplase, aspirin, and intravenous heparin infusion; all but two groups also received an intravenous heparin bolus. The highest Integrilin dose group from the nonrandomized phase and the randomized patients were pooled for analysis and compared with placebo-treated patients. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 90-minute angiography. Secondary end points were time to ST-segment recovery, an in-hospital composite (death, reinfarction, stroke, revascularization procedures, new heart failure, or pulmonary edema), and bleeding variables. The highest Integrilin dose groups had more complete reperfusion (TIMI grade 3 flow, 66% versus 39% for placebo-treated patients; P = .006) and a shorter median time to ST-segment recovery (65 versus 116 minutes for placebo; P = .05). The groups had similar rates of the composite end point (43% versus 42% for placebo-treated patients) and severe bleeding (4% versus 5%, respectively). CONCLUSIONS The incidence and speed of reperfusion can be enhanced when a potent inhibitor of the glycoprotein IIb/IIIa integrin receptor, such as Integrilin, is combined with accelerated alteplase, aspirin, and intravenous heparin.

Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience.

OBJECTIVES The purpose of the study was to determine the efficacy and safety of left atrial appendage (LAA) closure via a percutaneous LAA ligation approach. BACKGROUND Embolic stroke is the most devastating consequence of atrial fibrillation. Exclusion of the LAA is believed to decrease the risk of embolic stroke. METHODS Eighty-nine patients with atrial fibrillation were enrolled to undergo percutaneous ligation of the LAA with the LARIAT device. The catheter-based LARIAT device consists of a snare with a pre-tied suture that is guided epicardially over the LAA. LAA closure was confirmed with transesophageal echocardiography (TEE) and contrast fluoroscopy immediately, then with TEE at 1 day, 30 days, 90 days, and 1 year post-LAA ligation. RESULTS Eighty-five (96%) of 89 patients underwent successful LAA ligation. Eighty-one of 85 patients had complete closure immediately. Three of 85 patients had a ≤ 2-mm residual LAA leak by TEE color Doppler evaluation. One of 85 patients had a ≤ 3-mm jet by TEE. There were no complications due to the device. There were 3 access-related complications (during pericardial access, n = 2; and transseptal catheterization, n = 1). Adverse events included severe pericarditis post-operatively (n = 2), late pericardial effusion (n = 1), unexplained sudden death (n = 2), and late strokes thought to be non-embolic (n = 2). At 1 month (81 of 85) and 3 months (77 of 81) post-ligation, 95% of the patients had complete LAA closure by TEE. Of the patients undergoing 1-year TEE (n = 65), there was 98% complete LAA closure, including the patients with previous leaks. CONCLUSIONS LAA closure with the LARIAT device can be performed effectively with acceptably low access complications and periprocedural adverse events in this observational study.

Non–Polymer-Based Paclitaxel-Coated Coronary Stents for the Treatment of Patients With De Novo Coronary Lesions: Angiographic Follow-Up of the DELIVER Clinical Trial

Background—Paclitaxel, a microtubule-stabilizing compound with potent antitumor activity, has been shown to inhibit smooth muscle cell proliferation and migration. The DELIVER trial was a prospective, randomized, blinded, multicenter clinical evaluation of the non–polymer-based paclitaxel-coated ACHIEVE stent compared with the stainless steel Multi-Link (ML) PENTA stent. Methods and Results—A total of 1043 patients with focal de novo coronary lesions, <25 mm in length, in 2.5- to 4.0-mm vessels were randomized (ACHIEVE n=524; ML PENTA n=519). Angiographic follow-up was performed in a subset of 442 patients (ACHIEVE n=228; ML PENTA n=214). Prespecified end points were a 40% reduction in target-vessel failure at 9 months (primary clinical end point) and a 50% reduction in binary restenosis at 8 months (major secondary end point). Baseline clinical characteristics were comparable between the groups. Patients in ACHIEVE had more type C lesions and a larger reference diameter. At follow-up, stent late loss was 0.81 versus 0.98 mm (P =0.003), stent binary restenosis was 14.9% versus 20.6% (P =0.076), and target-vessel failure was 11.9% versus 14.5% (P =0.12) for ACHIEVE and ML PENTA, respectively. Conclusions—The ACHIEVE paclitaxel-coated stent decreased neointimal proliferation compared with the bare-metal PENTA stent; however, this reduction was insufficient to meet the prespecified primary end point of target-vessel failure and the secondary end point of binary restenosis.

Quantitative Assessment of Angiographic Restenosis After Sirolimus-Eluting Stent Implantation in Native Coronary Arteries

Background—Sirolimus-eluting stents (SESs) reduce angiographic restenosis in patients with focal, native coronary artery stenoses. This study evaluated the usefulness of SESs in complex native-vessel lesions at high risk for restenosis. Methods and Results—Angiographic follow-up at 240 days was obtained in 701 patients with long (15- to 25-mm) lesions in small-diameter (2.5- to 3.5-mm) native vessels who were randomly assigned to treatment with SESs or bare-metal stents (BMSs) in the SIRIUS trial. Quantitative angiographic measurements of minimal lumen diameter and percent diameter stenosis were obtained within the treated segment, within the stent, and within its 5-mm proximal and distal edges. Patients treated with SESs had lower rates of binary (>50% diameter stenosis) angiographic restenosis within the segment (8.9% versus 36.3% with the BMS; P<0.001) and within the stent (3.2% versus 35.4% with the BMS; P<0.001). SESs were associated with significantly less late lumen loss within the treated segment, within the stent, and within its 5-mm proximal and distal edges (all P<0.001). The reduction of restenosis with the SES was consistent in patients at risk for restenosis, including those with small vessels, long lesions, and diabetes mellitus. The frequency of late aneurysms was similar in the 2 groups. Conclusions—Compared with BMSs, SESs reduced angiographic late lumen loss within the stent and its adjacent 5-mm margins in patients with complex native-vessel lesions.

Early safety and efficacy of percutaneous left atrial appendage suture ligation: results from the U.S. transcatheter LAA ligation consortium

BACKGROUND Transcatheter left atrial appendage (LAA) ligation may represent an alternative to oral anticoagulation for stroke prevention in atrial fibrillation. OBJECTIVES This study sought to assess the early safety and efficacy of transcatheter ligation of the LAA for stroke prevention in atrial fibrillation. METHODS This was a retrospective, multicenter study of consecutive patients undergoing LAA ligation with the Lariat device at 8 U.S. sites. The primary endpoint was procedural success, defined as device success (suture deployment and <5 mm leak by post-procedure transesophageal echocardiography), and no major complication at discharge (death, myocardial infarction, stroke, Bleeding Academic Research Consortium bleeding type 3 or greater, or cardiac surgery). Post-discharge management was per operator discretion. RESULTS A total of 154 patients were enrolled. Median CHADS2 score (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke, transient ischemic attack, or thromboembolism [doubled]) was 3 (interquartile range: 2 to 4). Device success was 94%, and procedural success was 86%. A major complication occurred in 15 patients (9.7%). There were 14 major bleeds (9.1%), driven by the need for transfusion (4.5%). Significant pericardial effusion occurred in 16 patients (10.4%). Follow-up was available in 134 patients at a median of 112 days (interquartile range: 50 to 270 days): Death, myocardial infarction, or stroke occurred in 4 patients (2.9%). Among 63 patients with acute closure and transesophageal echocardiography follow-up, there were 3 thrombi (4.8%) and 13 (20%) with residual leak. CONCLUSIONS In this initial multicenter experience of LAA ligation with the Lariat device, the rate of acute closure was high, but procedural success was limited by bleeding. A prospective randomized trial is required to adequately define clinical efficacy, optimal post-procedure medical therapy, and the effect of operator experience on procedural safety.

Effects of Integrelin, a Platelet Glycoprotein IIb/IIIa Receptor Antagonist, in Unstable Angina A Randomized Multicenter Trial

BACKGROUND Although aspirin is beneficial in patients with unstable angina, it is a relatively weak inhibitor of platelet aggregation. The effect of Integrelin, which inhibits the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa, on the frequency and duration of Holter ischemia was evaluated in 227 patients with unstable angina. METHODS AND RESULTS Patients received intravenous heparin and standard ischemic therapy and were randomized to receive oral aspirin and placebo Integrelin; placebo aspirin and low-dose Integrelin. 45 micrograms/kg bolus followed by a 0.5 microgram.kg-1. min-1 continuous infusion; or placebo aspirin and high-dose Integrelin, 90 micrograms/kg bolus followed by a 1.0-microgram.kg-1, min-1 constant infusion. Study drug was continued for 24 to 72 hours, and Holter monitoring was performed. Patients randomized to high-dose Integrelin experienced 0.24 +/- 0.11 ischemic episodes (mean +/- SEM) on Holter lasting 8.41 +/- 5.29 minutes over 24 hours of study drug infusion. Patients randomized to aspirin experienced a greater number (1.0 +/- 0.33, P < .05) and longer duration (26.2 +/- 9.8 minutes, P = .01) of ischemic episodes than the high-dose Integrelin group. There was no evidence of rebound ischemia after withdrawal of study drug. In 46 patients, platelet aggregation was rapidly inhibited by Integrelin in a dose-dependent fashion. The number of clinical events was small, and there were no bleeding differences in the three treatment arms. CONCLUSIONS Intravenous Integrelin is well tolerated, is a potent reversible inhibitor of platelet aggregation, and added to full-dose heparin reduces the number and duration of Holter ischemic events in patients with unstable angina compared with aspirin.