Dominic J. Allocco

Transcatheter aortic valve replacement for severe symptomatic aortic stenosis using a repositionable valve system: 30-day primary endpoint results from the REPRISE II study.

BACKGROUND Transcatheter aortic valve replacement provides results comparable to those of surgery in patients at high surgical risk, but complications can impact long-term outcomes. The Lotus valve, designed to improve upon earlier devices, is fully repositionable and retrievable, with a unique seal to minimize paravalvular regurgitation (PVR). OBJECTIVES The prospective, single-arm, multicenter REPRISE II study (REpositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus Valve System: Evaluation of Safety and Performance) evaluated the transcatheter valve system for treatment of severe symptomatic calcific aortic valve stenosis. METHODS Patients (n = 120; aortic annulus 19 to 27 mm) considered by a multidisciplinary heart team to be at high surgical risk received the valve transfemorally. The primary device performance endpoint, 30-day mean pressure gradient, was assessed by an independent echocardiographic core laboratory and compared with a pre-specified performance goal. The primary safety endpoint was 30-day mortality. Secondary endpoints included safety/effectiveness metrics per Valve Academic Research Consortium criteria. RESULTS Mean age was 84.4 years, 57% of the patients were female, and 76% were New York Heart Association functional class III/IV. Mean aortic valve area was 0.7 ± 0.2 cm(2). The valve was successfully implanted in all patients, with no cases of valve embolization, ectopic valve deployment, or additional valve implantation. All repositioning (n = 26) and retrieval (n = 6) attempts were successful; 34 patients (28.6%) received a permanent pacemaker. The primary device performance endpoint was met, because the mean gradient improved from 46.4 ± 15.0 mm Hg to 11.5 ± 5.2 mm Hg. At 30 days, the mortality rate was 4.2%, and the rate of disabling stroke was 1.7%; 1 (1.0%) patient had moderate PVR, whereas none had severe PVR. CONCLUSIONS REPRISE II demonstrates the safety and effectiveness of the Lotus valve in patients with severe aortic stenosis who are at high surgical risk. The valve could be positioned successfully with minimal PVR. (REPRISE II: REpositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus™ Valve System - Evaluation of Safety and Performance; NCT01627691).

A Prospective, Randomized Evaluation of a Novel Everolimus-Eluting Coronary Stent : The PLATINUM (A Prospective, Randomized, Multicenter Trial to Assess an Everolimus-Eluting Coronary Stent System [PROMUS Element] for the Treatment of up to Two De Novo Coronary Artery Lesions) Trial

OBJECTIVES We sought to evaluate the clinical outcomes with a novel platinum chromium everolimus-eluting stent (PtCr-EES) compared with a predicate cobalt chromium everolimus-eluting stent (CoCr-EES) in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND Randomized trials have demonstrated an excellent safety and efficacy profile for the CoCr-EES. The PtCr-EES uses the identical antiproliferative agent and polymer but with a novel platinum chromium scaffold designed for enhanced deliverability, vessel conformability, side-branch access, radiopacity, radial strength, and fracture resistance. METHODS A total of 1,530 patients undergoing PCI of 1 or 2 de novo native lesions were randomized at 132 worldwide sites to CoCr-EES (n = 762) or PtCr-EES (n = 768). The primary endpoint was the 12-month rate of target lesion failure (TLF), the composite of target vessel-related cardiac death, target vessel-related myocardial infarction (MI), or ischemia-driven target lesion revascularization (TLR) in the per-protocol population (patients who received ≥1 assigned study stent), powered for noninferiority. RESULTS The 12-month rate of TLF in the per-protocol population occurred in 2.9% versus 3.4% of patients assigned to CoCr-EES versus PtCr-EES, respectively (difference: 0.5%, 95% confidence interval: -1.3% to 2.3%, p(noninferiority) = 0.001, p(superiority) = 0.60). By intention-to-treat, there were no significant differences between CoCr-EES and PtCr-EES in the 12-month rates of TLF (3.2% vs. 3.5%, p = 0.72), cardiac death or MI (2.5% vs. 2.0%, p = 0.56), TLR (1.9% vs. 1.9%, p = 0.96), or Academic Research Consortium definite or probable stent thrombosis (0.4% vs. 0.4%, p = 1.00). CONCLUSIONS In this large-scale, prospective, single-blind randomized trial, a novel PtCr-EES was noninferior to the predicate CoCr-EES for TLF, with nonsignificant differences in measures of safety and efficacy through 12-month follow-up after PCI.

Primary endpoint results of the EVOLVE trial: a randomized evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent.

OBJECTIVES This study sought to compare the safety and efficacy of 2 dose formulations of SYNERGY, a novel bioabsorbable polymer everolimus-eluting stent (EES) (Boston Scientific Corp., Natick, Massachusetts) compared with the durable polymer PROMUS Element EES (Boston Scientific Corp.). BACKGROUND Durable polymer coatings on drug-eluting stents have been associated with chronic inflammation and impaired healing. Bioabsorbable polymer-coated drug-delivery systems may reduce the risk of late adverse events, including stent thrombosis, and thus the need for prolonged dual-antiplatelet therapy. METHODS A total of 291 patients with a de novo lesion ≤28 mm in length, in a coronary artery of ≥2.25 to ≤3.5 mm diameter, were enrolled in the EVOLVE study, a prospective, randomized, single-blind, noninferiority trial. Patients were randomly assigned in a 1:1:1 ratio to PROMUS Element, SYNERGY, or SYNERGY half dose. The primary clinical endpoint was the 30-day rate of target lesion failure, defined as cardiac death or myocardial infarction related to the target vessel, or target lesion revascularization. The primary angiographic endpoint was 6-month in-stent late loss measured by quantitative coronary angiography. RESULTS The 30-day primary clinical endpoint of target lesion failure occurred in 0%, 1.1%, and 3.1% of patients in the PROMUS Element, SYNERGY, and SYNERGY half dose groups, respectively. The 6-month in-stent late loss was 0.15 ± 0.34 mm for PROMUS Element, 0.10 ± 0.25 mm for SYNERGY, and 0.13 ± 0.26 mm for SYNERGY half dose (SYNERGY, difference -0.06, upper 95.2% confidence limit: 0.02, p for noninferiority <0.001; SYNERGY half dose, difference -0.03, upper 95.2% confidence limit: 0.05, p for noninferiority <0.001). Clinical event rates remained low and comparable between groups, with no stent thromboses in any group at 6 months. CONCLUSIONS The EVOLVE trial confirms the effective delivery of everolimus by a unique directional bioabsorbable polymer system utilizing the SYNERGY stent. (A Prospective Randomized Multicenter Single-Blind Noninferiority Trial to Assess the Safety and Performance of the Evolution Everolimus-Eluting Monorail Coronary Stent System [Evolution Stent System] for the Treatment of a De Novo Atherosclerotic Lesion [EVOLVE]; NCT01135225).

Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II Randomized Trial.

Background—Drug eluting stents with durable polymers may be associated with hypersensitivity, delayed healing, and incomplete endothelialization, which may contribute to late/very late stent thrombosis and the need for prolonged dual antiplatelet therapy. Bioabsorbable polymers may facilitate stent healing, thus enhancing clinical safety. The SYNERGY stent is a thin-strut, platinum chromium metal alloy platform with an ultrathin bioabsorbable Poly(D,L-lactide-co-glycolide) abluminal everolimus-eluting polymer. We performed a multicenter, randomized controlled trial for regulatory approval to determine noninferiority of the SYNERGY stent to the durable polymer PROMUS Element Plus everolimus-eluting stent. Methods and Results—Patients (n=1684) scheduled to undergo percutaneous coronary intervention for non–ST-segment–elevation acute coronary syndrome or stable coronary artery disease were randomized to receive either the SYNERGY stent or the PROMUS Element Plus stent. The primary end point of 12-month target lesion failure was observed in 6.7% of SYNERGY and 6.5% PROMUS Element Plus treated subjects by intention-to-treat (P=0.83 for difference; P=0.0005 for noninferiority), and 6.4% in both the groups by per-protocol analysis (P=0.0003 for noninferiority). Clinically indicated revascularization of the target lesion or definite/probable stent thrombosis were observed in 2.6% versus 1.7% (P=0.21) and 0.4% versus 0.6% (P=0.50) of SYNERGY versus PROMUS Element Plus–treated subjects, respectively. Conclusions—In this randomized trial, the SYNERGY bioabsorbable polymer everolimus-eluting stent was noninferior to the PROMUS Element Plus everolimus-eluting stent with respect to 1-year target lesion failure. These data support the relative safety and efficacy of SYNERGY in a broad range of patients undergoing percutaneous coronary intervention. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01665053.

Transfemoral aortic valve replacement with the repositionable Lotus Valve System in high surgical risk patients: the REPRISE I study.

AIMS To assess outcomes with a new fully repositionable and retrievable valve for transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS The Lotus Aortic Valve System is designed to facilitate precise positioning and minimise paravalvular regurgitation. REPRISE I enrolled symptomatic, high-surgical-risk patients with severe aortic stenosis. The primary endpoint (clinical procedural success) included successful implantation without major adverse cardiovascular or cerebrovascular events (MACCE). In all patients (N=11) the first Lotus Valve was successfully deployed. Partial resheathing to facilitate accurate placement was attempted and successfully performed in four patients; none required full retrieval. The primary endpoint was achieved in 9/11 with no in-hospital MACCE in 10/11. There was one major stroke; in another patient, discharge mean aortic gradient was 22 mmHg (above the primary endpoint threshold of 20 mmHg), but improved to 15 mmHg at 30 days. The cohorts mean aortic gradient decreased from 53.9±20.9 mmHg at baseline to 15.4±4.6 mmHg (p<0.001) at one year; valve area increased from 0.7±0.2 cm2 to 1.5±0.2 cm2 (p<0.001). Discharge paravalvular aortic regurgitation, adjudicated by an independent core laboratory, was mild (n=2), trivial (n=1), or absent (n=8). Four patients required a permanent pacemaker post-procedure. There were no deaths, myocardial infarctions or new strokes through one year. CONCLUSIONS Initial results support proof-of-concept with the Lotus Valve for TAVR.

A prospective evaluation of the safety and efficacy of the TAXUS Element paclitaxel-eluting coronary stent system for the treatment of de novo coronary artery lesions: Design and statistical methods of the PERSEUS clinical program

BackgroundPaclitaxel-eluting stents decrease angiographic and clinical restenosis following percutaneous coronary intervention compared to bare metal stents. TAXUS Element is a third-generation paclitaxel-eluting stent which incorporates a novel, thinner-strut, platinum-enriched metal alloy platform. The stent is intended to have enhanced radiopacity and improved deliverability compared to other paclitaxel-eluting stents. The safety and efficacy of the TAXUS Element stent are being evaluated in the pivotal PERSEUS clinical trials.Methods/DesignThe PERSEUS trials include two parallel studies of the TAXUS Element stent in single, de novo coronary atherosclerotic lesions. The PERSEUS Workhorse study is a prospective, randomized (3:1), single-blind, non-inferiority trial in subjects with lesion length ≤28 mm and vessel diameter ≥2.75 mm to ≤4.0 mm which compares TAXUS Element to the TAXUS Express2 paclitaxel-eluting stent system. The Workhorse study employs a novel Bayesian statistical approach that uses prior information to limit the number of study subjects exposed to the investigational device and thus provide a safer and more efficient analysis of the TAXUS Element stent. PERSEUS Small Vessel is a prospective, single-arm, superiority trial in subjects with lesion length ≤20 mm and vessel diameter ≥2.25 mm to <2.75 mm that compares TAXUS Element with a matched historical bare metal Express stent control.DiscussionThe TAXUS PERSEUS clinical trial program uses a novel statistical approach to evaluate whether design and metal alloy iterations in the TAXUS Element stent platform provide comparable safety and improved procedural performance compared to the previous generation Express stent. PERSEUS trial enrollment is complete and primary endpoint data are expected in 2010. PERSEUS Workhorse and Small Vessel are registered at http://www.clinicaltrials.gov, identification numbers NCT00484315 and NCT00489541.

Strut Coverage and Vessel Wall Response to a New-Generation Paclitaxel-Eluting Stent With an Ultrathin Biodegradable Abluminal Polymer Optical Coherence Tomography Drug-Eluting Stent Investigation (OCTDESI)

Background—Polymer-coated drug-eluting stents are effective in preventing restenosis but have been associated with delayed healing and incomplete strut coverage. It is unknown whether paclitaxel-eluting stents (PES) with minimal biodegradable abluminal coating enhances strut coverage while preventing neointimal hyperplasia. Using optical coherence tomography (OCT) as a primary imaging modality, we assessed the proportion of uncovered struts at 6-month follow-up in PES coated with durable versus ultrathin (<1 &mgr;m) biodegradable abluminal polymers. Methods and Results—In this pilot trial, 60 patients with de novo lesions (⩽25 mm) in native coronary vessels were randomly assigned to receive either TAXUS Liberté PES or JACTAX PES, a Liberté stent with polymer deposited abluminally as microdots (JACTAX HD: 9.2 &mgr;g each of polymer and paclitaxel per 16-mm stent; JACTAX LD: 5 &mgr;g each). OCT follow-up occurred at 6 months with clinical follow-up through 1 year. The primary end point was percent uncovered struts by OCT. An independent core laboratory blinded to stent assignment analyzed images. The 6-month rate of uncovered struts per patient was 5.3±14.7% for TAXUS Liberté, 7.0±12.2% for JACTAX HD, and 4.6±7.3% for JACTAX LD (P=0.81); percent malapposed struts was 1.4±4.4%, 0.8±1.9%, and 1.1±2.8%, respectively (P=0.86). Strut-level intimal thickness was 0.20±0.10, 0.22±0.15, and 0.24±0.15 mm (P=0.64); percent volume obstruction by OCT was 22.2±12.8, 22.5±16.2, and 25.8±15.2 (P=0.69). There were no deaths, Q-wave myocardial infarctions, or stent thromboses through 1 year. Conclusions—JACTAX PES with an ultrathin microdot biodegradable abluminal polymer did not result in improved strut coverage at 6 months compared with TAXUS Liberté. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00776204.

Boston Scientific Lotus valve.

As a result of recent randomised controlled trials and registry observations, transcatheter aortic valve replacement (TAVR) enjoys growing appeal for the treatment of patients at high or extreme risk from surgical aortic valve replacement. However, the current technologies and techniques have important limitations, including risk of stroke, vascular complications and paravalvular aortic regurgitation, which may in turn influence survival. While careful patient selection and screening may improve outcomes, new valve designs and iterations are required. The Lotus aortic valve replacement system is a new fully repositionable device designed to facilitate more precise delivery and minimise paravalvular regurgitation. The safety and efficacy of the Lotus valve are being studied systematically in the REPRISE clinical trial programme.

Prasugrel Plus Aspirin Beyond 12 Months Is Associated With Improved Outcomes After Taxus Liberté Paclitaxel-Eluting Coronary Stent Placement

Background— The TAXUS Liberté Post Approval Study (TL-PAS) contributed patients treated with TAXUS Liberté paclitaxel-eluting stent and prasugrel to the Dual Antiplatelet Therapy Study (DAPT) that compared 12 and 30 months thienopyridine plus aspirin therapy after drug-eluting stents. Methods and Results— Outcomes for 2191 TL-PAS patients enrolled into DAPT were assessed. The DAPT coprimary composite end point (death, myocardial infarction [MI], or stroke) was lower with 30 compared with 12 months prasugrel treatment (3.7% versus 8.8%; hazard ratio [HR], 0.407; P<0.001). Rates of death and stroke were similar between groups, but MI was significantly reduced with prolonged prasugrel treatment (1.9% versus 7.1%; HR, 0.255; P<0.001). The DAPT coprimary end point, stent thrombosis, was also lower with longer therapy (0.2% versus 2.9%; HR, 0.063; P<0.001). MI related to stent thrombosis (0% versus 2.6%; P<0.001) and occurring spontaneously (1.9% versus 4.5%; HR, 0.407; P=0.007) were both reduced with prolonged prasugrel. MI rates increased within 90 days of prasugrel cessation after both 12 and 30 months treatment. Composite Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate or severe bleeds were modestly increased (2.4% versus 1.7%; HR, 1.438; P=0.234) but severe bleeds were not more frequent (0.3% versus 0.5%; HR, 0.549; P=0.471) in the prolonged treatment group. Conclusions— Prasugrel and aspirin continued for 30 months reduced ischemic events for the TAXUS Liberté paclitaxel-eluting stent patient subset from DAPT through reductions in MI and stent thrombosis. Withdrawal of prasugrel was followed by an increase in MI after both 12 and 30 months therapy. The optimal duration of dual antiplatelet therapy with prasugrel after TAXUS Liberté paclitaxel-eluting stent remains unknown, but appears to be >30 months. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00997503.

Strut Coverage and Vessel Wall Response to a New-Generation Paclitaxel-Eluting Stent With an Ultrathin Biodegradable Abluminal Polymer

Background—Polymer-coated drug-eluting stents are effective in preventing restenosis but have been associated with delayed healing and incomplete strut coverage. It is unknown whether paclitaxel-eluting stents (PES) with minimal biodegradable abluminal coating enhances strut coverage while preventing neointimal hyperplasia. Using optical coherence tomography (OCT) as a primary imaging modality, we assessed the proportion of uncovered struts at 6-month follow-up in PES coated with durable versus ultrathin (<1 &mgr;m) biodegradable abluminal polymers. Methods and Results—In this pilot trial, 60 patients with de novo lesions (⩽25 mm) in native coronary vessels were randomly assigned to receive either TAXUS Liberté PES or JACTAX PES, a Liberté stent with polymer deposited abluminally as microdots (JACTAX HD: 9.2 &mgr;g each of polymer and paclitaxel per 16-mm stent; JACTAX LD: 5 &mgr;g each). OCT follow-up occurred at 6 months with clinical follow-up through 1 year. The primary end point was percent uncovered struts by OCT. An independent core laboratory blinded to stent assignment analyzed images. The 6-month rate of uncovered struts per patient was 5.3±14.7% for TAXUS Liberté, 7.0±12.2% for JACTAX HD, and 4.6±7.3% for JACTAX LD (P=0.81); percent malapposed struts was 1.4±4.4%, 0.8±1.9%, and 1.1±2.8%, respectively (P=0.86). Strut-level intimal thickness was 0.20±0.10, 0.22±0.15, and 0.24±0.15 mm (P=0.64); percent volume obstruction by OCT was 22.2±12.8, 22.5±16.2, and 25.8±15.2 (P=0.69). There were no deaths, Q-wave myocardial infarctions, or stent thromboses through 1 year. Conclusions—JACTAX PES with an ultrathin microdot biodegradable abluminal polymer did not result in improved strut coverage at 6 months compared with TAXUS Liberté. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00776204.