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Long-term Safety with the SYNERGY Stent System

Long-term Safety with the SYNERGY Stent System

SYNERGY EVOLVE Clinical Data Infographic

EVOLVE II Trial 2-Year Results

Dr. Dean Kereiakes highlights the key 2-Year data coming out of the EVOLVE II Trial including exceptionally low ST rates for the SYNERGY Stent System.

Source: Boston Scientific

Eluvia™ Drug-eluting Vascular Stent System Demonstrates 12-month Primary Patency Of 96.1 Percent

28 Sep 2015

MAJESTIC Trial Data Support Strong Safety Profile with Low Target Lesion Revascularization Rate

MARLBOROUGH, Mass. – New 12-month clinical trial outcomes assessing the safety and performance of the Boston Scientific Eluvia™ Drug-Eluting Vascular Stent System reflect a primary patency rate1 of more than 96 percent. These results represent the highest 12-month primary patency reported for an interventional treatment of femoropopliteal artery lesions among comparable trials. The Eluvia Stent System is an advanced treatment option for patients with narrowing or blockages in the superficial femoral artery (SFA) or proximal popliteal artery (PPA), a result of peripheral artery disease (PAD).

Experience the interactive Multimedia News Release here:
http://www.multivu.com/players/English/7223457-boston-scientific-eluvia-clinical-trial/

Results from the MAJESTIC trial, which were presented at the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) annual meeting in Lisbon, Portugal, also included a low 12-month target lesion revascularization (TLR) rate of 3.8 percent, with no observed stent fractures and no amputations.

“Achieving a 96 percent primary patency rate at one year, with low major adverse events, is exceptional,” said Professor Stefan Muller-Hulsbeck, M.D., PhD, principal investigator and chairman, Vascular Center Diako Flensburg and head of the Department of Diagnostic and Interventional Radiology /Neuroradiology, Academic Hospitals Flensburg, Germany. “In my opinion, the sustained release of paclitaxel enabled by this technology could represent a significant advancement in the treatment of patients with peripheral arterial disease.”

The MAJESTIC trial, a prospective, multicenter clinical trial, enrolled 57 patients across Europe, Australia and New Zealand, with an average lesion length of 70.8 mm. The trial included a high percentage of complex lesions, with 46% of lesions classified as total occlusions and 65% identified as severely calcified.

Data from the MAJESTIC trial are expected to support global regulatory submissions. In addition, Boston Scientific has received an Investigational Device Exemption (IDE) from the Food and Drug Administration (FDA) to begin a global, pivotal study of the Eluvia Stent System. The study, named the IMPERIAL trial, is designed to support future regulatory submissions and patient enrollment is expected to begin in the coming months.

“The MAJESTIC trial demonstrates our commitment to bringing forward innovative therapies that can make a difference in the lives of patients with PAD who face risks of serious complications including infections and amputations,” said Jeff Mirviss, senior vice president and president, Peripheral Interventions, Boston Scientific. “The Eluvia Stent is built on a foundation of more than 15 years of design, development and clinical leadership in drug-eluting technologies at Boston Scientific.”

About the Eluvia Stent System

The Eluvia Stent System is the first stent specifically designed for deployment in the superficial femoral artery (SFA) that utilizes the anti-restenotic drug paclitaxel in conjunction with a polymer. This drug and polymer combination is intended to facilitate sustained release of the drug over the period of time when restenosis is most likely to occur, preventing tissue growth that might otherwise block the stented artery. The Eluvia Stent System is built on the Innova™ Stent System platform, consisting of a self-expanding nitinol stent and an advanced, 6F low-profile triaxial delivery system for added support and placement accuracy. The innovative stent architecture features a closed-cell design at each end of the stent for more predictable deployment, and an open-cell design along the stent body for improved flexibility, strength and fracture resistance. View or download an image of the Eluvia Stent System.

The Eluvia Stent System is pending CE Mark approval. In the U.S., the Eluvia Stent System is an investigational device and is not available for sale.

About Peripheral Artery Disease

Peripheral artery disease is a circulatory disorder that results from a build-up of plaque in one or more of the arteries, most often in the legs. As the disease progresses, plaque accumulation may significantly reduce blood flow through the arteries, resulting in pain and increasing disability, with severe cases often leading to amputation of the affected limb. It is estimated that 200 million people are affected by PAD worldwide.

About Boston Scientific

Boston Scientific transforms lives through innovative medical solutions that improve the health of patients around the world. As a global medical technology leader for more than 35 years, we advance science for life by providing a broad range of high performance solutions that address unmet patient needs and reduce the cost of healthcare.

  1. Primary patency defined as duplex ultrasound peak systolic velocity ratio < 2.5 and absence of TLR or bypass; data reflect actual values (not Kaplan Meier estimates).

 

Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements may be identified by words like “anticipate,” “expect,” “project,” “believe,” “plan,” “estimate,” “intend” and similar words. These forward-looking statements are based on our beliefs, assumptions and estimates using information available to us at the time and are not intended to be guarantees of future events or performance. These forward-looking statements include, among other things, statements regarding clinical trials and impact of data and product performance. If our underlying assumptions turn out to be incorrect, or if certain risks or uncertainties materialize, actual results could vary materially from the expectations and projections expressed or implied by our forward-looking statements. These factors, in some cases, have affected and in the future (together with other factors) could affect our ability to implement our business strategy and may cause actual results to differ materially from those contemplated by the statements expressed in this press release. As a result, readers are cautioned not to place undue reliance on any of our forward-looking statements.

Factors that may cause such differences include, among other things: future economic, competitive, reimbursement and regulatory conditions; new product introductions; demographic trends; intellectual property; litigation; financial market conditions; and future business decisions made by us and our competitors. All of these factors are difficult or impossible to predict accurately and many of them are beyond our control. For a further list and description of these and other important risks and uncertainties that may affect our future operations, see Part I, Item 1A – Risk Factors in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission, which we may update in Part II, Item 1A – Risk Factors in Quarterly Reports on Form 10-Q we have filed or will file hereafter. We disclaim any intention or obligation to publicly update or revise any forward-looking statements to reflect any change in our expectations or in events, conditions or circumstances on which those expectations may be based, or that may affect the likelihood that actual results will differ from those contained in the forward-looking statements. This cautionary statement is applicable to all forward-looking statements contained in this document.

 

Source: Boston Scientific

Boston Scientific receives CE mark for Eluvia™ drug-eluting vascular stent and announces initiation of new clinical trial

22 Feb 2016

First polymer-based, drug-eluting stent designed to treat peripheral lesions above the knee approved in Europe; IMPERIAL trial initiated to seek regulatory approvals in U.S. and Asia

Boston Scientific, today announced that the Eluvia™ Drug-Eluting Vascular Stent System has received CE Mark and is commencing commercialization immediately in the European Union and other countries where CE Mark is recognized.

The Eluvia Stent System is designed to restore blood flow in the peripheral arteries above the knee – specifically the superficial femoral artery and proximal popliteal artery. The stent features a unique drug-polymer combination intended to facilitate sustained release of the drug (paclitaxel) that can prevent narrowing (restenosis) of the vessel, often the cause of pain and disability for patients diagnosed with peripheral artery disease.

CE Mark approval was based on data from the MAJESTIC trial, a prospective, multicenter clinical trial that assessed the safety and performance of the Eluvia Stent System and reflected a primary patency rate of more than 96 percent1.  The MAJESTIC trial results represented the highest 12-month primary patency reported for an interventional treatment of femoropopliteal artery lesions among comparable trials.

“The exceptional 12-month results presented in the MAJESTIC trial, which included a high percentage of patients with complex lesions, demonstrate that this technology is a safe and efficacious solution for patients needing stents for the treatment of peripheral artery disease,” said Professor Stefan Müller-Hülsbeck, M.D., PhD, principal investigator at the Vascular Center Diako Flensburg and head of the Department of Diagnostic and Interventional Radiology / Neuroradiology, Academic Hospitals Flensburg, Germany. “The approval is a testament to the strength of the data, and will be welcome news to physicians and patients who have not previously had access to a polymer based, drug-eluting stent, specifically developed for the superficial femoral and proximal popliteal arteries.”

Boston Scientific received an Investigational Device Exemption (IDE) to conduct a global, prospective trial called the IMPERIAL trial, which will assess the safety and efficacy of the Eluvia Stent System compared to the Zilver® PTX® Stent manufactured by Cook Medical. Enrollment began in Q4 last year and the study will include approximately 485 patients in 75 sites worldwide.

“The availability of the Eluvia Stent System to European patients, paired with the expansion of our existing clinical program, demonstrates the momentum of our drug-eluting portfolio in combatting peripheral artery disease,” said Jeff Mirviss, senior vice president and president, Peripheral Interventions, Boston Scientific. “Our legacy with drug-eluting technology combined with our commitment to further advance treatment options for peripheral artery disease, enables Boston Scientific to continue bringing ground breaking solutions for patients around the world.”

About the Eluvia Stent System

The Eluvia Stent System is the first stent specifically designed for deployment in the superficial femoral artery (SFA) that utilizes the anti-restenotic drug paclitaxel in conjunction with a polymer. This drug and polymer combination is intended to facilitate sustained release of the drug over the period of time when restenosis is most likely to occur, preventing tissue growth that might otherwise block the stented artery. The Eluvia Stent System is built on the Innova™ Stent System platform, consisting of a self-expanding nitinol stent and an advanced, 6F low-profile triaxial delivery system for added support and placement accuracy. The innovative stent architecture features a closed-cell design at each end of the stent for more predictable deployment, and an open-cell design along the stent body for improved flexibility, strength and fracture resistance. View or download an image of the Eluvia Stent System.

In the U.S., the Eluvia Stent System is an investigational device and is not available for sale.

About Peripheral Artery Disease

Peripheral artery disease (PAD) occurs when fatty (plaque) or calcified material builds up in the walls of the arteries and makes them narrower, thus restricting blood flow. When this occurs, the muscles in the legs cannot get enough blood and oxygen, especially during exertion such as exercise or walking. The main symptoms of PAD are pain, burning, or general discomfort in muscles of the feet, calves, or thighs. As the disease progresses, plaque accumulation may significantly reduce blood flow through the arteries, resulting in pain (claudication) and increasing disability, with severe cases often leading to amputation of the affected limb. It is estimated that 200 million people are affected by PAD worldwide.

About Boston Scientific

Boston Scientific transforms lives through innovative medical solutions that improve the health of patients around the world.  As a global medical technology leader for more than 35 years, we advance science for life by providing a broad range of high performance solutions that address unmet patient needs and reduce the cost of healthcare.  For more information, visitwww.bostonscientific.eu

Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934.  Forward-looking statements may be identified by words like “anticipate,” “expect,” “project,” “believe,” “plan,” “estimate,” “intend” and similar words.  These forward-looking statements are based on our beliefs, assumptions and estimates using information available to us at the time and are not intended to be guarantees of future events or performance.  These forward-looking statements include, among other things, statements regarding our business plans, regulatory approvals, clinical trials, and product performance and impact.  If our underlying assumptions turn out to be incorrect, or if certain risks or uncertainties materialize, actual results could vary materially from the expectations and projections expressed or implied by our forward-looking statements.  These factors, in some cases, have affected and in the future (together with other factors) could affect our ability to implement our business strategy and may cause actual results to differ materially from those contemplated by the statements expressed in this press release.  As a result, readers are cautioned not to place undue reliance on any of our forward-looking statements.

Factors that may cause such differences include, among other things: future economic, competitive, reimbursement and regulatory conditions; new product introductions; demographic trends; intellectual property; litigation; financial market conditions; and future business decisions made by us and our competitors.  All of these factors are difficult or impossible to predict accurately and many of them are beyond our control.  For a further list and description of these and other important risks and uncertainties that may affect our future operations, see Part I, Item 1A – Risk Factors in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission, which we may update in Part II, Item 1A – Risk Factors in Quarterly Reports on Form 10-Q we have filed or will file hereafter.  We disclaim any intention or obligation to publicly update or revise any forward-looking statements to reflect any change in our expectations or in events, conditions or circumstances on which those expectations may be based, or that may affect the likelihood that actual results will differ from those contained in the forward-looking statements.  This cautionary statement is applicable to all forward-looking statements contained in this document.

  1.  Primary patency defined as duplex ultrasound peak systolic velocity ratio < 2.5 and absence of TLR or bypass; data reflect actual values (not Kaplan Meier estimates).

Source: Boston Scientific

Tryton Medical Announces Publication of Post Hoc Analysis of Randomized Clinical Trial in Treatment of Bifurcation Lesions using Tryton Side Branch Stent

Analysis showed reductions in target vessel failure and improved side branch percent diameter stenosis in patients with a coronary bifurcation lesion in vessels 2.25mm in diameter or greater

September 30, 2015 06:30 AM Eastern Daylight Time

DURHAM, N.C.–(BUSINESS WIRE)–Tryton Medical, Inc., the leading developer of stents designed to treat coronary bifurcation lesions, today announced that results of a post hoc analysis of the pivotal Tryton Randomized Clinical Trial (RCT) have been published in the peer-reviewed journal Catheterization and Cardiovascular Interventions (CCI), the official publication of the Society for Cardiovascular Angiography and Interventions (SCAI). The analysis, “Outcomes of a dedicated stent in coronary bifurcations with large side branches: A subanalysis of the randomized TRYTON bifurcation study,” examines the use of the Tryton Side Branch Stent compared with provisional stenting in the intended treatment population of patients with a coronary bifurcation lesion in vessels 2.25mm in diameter or greater determined by quantitative coronary angiography (QCA).

“We welcome the results of this post hoc analysis in patients with large side branches as an important step towards bringing a dedicated stent to cardiologists in the United States, and addressing challenges in treating significant coronary bifurcation lesions”

The study authors, led by Martin B. Leon, MD, director of the Center for Interventional Vascular Therapy at Columbia University Medical Center, New York-Presbyterian Hospital, conclude that treatment with the Tryton Side Branch Stent showed reductions in target vessel failure and improved side branch percent diameter stenosis in the population of patients with lesions involving side branches that were 2.25mm in diameter or greater. Both the Tryton Side Branch Stent and provisional treatment strategies were shown to have similarly low rates of stent thrombosis and no cardiac deaths were reported at nine months.

“Coronary bifurcation lesions present a number of challenges for interventional cardiologists because each patient can present with varying vessel sizes and there is a wide range of angulations between the main vessel and side branch,” said Dr. Leon. “For the treatment of bifurcation lesions involving significant side branches, this analysis of the pivotal Tryton RCT provides strong support for the safety and efficacy of the Tryton Side Branch Stent compared with a provisional stenting strategy.”

In the post hoc analysis of 289 patients with a coronary bifurcation lesion involving a side branch greater than or equal to 2.25mm in diameter, target vessel failure, the primary endpoint, was numerically lower among the Tryton group compared to the provisional group. The Tryton Side Branch Stent demonstrated a statistically significant lower side branch percent diameter stenosis at nine month follow up compared with the provisional group (30.4% vs. 40.6%, P = 0.004). In addition, the Tryton Side Branch Stent reduced the need for additional side branch “bail-out” stenting compared with the provisional approach (0.7% vs. 5.6%, P = 0.02). There was no significant difference in the rate of binary restenosis.

“We welcome the results of this post hoc analysis in patients with large side branches as an important step towards bringing a dedicated stent to cardiologists in the United States, and addressing challenges in treating significant coronary bifurcation lesions,” said Shawn P. McCarthy, president and CEO of Tryton Medical. “We recently completed enrollment in the Tryton Confirmatory Study, a single-arm study of our dedicated stent designed to confirm results from the pivotal Tryton RCT study in our intended population of patients with coronary bifurcation lesions involving side branches that are 2.25mm in diameter or greater. We plan to present findings from this study at the Transcatheter Cardiovascular Therapeutics (TCT) 2015 meeting in the coming weeks.”

About Tryton Side Branch Stent

Tryton Side Branch Stent System is built using proprietary Tri-ZONE® technology to offer a dedicated strategy for treating bifurcation lesions. Tryton’s cobalt chromium stent is deployed in the side branch artery using a standard single wire balloon-expandable stent delivery system. A conventional drug eluting stent is then placed in the main vessel. Tryton Side Branch Stent has now been used to treat more than 11,000 patients worldwide. The Tryton Side Branch Stent is commercially available in multiple countries within Europe, Middle East & Africa, is investigational in the US, and is not available in Japan.

About Tryton Medical, Inc.

Tryton Medical, Inc., located in Durham, N.C., is the leading developer of novel stent systems for the treatment of bifurcation lesions. The company was founded in 2003 by Aaron V. Kaplan, M.D., professor of medicine at Dartmouth Medical School/Dartmouth-Hitchcock Medical Center, to develop stents for the definitive treatment of bifurcation lesions. For more information please visit www.trytonmedical.com and follow the company on Twitter at @TrytonMedical1.

 

Source: Business Wire

News Releases Eluvia™ Drug-eluting Vascular Stent System Demonstrates 12-month Primary Patency Of 96.1 Percent

MAJESTIC Trial Data Support Strong Safety Profile with Low Target Lesion Revascularization Rate

Sep 28, 2015

MARLBOROUGH, Mass., Sept. 28, 2015 /PRNewswire/ — New 12-month clinical trial outcomes assessing the safety and performance of the Boston Scientific (NYSE: BSX) Eluvia™ Drug-Eluting Vascular Stent System reflect a primary patency rate1 of more than 96 percent. These results represent the highest 12-month primary patency reported for an interventional treatment of femoropopliteal artery lesions among comparable trials. The Eluvia Stent System is an advanced treatment option for patients with narrowing or blockages in the superficial femoral artery (SFA) or proximal popliteal artery (PPA), a result of peripheral artery disease (PAD).

Experience the interactive Multimedia News Release here:
http://www.multivu.com/players/English/7223457-boston-scientific-eluvia-clinical-trial/

Results from the MAJESTIC trial, which were presented at the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) annual meeting in Lisbon, Portugal, also included a low 12-month target lesion revascularization (TLR) rate of 3.8 percent, with no observed stent fractures and no amputations.

“Achieving a 96 percent primary patency rate at one year, with low major adverse events, is exceptional,” said Professor Stefan Muller-Hulsbeck, M.D., PhD, principal investigator and chairman, Vascular Center Diako Flensburg and head of the Department of Diagnostic and Interventional Radiology /Neuroradiology, Academic Hospitals Flensburg, Germany. “In my opinion, the sustained release of paclitaxel enabled by this technology could represent a significant advancement in the treatment of patients with peripheral arterial disease.”

The MAJESTIC trial, a prospective, multicenter clinical trial, enrolled 57 patients across Europe,Australia and New Zealand, with an average lesion length of 70.8 mm. The trial included a high percentage of complex lesions, with 46% of lesions classified as total occlusions and 65% identified as severely calcified.

Data from the MAJESTIC trial are expected to support global regulatory submissions. In addition, Boston Scientific has received an Investigational Device Exemption (IDE) from the Food and Drug Administration (FDA) to begin a global, pivotal study of the Eluvia Stent System. The study, named the IMPERIAL trial, is designed to support future regulatory submissions and patient enrollment is expected to begin in the coming months.

“The MAJESTIC trial demonstrates our commitment to bringing forward innovative therapies that can make a difference in the lives of patients with PAD who face risks of serious complications including infections and amputations,” said Jeff Mirviss, senior vice president and president, Peripheral Interventions, Boston Scientific. “The Eluvia Stent is built on a foundation of more than 15 years of design, development and clinical leadership in drug-eluting technologies at Boston Scientific.”

About the Eluvia Stent System
The Eluvia Stent System is the first stent specifically designed for deployment in the superficial femoral artery (SFA) that utilizes the anti-restenotic drug paclitaxel in conjunction with a polymer. This drug and polymer combination is intended to facilitate sustained release of the drug over the period of time when restenosis is most likely to occur, preventing tissue growth that might otherwise block the stented artery. The Eluvia Stent System is built on the Innova™ Stent System platform, consisting of a self-expanding nitinol stent and an advanced, 6F low-profile triaxial delivery systemfor added support and placement accuracy. The innovative stent architecture features a closed-cell design at each end of the stent for more predictable deployment, and an open-cell design along the stent body for improved flexibility, strength and fracture resistance. View or download an image of the Eluvia Stent System.

The Eluvia Stent System is pending CE Mark approval. In the U.S., the Eluvia Stent System is an investigational device and is not available for sale.

About Peripheral Artery Disease
Peripheral artery disease is a circulatory disorder that results from a build-up of plaque in one ormore of the arteries, most often in the legs. As the disease progresses, plaque accumulation may significantly reduce blood flow through the arteries, resulting in pain and increasing disability, with severe cases often leading to amputation of the affected limb. It is estimated that 200 million people are affected by PAD worldwide.

About Boston Scientific
Boston Scientific transforms lives through innovative medical solutions that improve the health of patients around the world. As a global medical technology leader for more than 35 years, we advance science for life by providing a broad range of high performance solutions that address unmet patient needs and reduce the cost of healthcare. For more information, visitwww.bostonscientific.com and connect on Twitter and Facebook.

Primary patency defined as duplex ultrasound peak systolic velocity ratio < 2.5 and absence of TLR or bypass; data reflect actual values (not Kaplan Meier estimates).

Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements may be identified by words like “anticipate,” “expect,” “project,” “believe,” “plan,” “estimate,” “intend” and similar words. These forward-looking statements are based on our beliefs, assumptions and estimates using information available to us at the time and are not intended to be guarantees of future events or performance. These forward-looking statements include, among other things, statements regarding clinical trials and impact of data and product performance. If our underlying assumptions turn out to be incorrect, or if certain risks or uncertainties materialize, actual results could vary materially from the expectations and projections expressed or implied by our forward-looking statements. These factors, in some cases, have affected and in the future (together with other factors) could affect our ability to implement our business strategy and may cause actual results to differ materially from those contemplated by the statements expressed in this press release. As a result, readers are cautioned not to place undue reliance on any of our forward-looking statements.

Factors that may cause such differences include, among other things: future economic, competitive, reimbursement and regulatory conditions; new product introductions; demographic trends; intellectual property; litigation; financial market conditions; and future business decisions made by us and our competitors. All of these factors are difficult or impossible to predict accurately and many of them are beyond our control. For a further list and description of these and other important risks and uncertainties that may affect our future operations, see Part I, Item 1A – Risk Factors in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission, which we may update in Part II, Item 1A – Risk Factors in Quarterly Reports on Form 10-Q we have filed or will file hereafter. We disclaim any intention or obligation to publicly update or revise any forward-looking statements to reflect any change in our expectations or in events, conditions or circumstances on which those expectations may be based, or that may affect the likelihood that actual results will differ from those contained in the forward-looking statements. This cautionary statement is applicable to all forward-looking statements contained in this document.

Source: Boston Scientific

One-year outcomes in unselected patients treated with a thin-strut, platinum-chromium, paclitaxel-eluting stent: primary endpoint results from the TAXUS Element European post-approval surveillance study (TE-PROVE)

Corrado Tamburino1, MD, PhD; Davide Capodanno1*, MD, PhD; Andrejs Erglis2, MD; Ian B.A. Menown3, MD, FRCP; Iván G. Horváth4, MD, PhD; Raul Moreno5, MD; Timothy J. Gilbert6, MB, FRCP; James J. Crowley7, MD; Paolo Calabria8, MD; Dominic J. Allocco9, MD; Keith D. Dawkins9, MD

1. Ferrarotto Hospital, University of Catania, Catania, Italy; 2. Pauls Stradins Clinical University Hospital, University of Latvia, Riga, Latvia; 3. Craigavon Cardiac Centre, Craigavon, United Kingdom; 4. Heart Institute, University of Pécs, Pécs, Hungary; 5. University Hospital La Paz, Madrid, Spain; 6. Norfolk and Norwich University Hospital NHS Trust, Norwich, United Kingdom; 7. Galway University Hospital, Galway, Ireland; 8. Ospedale della Misericordia, Grosseto, Italy; 9. Boston Scientific Corporation, Marlborough, MA, USA

Abstract

Aims: To evaluate clinical outcomes in patients receiving the next-generation, paclitaxel-eluting, platinum-chromium TAXUS Element stent in a real-world setting. The PERSEUS Workhorse and Small Vessel studies showed positive results with the TAXUS Element stent in a clinical trial setting.

Methods and results: TE-PROVE was a prospective, open-label, multicentre, “all-comers” study which enrolled 1,014 patients at 37 European sites. Follow-up was at 30 days, six months and one year, and will continue annually up to five years. The primary endpoint was overall and stent-related target vessel failure (TVF), defined as cardiac death, target vessel-related myocardial infarction (MI) and target vessel revascularisation (TVR) at one year post implantation. Secondary endpoints included the components of TVF, all-cause mortality, and ARC definite/probable stent thrombosis. Follow-up was available in 97.3% (987/1,014) of patients. Patients were 75.0% male (760/1,014), mean age was 65.1±10.8 years, 25.5% had medically treated diabetes (259/1,014), and 10.7% (109/1,014) were treated for STEMI. At baseline, mean lesion length among 1,299 treated lesions was 19.8±12.0 mm and mean reference vessel diameter was 3.1±0.5 mm. At one year, the rate of TVF (primary endpoint) was 6.0% (59/987) overall; 3.7% (37/987) of TVF events were stent-related. Cardiac death was 0.7% (7/987), target vessel-related MI was 1.1% (11/987), and TVR was 4.7% (46/987). All-cause death occurred in 1.2% (12/987) of patients and ARC definite/probable ST was 0.5% (5/987).

Conclusions: The primary endpoint results from the TE-PROVE registry demonstrate good performance and safety for the TAXUS Element paclitaxel-eluting stent at one year in everyday clinical practice. Clinical Trial Registration Information: NCT01242696.

Introduction

First-generation stainless steel paclitaxel-eluting stents (PES) are known to reduce angiographic restenosis and target vessel revascularisation (TVR) compared with bare metal stents1,2,3,4,5,6. However, repeat revascularisation with first-generation PES is still required in 7-10% of patients7. Strut thickness may impact on the ability of a stent to reduce restenosis: thinner struts are associated with less stent-induced arterial injury and inflammation, potentially resulting in better deliverability but at the price of reduced radiopacity and radial strength8,9,10.

The TAXUS Element™ stent (Boston Scientific, Marlborough, MA, USA) uses the same polymer, antiproliferative agent and drug release kinetics as previous-generation PES, but incorporates a thin-strut platinum-chromium (PtCr) alloy platform intended to improve deliverability, radial strength and radiopacity while preserving safety and efficacy. In the PERSEUS (Prospective Evaluation in a Randomized Trial of the Safety and Efficacy of the Use of the TAXUS Element Paclitaxel-Eluting Coronary Stent System) Workhorse trial, the TAXUS Element PES showed comparable efficacy to the TAXUS Express PES (Boston Scientific), with no safety concerns related to the novel PtCr platform11. In this manuscript, we report the one-year results of all-comers patients undergoing implantation of TAXUS Element PtCr PES in a real-life setting.

Methods

STUDY DESIGN

The TE-PROVE (TAXUS Element™ Paclitaxel-Eluting Coronary Stent System European Post-Approval Surveillance Study) was an international multicentre, prospective, open-label, single-arm, post-marketing, observational study (ClinicalTrials.gov identifier NCT01242696).

All candidates for percutaneous coronary intervention (PCI) with stent implantation were eligible for inclusion. PCI procedures and periprocedural adjunctive pharmacotherapy were performed according to local practice. Follow-up was conducted via standard practice or telephone. Additional methods are described in the Online Appendix.

The study was conducted according to the Declaration of Helsinki and was approved by local medical ethics committees at enrolling sites. Written informed consent was obtained from all patients.

DEVICE DESCRIPTION

The TAXUS Element stent system is a PtCr alloy stent with a nominal strut thickness of 81 μm, coated with paclitaxel incorporated at 1 μg/mm2 into a poly(styrene-b-isobutylene-b-styrene) polymer11.

STUDY ENDPOINTS

The primary endpoint was target vessel failure (TVF): cardiac death, myocardial infarction (MI) related to the target vessel, and TVR at 12 months post stent implantation. Additional endpoints are described in the Online Appendix.

STATISTICAL ANALYSIS

The analysis consisted of all enrolled patients in whom a TAXUS Element stent was attempted and/or implanted. A secondary analysis compared outcomes in the PERSEUS-like and non-PERSEUS-like patient subgroups. Additional statistical methods are described in the Online Appendix.

ESTIMATION OF COMPARATOR 12-MONTH OUTCOMES

The pooled rates of TVF, MACE, and death at 12 months from recent, published all-comers PCI studies were assessed. In keeping with established methodologies and the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) group recommendations12,13, studies were included after a literature search if they satisfied the criteria included in the Online Appendix (Methods). No statistical comparison was performed.

Results

PATIENT POPULATION

A total of 1,014 patients from 37 centres in 10 European countries were enrolled between November 2010 and October 2011. Clinical follow-up at 12 months was available in 987/1,014 (97.3%) patients. Baseline patient and lesion characteristics are listed in Online Table 1 and Online Table 2. The mean age was 65±11 years, and diabetes mellitus was present in 28.9% (8.9% were on insulin therapy). Mean lesion reference vessel diameter and length were 3.1±0.5 and 19.8±12.0 mm, respectively. More than half (56%) of lesions were of class B2/C.

PROCEDURAL DETAILS AND MEDICATIONS

A total of 1,566 stents in 1,029 procedures were implanted. Predilatation was performed in 61% of lesions. The mean numbers of treated lesions and vessels per patient were 1.3±0.57 and 1.1±0.37, respectively. Mean stent length per patient was 31.3±20.4 mm and placement of overlapping stents was required in 12.6% of lesions. Technical success was achieved in 1,010/1,014 (99.6%) of patients. Clinical procedural success was achieved in 997/1,014 (98.3%) of patients. Dual antiplatelet therapy was prescribed at discharge in 96.9% of patients and maintained at 12-month follow-up in 84.3%.

CARDIAC EVENTS AT FOLLOW-UP

Binary rates of cardiac events at 12 months are reported in Table 1. Corresponding Kaplan-Meier curves for TVF and cardiac death/MI are shown in Figure 1. At 12 months, TVF (primary endpoint) occurred in 59 (6.0%) patients. The clinical events committee adjudicated 37 TVRs as stent-related (3.7%). This figure was reasonably consistent across multiple subgroups (Figure 2). MACE occurred in 6.2% and death in 1.2% of patients over 12 months (Table 1).

01tab_Tamburino.pdf

01_TamburinoSR81.eps

Figure 1. Cumulative 12-month incidences of target vessel failure (TVF: panels A and C), and the composite of cardiac death or myocardial infarction (MI: panels B and D) in the overall cohort (panels A and B) and in the non-PERSEUS-like (solid line) and PERSEUS-like (dotted line) subgroups (panels C and D).

02_TamburinoSR81.eps

Figure 2. Incidence of 12-month target vessel failure in subgroups of interest.

ESTIMATION OF COMPARATOR RATES OF TVF, MACE AND DEATH AT 12 MONTHS

To put the results of the TE-PROVE registry into the perspective of recent all-comers PCI studies, we identified 13 stent studies reporting on TVF, MACE and/or death at 12 months (Online Table 3-Online Table 5, Online Figure 2). After weighting each rate by the number of patients per study, the overall weighted means for TVF, MACE and death at 12 months by a random effects model were 8.1%, 7.4% and 2.1%, respectively (Online Figure 1).

OUTCOMES OF NON-PERSEUS-LIKE VERSUS PERSEUS-LIKE PATIENTS

A total of 69.8% of patients presented with ≥1 clinical and/or angiographic characteristics of extended use over the eligibility criteria of the PERSEUS trial. At 12 months, PERSEUS-like patients had a lower incidence of MACE, the composite of cardiac death or MI, and non-Q-wave MI compared to those with more complex characteristics included in the non-PERSEUS-like group (Table 2, Figure 1). There was an overall trend towards lower event rates in the less complex group though these differences did not reach significance (Table 2).

02tab_Tamburino.pdf

Discussion

The TE-PROVE study demonstrates that, in unselected patients with coronary artery disease undergoing PCI with implantation of a novel PtCr PES, TVF occurs at the relatively low rate of 6.0% at 12 months. These findings compare favourably with recent all-comers PCI trials and registries of DES. In particular, from studies between 2010 and 2013, we calculated a weighted mean of 8.1% for TVF (versus 6.0% in TE-PROVE), 7.4% for MACE (versus 6.2%), and 2.1% for death (versus 1.2%). Although useful to put the TE-PROVE results into perspective, and despite the baseline characteristics of those studies being largely similar to those of TE-PROVE, this comparison is intended for descriptive purposes only. Interestingly, the TVF rate of the overall population at 12 months was reasonably consistent in multiple subgroups of interest (with 8.8% and 6.6% estimates for patients with diabetes mellitus and B2/C lesions, respectively).

Strut thickness is known to impact on angiographic and clinical outcomes after coronary artery stenting8,9. Newer-generation 316L stainless steel stent designs have reduced strut thickness while preserving radial strength and minimising recoil, but with significantly less radiopacity14. The TAXUS Element PES incorporates a new PtCr alloy with high radial strength and high radiopacity which enabled the design of a thin-strut, flexible, trackable and conformable stent platform, while improving stent visibility15.

The TAXUS PERSEUS clinical trial programme evaluated the TAXUS Element PES in two parallel studies10. In the PERSEUS Workhorse trial, target lesion failure (TLF) at 12 months was reported in 5.6% of patients treated with the TAXUS Element PES and in 6.1% of patients treated with the TAXUS Express PES, meeting the criteria for non-inferiority (posterior probability p=0.9996)11. In the PERSEUS Small Vessel trial, the TAXUS Element PES was superior to the Express BMS in terms of late loss (0.38±0.51 vs. 0.80±0.53 mm, respectively, p<0.001), and TLF (7.3% vs. 19.5%, p<0.001)16. TE-PROVE provides further assurance of the safety and efficacy of the PtCr PES in a larger real-world population than those included in the PERSEUS trials. No safety concerns were observed, with low incidences of death and MI at 12 months.

The incidence of ARC definite and probable ST was 0.5% overall, with 0.4% occurring early (0 to 30 days) and 0.1% occurring late (31 to 365 days). These figures are reassuring for a PES17, and may suggest a role of the PtCr platform in reducing thrombogenicity and promoting vascular healing18. Additionally, increased radiopacity of PtCr platforms may help to identify underexpanded stents and, potentially, aid in reducing the rate of ST. The optimal length of dual antiplatelet therapy after placement of a stent is a matter of ongoing investigation. In this registry, about 84% of patients were taking dual antiplatelet therapy at 12 months, a high rate and in keeping with the guidelines available at the time of the study19.

Limitations

This study carries some obvious limitations. First, the TE-PROVE registry lacked a concurrent comparator, but the objectives were to extend the results of the PERSEUS trials in a broader patient population and more precise detection of low-frequency events. Second, although random monitoring of source data from 20% of patients enrolled at each site was employed, the potential for under-reporting of adverse events cannot be entirely ruled out. Third, quantitative coronary angiography data were based on site-reported data with no collection by a core laboratory reflecting the “real-world” approach of the study. Fourth, patients were not consecutively enrolled and there may have been some selection bias. Lastly, we do not know the total number of DES patients treated at these sites during the enrolment.

Conclusions

The post-marketing surveillance TE-PROVE study showed favourable early and 12-month safety profiles and high-level efficacy of the novel PtCr PES in the treatment of coronary lesions in a “real-world” patient population. The 12-month rate of TVF was comparable to rates reported across other contemporary studies.

Impact on daily practiceThe introduction of a thin-strut platinum-chromium alloy platform with increased radiopacity is intended to address multiple technical conundrums of stent-based percutaneous coronary intervention, including stent deliverability, radial strength and visibility. The TE-PROVE, a large post-marketing surveillance real-world registry of a novel platinum-chromium paclitaxel-eluting stent, demonstrated low 12-month rates of target vessel failure, in the range of those reported across other contemporary stent studies, and low rates of stent thrombosis.

Acknowledgements

The authors thank Kristine Roy (Boston Scientific Corporation) for assistance in manuscript preparation and Songtao Jiang (Boston Scientific Corporation) for statistical analysis.

Funding

The TE-PROVE study was supported by Boston Scientific Corporation.

Conflict of interest statement

D. Capodanno reports receiving speaker’s bureau/advisory board fees from Eli Lilly, AstraZeneca and The Medicines Company. A. Erglis reports receiving consulting/speaker’s bureau fees from Boston Scientific, Abbott Vascular, Cordis J&J, Medtronic, Biosensors. I. Menown reports receiving institutional grants/conference sponsorship from Boston Scientific, Biosensors, Biotronik, Eurocor, and OrbusNeich. R. Moreno reports receiving consulting fees from Cordis, Biotronik, Medtronic, Boston Scientific, Abbott Vascular, Eli Lilly, Iroko, Covidien, General Electric, Ferrer, and St. Jude Medical. T. Gilbert reports receiving travel and accommodation support to attend educational meetings from BSC and was a member of the BSC Advisory Board in the development stages of the Element platform. D. Allocco and K. Dawkins are full-time employees and stockholders of BSC. C. Tamburino, J. Crowley, I. Horváth, and P. Calabria have no conflicts of interest to declare.

Online data supplement

Appendix. Methods

STUDY DESIGN

No exclusion criteria were applied beyond contraindications to TAXUS Element implantation according to the “Instructions for Use”. The non-PERSEUS-like group was defined as patients with acute myocardial infarction (AMI), graft stenting, left main disease, chronic total occlusion, in-stent restenosis, failed brachytherapy, a bifurcation lesion, an ostial lesion, severe tortuosity, moderate or severe calcification by visual estimate in target lesion or target vessel proximal to target lesion, multivessel stenting, RVD <2.25 mm, RVD >4.00 mm, lesion length >28 mm, cardiogenic shock, or acute or chronic renal dysfunction (serum creatinine >3.0 mg/dL or subject on dialysis). Twelve-month follow-up was conducted via standard practice (n=56) or telephone (n=917).

DEVICE DESCRIPTION

The TAXUS Element stent system is a PtCr alloy stent with a nominal strut thickness of 81 μm, coated with a slow release formulation of paclitaxel incorporated at 1 μg/mm2 into a poly(styrene-b-isobutylene-b-styrene) polymer11. The stent was available in seven sizes between 2.25 and 4.5 mm and eight lengths ranging from 8 to 38 mm. At the time of the study, the TAXUS Element stent had a CE mark and was available for use in routine clinical practice in the participating hospitals.

ENDPOINTS

Secondary endpoints included technical success (defined as successful delivery or deployment of the stent to the target lesion without device malfunction), clinical procedural success (defined as mean lesion diameter stenosis <30%, a TIMI flow of 3 as visually assessed by the physician, and no occurrence of in-hospital cardiac events), the components of TVF, major adverse cardiac events (MACE: including cardiac death, MI and TVR), the composite of cardiac death or MI, all-cause death and definite/probable stent thrombosis using the Academic Research Consortium (ARC) definition at 30 days, six months and 12 months20. MI was categorised as either Q-wave MI, defined as the development of new pathological Q-waves in two or more leads lasting ≥0.04 seconds with post-procedure CK-MB levels elevated above normal, or non-Q-wave MI, defined as de novo elevation of CK total levels >2.0 × ULN without the presence of new Q-waves. Clinical follow-up was at 30 days, six months and one year, and will continue annually up to five years. Source data verification was carried out for 20% of subjects randomly selected at each site and with a risk-based monitoring approach, and on all subjects with reported death, MACE, ST and device malfunction. Overall and stent-related TVF, MACE, cardiac death, MI, TVR and ARC ST definite/probable rates were calculated. A clinical events committee (CEC) adjudicated all deaths, MACE and stent thrombosis events. The CEC classified an event as ‘‘stent-related’’ if the event occurred at the stented segment or relationship to the TAXUS stent could not be excluded based upon available information. Blood samples were taken as per local practice.

STATISTICAL METHODS

The pre-specified plan was to collect outcome data for approximately 1,000 patients. All statistical analyses were performed using SAS Version 9.2 (SAS Institute Inc., Cary, NC, USA). Subject baseline characteristics, lesion characteristics, procedure characteristics, and outcome variables were summarised using descriptive statistics for continuous variables and frequency tables for discrete variables. Continuous variables following a normal distribution were compared using the Student’s unpaired t-test, while continuous variables not following a normal distribution were compared with the Mann-Whitney rank-sum test. Categorical variables were compared by means of the chi-square test or Fisher’s exact test when at least 25% of values showed an expected cell frequency below five. Kaplan-Meier plots of time-to-event variables were constructed with 95% confidence intervals at appropriate time points. The log-rank test was used for comparison of Kaplan-Meier estimates.

ESTIMATION OF COMPARATOR 12-MONTH OUTCOMES

To put the results of the TE-PROVE into clinical perspective, we assessed the rates of TVF, MACE, and death at 12 months from published results of recent large, all-comers PCI studies. In keeping with established methodologies and the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) group12,13, the studies were included after a literature search if they satisfied all of the following criteria: 1) 100 or more patients; 2) published in the English language in peer-reviewed journals, or presented at major cardiology conferences; 3) published between January 2010 and August 2013; and 4) provided the rate of TVF, MACE, and/or death at 12 months. The TVF, MACE rates reported were consistent with each individual study definition and death was defined as death from any cause, unless only cardiac death was available. Pooled incidence rates of individual outcomes were estimated (as detailed in single-arm studies or in each arm of comparative studies) with associated 95% confidence interval (95% CI), by using both fixed and random effects (DerSimonian-Laird method) models to address heterogeneity, if any, among reported rates. Such evaluation was descriptive only and did not lead to any statistical comparison.

Online results

Of all patients in the study population, 12 (1.2%) died, seven of a cardiac cause (0.7%). MACE and the composite of cardiac death or MI occurred in 61 (6.2%) and 20 (2.0%) patients, respectively. Forty-six (4.7%) patients underwent a TVR. Definite/probable ST according to the ARC definitions were adjudicated in five (0.5%) patients (four occurred within 30 days). There were four definite ST and one probable ST.

OL01_TamburinoSR81.eps

Online Figure 1. Cumulative 12-month incidences of major adverse cardiac events (MACE; panels A and C) and all-cause death (panels B and D) in the overall cohort (panels A and B) and in the non-PERSEUS-like (solid line) and PERSEUS-like (dotted line) subgroups (panels C and D).

OL02_Tamburino.eps

Online Figure 2. Cardiac outcomes at 12 months in the TE-PROVE cohort in the weighted meta-analyses of large contemporary trials of percutaneous coronary intervention.

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Source: EuroIntervention

Percutaneous left atrial appendage closure in patients with left atrial appendage thrombus

Felix Meincke, MD; Felix Kreidel, MD; Jasper von Wedel, MD; Ulrich Schäfer, MD; Karl-Heinz Kuck, MD; Martin W. Bergmann*, MD

Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany

This paper also includes accompanying supplementary data published online at: http://www.pcronline.com/eurointervention/81st_issue/199

Occlusion of the left atrial appendage (LAA) using the WATCHMAN™ device (Boston Scientific, Natick, MA, USA) proved its safety and efficacy in the PROTECT-AF trial and has found its way into daily clinical routine since then. However, patients with known thrombus formation within the LAA have been excluded from this technique so far because of the high risk of embolisation during the procedure in these patients. We report the first two cases of successful LAA occlusion using the WATCHMAN™ device and cerebral protection systems in patients with known thrombus within the LAA. Both patients were successfully treated with a WATCHMAN™ device without procedural complications. As cerebral protection devices, a SpiderFX™ system (ev3 Endovascular, Inc., Plymouth, MN, USA) was used in the first case and a Claret Medical Montage™ (Claret Medical, Inc., Santa Rosa, CA, USA) for the second patient. We conclude that LAA occlusion with cerebral protection devices is feasible in selected patients with LAA thrombus at high risk for embolic complications.

01_Meincke.tif

Figure 1. Patient 1. A) Transoesophageal echocardiographic (TEE) view of the left atrial appendage (LAA) thrombus prior to implantation. B) WATCHMAN™ device after implantation with remaining thrombus in the distal LAA. C) 3D-TEE view of the LAA ostium with thrombus visible within the LAA. D) 3D-TEE after implantation of the WATCHMAN™ device.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Online data supplement

Moving image 1. Angiographic view of the atypical approach for unfolding of the device used in the first patient. The delivery sheath is placed at the ostium of the left atrial appendage (LAA) and the device is unfolded by pushing the device forward into the LAA.

Moving image 2. Transoesophageal echocardiography after implantation of the WATCHMAN™ device in the first patient showing the device position and the thrombus further distal within the left atrial appendage.

Online data supplement

02_Meincke.tif

Online Figure 1. Patient 2. A) Transoesophageal echocardiography (TEE) prior to implantation with thrombus and “smoke” within the left atrial appendage. B) Angiographic view of the Claret™ system placed in the left carotid artery and the brachiocephalic trunk. C) TEE view of the WATCHMAN™ device after implantation.

Media

Moving image 1. Angiographic view of the atypical approach for unfolding of the device used in the first patient. The delivery sheath is placed at the ostium of the left atrial appendage (LAA) and the device is unfolded by pushing the device forward into the LAA.

Moving image 2. Transoesophageal echocardiography after implantation of the WATCHMAN™ device in the first patient showing the device position and the thrombus further distal within the left atrial appendage.

Source: EuroIntervention

One-year outcomes in 1,010 unselected patients treated with the PROMUS Element everolimus-eluting stent: the multicentre PROMUS Element European Post-Approval Surveillance Study

Martyn R. Thomas1*, MD, PhD; Ralf Birkemeyer2, MD; Peter Schwimmbeck3, MD, PhD; Victor Legrand4, MD, PhD; Raul Moreno5, MD; Carlo Briguori6, MD; Nikos Werner7, MD; Ezio Bramucci8, MD; Imre Ungi9, MD; Gert Richardt10, MD, PhD; Paul L. Underwood11, MD; Keith D. Dawkins11, MD

1. Guy’s and St. Thomas’ National Health Service Foundation Trust, London, United Kingdom; 2. Universitätsklinikum Rostock, Rostock, Germany; 3. Klinikum Leverkusen, Leverkusen, Germany; 4. Centre Hospitalier Universitaire Sart Tilman, Liege, Belgium; 5. Hospital La Paz, Madrid, Spain; 6. Clinica Mediterranea, Naples, Italy; 7. Universitätsklinikum Bonn, Bonn, Germany; 8. IRCCS Policlinico S. Matteo, Pavia, Italy; 9. University of Szeged, Szeged, Hungary; 10. Herzzentrum, Segeberger Kliniken GmbH, Bad Segeberg, Germany; 11. Boston Scientific Corporation, Marlborough, MA, USA

Abstract

Aims: The PROMUS™ Element™ European Post-Approval Surveillance Study (PE-Prove) is a prospective, open-label, multicentre observational study designed to assess outcomes following PROMUS Element everolimus-eluting stent implantation in an unselected patient population.

Methods and results: A total of 1,010 patients were enrolled at 40 clinical sites in Europe, including 24.9% with medically treated diabetes, 50.0% with Type B2/C lesions, 6.1% with chronic total occlusion, 17.8% with acute myocardial infarction (MI ≤24 hours pre-procedure), and 20.1% with unstable angina. The target lesion was the culprit for ST-segment elevation MI in 7.3% of patients. The one-year, per patient target vessel failure rate was 6.2% (60/975), 3.4% (33) being related to the PROMUS Element stent. Rates of cardiac death, MI, and Academic Research Consortium (ARC) definite/probable stent thrombosis were 1.7%, 3.5%, and 0.6%, respectively. The target vessel revascularisation rate was 3.2% (31/975), 2.1% (20) being related to the PROMUS Element stent.

Conclusions: In a large and relatively complex group of “real-world” patients, coronary artery revascularisation with the PROMUS Element everolimus-eluting stent provides favourable results with low event rates consistent with those reported for other contemporary drug-eluting stents.

Introduction

As new coronary stent designs become approved and more widely available for use in large, unselected populations outside of controlled clinical trials, it is important to evaluate their safety and effectiveness in broader “real-world” application. The PROMUS Element™ coronary stent (Boston Scientific Corporation, Marlborough, MA, USA) is a thin-strut, platinum chromium alloy stent coated with a durable, biocompatible, inert fluorocopolymer and everolimus as the antiproliferative agent. In the randomised controlled PLATINUM trial, the PROMUS Element stent was shown to be non-inferior to the predicate XIENCE V/PROMUS stent (Boston Scientific) for the primary endpoint of one-year target lesion failure1. Rates of all-cause death, cardiac death, myocardial infarction, stent thrombosis, and revascularisation were comparable between the two treatment groups at three-year follow-up2.

The PROMUS™ Element™ European Post-Approval Surveillance Study (PE-Prove) is an observational study designed to collect data on long-term outcomes in a large and relatively complex group of “real-world” patients treated with the PROMUS stent. We report here the one-year primary endpoint clinical outcomes, evaluating the safety and efficacy of this stent in a large, unselected patient population.

Methods

This prospective, open-label, multicentre study with an all-comers approach was designed to enrol approximately 1,000 patients at 40 sites in Europe.

PATIENT SELECTION, PROCEDURE, AND FOLLOW-UP

All patients who were candidates for coronary artery stenting and eligible to receive a PROMUS Element stent were evaluated for enrolment in this study. All enrolled patients signed a written informed consent form that had been approved by the independent ethics committee at each study site. Enrolment was considered complete upon signing the informed consent form. This study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki and consistent with good clinical practice and applicable local regulatory requirements (ClinicalTrials.gov NCT01148329).

Follow-up assessments, including medications, NYHA/CCS classification, adverse events, and coronary angiograms performed according to standard of care at each study site, were carried out by clinic visit or phone call at 30 days, six months, and 12 months post index stent implantation, and will continue annually to five years.

STUDY ENDPOINTS

The primary endpoint of this study was the overall and PROMUS Element stent-related target vessel failure (TVF) rate, defined as cardiac death, myocardial infarction (MI) related to the target vessel, or target vessel reintervention (TVR), at 12 months post stent implantation. Secondary endpoints are detailed in the Online Appendix. An independent clinical events committee adjudicated all deaths, MI, TVR, and stent thrombosis, including the relationship of the event to the study stent.

STATISTICAL METHODS

Enrolled patients who received at least one PROMUS Element stent in the target lesion were included in the analysis. Statistical analyses were performed using SAS, Version 9 or later (SAS Institute Inc., Cary, NC, USA). Further details are provided in the Online Appendix.

Results

PATIENT, LESION, AND PROCEDURAL CHARACTERISTICS

Of 1,010 patients enrolled at 40 clinical sites in Europe between 28 June 2010 and 20 April 2011, one-year clinical follow-up was available for 975 (96.5%) patients (Figure 1). Baseline patient and lesion characteristics are shown in Table 1.

01_Thomas.eps

Figure 1. PE-Prove registry enrolment and follow-up.

01tab_Thomas.pdf

Procedural characteristics are shown in Online Table 1. Successful deployment of the PROMUS Element stent to the target lesion without device malfunction (i.e., technical success) was achieved in 99.8% (1,008/1,010) of patients. Two cases of longitudinal stent deformation were detected by angiography during the index procedure, both of which involved <5% proximal stent compression. Details of these cases are provided in the Online Appendix.

ONE-YEAR CLINICAL OUTCOMES

As shown in Table 2, the overall one-year TVF rate was 6.2% and TVF related to the PROMUS Element stent was 3.4%. The rates of cardiac death, MI, and TVR related to the PROMUS Element stent were 0.4%, 2.1%, and 2.1%, respectively. ARC-defined definite/probable stent thrombosis related to the PROMUS Element stent was reported in six patients (0.6%). In Figure 2, showing Kaplan-Meier time-to-event analyses for overall TVF and definite/probable stent thrombosis at one-year follow-up, there were no stent thromboses reported beyond eight months post procedure. One-year clinical outcomes for selected high-risk patient subgroups are also shown in Table 2. Relative to the study population as a whole, rates of overall and PROMUS Element-related TVF and ARC-defined definite/probable stent thrombosis were only modestly higher in patients with medically treated diabetes or long lesions (>28 mm single lesion), whereas rates among patients with small vessels (≤2.5 mm) were similar to the overall study population rates.

02tab_Thomas.pdf

02_Thomas.eps

Figure 2. Kaplan-Meier time-to-event analyses baseline to one year. A) Target vessel failure. B) ARC-defined definite/probable stent thrombosis.

At the time of the one-year follow-up visit, 79.6% (756/950) of patients were taking dual antiplatelet therapy, including 96.8% (920/950) on aspirin, 76.1% (723/950) on clopidogrel, 6.2% (59/950) on prasugrel, and 0.1% (1/950) on ticagrelor.

PREDICTORS OF TARGET VESSEL FAILURE AT ONE YEAR

Multivariate predictors of TVF within one year of stent implantation are shown in Online Figure 1. Diabetes, post-procedure dilation, and prior PCI were identified as predictors of both overall TVF and PROMUS Element stent-related TVF. The strongest predictor of overall TVF was the use of thienopyridines for six months or less, and the strongest predictor of TVF associated with the PROMUS Element stent was implantation in a vein graft.

Discussion

In this large, “real-world” population, one-year rates of cardiac death, MI, TVR, and stent thrombosis related to the PROMUS Element stent were low and consistent with rates in the randomised controlled PLATINUM trial of this stent1. Overall, clinical event rates for patients with small calibre vessels (≤2.5 mm) were similar to the rates in the study population as a whole.

As might be expected, medically treated diabetes and single lesion length >28 mm were each associated with modestly increased rates of cardiac events. The technical success rate of 99.8% reflects good deliverability of this stent, which is perhaps a reflection of the conformability and flexibility of this stent platform.

DES IN ROUTINE PRACTICE

This study contributes to a vast and growing body of “real-world” data on contemporary DES outcomes. Studies of DES that have used broad inclusion criteria or an all-comers approach include the PEXIP study of the XIENCE Prime and PROMUS Element everolimus-eluting stents3, the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) analysis of the PROMUS Element stent relative to other contemporary DES4, the XIENCE V USA study of the XIENCE V stent5, the PROENCY registry of the PROMUS everolimus-eluting stent, CYPHER sirolimus-eluting stent, and ENDEAVOR zotarolimus-eluting stent6, the COMPARE study of the PROMUS everolimus-eluting stent and the TAXUS Liberté stent7, and three studies of the Resolute zotarolimus-eluting stent, including the RESOLUTE International Registry8, the Resolute All Comers trial9, and the TWENTE trial10, the latter two both evaluating the Resolute stent versus the XIENCE V stent.

One-year clinical event rates with the PROMUS Element stent in this study are well within the one-year ranges reported from these other all-comers DES studies. The PROMUS Element all-cause mortality rate was 2.7% (other studies 1.6% to 2.8%), the rate of MI related to the PROMUS Element was 2.1% (other studies 0.7% to 7.9%), and the rate of TVR related to the PROMUS Element was 2.1% (other studies 1.3% to 8.2%)3,4,5,6,7,8,9,10. The 0.6% rate of ARC-defined definite/probable stent thrombosis is in the lower range among the all-comers DES studies (other studies 0.0% to 1.6%)3,4,5,6,8,9,10,11.

STENT DEFORMATION

The occurrence of two cases of longitudinal stent deformation (change in axial length) out of 1,679 stents placed in this study highlights the low frequency of this procedural complication. These two cases of stent deformation, which were detected by angiography during the index procedure, represent classic examples of stent deformation resulting from interaction between an ancillary device and a stent that were easily treated without severe adverse consequences.

Limitations

As a single-arm registry, this study has inherent limitations. Without a control group, the performance of the PROMUS Element stent cannot be directly compared with other contemporary DES. In addition, the broad inclusion criteria and observational design present challenges for evaluating outcomes across studies in which the “all-comers” design results in diverse patient and lesion characteristics. Finally, clinical follow-up at one year was not available for 3.5% of these unselected patients, mostly due to missed visits. Although this represents an acceptable rate of follow-up for a post-market, all-comers registry, given the very low rate of events at one year with this contemporary stent, the potential effect of these missing data should be taken into account when considering the one-year clinical event rates.

Conclusions

In this large and relatively complex group of “real-world” patients, coronary artery revascularisation with the PROMUS Element everolimus-eluting stent resulted in low clinical event rates consistent with those reported for other contemporary DES.

Impact on daily practiceAlthough randomised controlled trials remain the gold standard for proving the safety and efficacy of new devices in clinical practice, the strict inclusion and exclusion criteria typically used in these trials mean that the results may not be generalisable to an unselected, “real-world” clinical population. This large, multicentre registry presents valuable information on outcomes from everyday clinical practice with the use of the PROMUS Element stent in more than 1,000 patients in Europe. The consistency of the results from this more complex clinical population with those of the randomised controlled trial provide reassurance to the treating physician of good clinical outcomes with the PROMUS Element stent, regardless of patient comorbidities and anatomic complexity.

Acknowledgements

The authors would like to thank all of the sites that enrolled patients in the PE-Prove study, as well as the clinical events committee members and the associated research organisations (Online Table 2, Online Table 3). In addition, the authors gratefully acknowledge Laurie LaRusso (Chestnut Medical Communications) and Kristin L. Hood (Boston Scientific Corporation) for assistance with manuscript preparation, Shannon Song (Boston Scientific) and Srikanth Garre (Quintiles) for statistical assistance, and Thomas Naeschen (Boston Scientific) for project management.

Funding

This study was sponsored and funded by Boston Scientific Corporation, Marlborough, MA, USA.

Conflict of interest statement

R. Moreno reports lecture and consulting fees from Boston Scientific, Abbott, Cordis, Medtronic, Terumo, and Biotronik. G. Richardt reports serving on an advisory board and receiving speakers’ honoraria from Boston Scientific. M. Thomas reports serving on an advisory board for Boston Scientific. P. Underwood and K. Dawkins are full-time employees with equity interest in Boston Scientific. The other authors have no conflicts of interest to declare.

Online data supplement

Online Appendix

METHODS

PATIENT SELECTION, PROCEDURE, AND FOLLOW-UP

The following procedural data were collected: lesion characteristics, total procedure time, antithrombotic and antiplatelet medications administered, and serious adverse events (SAEs), including serious bleeding according to GUSTO classification12. Patients with unsuccessful implant of a study device were followed only up to hospital discharge following the initial attempted index procedure. Enrolment at 14 centres was eventually capped at approximately 40 patients to prevent skewing the results with overrepresentation from high-volume centres.

STUDY ENDPOINTS

Secondary endpoints included stent thrombosis using Academic Research Consortium (ARC) definitions (i.e., definite or probable), major adverse cardiac events (i.e., cardiac death, MI, TVR), cardiac death, MI, TVR, all deaths, and non-cardiac deaths. Technical success was defined as successful deployment of the PROMUS Element stent to the target lesion without device malfunction.

STATISTICAL METHODS

Patient demographics, clinical history, risk factors, pre- and post-procedure lesion characteristics, procedure characteristics, and outcome variables were summarised using descriptive statistics for continuous variables (mean, standard deviation, number of observations, minimum, and maximum) and frequency tables for discrete variables. Kaplan-Meier plots of time-to-event variables were constructed with 95% confidence intervals. Cox models were performed to identify risk predictors with respect to TVF rates. Backward selection was used to identify significant predictors with the threshold to stay in the model set at 0.10.

RESULTS

LONGITUDINAL STENT DEFORMATION

One case was attributed to a deep-seated guide catheter interacting with the proximal end of a deployed PROMUS Element stent, causing slight longitudinal compression, which was resolved with post-dilation and additional stent deployment, without associated patient injury. In the second case, an LAD/diagonal branch bifurcation intervention, the guidewire was jailed by the proximal end of the stent, leading to subsequent unravelling of the guidewire into a filament proximal to the diagonal. During manoeuvres for successful retrieval of the wire with a snare, the proximal end of the implanted stent was minimally damaged. Post-dilation balloon inflations were performed along the entire stented segment and a stent was placed in the proximal LAD/left main. A small non-Q-wave MI (peak CK-MB 43 U/L, troponin 2.4 ng/mL) occurred post procedure and the patient was discharged two days later. Of these two patients with longitudinal stent deformation, only one experienced a small periprocedural enzyme leak. Neither patient has had any other clinical events reported up to the time this manuscript was published.

Reference

OL1_Thomas.eps

Online Figure 1. Multivariate predictors of target vessel failure within 1 year of stent implantation.

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OL02tab_Thomas.pdf

OL03tab_Thomas.pdf

Source: EuroIntervention

Renal denervation with a percutaneous bipolar radiofrequency balloon catheter in patients with resistant hypertension: 6-month results from the REDUCE-HTN clinical study

Horst Sievert1*, MD; Joachim Schofer2, MD; John Ormiston3, MBChB; Uta C. Hoppe4, MD; Ian T. Meredith5, MD; Darren L. Walters6, MD; Michel Azizi7,8, MD; Juan Diaz-Cartelle9, MD; Meital Cohen-Mazor9,10, PhD; on behalf of the REDUCE-HTN investigators

1. CardioVascular Center Frankfurt CVC, Frankfurt, Germany; 2. Universitäres Herz- und Gefäßzentrum, Hamburg, Germany; 3. Mercy Angiography, Auckland, New Zealand; 4. Paracelsus Medical University, Salzburg, Austria; 5. MonashHEART, Monash Health, Melbourne, Australia; 6. The Prince Charles Hospital, Brisbane, Australia; 7. APHP, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France; 8. Paris Descartes University, Paris, France; 9. Boston Scientific Corporation, Marlborough, MA, USA; 10. Vessix Vascular, Laguna Hills, CA, USA

Abstract

Aims: To evaluate the safety and efficacy of the balloon-based bipolar Vessix Renal Denervation System in treating patients with resistant hypertension.

Methods and results: In this prospective, multicentre, single-arm study, 146 patients (age 58.6±10.5 years; 61% men) with office systolic blood pressure (BP) ≥160 mmHg despite ≥3 antihypertensive medications at maximally tolerated doses were treated with the Vessix System. Efficacy endpoints were reductions in office and 24-hour ambulatory systolic and diastolic BPs at six months. Acute and long-term safety, with a focus on the renal artery and estimated glomerular filtration rate (eGFR), were assessed. Baseline office and ambulatory BPs were 182.4±18.4/100.2±14.0 mmHg and 153.0±15.1/87.5±13.2 mmHg, respectively. No acute renal artery injury requiring intervention or serious periprocedural cardiovascular events occurred. At six months, office BP was reduced by 24.7±22.1/10.3±12.7 mmHg (p<0.0001) and ambulatory BP was reduced by 8.4±14.4/5.9±9.1 mmHg (N=69; p<0.0001). Twenty-six patients (18%) achieved an office systolic BP <140 mmHg. One patient had renal artery stenosis which required stenting. Mean eGFR remained stable.

Conclusions: Renal artery denervation with the Vessix System reduced both office and ambulatory BP at six months in patients with resistant hypertension. Renal artery safety and renal function results are favourable.

Introduction

The relationships between elevated BP and increased cardiovascular and renal-related morbidity and mortality risks are well known1,2. Conversely, lowering BP in patients with hypertension yields benefits such as decreased incidence of stroke, major cardiovascular events, end-stage renal disease, and death1,3,4.

Renal denervation provides a novel adjunctive option for treating patients with hypertension despite lifestyle modifications and multiple antihypertensive medications5,6. Clinical studies of percutaneous renal denervation with radiofrequency energy have shown significant and sustained BP reductions for patients with resistant hypertension following treatment with either single-electrode7,8,9,10 or multielectrode11 monopolar systems. The Vessix™ Renal Denervation System (Boston Scientific, Marlborough, MA, USA), by contrast, is a balloon-based bipolar multielectrode system.

We report here the six-month results of the REDUCE-HTN study, which was designed to evaluate safety and efficacy of renal denervation with the Vessix System for the treatment of resistant hypertension.

Methods

STUDY DESIGN

The REDUCE-HTN clinical study is an international, prospective, non-randomised, single-arm study. This report describes the study results obtained up to six months (i.e., the primary endpoint) for patients enrolled in the initial first-in-man cohort and those enrolled under an amended post-market protocol. The REDUCE-HTN study is registered at ClinicalTrials.gov (NCT01541865).

The study was conducted in accordance with ethical principles which have their origins in the Declaration of Helsinki. Institutional committees on research or appropriate ethics committees at study sites approved the study protocol. Patients were required to provide written informed consent prior to receiving any study-specific tests or procedures.

PATIENTS

Inclusion and exclusion criteria for the first-in-man and post-market protocols are summarised in Table 1. Eligible patients had office-based systolic BP ≥160 mmHg and were on a stable medication regimen with at least three antihypertensive drugs (including a diuretic, unless intolerant) at maximally tolerated doses.

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BP, renal function, and renal artery anatomy were assessed at the screening visit. Seated office BP measurements2 were taken with a validated electronic device (Omron model HEM-705 CP; Omron Healthcare, Lake Forest, IL, USA). Eligible patients had an estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m2. Patients underwent renal duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to screen for anatomic abnormalities. Antihypertensive medication regimen stability over the previous two weeks was confirmed by reviewing the patients’ medical records and patient-reported compliance.

VESSIX RENAL DENERVATION SYSTEM

The Vessix Renal Denervation System comprises the Vessix catheter and generator. The catheter is an over-the-wire low-pressure (3 atm) balloon catheter designed to transmit radiofrequency energy via multiple bipolar electrodes mounted on its surface in a helical pattern. The catheters used in this study were compatible with 0.36 mm (0.014 inch) and 0.46 mm (0.018 inch) guidewires and 8 Fr guide sheaths; the balloons had 4, 5, 6, or 7 mm diameters and four to eight bipolar electrodes (depending on their size).

The Vessix balloon enables electrode apposition to the artery wall while eliminating variable cooling from blood flow. The generator delivers radiofrequency energy simultaneously to all apposed electrodes and adjusts to maintain a 68°C temperature, while thermistors on the balloon surface monitor temperature throughout the 30-second treatment period. The temporary no-flow environment, bipolar electrodes, and temperature control enable a therapeutic temperature to be reached with <1 W12.

RENAL DENERVATION PROCEDURE

Patients who met general and anatomic criteria underwent standard angiography to confirm renal artery anatomy suitability immediately prior to the denervation procedure. Anxiolytic and analgesic medications were administered and systemic anticoagulation (e.g., activated clotting time ≥200 seconds) was attained. The Vessix catheter was delivered to the renal artery via femoral access and inflated using standard angioplasty techniques. After acceptable apposition was confirmed, the generator was activated to deliver radiofrequency energy. The balloon could be deflated, moved proximally, and re-inflated in order to treat along the full artery length. No more than two treatments per artery were recommended. The balloon was then positioned in the opposite renal artery and the radiofrequency treatment procedure was repeated. Manual compression or commercialised closure devices were used to achieve haemostasis at the puncture site.

FOLLOW-UP PROCEDURES

Patients were instructed to remain compliant with their baseline antihypertensive medication regimen throughout the study unless changes were clinically indicated. Seated BP measurements2 were repeated during office visits at one, three, and six months following the renal denervation procedure. Ambulatory BP over 24 hours was monitored with Spacelabs ABP monitors (Spacelabs Healthcare, Snoqualmie, WA, USA) and validated by a core laboratory (Biomedical Systems Corporation, St. Louis, MO, USA) at baseline and six months. A 70% success rate (e.g., excluding movement artefacts) from hourly recordings over 24 hours was required. Monitoring results that did not meet the required validation criteria were excluded from analysis.

Renal function was monitored with eGFR and creatinine levels. A renal artery duplex ultrasound was required at six months and reviewed by an independent core laboratory (VasCore, Boston, MA, USA). Angiographic images were also evaluated by a core laboratory (SynvaCor, Springfield, IL, USA).

EFFICACY AND SAFETY ENDPOINT DEFINITIONS

Efficacy was assessed as the magnitude of the changes in office-based and 24-hour ambulatory BPs from baseline to six months following treatment with the Vessix System.

The primary first-in-man study objective was to assess acute safety, defined as freedom from each of five periprocedural events: renal artery dissection/perforation that required stenting or surgery, renal artery infarction/embolus, cerebrovascular accident, myocardial infarction, and sudden cardiac death. These acute events continued to be monitored for the expanded cohort.

Long-term safety endpoint events were: chronic symptomatic orthostatic hypotension, hypertensive emergency necessitating hospital admission (unrelated to antihypertensive medication non-compliance), eGFR reduction >25%, angiographically documented renal stenosis requiring an intervention, and flow-limiting stenosis (≥60%) in the renal artery.

A data safety monitoring board adjudicated all adverse events for seriousness and relatedness to the procedure and device.

STATISTICAL METHODS

All treated patients were included in the analyses. The study sample size was not powered for efficacy or safety endpoints. Descriptive statistics are presented and confidence intervals (95%) were constructed for BP results. A paired t-test was used to assess the BP change from baseline to six months; the data normality assumption was verified with the Shapiro-Wilk test. A p-value <0.05 was considered statistically significant.

Post hoc office BP reduction comparisons in patient subgroups were made with two-sample t-tests. Logistic regression was used to analyse the relationships between baseline/treatment characteristics and a six-month office systolic BP reduction >10 mmHg or ambulatory systolic BP reduction >5 mmHg. All analyses were conducted with SAS version 9.2 or later (SAS Institute Inc., Cary, NC, USA).

Results

PATIENT CHARACTERISTICS

A total of 146 patients were treated with the Vessix System at 23 sites in Europe, Australia, and New Zealand from February 2012 to April 2013 (Figure 1, Online Appendix 1). Baseline patient characteristics are shown in Table 2. The mean (±SD) diameter of treated renal arteries was 5.3±0.7 mm and length was 34.7±8.4 mm. Twenty-four patients enrolled under the post-market protocol had accessory renal arteries treated.

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Figure 1. REDUCE-HTN patient flow. ABPM: ambulatory blood pressure monitoring; CTA: computed tomography angiography; DUS: duplex ultrasound; FIM: first-in-man; MRA: magnetic resonance angiography; PMS: post-market study. 103 patients had valid 24-hour ABPM at baseline. 89 patients had valid 24-hour ABPM at 6 months; 69 of these patients also had valid baseline ABPM.

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Nine patients who received radiofrequency treatment met exclusion criteria: one had baseline systolic BP of 157 mmHg, two had eGFRs below the eligibility threshold, two were on hormonal therapy, one had a pacemaker, one had renal artery length <15 mm, one had a previous renal denervation and renal artery stenosis >30%, and one had been placed on an antihypertensive drip within two weeks prior to the procedure. None of these patients experienced procedure-related adverse events associated with these baseline conditions during six months of follow-up.

PROCEDURE CHARACTERISTICS

Catheters with 7 mm (35%) or 6 mm (34%) balloon diameters were selected most often; the remainder were 5 mm (22%) and 4 mm (9%). Patients underwent a mean of 3.5±1.1 treatments (i.e., 30-second generator activations) with 21.2±6.4 electrode activations. All patients had at least one complete treatment cycle. To treat the full artery length, investigators administered two treatments in 54% of main renal arteries (158/292) and 41% (11/27) of treated accessory arteries. Treatments required 0.7±0.2 W per electrode to achieve temperature control. Mean procedure time (i.e., first balloon inserted to last balloon removed) was 24.9±15.8 min.

CHANGES TO ANTIHYPERTENSIVE MEDICATION REGIMENS

At six months, the mean number of antihypertensive medications per patient remained stable at 5.2±1.9, and 85.6% remained on the same number of medications as at baseline. Fifteen (10.3%) reduced their antihypertensive regimen by one drug, two patients reduced their regimen by two medications, three reduced their regimen by three medications, and one was on four fewer antihypertensive drugs at the six-month follow-up visit than at baseline; no patient had an increased number of antihypertensive drugs.

Efficacy endpoints

OFFICE BLOOD PRESSURE

Significant office-based BP reductions were observed at all follow-up time points (Figure 2). At six months, systolic/diastolic BP was reduced by 24.7±22.1/10.3±12.7 mmHg. Systolic BP reductions ≥5 mmHg or ≥10 mmHg were observed in 85% (121/142) and 76% (108/142), respectively. Six patients (4%) had a reduction in systolic BP of <5 mmHg, and 15 (11%) had an increase at six months. Systolic BP <140 mmHg was achieved by 18% (26/142) of patients at six months (Figure 3).

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Figure 2. Change in office-based blood pressure (95% confidence intervals). p<0.0001 for each time point vs. baseline.

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Figure 3. Distribution of office systolic blood pressures at baseline and follow-up up to six months.

No significant differences in the changes in office systolic BP at six months were observed between subgroups based on age, diabetic status, or sex (p>0.05 for each comparison) (Online Table 1). The mean (±SD) BP reduction observed among patients without any changes in the number of antihypertensive medications was –23.8±21.2/–9.8±12.2 mmHg, and for the 21 patients who decreased their number of medications it was –29.5±26.8/–13.7±15.2 mmHg. No significant relationships were identified between baseline characteristics and systolic BP reduction >10 mmHg at six months in logistic regression analysis (Online Table 2).

24-HOUR AMBULATORY BLOOD PRESSURE

Baseline mean (±SD) 24-hour ambulatory BP was 153.0±15.1/ 87.5±13.2 mmHg (N=103). At six months, mean ambulatory BP decreased to 147.0±16.1/83.1±12.7 mmHg (N=89) and 17% of patients (15/89) had systolic pressure <130 mmHg (vs. 4% [4/103] at baseline). The mean reduction among the 69 individuals with valid 24-hour ambulatory measurements at baseline and six months was 8.4±14.4/5.9±9.1 mmHg (p<0.0001) (Figure 4). In logistic regression analysis, greater baseline systolic BP (office or ambulatory) and greater ambulatory diastolic BP were associated with greater odds of a six-month reduction in ambulatory systolic BP >5 mmHg (Online Table 3). The mean changes in daytime and night-time ambulatory BP were similar (Online Table 4).

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Figure 4. Change in 24-hour ambulatory blood pressure (95% confidence intervals). p<0.0001 for both systolic and diastolic vs. baseline.

Safety objectives

ACUTE SAFETY

No patient had periprocedural renal artery dissection or perforation that required intervention, or renal artery infarction or embolus. One mild procedural vessel dissection which did not require intervention was reported. No cerebrovascular accidents, myocardial infarctions, or sudden cardiac deaths occurred within 30 days. Seven serious adverse events that were determined by the data safety monitoring board to be related to the procedure occurred within the first month post procedure, including two access-site infections, one pseudoaneurysm at the access site, and one femoral artery thrombus. One haematoma, one instance of bilateral flank pain, and one case of vomiting, all of which occurred within one day of the procedure, were classified as serious because hospitalisation was prolonged for observation. All events have resolved.

LONG-TERM SAFETY ENDPOINTS

Up to six months, one patient had a hypertensive emergency necessitating hospital admission and none had symptomatic orthostatic hypotension. Fifteen patients (11%) had an eGFR reduction >25% at six months. Two of these 15 patients presented with acute renal insufficiency which was related to medication use: one occurred approximately three months post procedure and was treated by lowering the diuretic dose, and the other was treated by withholding an ACE inhibitor and statin at approximately six months post procedure. Mean eGFR and serum creatinine remained stable at 82.9±23.7 mL/min per 1.73 m2 (change: −0.9±16.4 mL/min per 1.73 m2; N=138) and 85.2±24.2 µmol/L (change: 2.4±13.4 µmol/L; N=140) at six months, respectively.

Evaluable duplex ultrasounds were obtained from 123 patients at the six-month follow-up visit. Two of these patients had stenosis ≥60% based on core laboratory analysis and underwent subsequent imaging. The first had a 26% left renal artery stenosis at baseline which progressed to 65% in the treated area according to renal angiography conducted approximately seven months post procedure (core laboratory analysis). The second patient had 14% stenosis at baseline, and computed tomography angiography at eight months confirmed moderate left renal artery narrowing. These two patients have not undergone renal angioplasty or stenting and continue to be monitored.

Two additional patients with non-interpretable or abnormal duplex ultrasounds who underwent subsequent imaging studies were found to have renal artery stenoses within six months. One of these patients had 17% stenosis at baseline, and angiography at six months showed 60% stenosis within the treated area of the right renal artery. The patient underwent angioplasty and stenting, and continues to be monitored. This event was considered by the data safety monitoring board to be serious and both procedure- and device-related. The remaining patient had progression of a pre-existing 25% stenosis of the left renal artery to 73% at six months (core laboratory angiogram analysis) which did not need angioplasty or stenting.

Discussion

The REDUCE-HTN study results show that BP was reduced significantly for patients with resistant hypertension following multielectrode balloon-based renal denervation. Significant office-based BP reductions were observed one month post treatment and sustained up to six months, while 24-hour ambulatory monitoring results at six months further support the clinical effectiveness of the Vessix System. BP reductions were similar to results from other uncontrolled and controlled studies six months after treatment13 with various monopolar radiofrequency systems7,9-11,14.

At six months, clinically relevant reductions of at least 5 mmHg15 were observed in 85% of patients (76% had a reduction of ≥10 mmHg): this response rate is within the range reported in previous renal denervation studies (58% to 84%)7,10,11,16,17,18. Baseline and treatment characteristics were not significantly associated with the office systolic BP response in post hoc analyses, although baseline BP was significantly associated with an ambulatory systolic BP reduction >5 mmHg. These analyses were limited by the subgroup sizes, and additional research is needed to identify or rule out possible predictors of the response to treatment. Achieving systolic BP <140 mmHg reduces the risk for cardiovascular morbidity2, and 18% of patients in the REDUCE-HTN study had BP below this level at the six-month visit. Two previous studies have reported BP control rates of approximately 40% at six months following renal denervation10,11; however, comparisons are limited because baseline BP for patients in REDUCE-HTN was greater on average than in the other studies (182 mmHg vs. 176-178 mmHg), necessitating a greater reduction in order to reach the target level, and because the sample sizes in previous studies were relatively small (<50 subjects assessed vs. 142 subjects in REDUCE-HTN). These findings suggest that radiofrequency treatment with the bipolar balloon-based Vessix System may provide clinically meaningful BP reductions for patients with resistant hypertension.

Like other first-in-man and post-market studies of radiofrequency renal denervation devices, the REDUCE-HTN study was designed as a single-arm, non-blinded, non-randomised study7,9,11,14. The study design is prone to observer bias, and lack of a control arm precludes definitive conclusions regarding efficacy19. However, relevant variables are difficult to control, even with a control arm. The recently published results of the sham-controlled, blinded SYMPLICITY HTN-3 study did not show a significant difference in the BP reduction at six months between patients treated with a single-electrode, monopolar renal denervation device (Symplicity™ Renal Denervation System; Medtronic, Minneapolis, MN, USA) and those in the control arm18. This lack of difference between treatment and control has raised many questions, including whether medication regimens were stable and whether denervation procedures were adequately performed with the single-point device, which may be highly influenced by the operator18,20,21,22. In contrast to the SYMPLICITY HTN-3 results, Global SYMPLICITY registry23 data showed significant BP reductions for patients who had renal denervation with the Symplicity catheter, including those whose office BP aligned with the HTN-3 criteria21. Additional research is needed to reconcile the results of this and other previous studies with those of the SYMPLICITY HTN-3 trial.

The single-arm design of the REDUCE-HTN study limits our ability to investigate possible confounding effects of antihypertensive medications. Two weeks may be an insufficient duration for pre-treatment changes to the antihypertensive regimen to have observable effects on baseline BP, and patient-reported adherence may inadequately gauge regimen stability. Notwithstanding these limitations, the sample size was relatively large compared with previous uncontrolled studies7,9,11,14, and the inclusion of 24-hour ambulatory BP measurements mitigates observer bias, which is possible with office-based BP measurements19.

Results from the REDUCE-HTN study demonstrate a favourable safety profile for the Vessix System. No acute events indicative of seriously compromised renal artery integrity or cardiovascular complications occurred, and fewer than 6% of patients had serious procedure-related adverse events during six months of follow-up. Mean eGFR remained stable over six months, similar to other studies10,11,16. Of the four patients in this study with renal artery stenosis detected up to six months, only one required angioplasty and stenting. Two were found to have progression of pre-existing stenoses, as has been reported in other studies10,11,14. The requirement for core laboratory evaluation of the six-month duplex ultrasound contributed to the stenosis detection rate, and renal artery stenosis must continue to be examined in larger trials and registries17.

Conclusion

Patients with resistant hypertension were safely treated with a percutaneous balloon-based multielectrode bipolar radiofrequency system and achieved significant, clinically meaningful15, BP reductions over six months of follow-up.

Impact on daily practiceIn addition to lifestyle modifications and antihypertensive medications, renal denervation may be a treatment option for some patients with hypertension. This study suggests that denervation with a balloon-based multielectrode bipolar radiofrequency system provides clinically meaningful blood pressure reductions and a favourable safety profile for patients with resistant hypertension.

Acknowledgements

This work was supported by Vessix Vascular, Laguna Hills, CA, USA, and Boston Scientific, Marlborough, MA, USA. The authors thank Ana Becker for clinical programme management and Elizabeth J. Davis, PhD, for medical writing assistance (Boston Scientific, Maple Grove, MN, USA) and H. Terry Liao, PhD (Boston Scientific, Marlborough, MA, USA) for statistical analysis. Preliminary analyses were presented at VIVA 2013, October 8-11, Las Vegas, NV, USA, at TCT 2013, October 27-November 1, San Francisco, CA, USA, and at CRT 2014, February 22-25, Washington, DC, USA.

Funding

This work was supported by Vessix Vascular, Laguna Hills, CA, USA, and Boston Scientific, Marlborough, MA, USA.

Conflict of interest statement

H. Sievert has received study honoraria, travel expenses and consulting fees from Abbott, Access Closure, AGA, Angiomed, Aptus, Atrium, Avinger, Bard, Boston Scientific, BridgePoint, Cardiac Dimensions, CardioKinetix, CardioMEMS, Coherex, Contego, Covidien, CSI, CVRx, EndoCross, ev3, FlowCardia, Gardia, Gore, Guided Delivery Systems, InSeal Medical, Lumen Biomedical, HLT, Lifetech, Lutonix, Maya Medical, Medtronic, NDC, Occlutech, Osprey, Ostial, PendraCare, pfm Medical, ReCor, ResMed, Rox Medical, SentreHeart, Spectranetics, SquareOne, Svelte Medical Systems, Trireme, Trivascular, Venus Medical, Veryan, and Vessix Vascular; grant support from Cook and St. Jude Medical; and has stock options with Cardiokinetix, Access Closure, Velocimed, Lumen Biomedical, Coherex, SMT. J. Schofer has received speakers’ honoraria from Boston Scientific. U. Hoppe has received grant support and honoraria from Boston Scientific/Vessix Vascular, grant support and consultancy fees from Medtronic, and consultancy fees from St. Jude Medical. I. Meredith has received honoraria and consulting fees from Boston Scientific. M. Azizi has received honoraria for advisory board meetings from Vessix, Boston Scientific, and Cordis, and speakers’ honoraria from Cordis and CVRx. J. Diaz-Cartelle is an employee of Boston Scientific and holds stock in the company. M. Cohen-Mazor is an employee of Boston Scientific and holds stock in the company. The other authors have no conflicts of interest to declare.

Online data supplement

Appendix 1. REDUCE-HTN Investigators

Writing Committee: Horst Sievert (CardioVascular Center Frankfurt, Frankfurt, Germany), Joachim Schofer (Universitäres Herz- und Gefäßzentrum, Hamburg, Germany), John Ormiston (Mercy Angiography, Auckland, New Zealand), Uta C. Hoppe (Paracelsus Medical University, Salzburg, Austria), Ian Meredith (MonashHEART, Monash Health, Melbourne, Australia), Darren Walters (The Prince Charles Hospital, Brisbane, Australia), Michel Azizi (Hôpital Européen Georges Pompidou, Paris, France ), Juan Diaz-Cartelle (Boston Scientific, Natick, MA, USA) and Meital Cohen-Mazor (Vessix Vascular, Laguna Hills, CA, USA, and Boston Scientific, Natick, MA, USA).

Clinical Investigators: Uta C. Hoppe (Paracelsus Medical University, Salzburg, Austria), Clemens Steinwender (Allgemeines öffentliches Krankenhaus der Stadt Linz, Linz, Austria), Eric Wyffels (Onze-Lieve-Vrouwziekenhuis, Aalst, Belgium), Ian Meredith (MonashHEART Monash Health, Melbourne, Australia), Horst Sievert (CardioVascular Center Frankfurt, Frankfurt, Germany), Michel Azizi, Marc Sapoval (Hôpital Européen Georges Pompidou, Paris, France), Darren Walters (The Prince Charles Hospital, Brisbane, Australia), Georg Ehret (Cardiology Center, Geneva University Hospitals, Geneva, Switzerland), Mark Webster (Auckland City Hospital, Auckland, New Zealand), Ajay Sinhal (Flinders Medical Centre, Bedford Park, South Australia, Australia), Joost Daemen (Erasmus Medical Center, Rotterdam, The Netherlands), Ralf Langhoff (Vascular Center Berlin, Berlin, Germany), Nicolaus Reifart (Main Tanus Kliniken, Bad Soden, Germany), David Muller (St. Vincent’s, Sydney, Australia), Dierk Scheinert (Zentrum für Gefäßmedizin, Leipzig, Germany), Robbert-Jan de Winter (Academic Medical Center, Amsterdam, The Netherlands), Alexandre Persu (Cliniques Universitaires Saint Luc, Bruxelles, Belgium), Jean Fajadet (Clinique Pasteur, Toulouse, France), Ilka Ott (German Heart Centre, Munich, Germany), Joachim Schofer (Universitäres Herz- und Gefäßzentrum Hamburg, Hamburg, Germany), Ahmed Farah (Zentralklinik Bad Berka, Bad Berka, Germany), Steven Worthley (Royal Adelaide Hospital, Adelaide, Australia), John Ormiston (Mercy Angiography, Auckland, New Zealand).

Data Safety Monitoring Board: Farrell Mendelsohn (Cardiology PC, Birmingham, AL, USA), William Gray (Columbia University Medical Center, New York, NY, USA), Daniel Clair (Cleveland Clinic Foundation, Cleveland, OH, USA).

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Vessix™ – Renal Denervation System

Study Design

The REDUCE-HTN Post-Market Study (PMS), including the First in Man (FIM) cohort, is a prospective, non-randomized, single arm, multicenter study evaluating the Vessix™ Renal Denervation System in patients with resistant hypertension. Enrolled patients had office-based systolic blood pressure (SBP) ≥ 160 mm Hg while on ≥ 3 antihypertensive medications (including a diuretic unless the patient had a documented intolerance to diuretics) at maximally tolerated doses.

A total of 146 patients were enrolled and treated at 23 centers in Europe, Australia, and New Zealand.

graphic reduce

Office Blood Pressure Reduction

24-hours Ambulatory Blood Pressure Reduction

 

 

No patients experienced prespecified acute safety events
Procedure-related serious adverse events* of 5.5% among the 146 patients to date Hematoma, bilateral flank pain, vomiting, pseudoaneurysm at access site, thrombus at access site, access site infection (2), renal artery stenosis requiring treatment
6-month patency§ 99.2% (252/254 arteries**) by core lab duplex ultrasound analysis.

Scientific Commitment

Boston Scientific collaborates with researchers, physicians and hospital systems worldwide to advance the science of cardiovascular medicine. A key component of that commitment is the Vessix Global Clinical Program, which includes both the REDUCE-HTN and RELIEVE Clinical Series. The REDUCE-HTN Clinical Series plans to enroll more than 1,200 resistant hypertension patients worldwide and already includes the largest cohort of patients studied following treatment with a multi-electrode renal denervation system. The RELIEVE Clinical Series includes pre-clinical, clinical and investigator initiated research evaluating the Vessix System technology in additional disease states including end-stage renal disease, heart failure, atrial fibrillation and diabetes.

REDUCE – HTN Interim 6 Month Data

Presenter: Horst Sievert MD

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Blood pressure reductions are mean values.
Caution: Investigational device limited under U.S. law for investigational use only. Not for sale in the U.S.
* Serious adverse events (SAEs) defined according to International Organization for Standardization ISO14155.
† Baseline stenosis was 17% based on core lab assessment of angiogram; stenosis of 60% noted by angiography at 6 month follow-up; patient received percutaneous transluminal angioplasty/stent and continues to be monitored.
§ Patency defined as stenosis < 60%.
** Treated renal arteries with 6 month post-treatment diagnostic DUS.
Schofer J, MD. REDUCE-HTN Clinical Study interim 12- and 18-month Data. Presented at EuroPCR; May 2014.
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