Horst Sievert

Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future

Abstract

Coronary sinus-based percutaneous annuloplasty as treatment for functional mitral regurgitation: the TITAN II trial

Objective Functional (or secondary) mitral regurgitation (FMR) is associated with greater morbidity and worse outcomes in patients with congestive heart failure (CHF) and cardiomyopathy. The Carillon® Mitral Contour System® is a coronary sinus-based percutaneous therapy to reduce FMR. We evaluated the safety and efficacy of a modified version of the Carillon device in the treatment of patients with cardiomyopathy and FMR. Methods 36 patients with CHF, depressed left ventricular function (ejection fraction <40%) and at least moderate FMR underwent the Carillon device implant. Results There was 1 major adverse event within 30 days—a death (not device related)—occurring 17 days after the implant. Reductions in FMR and improvements in functional class and 6 min walk tests were seen, similar to prior studies. Device fractures in the high strain region of the proximal anchor (seen in prior studies) were not seen in this study. Conclusions The modified Carillon device was associated with improvements in clinical and echocardiographic parameters in treating patients with FMR, while successfully addressing the issue of anchor fracture. This version of the Carillon device will be used in a blinded randomised trial of symptomatic patients with FMR.

Percutaneous Closure Versus Medical Treatment in Stroke Patients With Patent Foramen Ovale: A Systematic Review and Meta-analysis

Patent foramen ovale (PFO) is a common finding that has been reported in 10% to 35% of persons (1, 2). The presence of PFO increases the risk for cardioembolic cerebrovascular accidents, such as stroke transient ischemic attacks (TIA), but most persons with PFOs remain asymptomatic and do not develop serious complications (2). Among young persons with a cryptogenic stroke, the prevalence of PFO is high (3), and approximately half have no apparent underlying causes (4). Because PFO may be a nest of thrombus formation or the conduit for paradoxical embolism (1, 5, 6), percutaneous closure was introduced to prevent recurrent stroke in high-risk persons (7). Until 2017, evidence and guideline recommendations did not support the routine use of PFO closure (812): Individual randomized controlled trials suggested no benefit of closure over medical therapy alone (1113), and meta-analyses of the trials showed no statistically significant reductions in recurrent stroke but possible increased risks for adverse effects (1417). In late 2017, the results of 2 new randomized trialsCLOSE (Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence) and REDUCE (Gore Helex Septal Occluder/Gore Cardioform Septal Occluder for Patent Foramen Ovale Closure in Stroke Patients)as well as a long-term analysis of the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial changed the landscape of evidence (1820). We undertook this systematic review to summarize the new evidence and compare risks for recurrent cerebrovascular events and adverse events in adults with PFO and cryptogenic stroke who received treatment with PFO closure versus those who received medical therapy alone. Methods We developed a protocol for the review on 5 June 2017 and registered it at PROSPERO (www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017074686) on 8 August 2017. Data Sources and Searches We searched PubMed, Scopus, and Google Scholar electronic databases from 1 December 2004 through 14 September 2017 using the following keywords and corresponding MeSH (Medical Subject Headings) terms: PFO closure, cryptogenic stroke, patent foramen ovale, and randomized controlled trial. We also checked the reference lists of eligible studies and screened scientific abstracts and relevant Web sites (www.clinicaltrialresults.org, www.escardio.org, www.tctmd.com, https://accscientificsession.acc.org, and https://exhibitatsessions.org). Further details on search sources are reported in Appendix Table 1. Appendix Table 1. Information on Search Sources Study Selection Two investigators (J.S and S.D.R.) independently screened search records to identify eligible trials. No disagreements occurred. Inclusion criteria were randomized controlled trials of patients with PFO and cryptogenic stroke that compared an intervention with a percutaneous PFO closure device versus medical therapy alone and reported at least 1 of the following outcomes: stroke or TIA (main outcome) or new-onset atrial fibrillation (AF) or atrial flutter (AFL). Exclusion criteria were duplicate publications, trials published in a language other than English, and studies in which the end point measure was not specified (at least stroke or TIA, or AF or AFL). Data Extraction and Quality Assessment Two reviewers (J.S. and S.D.R.) independently extracted data about study characteristics and event rates from full articles. Two investigators (S.D.R. and A.P.) independently assessed study quality for each trial by using the Cochrane Risk of Bias Tool (http://methods.cochrane.org/bias/assessing-risk-bias-included-studies). The following domains were evaluated: randomization method; allocation concealment; blinding of patient, investigator, and outcome adjudication committee; reporting bias; attrition bias; and any other potential sources of bias, such as those related to trial designs, or the risk for contamination or crossover between the groups. The assessment was done at the study level and focused on the main study outcome (stroke or TIA). Disagreements were resolved by consensus. Data Synthesis and Analysis We focused our primary summary of data on trials evaluating closure devices that are currently available commercially and used data extracted from the original primary publications (11, 12, 18, 19) because the longer-term follow-up data for 1 trial were deemed less complete because of poor retention (20). We based our primary analyses on the composite end point of stroke or TIA. We analyzed ischemic stroke and death as secondary end points and the new onset of AF or AFL, major bleeding, and serious adverse events as safety end points. We used the risk difference (RD) with 95% CI as the summary measure. The random-effects model with the HartungKnappSidikJonkman method to estimate tau was used to compute estimates for the summary effect (21, 22). We used the treatment group correction for continuity described by Sweeting and colleagues (23) when one of the study groups had zero events. We used the double arcsine transformation when both treatment groups of a study reported zero events (24). Heterogeneity was assessed by using the Cochran Q test by means of a chi-square function. P values below 0.10 were considered indicative of heterogeneity. I 2 values were calculated to estimate variation among studies attributable to heterogeneity. Meta-analysis results were displayed with forest plots in which the measure of effect (RD) for each study is represented by a square and the area of each square is proportional to study weight. A metaregression analysis was performed to examine the potential effect of interatrial shunt (IAS) size on ischemic stroke. Subgroup and sensitivity analyses were conducted using recently published long-term follow-up data (rather than the original shorter-term follow-up data) for 1 trial (20) and fixed-effects (MantelHaenszel) and random-effects (HedgesOlkin and SidikJonkman) models (22, 25, 26). Analyses were performed by using Open Meta-Analyst and R (The R Foundation). Role of the Funding Source The funding bodies had no role in the studys design, conduct, review, or reporting or the decision to submit the manuscript for publication. Results Of 114 screened records, we identified 5 trials that compared PFO closure with medical therapy (Figure 1) (1113, 1820). We excluded 1 of these studies from our primary synthesis because it evaluated a device that was removed from the market because of low procedural success and a high risk for complications (13). Another trial (12) recently reported long-term results (20), which we used only in our sensitivity analyses. Figure 1. Evidence search and selection. CLOSURE I= Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale; RCT= randomized controlled trial; RESPECT= Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment. Characteristics of the trials are presented in Tables 1 and 2 and Appendix Tables 2 and 3. All trials were multicenter, open-label superiority studies, and all except CLOSE were funded by industry. The RESPECT trial (funded by St. Jude Medical) randomly assigned 980 patients to receive either PFO closure with the Amplatzer PFO Occluder (St. Jude Medical) plus antiplatelet therapy or medical treatment alone (12). Mean follow-up was 2.6 years for the initial publication; recently, results of a prolonged follow-up (median, 5.9 years) were published (20). Between 2000 and 2009, the PC-Trial (Randomized Clinical Trial Comparing the Efficacy of Percutaneous Closure of PFO With Medical Treatment in Patients With Cryptogenic Embolism), funded by St. Jude Medical, randomly assigned 414 patients to undergo PFO closure with the Amplatzer PFO Occluder plus antiplatelet therapy or receive medical treatment at the physicians discretion. Mean follow-up was 4.0 years (11). The CLOSE study, funded by the French Ministry of Health, was a multicenter, open-label, 3-group superiority trial with blinded event adjudication. The trial was designed to enroll 900 patients with a 1:1:1 randomization to receive transcatheter PFO closure with any approved implantable medical device plus long-term antiplatelet therapy, long-term oral anticoagulation, or long-term antiplatelet therapy (18). Mean follow-up was 5.32.0 years. The open-label REDUCE study (funded by W.L. Gore and Associates) assessed the efficacy and safety of PFO closure using a Gore septal occluder device (Helex or Cardioform) in 664 patients with a history of cryptogenic stroke randomly assigned in a 2:1 proportion (19). Mean follow-up was 3.2 years. Table 1. Characteristics of Trials of PFO Closure in Adults With PFO and Cryptogenic Stroke Table 2. Characteristics of Patients in PFO Closure Trials Appendix Table 2. Definition of Large IAS Appendix Table 3. Effective PFO Closure Across All Studies Risk-of-bias assessments are reported in Appendix Figure 1. All trials used an adequate method of randomization and allocation concealment. Blinding of patients and caregivers was not possible because no sham procedure was performed in the medical treatment group in any of the trials. End point adjudication committees were blinded to the treatment strategy in all trials. Risk of selection, detection, attrition, and reporting bias was judged as low. Risk of performance bias was present. Appendix Figure 1. Study quality assessment. Quality assessment was performed at the trial level for the primary study outcome. The funding sources are listed on the right. CLOSE = Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence; PC-Trial = Randomized Clinical Trial Comparing the Efficacy of Percutaneous Closure of PFO With Medical Treatment in Patients With Crypt

Six-Month Results From the Initial Randomized Study of the Ranger Paclitaxel-Coated Balloon in the Femoropopliteal Segment:

Purpose: To evaluate the performance of the Ranger paclitaxel-coated balloon vs uncoated balloon angioplasty for femoropopliteal lesions. Methods: Between January 2014 and October 2015, the prospective, randomized RANGER SFA study ( ClinicalTrials.gov identifier NCT02013193) enrolled 105 patients with symptomatic lower limb ischemia (Rutherford category 2–4) and stenotic lesions in the nonstented femoropopliteal segment at 10 European centers. Seventy-one patients (mean age 68±8 years; 53 men) were enrolled in the Ranger drug-coated balloon (DCB) arm and 34 patients (mean age 67±9 years; 23 men) were assigned to the control group. Six-month analysis included angiographic late lumen loss and safety and clinical outcomes assessments. Results: Baseline characteristics of the DCB and control groups were similar, as were lesion lengths (68±46 vs 60±48 mm; p=0.731), severity of calcification (p=0.236), and the prevalence of occlusions (34% vs 34%; p>0.999). At 6 months, late lumen loss was significantly less for the DCB group vs controls (–0.16±0.99 vs 0.76±1.4; p=0.002). The DCB group had significantly greater freedom from binary restenosis (92% vs 64%; p=0.005) and primary patency rates (87% vs 60%; p=0.014). Target lesion revascularization rates were 5.6% in the DCB group and 12% in the control group (p=0.475). No target limb amputations or device-related deaths occurred in either group. Conclusion: Six-month results suggest that Ranger DCB treatment effectively inhibited restenosis in symptomatic femoropopliteal disease, resulting in improved vessel patency and a low revascularization rate in the short term compared with uncoated balloon angioplasty.

A randomized double-blind trial of an interventional device treatment of functional mitral regurgitation in patients with symptomatic congestive heart failure-Trial design of the REDUCE FMR study

The Carillon Mitral Contour System has been studied in 3 nonrandomized trials in patients with symptomatic congestive heart failure and functional mitral regurgitation. The REDUCE FMR study is a uniquely designed, double-blind trial evaluating the impact of the Carillon device on reducing regurgitant volume, as well as assessing the safety and clinical efficacy of this device. Carillon is a coronary sinus-based indirect annuloplasty device. Eligible patients undergo an invasive venogram to assess coronary sinus vein suitability for the Carillon device. If the venous dimensions are suitable, they are randomized on a 3:1 basis to receive a device or not. Patients and assessors are blinded to the treatment assignment. The primary end point is the difference in regurgitant volume at 1 year between the implanted and nonimplanted groups. Other comparisons include clinical parameters such as heart failure hospitalizations, 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), and other echocardiographic parameters. An exercise echo substudy will also be included.

To close or not to close: contemporary indications for patent foramen ovale closure

ABSTRACT Introduction: Patent foramen ovale (PFO) is a common congenital cardiac abnormality and that has been associated with several disease processes including transient ischemic attacks (TIA), stroke, migraine headaches with aura, decompression sickness, platypnea-orthodeoxia syndrome, and shunt induced cyanosis. Controversy exists regarding closure of PFO as a therapeutic treatment modality for these disease processes. This review addresses the contemporary clinical indications for PFO closure. Areas covered: We conducted a comprehensive literature search of contemporary research studies focusing on randomized trials and meta-analyses comparing medical therapy and device closure of PFOs for the treatment of PFO associated clinical syndromes. We synthesized this literature into a review addressing indications for PFO closure in stroke, TIA, migraine headaches with aura, decompression sickness, platypnea-orthodeoxia syndrome, and shunt induced cyanosis. Expert commentary: Because in many PFO associated conditions it can be difficult to determine the degree to which the PFO is a causative factor in the disease process, we recommend a comprehensive diagnostic evaluation to exclude other obvious etiologies of PFO associated conditions before implicating the PFO and proceeding with closure. However in the properly selected patient population there is growing clinical experience and experimental evidence suggesting that closure of PFO is a safe and effective treatment modality.

Left atrial appendage occlusion with lambre in atrial fibrillation: Initial European experience

BACKGROUND We here report the first European experience with the novel LAmbre left atrial appendage (LAA) occluder, a self-expanding device consisting of an umbrella and a cover connected by a central waist. METHODS AND RESULTS A total of 60 patients (74.4 ± 8.3 years; 66.7% men; CHA2DS2-VASc: 4.0 ± 1.6, HAS-BLED score: 3.2 ± 1.3) with atrial fibrillation and contraindications to oral anticoagulation underwent left atrial appendage occlusion (LAAO) with the LAmbre device at two German centers between November 2013 and September 2015. Device success defined as correct placement of the device was achieved in all patients (100%). Resizing of the device was necessary in 3 (5%) patients. Device-related complications included 2 (3.3%) pericardial effusions on day 8 and 33 after the index procedure requiring pericardiocentesis. Transesophageal echocardiography at 6 months showed complete sealing of the LAA (residual jet flow of <5 mm) in 51/54 (94.4%) patients. No device-related thrombus was documented. At 12 months transient ischemic attack was observed in 1 patient (1.6%) and minor bleeding in 3 patients (5%). CONCLUSIONS Although minimizing procedure-related complications remains challenging, LAAO with the LAmbre showed high device success and good mid-term performance regarding prevention of stroke and bleeding.

Novel Percutaneous LAA Closure Devices in Clinical or Preclinical Trials

The field of left atrial appendage closure is growing rapidly. A host of new companies have introduced new closure devices. The devices seek to improve intraprocedur al, short-term, and long-term outcomes. This chapter will describe four devices and their current stages of preclinical and clinical trial development.

Left Atrial Appendage Closure – Techniques and Devices

The history of percutaneous occlusion of the left atrial appendage (LAA) for stroke prevention started back in 2001 with the first implantation of the percutaneous LAA transcatheter occlusion system (PLAATO; Appriva Medical, Sunnyvale, CA, USA) [1]. The PLAATO device was a self-expanding nitinol cage covered with a polytetrafluoroethylene membrane, anchoring in the LAA using hooks positioned on the struts of the cage (Fig. 17.1). Despite favorable clinical results with an annual ischemic stroke rate substantially lower than predicted by CHADS2 score (3.8 % vs. 6.6 %) [2], the manufacturer discontinued the development of the device in 2006. This was the result of the strict and therefore costly requirements of the FDA, which is why approval of the occluder on the American market did not appear possible. But the development of other endo- and epicardial systems for LAA closure continued. This section presents requirements and techniques for the occlusion of the LAA considering commercially available devices to which CE Mark or FDA approval was granted.

Bipolar radiofrequency renal denervation with the Vessix catheter in patients with resistant hypertension: 2-year results from the REDUCE-HTN trial

&NA; One hundred forty‐six hypertensive patients were treated with bipolar radiofrequency balloon‐based renal denervation. Significant office blood pressure (BP) reductions were sustained through 2 years of follow‐up, with few patients experiencing related serious adverse events. Although confirmatory randomised controlled trials with designs to minimise confounding factors are needed, long‐term follow‐up after renal denervation continues to support procedure safety and suggests that it may have a lowering effect on BP.