Endovascular Ablation of the Right Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: Rationale, Design and Lead-in Phase Results of the REBALANCE-HF Trial.

OBJECTIVE: Splanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled, randomized clinical trial of splanchnic nerve ablation for HFpEF and (2) the 12-month results of the lead-in (open-label) trial's participants. METHODS: REBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter, right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association class, and NTproBNP levels at 3, 6 and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at the 1-month follow-up. RESULTS: The lead-in phase of the study, which enrolled 26 patients with HFpEF who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1 month post-procedure and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (n = 44 SAVM; n = 46 sham) has completed enrollment, and follow-up is ongoing. CONCLUSION: REBALANCE-HF is the first sham-controlled randomized clinical trial of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF. TRIAL REGISTRATION: NCT04592445.

Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial.

BACKGROUND: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients. METHODS: In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033. FINDINGS: Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8-1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (pinteraction=0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (pinteraction=0·012 [≥29·7 mL/m2, worse outcomes]), and sex (pinteraction=0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11). INTERPRETATION: Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. FUNDING: Corvia Medical.

Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): A Phase 2, Randomized, Sham-Controlled Trial.

BACKGROUND: In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%. METHODS: REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise. RESULTS: A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group (P=0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group (P=1.0). CONCLUSIONS: In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02600234.

Percutaneous repair or surgery for mitral regurgitation.

BACKGROUND: Mitral-valve repair can be accomplished with an investigational procedure that involves the percutaneous implantation of a clip that grasps and approximates the edges of the mitral leaflets at the origin of the regurgitant jet. METHODS: We randomly assigned 279 patients with moderately severe or severe (grade 3+ or 4+) mitral regurgitation in a 2:1 ratio to undergo either percutaneous repair or conventional surgery for repair or replacement of the mitral valve. The primary composite end point for efficacy was freedom from death, from surgery for mitral-valve dysfunction, and from grade 3+ or 4+ mitral regurgitation at 12 months. The primary safety end point was a composite of major adverse events within 30 days. RESULTS: At 12 months, the rates of the primary end point for efficacy were 55% in the percutaneous-repair group and 73% in the surgery group (P=0.007). The respective rates of the components of the primary end point were as follows: death, 6% in each group; surgery for mitral-valve dysfunction, 20% versus 2%; and grade 3+ or 4+ mitral regurgitation, 21% versus 20%. Major adverse events occurred in 15% of patients in the percutaneous-repair group and 48% of patients in the surgery group at 30 days (P<0.001). At 12 months, both groups had improved left ventricular size, New York Heart Association functional class, and quality-of-life measures, as compared with baseline. CONCLUSIONS: Although percutaneous repair was less effective at reducing mitral regurgitation than conventional surgery, the procedure was associated with superior safety and similar improvements in clinical outcomes. (Funded by Abbott Vascular; EVEREST II ClinicalTrials.gov number, NCT00209274.).

2-Year Outcomes of an Atrial Shunt Device in HFpEF/HFmrEF: Results From REDUCE LAP-HF II.

BACKGROUND: The REDUCE LAP-HF II (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II) trial found that, compared with a sham procedure, the Corvia Atrial Shunt did not improve outcomes in heart failure with preserved or mildly reduced ejection fraction. However, after 12-month follow-up, "responders" (peak-exercise pulmonary vascular resistance <1.74 WU and absence of a cardiac rhythm management device) were identified. OBJECTIVES: This study sought to determine: 1) the overall efficacy and safety of the atrial shunt vs sham control after 2 years of follow-up; and 2) whether the benefits of atrial shunting are sustained in responders during longer-term follow-up or are offset by adverse effects of the shunt. METHODS: The study analyzed 2-year outcomes in the overall REDUCE LAP-HF II trial, as well as in responder and nonresponder subgroups. The primary endpoint was a hierarchical composite of cardiovascular death or nonfatal ischemic/embolic stroke, total heart failure events, and change in health status. RESULTS: In 621 randomized patients, there was no difference between the shunt (n = 309) and sham (n = 312) groups in the primary endpoint (win ratio: 1.01 [95% CI: 0.82-1.24]) or its individual components at 2 years. Shunt patency at 24 months was 98% in shunt-treated patients. Cardiovascular mortality and nonfatal ischemic stroke were not different between the groups; however, major adverse cardiac events were more common in those patients assigned to the shunt compared with sham (6.9% vs 2.7%; P = 0.018). More patients randomized to the shunt had an increase in right ventricular volume of ≥30% compared with the sham control (39% vs 28%, respectively; P < 0.001), but right ventricular dysfunction was uncommon and not different between the treatment groups. In responders (n = 313), the shunt was superior to sham (win ratio: 1.36 [95% CI: 1.02-1.83]; P = 0.037, with 51% fewer HF events [incidence rate ratio: 0.49 [95% CI: 0.25-0.95]; P = 0.034]). In nonresponders (n = 265), atrial shunting was inferior to sham (win ratio: 0.73 [95% CI: 0.54-0.98]). CONCLUSIONS: At 2 years of follow-up in REDUCE LAP-HF II, there was no difference in efficacy between the atrial shunt and sham groups in the overall trial group. The potential clinical benefit identified in the responder group after 1 and 2 years of follow-up is currently being evaluated in the RESPONDER-HF (Re-Evaluation of the Corvia Atrial Shunt Device in a Precision Medicine Trial to Determine Efficacy in Mildly Reduced or Preserved Ejection Fraction Heart Failure) trial. (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II [REDUCE LAP-HF II]; NCT03088033).

No-Implant Interatrial Shunt for HFpEF: 6-Month Outcomes From Multicenter Pilot Feasibility Studies.

BACKGROUND: Most approaches to the creation of an interatrial shunt require placement of a permanent implant to maintain patency. OBJECTIVES: The goal of this study was to investigate the safety and efficacy of a no-implant interatrial shunt for patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF). METHODS: This was a multicenter, uncontrolled study of patients with HFpEF/HFmrEF and NYHA functional class ≥II, ejection fraction >40%, and pulmonary capillary wedge pressure (PCWP) during supine exercise ≥25 mm Hg with PCWP-to-right atrial gradient ≥5 mm Hg. Follow-up was through 6 months with imaging to assess shunt durability. RESULTS: A total of 28 patients were enrolled: mean age was 68 ± 9 years, and 68% were female. Baseline resting and peak exercise PCWP were 19 ± 7 mm Hg and 40 ± 11 mm Hg, respectively. All procedures displayed technical success with confirmation of left-to-right flow (shunt diameter 7.1 ± 0.9 mm). At 1 month, peak exercise PCWP decreased 5.4 ± 9.6 mm Hg (P = 0.011) with no change in right atrial pressure. There were no serious device or procedure-related adverse events through 6 months. Mean 6-minute walk distance increased 101 ± 71 meters (P < 0.001); Kansas City Cardiomyopathy Questionnaire Overall Summary Score increased 26 ± 19 points (P < 0.001); N-terminal pro-B-type natriuretic peptide decreased 372 ± 857 pg/mL (P = 0.018); and shunt patency was confirmed with unchanged diameter. CONCLUSIONS: In these feasibility studies of a no-implant interatrial shunt, HFpEF/HFmrEF shunts exhibited stability with favorable safety and early efficacy signals. The results show promise toward this new approach for treating patients with HFpEF/HFmrEF and an appropriate hemodynamic profile. (Evaluation of the Safety and Feasibility of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-1]; NCT04583527; Evaluation of the Safety and Effectiveness of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-2]; NCT04838353).

Exercise-Induced Left Atrial Hypertension in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Many patients with heart failure and preserved ejection fraction have no overt volume overload and normal resting left atrial (LA) pressure. OBJECTIVES: This study sought to characterize patients with normal resting LA pressure (pulmonary capillary wedge pressure [PCWP] <15 mm Hg) but exercise-induced left atrial hypertension (EILAH). METHODS: The REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial randomized 626 patients with ejection fraction ≥40% and exercise PCWP ≥25 mm Hg to atrial shunt or sham procedure. The primary trial outcome, a hierarchical composite of death, heart failure hospitalization, intensification of diuretics, and change in health status was compared between patients with EILAH and those with heart failure and resting left atrial hypertension (RELAH). RESULTS: Patients with EILAH (29%) had similar symptom severity, but lower natriuretic peptide levels, higher 6-minute walk distance, less atrial fibrillation, lower left ventricular mass, smaller LA volumes, lower E/e', and better LA strain. PCWP was lower at rest, but had a larger increase with exercise in EILAH. Neither group as a whole had a significant effect from shunt therapy vs sham. Patients with EILAH were more likely to have characteristics associated with atrial shunt responsiveness (peak exercise pulmonary vascular resistance <1.74 WU) and no pacemaker (63% vs 46%; P < 0.001). The win ratio for the primary outcome was 1.56 (P = 0.08) in patients with EILAH and 1.51 (P = 0.04) in those with RELAH when responder characteristics were present. CONCLUSIONS: Patients with EILAH had similar symptom severity but less advanced myocardial and pulmonary vascular disease. This important subgroup may be difficult to diagnose without invasive exercise hemodynamics, but it has characteristics associated with favorable response to atrial shunt therapy. (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure [REDUCE LAP-HF TRIAL II]; NCT03088033).

Prevalence and echocardiographic features of iatrogenic atrial septal defect after catheter-based mitral valve repair with the MitraClip system.

OBJECTIVES: Review the prevalence, echocardiographic features and potential predictors of iatrogenic ASD (iASD) created with the MitraClip guiding catheter. BACKGROUND: Catheter-based repair of mitral regurgitation (MR) with the MitraClip device (Abbott Vascular, Menlo Park, CA), is performed through a 22-French transseptal guiding catheter. The echocardiographic prevalence of iASDs after the MitraClip procedure has not been reported. METHODS: Thirty subjects undergoing MitraClip repair during the roll-in phase of the EVEREST II randomized trial who had baseline, 30 day, 6 and 12 month transthoracic echocardiograms (TTEs) available for review were included. Patients who underwent surgery for MR within the first 12 months were excluded. Residual iASD size, right ventricular (RV) size, left atrial (LA) volume, and tricuspid/MR grade were quantified. RESULTS: iASDs were found at 12 months in 8 patients (27%) with a mean diameter of 6.6 ± 3.1 mm. Subjects with iASD at 12 months had more residual MR, increased TR and a trend toward larger LA volumes than non-iASD patients. 83% of non-ASD patients were free from MR > 2+ at 12 mos. vs. 38% of those with iASD (p=0.016). There were no other significant associations between clinical and echocardiographic variables and the persistence of iASD. CONCLUSIONS: After MitraClip repair, persistent iASDs occur at a rate comparable to reports after other transseptal interventional procedures and do not appear hemodynamically significant. Patients with persistent iASDs had less MR reduction at 12-months and a trend toward larger LA volumes, suggesting that increased LA pressure may be a mechanism for persistent iASD.

Feasibility of a No-Implant Approach to Interatrial Shunts: Preclinical and Early Clinical Studies.

Background: Heart failure with preserved ejection fraction represents a major unmet clinical need with limited treatment options. Recent device therapies under investigation have focused on decompression of the left atrium through an implantable interatrial shunt. Although these devices have shown favorable safety and efficacy signals, an implant is required to maintain shunt patency, which may increase the patient risk profile and complicate subsequent interventions requiring transseptal access. Methods: The Alleviant System is a no-implant approach to creating an interatrial shunt using radiofrequency energy to securely capture, excise, and extract a precise disk of tissue from the interatrial septum. Acute preclinical studies in healthy swine (n = 5) demonstrated the feasibility of the Alleviant System to repeatably create a 7 mm interatrial orifice with minimal collateral thermal effect and minimal platelet and fibrin deposition observed histologically. Results: Chronic animal studies (n = 9) were carried out to 30- and 60-day time points and exhibited sustained shunt patency with histology demonstrating completely healed margins, endothelialization, and no trauma to adjacent atrial tissue. Preliminary clinical safety and feasibility were validated in a first-in-human study in patients with heart failure with preserved ejection fraction (n = 15). All patients demonstrated shunt patency by transesophageal echocardiographic imaging at 1, 3, and 6 months, as well as cardiac computed tomography imaging at 6-month follow-up timepoints. Conclusions: Combined, these data support the safety and feasibility of a novel no-implant approach to creating an interatrial shunt using the Alleviant System. Continued follow-up and subsequent clinical studies are currently ongoing.

Endovascular ablation of the right greater splanchnic nerve in heart failure with preserved ejection fraction: early results of the REBALANCE-HF trial roll-in cohort.

AIMS: In heart failure (HF) with preserved ejection fraction (HFpEF), excessive redistribution of blood volume into the central circulation leads to elevations of intracardiac pressures with exercise limitations. Splanchnic ablation for volume management (SAVM) has been proposed as a therapeutic intervention. Here we present preliminary safety and efficacy data from the initial roll-in cohort of the REBALANCE-HF trial. METHODS AND RESULTS: The open-label (roll-in) arm of REBALANCE-HF will enrol up to 30 patients, followed by the randomized, sham-controlled portion of the trial (up to 80 additional patients). Patients with HF, left ventricular ejection fraction (LVEF) ≥50%, and invasive peak exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg underwent SAVM. Baseline and follow-up assessments included resting and exercise PCWP, New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire (KCCQ), 6-min walk test, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Efficacy and safety were assessed at 1 and 3 months. Here we report on the first 18 patients with HFpEF that have been enrolled into the roll-in, open-label arm of the study across nine centres; 14 (78%) female; 16 (89%) in NYHA class III; and median (interquartile range) age 75.2 (68.4-81) years, LVEF 61.0 (56.0-63.2)%, and average (standard deviation) 20 W exercise PCWP 36.4 (±8.6) mmHg. All 18 patients were successfully treated. Three non-serious moderate device/procedure-related adverse events were reported. At 1-month, the mean PCWP at 20 W exercise decreased from 36.4 (±8.6) to 28.9 (±7.8) mmHg (p < 0.01), NYHA class improved by at least one class in 33% of patients (p = 0.02) and KCCQ score improved by 22.1 points (95% confidence interval 9.4-34.2) (p < 0.01). CONCLUSION: The preliminary open-label results from the multicentre REBALANCE-HF roll-in cohort support the safety and efficacy of SAVM in HFpEF. The findings require confirmation in the ongoing randomized, sham-controlled portion of the trial.

Preventing Coronary Obstruction During Transcatheter Aortic Valve Replacement: Results From the Multicenter International BASILICA Registry.

OBJECTIVES: This study sought to determine the safety of the BASILICA (bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction) procedure. BACKGROUND: Transcatheter aortic valve replacement causes coronary artery obstruction in 0.7% of cases, with 40% to 50% mortality. BASILICA is a procedure to prevent coronary obstruction. Safety and feasibility in a large patient cohort is lacking. METHODS: The international BASILICA registry was a retrospective, multicenter, real-world registry of patients at risk of coronary artery obstruction undergoing BASILICA and transcatheter aortic valve replacement. Valve Academic Research Consortium-2 definitions were used to adjudicate events. RESULTS: Between June 2017 and December 2020, 214 patients were included from 25 centers in North America and Europe; 72.8% had bioprosthetic aortic valves and 78.5% underwent solo BASILICA. Leaflet traversal was successful in 94.9% and leaflet laceration in 94.4%. Partial or complete coronary artery obstruction was seen in 4.7%. Procedure success, defined as successful BASILICA traversal and laceration without mortality, coronary obstruction, or emergency intervention, was achieved in 86.9%. Thirty-day mortality was 2.8% and stroke was 2.8%, with 0.5% disabling stroke. Thirty-day death and disabling stroke were seen in 3.4%. Valve Academic Research Consortium-2 composite safety was achieved in 82.8%. One-year survival was 83.9%. Outcomes were similar between solo and doppio BASILICA, between native and bioprosthetic valves, and with the use of cerebral embolic protection. CONCLUSIONS: BASILICA is safe, with low reported rates of stroke and death. BASILICA is feasible in the real-world setting, with a high procedure success rate and low rates of coronary artery obstruction.

Clinical outcomes of TAVI or SAVR in men and women with aortic stenosis at intermediate operative risk: a post hoc analysis of the randomised SURTAVI trial.

AIMS: In patients with aortic stenosis randomised to transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR), sex-specific differences in complication rates are unclear in intermediate-risk patients. The purpose of this analysis was to identify sex-specific differences in outcome for patients at intermediate surgical risk randomised to TAVI or SAVR in the international Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) trial. METHODS AND RESULTS: A total of 1,660 intermediate-risk patients underwent TAVI with a supra-annular, self-expanding bioprosthesis or SAVR. The population was stratified by sex and treatment modality (female TAVI=366, male TAVI=498, female SAVR=358, male SAVR=438). The primary endpoint was a composite of all-cause mortality or disabling stroke at two years. Compared to males, females had a smaller body surface area, a higher Society of Thoracic Surgeons score (4.7±1.6% vs 4.3±1.6%, p<0.01) and were more frail. Men required more concomitant revascularisation (23% vs 16%). All-cause mortality or disabling stroke at two years was similar between TAVI and SAVR for females (10.2% vs 10.5%, p=0.90) and males (14.5% vs 14.4%, p=0.99); the difference between females and males was 10.2% vs 14.5%, for TAVI (p=0.08) and 10.5% vs 14.4%, SAVR (p=0.13). Functional status improvement was more pronounced after TAVI in females than in males. CONCLUSIONS: Aortic valve replacement, either by surgical or transcatheter approach, appears similarly effective and safe for males and females at intermediate surgical risk. Functional status appears to improve most in females after TAVI. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov NCT01586910.

One-Year Safety and Clinical Outcomes of a Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction in the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (REDUCE LAP-HF I) Trial: A Randomized Clinical Trial.

Importance: In patients with heart failure (HF) and left ventricular ejection fraction (LVEF) equal to or greater than 40%, a transcatheter interatrial shunt device (IASD; Corvia Medical) reduces exercise pulmonary capillary wedge pressure (PCWP) and is safe compared with sham control treatment at 1 month of follow-up. The longer-term safety and patency of the IASD has not yet been demonstrated in the setting of a randomized clinical trial (RCT). Objective: To evaluate the 1-year safety and clinical outcomes of the IASD compared with a sham control treatment. Design, Setting, and Participants: This phase 2, double-blind, 1-to-1 sham-controlled multicenter RCT of IASD implantation vs a sham procedure (femoral venous access and imaging of the interatrial septum without IASD) was conducted in 22 centers in the United States, Europe, and Australia on patients with New York Heart Association (NYHA) class III or ambulatory class IV HF, LVEF equal to or greater than 40%, exercise PCWP equal to or greater than 25 mm Hg, and PCWP-right atrial pressure gradient equal to or greater than 5 mm Hg. Main Outcomes and Measures: Safety was assessed by major adverse cardiac, cerebrovascular, or renal events (MACCRE). Exploratory outcomes evaluated at 1 year were hospitalizations for HF, NYHA class, quality of life, a 6-minute walk test, and device patency. Results: After 1 year, shunts were patent in all IASD-treated patients; MACCRE did not differ significantly in the IASD arm (2 of 21 [9.5%]) vs the control arm (5 of 22 [22.7%]; P = .41), and no strokes occurred. The yearly rate of hospitalizations for HF was 0.22 in the IASD arm and 0.63 in the control arm (P = .06). Median improvement in NYHA class was 1 class in the IASD arm (IQR, -1 to 0) vs 0 in the control arm (IQR, -1 to 0; P = .08). Quality of life and 6-minute walk test distance were similar in both groups. At 6 months, there was an increase in right ventricular size in the IASD arm (mean [SD], 7.9 [8.0] mL/m2) vs the control arm (-1.8 [9.6] mL/m2; P = .002), consistent with left-to-right shunting through the device; no further increase occurred in the IASD arm at 12 months. Conclusions and Relevance: The REDUCE LAP-HF I phase 2, sham-controlled RCT confirms the longer-term patency of the IASD. Through 1 year of follow-up, IASD treatment appears safe, with no significant differences in MACCRE in patients receiving IASD compared with those who received sham control treatment. Trial Registration: ClinicalTrials.gov identifier: NCT02600234.

A safety and feasibility report of combined direct thrombin and GP IIb/IIIa inhibition with bivalirudin and tirofiban in peripheral vascular disease intervention: treating critical limb ischemia like acute coronary syndrome.

BACKGROUND: The combination of glycoprotein (GP) IIb-IIIa inhibition and direct thrombin inhibition (DTI) with bivalirudin (Angiomax, The Medicines Company, Cambridge, Massachusetts) have shown ischemic and hemorrhagic outcomes benefit in coronary interventions and may have similar benefits in percutaneous peripheral interventions (PPI). The high incidence of diabetes, chronic renal disease, platelet dysfunction, hypercoagulability, inflammation and a thrombus-rich environment make a GP IIb-IIIa and DTI combination with tirofiban (Aggrastat Merck and Company, Inc., Whitehouse Station, New Jersey) an attractive anticoagulation strategy in the PPI treatment of critical limb ischemia (CLI). METHODS: Between May 1, 2001 and January 31, 2003, a CLI treatment group of 149 patients received PPI with bivalirudin (0.75 mg per kg bolus with 1.75 mg per kg per hour periprocedural infusion) and tirofiban (10 mcg per kg per minute bolus with 12-hour 0.1 mcg per kg per minute infusion) as an anticoagulation and antiplatelet strategy, and were compared to a matched unfractionated heparin (UFH) control group without GP IIb-IIIa inhibitors. Clinical and hemostasis outcomes were analyzed, including distal embolization (DE). RESULTS: Procedural success was 95.9% and 97.3% in the UFH control group and DTI-GP IIb-IIIa group, respectively. Significant differences were observed in the sheath removal time < 2 hours (60.5% UFH group versus 19.4% DTI-GP IIb-IIIa group; p = < 0.0001). Vascular closure devices were used equally in both groups. No statistical significance was observed in major and minor complications, femoral access complications, acute (< 48 hours) or subacute (30 days) vessel thrombosis, and 6-month duplex ultrasound restenosis rate between the DTI-GP IIb-IIIa versus the UFH group. A trend towards statistical significance was observed in the 6-month secondary re-intervention and limb salvage rates (10.7% versus 18.8%; p = 0.0501 and 93.9% versus 88.5%; p = 0.053) in the DTI-GP IIb-IIIa versus the UFH group, respectively. Angiographically relevant DE occurred in 4 of 149 (1.3%) and 8 of 149 (5.4%) of the bivalirudin-tirofiban and UFH groups, respectively. CONCLUSION: The combination of DTI with bivalirudin and GP IIb-IIIa inhibition with tirofiban is a safe and feasible alternative anticoagulation and antiplatelet strategy in PPI, and may offer improved clinical and hemostasis outcomes in treating CLI. A larger, prospective randomized trial is warranted.

Randomized Comparison of Percutaneous Repair and Surgery for Mitral Regurgitation: 5-Year Results of EVEREST II.

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

Bivalirudin as a foundation anticoagulant in peripheral vascular disease: a safe and feasible alternative for renal and iliac interventions.

BACKGROUND: Many heparin (UFH) limitations are overcome by bivalirudin (Angiomax ). The pharmacokinetic profile of bivalirudin appears well suited for percutaneous peripheral intervention (PPI), yet few data exist regarding its safety and feasibility in this setting. METHODS: One hundred and eighty renal and 75 iliac PPIs performed between May 2001 and June 2002 with bivalirudin as anticoagulation were compared to a historical UFH control. Variables evaluated included thrombotic events, intracranial bleeding, major surgical complications, sheath removal time, vascular access complication, time to ambulate and length of stay (LOS). Follow-up included 6-month renal and iliac duplex ultrasound and ankle-brachial index. RESULTS: Procedural success was achieved in 100% of patients treated with bivalirudin, with no thrombotic events, intracranial bleeding or major surgical complications observed. Procedural success was achieved in 179/180 (99%) renal and 74/75 (98.6%) iliac patients treated with UFH. Significant differences were observed for sheath removal time < 60 minutes (84% versus 59%; p < 0.0001), time to ambulation < 6 hours (75.5% versus 58%; p < 0.0005) and LOS < 24 hours (85.5% versus 72%; p = 0.002) in bivalirudin-treated renal PPI patients versus UFH-treated patients, respectively. Significant differences were also observed in favor of bivalirudin for the iliac PPIs for sheath removal time < 60 minutes (p = 0.012) and time to ambulation < 6 hours (p = 0.039). Following 6-month renal and iliac duplex ultrasound, repeat PPI was required in 7/180 (3.9%) and 9/180 (5%) of renal, and 3/75 (4%) and 4/75 (5.3%) of iliac patients treated with bivalirudin or UFH, respectively. CONCLUSION: Bivalirudin is a safe and feasible alternative anticoagulant in renal and iliac PPI and may offer decreased sheath removal time, time to ambulation and LOS. A larger prospective randomized multicenter trial is warranted.

Use of the REG1 anticoagulation system in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the phase II RADAR-PCI study.

AIMS: We sought to determine the feasibility of conducting percutaneous coronary intervention (PCI) in high-risk acute coronary syndrome (ACS) patients utilising the REG1 system consisting of pegnivacogin, an aptameric factor IXa inhibitor, and its controlling agent anivamersen. METHODS AND RESULTS: In RADAR, ACS patients were randomised to pegnivacogin 1 mg/kg with 25%, 50%, 75%, or 100% anivamersen reversal or unfractionated heparin. Of the 640 patients randomised, 388 (61%) underwent PCI. Major modified ACUITY 30-day bleeding rates were 18% (25% reversal), 12% (50% reversal), 9% (75% reversal), and 7% (100% reversal), compared with 11% with heparin. The corresponding total bleeding rates were 68%, 39%, 35%, 34%, and 38% (heparin). Ischaemic events were less frequent in those receiving pegnivacogin versus heparin (4.4% vs. 7.3%, p=0.3). Thirty-day urgent TVR (1.1% vs. 0.9%, p=1.0), myocardial infarction (4.0% vs. 6.4%, p=0.3), and angiographic complication (11.2% and 10.8%, p=0.9) rates were similar with pegnivacogin and heparin. There were no incidences of clot formation on guidewires or catheters. CONCLUSIONS: High-level factor IXa inhibition in ACS patients undergoing PCI, with at least 50% reversal, has a favourable bleeding profile and appears effective at suppressing ischaemic events and thrombotic complications. Larger phase trials in PCI are warranted. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT00932100.

Percutaneous mitral valve repair in the initial EVEREST cohort: evidence of reverse left ventricular remodeling.

BACKGROUND: Percutaneous repair of mitral regurgitation (MR) permits examination of the effect of MR reduction without surgery and cardiopulmonary bypass on left ventricular (LV) dimensions and function. The goal of this analysis was to determine the extent of reverse remodeling at 12 months after successful percutaneous reduction of MR with the MitraClip device. METHODS AND RESULTS: Of 64 patients with 3 and 4+ MR who achieved acute procedural success after treatment with the MitraClip device, 49 patients had moderate or less MR at 12-month follow-up. Their baseline and 12-month echocardiograms were compared between the group with and without LV dysfunction. In patients with persistent MR reduction and pre-existing LV dysfunction, there was a reduction in LV wall stress, reduced LV end-diastolic volume, LV end-systolic volume and increase in LV ejection fraction in contrast to those with normal baseline LV function, who showed reduction in LV end-diastolic volume, LV wall stress, no change in LV end-systolic volume, and a fall in LV ejection fraction. CONCLUSIONS: Patients with pre-existing LV dysfunction demonstrate reverse remodeling and improved LV ejection fraction after percutaneous mitral valve repair. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00209339, NCT00209274.

The acute hemodynamic effects of MitraClip therapy.

OBJECTIVES: The objective of this study was to evaluate the acute hemodynamic consequences of mitral valve (MV) repair with the MitraClip device (Abbott Vascular, Menlo Park, California). BACKGROUND: Whether surgical correction of mitral regurgitation (MR) results in a low cardiac output (CO) state because of an acute increase in afterload remains controversial. The acute hemodynamic consequences of MR reduction with the MitraClip device have not been studied. METHODS: We evaluated 107 patients with cardiac catheterization before and immediately following percutaneous MV repair with the MitraClip device. In addition, pre- and post-procedural hemodynamic parameters were studied by transthoracic echocardiography. RESULTS: MitraClip treatment was attempted in 107 patients, and in 96 (90%) patients, a MitraClip was deployed. Successful MitraClip treatment resulted in: 1) an increase in CO from 5.0 ± 2.0 l/min to 5.7 ± 1.9 l/min (p = 0.003); 2) an increase in forward stroke volume (FSV) from 57 ± 17 ml to 65 ± 18 ml (p < 0.001); and 3) a decrease in systemic vascular resistance from 1,226 ± 481 dyn·s/cm(5) to 1,004 ± 442 dyn·s/cm(5) (p < 0.001). In addition, there was left ventricular (LV) unloading manifested by a decrease in LV end-diastolic pressure from 11.4 ± 9.0 mm Hg to 8.8 ± 5.8 mm Hg (p = 0.016) and a decrease in LV end-diastolic volume from 172 ± 37 ml to 158 ± 38 ml (p < 0.001). None of the patients developed acute post-procedural low CO state. CONCLUSIONS: Successful MV repair with the MitraClip system results in an immediate and significant improvement in FSV, CO, and LV loading conditions. There was no evidence of a low CO state following MitraClip treatment for MR. These favorable hemodynamic effects with the MitraClip appear to reduce the risk of developing a low CO state, a complication occasionally observed after surgical MV repair for severe MR.

Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort.

OBJECTIVES: We undertook a prospective multicenter single-arm study to evaluate the feasibility, safety, and efficacy of the MitraClip system (Evalve Inc., Menlo Park, California). BACKGROUND: Mitral valve repair for mitral regurgitation (MR) has been performed by the use of a surgically created double orifice. Percutaneous repair based on this surgical approach has been developed by use of the Evalve MitraClip device to secure the mitral leaflets. METHODS: Patients with 3 to 4+ MR were selected in accordance with the American Heart Association/American College of Cardiology guidelines for intervention and a core echocardiographic laboratory. RESULTS: A total of 107 patients were treated. Ten (9%) had a major adverse event, including 1 nonprocedural death. Freedom from clip embolization was 100%. Partial clip detachment occurred in 10 (9%) patients. Overall, 79 of 107 (74%) patients achieved acute procedural success, and 51 (64%) were discharged with MR of < or =1+. Thirty-two patients (30%) had mitral valve surgery during the 3.2 years after clip procedures. When repair was planned, 84% (21 of 25) were successful. Thus, surgical options were preserved. A total of 50 of 76 (66%) successfully treated patients were free from death, mitral valve surgery, or MR >2+ at 12 months (primary efficacy end point). Kaplan-Meier freedom from death was 95.9%, 94.0%, and 90.1%, and Kaplan-Meier freedom from surgery was 88.5%, 83.2%, and 76.3% at 1, 2, and 3 years, respectively. The 23 patients with functional MR had similar acute results and durability. CONCLUSIONS: Percutaneous repair with the MitraClip system can be accomplished with low rates of morbidity and mortality and with acute MR reduction to < 2+ in the majority of patients, and with sustained freedom from death, surgery, or recurrent MR in a substantial proportion (EVEREST I; NCT00209339. EVEREST II; NCT00209274).