Routine Protamine Administration for Bleeding in Transcatheter Aortic Valve Implantation: The ACE-PROTAVI Randomized Clinical Trial.

Importance: Vascular complications after transfemoral transcatheter aortic valve implantation (TAVI) remain an important cause of procedure-related morbidity. Routine reversal of anticoagulation with protamine at the conclusion of transfemoral TAVI could reduce complications, but data remain scarce. Objective: To evaluate the efficacy and safety of routine protamine administration after transfemoral TAVI. Design, Setting, and Participants: The ACE-PROTAVI trial was an investigator-initiated, double-blind, placebo-controlled randomized clinical trial performed at 3 Australian hospitals between December 2021 and June 2023 with a 1-year follow-up period. All patients accepted for transfemoral TAVI by a multidisciplinary heart team were eligible for enrollment. Interventions: Eligible patients were randomized 1:1 between routine protamine administration and placebo. Main Outcomes and Measures: The coprimary outcomes were the rate of hemostasis success and time to hemostasis (TTH), presented as categorical variables and compared with a χ2 test or as continuous variables as mean (SD) or median (IQR), depending on distribution. The major secondary outcome was a composite of all-cause death, major and minor bleeding complications, and major and minor vascular complications after 30 days, reported in odds ratios (ORs) with 95% CIs and P values. Results: The study population consisted of 410 patients: 199 patients in the protamine group and 211 in the placebo group. The median (IQR) patient age in the protamine group was 82 (77-85) years, and 68 of 199 patients receiving protamine (34.2%) were female. The median (IQR) patient age in the placebo group was 80 (75-85) years, and 89 of 211 patients receiving the placebo (42.2%) were female. Patients receiving up-front protamine administration had a higher rate of hemostasis success (188 of 192 patients [97.9%]) than patients in the placebo group (186 of 203 patients [91.6%]; absolute risk difference, 6.3%; 95% CI, 2.0%-10.6%; P = .006); in addition, patients receiving up-front protamine had a shorter median (IQR) TTH (181 [120-420] seconds vs 279 [122-600] seconds; P = .002). Routine protamine administration resulted in a reduced risk of the composite outcome in the protamine group (10 of 192 [5.2%]) vs the placebo group (26 of 203 [12.8%]; OR, 0.37; 95% CI, 0.1-0.8; P = .01). This difference was predominantly driven by the difference in the prevalence of minor vascular complications. There were no adverse events associated with protamine use. Conclusions and Relevance: In the ACE-PROTAVI randomized clinical trial, routine administration of protamine increased the rate of hemostasis success and decreased TTH. The beneficial effect of protamine was reflected in a reduction in minor vascular complications, procedural time, and postprocedural hospital stay duration in patients receiving routine protamine compared with patients receiving placebo. Trial Registration: anzctr.org.au Identifier: ACTRN12621001261808.

Predictors and Trends of New Permanent Pacemaker Implantation: A Subanalysis of the International Navitor IDE Study.

Background: The Navitor Investigational Device Exemption (IDE) study is a prospective, multicenter, global study assessing the safety and effectiveness of the Navitor valve in a population with severe, symptomatic aortic stenosis who are at high and extreme surgical risk. The impact of pre-existing conduction abnormalities and implantation technique on new permanent pacemaker implantation (PPI) for the Navitor platform is not fully understood. Therefore, the goal of this analysis was to investigate the associations between patient and procedural factors and the 30-day new PPI rate. Methods: A total of 260 patients who underwent implantation of a Navitor valve in the Navitor IDE study were reviewed. Patients with preprocedural permanent pacemakers (n = 28) were excluded. Baseline risk factors were assessed for statistical significance. Multivariable logistic regression analyses were performed to identify independent predictors of new PPI. Results: Mean age of the pacemaker-naïve population was 83.3 ± 5.2 years, 58.6% were female, average Society of Thoracic Surgeons score was 3.8% ± 1.9%, median frailty score was 1 (interquartile range 1, 2), and 17.7% were deemed at extreme surgical risk. Pre-existing first-degree atrioventricular block and right bundle branch block significantly increased the risk of new PPI postimplantation, whereas left bundle branch block did not. Membranous septum length in relation to noncoronary cusp implant depth was a significant predictor of new PPI, with higher rates of new PPI observed when noncoronary cusp implant depth exceeded membranous septum length. Analysis of implant depth alone revealed deeper implants were associated with a higher rate of new PPI, regardless of patient baseline conduction abnormality. Conclusions: The 30-day rate of new PPI in the Navitor IDE study is associated with patient pre-existing baseline conduction disturbances and implantation depth.

Post-Procedure Monocyte Count Levels Predict Major Adverse Cardiovascular Events (MACE) Following Transcatheter Aortic Valve Implantation (TAVI) for Aortic Stenosis.

BACKGROUND: Aortic stenosis has recently been characterised as having an inflammatory aetiology, beyond the traditional degenerative model. Recruitment of monocytes has been associated with inflammation contributing to progression of calcific aortic-valve disease. Prior research has demonstrated that pre-procedure inflammatory biomarkers do not consistently discriminate poorer outcomes in those with aortic stenosis. It remains, however, unclear if postprocedure inflammatory biomarkers, which are influenced by intraprocedural pro-inflammatory insults, can predict major adverse cardiovascular events (MACE) post transcatheter aortic valve implantation (TAVI). METHOD: All patients with postprocedure monocyte levels undergoing transcatheter aortic valve implantation at The Alfred Hospital, Melbourne, Australia (2008-2019) were included. The highest monocyte count from postprocedure days 1 to 3 was used. Patients were divided into "high" or "low" postprocedure monocyte count groups using the Youden Index. The incidence of 30-day MACE a composite of stroke, acute myocardial infarction, and death) was then compared. RESULTS: In total, 472 patients were included (54% men, median age 84 years). Fourteen (14) patients (3%) suffered a 30-day MACE. Those with high postprocedure monocyte count were more likely to: be hypertensive (p=0.049); have a higher Society of Thoracic Surgeons risk score (p=0.032); and, undergo non-transfemoral access (p=0.018). A high (≥0.975) postprocedure monocyte count was significantly associated with 30-day MACE (odds ratio [OR] 1.16 for each 0.1 increase in monocyte, p=0.025). This association remained present on multivariable analysis adjusted for age, sex, Society of Thoracic Surgeons risk score, and self-expanding valve prosthesis type (OR 1.17, p=0.028). CONCLUSIONS: The association between postprocedure monocytosis and 30-day MACE suggests that minimising peri-procedural inflammatory insults may improve outcomes. This inexpensive and readily available biomarker may also aid in tailored risk stratification for patients.

Incidence, Predictors, and Outcomes of Nonhome Discharge Following Transcatheter Aortic Valve Implantation: A Multicenter Australian Experience-The NHD TAVI Study.

Patients who undergo transcatheter aortic valve implantation (TAVI) commonly experience nonhome discharge (NHD), a phenomenon associated with increased health care expenditure and possibly poorer outcomes. Despite its clinical relevance in TAVI, the incidence and predictors of NHD and its impact on the quality of life remain poorly characterized. Also unknown is the proportion of patients who undergo TAVI that require long-term residential care after initial NHD. Therefore, we aimed to address these questions using a large, multicenter Australian cohort. A total of 2,229 patients who underwent TAVI from 2010 to 2023 included in the Alfred-Cabrini-Epworth TAVI Registry were analyzed. The median age was 82 (interquartile range 78 to 86) years and 41% were women. A total of 257 patients (12%) were not discharged home after TAVI, with the incidence falling over time (R2 = 0.636, p <0.001). A multivariable logistic regression model for NHD prediction was developed with excellent calibration and discrimination (C-statistic = 0.835). The independent predictors of NHD were postprocedural stroke (adjusted odds ratio [aOR] 11.05), procedure at a private hospital (aOR 3.01), living alone (aOR 2.35), vascular access site complications (aOR 2.09), frailty (aOR 1.89), age >80 years (aOR 1.82), hypoalbuminemia (aOR 1.76), New York Heart Association III to IV (aOR 1.74), and hospital length of stay (aOR 1.13) (all p <0.05). NHD was not associated with mortality at 30 days and <1% of all patients required longer-term residential care. In conclusion, although common after TAVI, NHD does not predict short-term mortality, most patients successfully return home within 30 days, and when used appropriately, NHD may serve as a brief and effective method of optimizing functional status without compromising long-term independence.

Acute Kidney Injury Following Transcatheter Aortic Valve Implantation-A Contemporary Perspective of Incidence, Predictors, and Outcomes.

BACKGROUND: Acute kidney injury (AKI) is a known complication following transcatheter aortic valve implantation (TAVI), associated with increased morbidity and mortality. Most of this data relates to higher-risk patients with early-generation TAVI valves. With TAVI now established as a safe and cost-effective procedure for low-risk patients, there is a distinct need for updated analysis. We aimed to assess the incidence, predictors, and outcomes of AKI in a contemporary cohort of TAVI patients, concurrently examining the role of temporal evolution on AKI. METHOD: A total of 2,564 patients undergoing TAVI from 2008-2023 included in the Alfred-Cabrini-Epworth (ACE) TAVI Registry were analysed. Patients were divided into AKI and no AKI groups. Outcomes were reported according to the Valve Academic Research Consortium-3 (VARC-3) criteria. RESULTS: Of 2,564 patients, median age 83 (78-87) years, 57.4% men and a median Society of Thoracic Surgeons score of 3.6 (2.4-5.5), 163 (6.4%) patients developed AKI with incidence falling from 9.7% between 2008-2014 to 6% between 2015-2023 (p=0.022). On multivariable analysis, independent predictors of AKI were male sex (adjusted odds ratio [aOR] 1.89, p=0.005), congestive cardiac failure (aOR 1.52, p=0.048), estimated glomerular filtration rate 30-59 (aOR: 2.79, p<0.001), estimated glomerular filtration rate <30 (aOR 8.65, p<0.001), non-femoral access (aOR 5.35, p<0.001), contrast volume (aOR 1.01, p<0.001), self-expanding valve (aOR 1.60, p=0.045), and bleeding (aOR 2.88, p=0.005). Acute kidney injury was an independent predictor of 30-day (aOR: 6.07, p<0.001) and 12-month (aOR: 3.01, p=0.002) mortality, an association that remained consistent when excluding TAVIs performed prior to 2015. CONCLUSIONS: Acute kidney injury remains a relatively common complication of TAVI, associated with significant morbidity and mortality even in less comorbid, contemporary practice patients.

Stroke reduction by cerebral embolic protection devices in transcatheter aortic valve implantation: a systematic review and Bayesian meta-analysis.

OBJECTIVES: The use of cerebral embolic protection (CEP) during transcatheter aortic valve implantation (TAVI) has been studied in several randomised trials. We aimed to perform a systematic review and Bayesian meta-analysis of randomised CEP trials, focusing on a clinically relevant reduction in disabling stroke. METHODS: A systematic search was applied to three electronic databases, including trials that randomised TAVI patients to CEP versus standard treatment. The primary outcome was the risk of disabling stroke. Outcomes were presented as relative risk (RR), absolute risk differences (ARDs), numbers needed to treat (NNTs) and the 95% credible intervals (CrIs). The minimal clinically important difference was determined at 1.1% ARD, per expert consensus (NNT 91). The principal Bayesian meta-analysis was performed under a vague prior, and secondary analyses were performed under two informed literature-based priors. RESULTS: Seven randomised studies were included for meta-analysis (n=3996: CEP n=2126, control n=1870). Under a vague prior, the estimated median RR of CEP use for disabling stroke was 0.56 (95% CrI 0.28 to 1.19, derived ARD 0.56% and NNT 179, I2=0%). Although the estimated posterior probability of any benefit was 94.4%, the probability of a clinically relevant effect was 0-0.1% under the vague and informed literature-based priors. Results were robust across multiple sensitivity analyses. CONCLUSION: There is a high probability of a beneficial CEP treatment effect, but this is unlikely to be clinically relevant. These findings suggest that future trials should focus on identifying TAVI patients with an increased baseline risk of stroke, and on the development of new generation devices. PROSPERO REGISTRATION NUMBER: CRD42023407006.

Coronary Artery Disease Risk Prediction in Patients With Severe Aortic Stenosis: Development and Validation of the Aortic Stenosis-Coronary Artery Disease (AS-CAD) Score.

Patients at a low risk of coronary artery disease (CAD) could be triaged to noninvasive coronary computed tomography angiogram instead of invasive coronary angiography, reducing health care costs and patient morbidity. Therefore, we aimed to develop a CAD risk prediction score to identify those who underwent transcatheter aortic valve implantation (TAVI) at a low risk of CAD. We enrolled 1,782 patients who underwent TAVI and randomized the patients to the derivation or validation cohort 2:1. The aortic stenosis-CAD (AS-CAD) score was developed using logistic regression, followed by separation into low- (score 0 to 5), intermediate- (6 to 10), or high-risk (>11) categories. The AS-CAD was validated initially through the k-fold cross-validation, followed by a separately held validation cohort. The average age of the cohort was 82 ± 7 years, and 41% (730 of 1,782) were female; 35% (630) had CAD. The male sex, previous percutaneous coronary intervention, stroke, peripheral arterial disease, diabetes, smoking status, left ventricular ejection fraction <50%, and right ventricular systolic pressure >35 mm Hg were all associated with an increased risk of CAD and were included in the final AS-CAD model (all p <0.03). Within the validation cohort, the AS-CAD score stratified those into low, intermediate, and high risk of CAD (p <0.001). Discrimination was good within the internal validation cohort, with a c-statistic of 0.79 (95% confidence interval 0.74 to 0.84), with similar power obtained using k-fold cross-validation (c-statistic 0.74 [95% confidence interval 0.70 to 0.77]). In conclusion, The AS-CAD score robustly identified those at a low risk of CAD in patients with severe AS. The use of AS-CAD in practice could avoid potential complications of invasive coronary angiogram by triaging low-risk patients to noninvasive coronary assessment using existing computed tomography data.

Thirty-day and one-year outcomes of the Navitor transcatheter heart valve in patients with aortic stenosis: the prospective, multicentre, global PORTICO NG Study.

BACKGROUND: The Navitor transcatheter heart valve (THV) is a self-expanding valve, with an intra-annular leaflet position and an outer cuff intended to reduce paravalvular leak (PVL). AIMS: The aim of the PORTICO NG Study is to assess the safety and performance of the Navitor THV in patients with symptomatic, severe aortic stenosis who are at high or extreme surgical risk. METHODS: PORTICO NG is a prospective, multicentre, global, single-arm, investigational study with follow-up at 30 days, 1 year, and annually up to 5 years. The primary endpoints are all-cause mortality and moderate or greater PVL at 30 days. Valve Academic Research Consortium-2 events and valve performance are assessed by an independent clinical events committee and echocardiographic core laboratory. RESULTS: A total of 120 high- or extreme-risk subjects (age 83.5±5.4 years; 58.3% female; Society of Thoracic Surgeons score 4.0±2.0%) were enrolled in the European conformity (CE) mark cohort. Procedural success was high at 97.5%. At 30 days, the rate of all-cause mortality was 0%, and no subjects had moderate or greater PVL. The rate of disabling stroke was 0.8%, life-threatening bleeding was 2.5%, stage 3 acute kidney injury 0%, major vascular complications 0.8%, and new pacemaker implantation 15.0%. At 1 year, the rates of all-cause mortality and disabling stroke were 4.2% and 0.8%, respectively. The rate of moderate PVL was 1.0% at 1 year. Haemodynamic performance with a mean gradient of 7.5±3.2 mmHg and effective orifice area of 1.9±0.4 cm2 was sustained up to 1 year. CONCLUSIONS: The PORTICO NG Study demonstrates low rates of adverse events and PVL up to 1 year in patients at high or extreme surgical risk, confirming the safety and efficacy of the Navitor THV system.

30-Day Clinical Outcomes of a Self-Expanding Transcatheter Aortic Valve: The International PORTICO NG Study.

BACKGROUND: The self-expanding, intra-annular Navitor (Abbott Structural Heart) valve includes an outer cuff to reduce paravalvular leak (PVL) and large stent cells for future coronary access. OBJECTIVES: The purpose of the PORTICO NG (Evaluation of the Portico NG [Next Generation] Transcatheter Aortic Valve in High and Extreme Risk Patients With Symptomatic Severe Aortic Stenosis) study is to evaluate the safety and effectiveness of the Navitor valve in patients with symptomatic, severe aortic stenosis who are at high or extreme surgical risk. METHODS: PORTICO NG is a prospective, multicenter, global study with follow-up at 30 days, 1 year, and annually through 5 years. The primary endpoints are all-cause mortality and moderate or greater PVL at 30 days. Valve Academic Research Consortium-2 events and valve performance are assessed by an independent clinical events committee and echocardiographic core laboratory. RESULTS: A total of 260 subjects were treated at 26 clinical sites across Europe, Australia, and the United States between September 2019 and August 2022. The mean age was 83.4 ± 5.4 years, 57.3% were female, and the average Society of Thoracic Surgeons score was 3.9% ± 2.1%. At 30 days, the rate of all-cause mortality was 1.9%, and no subjects had moderate or greater PVL. The rate of disabling stroke was 1.9%, life-threatening bleeding was 3.8%, stage 3 acute kidney injury was 0.8%, major vascular complications were 4.2%, and new permanent pacemaker implantation was 19.0%. Hemodynamic performance included a mean gradient of 7.4 ± 3.5 mm Hg and an effective orifice area of 2.00 ± 0.47 cm2. CONCLUSIONS: The Navitor valve is safe and effective for the treatment of subjects with severe aortic stenosis who are at high or greater risk for surgery, which is supported by low rates of adverse events and PVL. (Evaluation of the Portico NG [Next Generation] Transcatheter Aortic Valve in High and Extreme Risk Patients With Symptomatic Severe Aortic Stenosis [PORTICO NG]; NCT04011722).

Long-Term Valve Durability in Patients Undergoing Transcatheter Aortic Valve Implantation.

AIMS: To evaluate the long-term incidence of structural valve deterioration (SVD) in patients who underwent transcatheter aortic valve implantation (TAVI). METHOD AND RESULTS: Between 2008 and 2018, 693 underwent TAVI at two centres. Four hundred and twenty-one (421) patients (mean age 83.6±6.0 yrs) survived for ≥2 years post TAVI and had at least two consecutive transthoracic echocardiographies (TTEs) with the latest TTE no less than 2 years after TAVI, and were therefore included in the analysis for SVD. Median follow-up was 4.7 (3.6-6.0) years and median echocardiography follow-up 3 (3.0-4.0) years. All-cause mortality was 30.9% (130) with a median time to death of 4.1 (3.0-5.6) years. The cumulative incidence of SVD increased from 1.7% (95% CI, 0.4-2.9) at 3 years to 3.5% (95% CI, 1.5-5.8) at 5 years and 4.7% (95% CI, 1.6-7.9) at 10 years. The overall median time to SVD was 3 (2-4) years. Twelve (12) patients demonstrated SVD stage 2, and 1 patient stage 3. No SVD required re-intervention. All other patients showed no significant changes in valve parameters over time. CONCLUSIONS: Structural valve deterioration is an uncommon event, occurring in 5% over a total follow-up of 10 years. Most patients show stable valve parameters. However, the analysis is limited by the loss of follow-up (owing to patient mortality), which renders extrapolation of the data to a younger patient population difficult.

Mitral Valve Regurgitation After Lung Transplantation: Aetiology, Management and Outcome.

BACKGROUND: Problematic mitral regurgitation (MR) may develop following lung transplantation (LTx). There is limited information on the management of MR in LTx patients, as such we sought to evaluate our centre's experience. METHODS: From 2000 to 2019, 1,054 patients underwent LTx at our centre (896 bilateral, 158 single). We identified patients in whom significant MR developed at any point post-LTx. The aetiology of MR, management and outcome were retrospectively analysed. RESULTS: Eight (8) patients developed severe MR post-LTx, six following bilateral LTx and two following single LTx. Lung transplantation indications included interstitial lung disease (n=5), chronic obstructive pulmonary disease (n=2) and pulmonary arterial hypertension (n=1). Severe MR occurred intraoperatively (n=1), postoperative day 1 (n=1) with the remaining six cases between 80 and 263 days post-LTx. The aetiology was noted to be due to severe left ventricular dysfunction following unmasking of a chronically pulmonary hypertension-related under-preloaded left ventricle in one case, and in the remaining seven patients causes included myxomatous degeneration, ischaemic MR, and functional MR due to annular dilatation. In the patient with intraoperative severe MR, the MR became mild with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and in the remaining seven patients a variety of procedures were used, including mitral valve repair, valve replacement and transcatheter edge-to-edge mitral valve repair. All patients survived the mitral procedure. Two (2) deaths occurred at 12.9 years (stroke) and 5 years (cancer) from mitral valve surgery. CONCLUSIONS: Development of significant mitral valve regurgitation is a rare but morbid complication after lung transplantation. This may represent the progressive natural history of pre-existing degenerative mitral valve disease and rarely, early after transplantation may be related to changes in ventricular geometry. Management of severe MR can follow the same management approach as in the non-transplant community, with the expectation of similarly good results.

Relation of Preprocedure Platelet-to-Lymphocyte Ratio and Major Adverse Cardiovascular Events Following Transcatheter Aortic Valve Implantation for Aortic Stenosis.

The platelet-to-lymphocyte ratio (PLR) is a novel inflammatory biomarker that has prognostic value in patients presenting with acute coronary syndrome. Transcatheter aortic valve implantation (TAVI) treats the inflammatory disease of aortic stenosis. However, the utility of preprocedure PLR in predicting major adverse cardiovascular events (MACE) after TAVI is not clear. Our study population included 470 patients who underwent TAVI at The Alfred Hospital in Melbourne, Australia from August 2008, to January 2019. Patients were divided into 4 groups based on PLR quartiles. The incidence of 30-day MACE (a composite of stroke, myocardial infarction, and death) was then compared. Outcomes were reported according to the Valve Academic Research Consortium-2 criteria. Of 470 patients, median age 84 years, 54% men, and median Society of Thoracic Surgeons score of 3.5%, 14 (3%) suffered a MACE within 30 days. Rates of MACE were low in all 4 groups (1.7%, 2.5%, 2.6%, 5.1%, respectively) with no statistically significant difference in the different PLR groups (p = 0.46). This nonsignificant association was supported by univariate logistic regression analysis of PLR as a continuous variable (odds ratio 1.01, p = 0.55). Using multivariable logistic regression analysis accounting for age, gender, self-expanding valve, and procedural risk, a higher PLR did not correlate with MACE (odds ratio 1.01, p = 0.60). In this study of a large cohort of TAVI patients, elevated preprocedure PLR was not independently associated with MACE after TAVI. This is a novel finding in comparison with previous studies.

Short- and Long-Term Outcomes After Transcatheter Aortic Valve Implantation in Public and Private Hospital Settings: A Propensity-Matched Analysis.

OBJECTIVES: To compare short- and long-term outcomes after transcatheter aortic valve implantation (TAVI) in the public and private hospital setting. DESIGN: Propensity-matched, retrospective analysis of a prospective registry. SETTING AND PARTICIPANTS: Patients with severe aortic stenosis who underwent TAVI at a tertiary public hospital (n=507) and an experienced private hospital (n=436). MAIN OUTCOME MEASURES: The primary endpoint was all-cause mortality. RESULTS: Patients that underwent TAVI in the public hospital were younger than patients in the private hospital (82±8 years vs 84±6 years, p<0.001), with lower estimated short-term mortality risk (Society of Thoracic Surgeons Predicted Risk of Mortality [STS-PROM] score >4.0%: 43% vs 56%, p<0.001). There was no difference between public and private hospitals in 30-day mortality (1.5% vs 1.2%, p=1.0), and the rate of complications was similar. Long-term survival was similar in propensity-matched public (n=344) and private (n=344) patient cohorts. The 1-year, 2-year, 5-year and 7-year survival rates were 95%, 90%, 67% and 47% in public patients, and 92%, 86%, 67% and 51% in private patients (p=0.94). In multivariable analysis, the hospital setting was not a predictor of mortality. CONCLUSION: Despite increased age and predicted mortality in private hospital patients, short- and long-term outcomes after TAVI were comparable between public and private hospital settings. This study demonstrates the feasibility of performing TAVI in a private hospital with a dedicated and experienced team and questions the current restricted access to TAVI in the private sector.

Transcatheter Versus Surgical Aortic Valve Replacement: An Updated Systematic Review and Meta-Analysis With a Focus on Outcomes by Sex.

BACKGROUND AND AIMS: Women at increased surgical risk have been shown to have better outcomes with transcatheter aortic valve implantation (TAVI) as compared to surgical valve replacement (SAVR). With the scope of TAVI moving into low-surgical risk patients, we aimed to update the current literature to include the new low-risk randomised controlled trial (RCT) data in investigating outcomes by sex. METHODS: We systematically searched MEDLINE (Ovid), PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov and reference lists for relevant RCTs comparing TAVI to SAVR published prior to 4 May 2020. Data extraction was performed by two independent authors and included trial design details, baseline characteristics and outcome data stratified by sex. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. Quantitative synthesis of pooled data was performed using Mantel-Haenszel fixed or random effects model. Q-statistic and the I2 test were used for assessment of heterogeneity. RESULTS: Our search yielded eight RCTs included in the final quantitative synthesis. The overall pooled cohort was 8,040, of whom 41.4% were female. Women had significantly lower rates of one-year all-cause mortality (12.2% vs 17.7%, pooled OR 0.59, 95% CI 0.40-0.86) and one-year composite endpoint (9.7% vs 12.4%, pooled OR 0.73, 95% CI 0.58-0.92) with TAVI as compared to SAVR. The selective mortality benefit with TAVI over SAVR in women did not persist to 5 years (pooled HR 1.01, 95% CI 0.87-1.17). At 30 days, women demonstrated lower rates of major bleeding and acute kidney injury following TAVI compared to SAVR. For men, these outcomes were similar regardless of type of intervention. Both sexes were at increased risk of major vascular complications with TAVI as compared to SAVR, however women demonstrated nearly double the odds of major vascular complication with TAVI compared to men. CONCLUSION: Our updated meta-analysis demonstrates that at one-year women undergoing TAVI have significantly lower mortality and better safety outcomes compared to those undergoing SAVR. These benefits are not seen in men. In the new low-risk era, these results are ever more important for guiding appropriate patient selection.

Long-Term Outcomes Stratified by Body Mass Index in Patients Undergoing Transcatheter Aortic Valve Implantation.

Transcatheter aortic valve implantation (TAVI) is emerging as the default strategy for older patients with severe, symptomatic, and trileaflet aortic stenosis. Increased body-mass index (BMI) is associated with a protective effect in patients undergoing percutaneous coronary intervention. We assessed whether elevated BMI was associated with a similar association in TAVI. We evaluated prospectively collected data from 634 patients who underwent TAVI at 2 centers from August 2008 to April 2019. Patients were stratified as normal weight (BMI 18.5 to 24.9 kg/m2, n = 214), overweight (25 to 29.9 kg/m2, n = 234), and obese (>30 kg/m2, n = 185). Outcomes were reported according to VARC-2 criteria. Mortality was assessed using Cox proportional hazards regression analysis (median follow-up 2 years). Kaplan-Meier analysis was used to estimate cumulative mortality. Baseline differences were seen in age (85 vs 84 vs 82, p <0.001), STS-PROM score (4.3 vs 3.4 vs 3.6, p <0.001), sex (50% vs 36% vs 55% female, p <0.001), clinical frailty score (p = 0.02), diabetes (21% vs 29% vs 40%, p <0.001), and presence of chronic obstructive pulmonary disease (COPD) (13% vs 13% vs 23%, p = 0.009). On multivariable analysis there was no mortality difference between normal and obese patients (hazard ratio [HR] 0.70, confidence interval [CI] 0.46 to 1.1 p = 0.11), however overweight patients had significantly lower mortality (HR 0.56 CI 0.38 to 0.85, p = 0.006). Variables independently associated with increased mortality were increasing age, male sex, COPD, previous balloon valvuloplasty, and higher STS-PROM. In conclusion, overweight patients have lower long-term mortality when compared with normal weight and obese patients undergoing TAVI.

Comparison of Early Outcomes in Patients at Estimated Low, Intermediate and High Risk Undergoing Transcatheter Aortic Valve Implantation: A Multicentre Australian Experience.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has been shown to be a safe and effective alternative to surgical aortic valve replacement (SAVR) in high- and intermediate-risk patients with severe aortic stenosis. TAVI for patients at lower risk of periprocedural mortality has not been extensively investigated. We aimed to describe outcomes in low-, intermediate- and high-risk patients undergoing TAVI in a multicentre Australian study. METHODS: We evaluated data from 601 patients who underwent TAVI at two hospitals in Melbourne, from August 2008 to February 2018. Patients were stratified according to low risk (STS <4%), intermediate risk (Society for Thoracic Surgeons [STS] 4.0-7.9%) and high risk (STS >8%). Outcomes were reported according to Valve Academic Research Consortium-2 (VARC-2) criteria. RESULTS: Mean age was 84±5 years and 49% were female. Two hundred and eighty-five (285) (47%) patients were low-risk, 243 (40%) were intermediate risk and 73 (12%) were high risk. Thirty-day (30-) mortality was low in all three groups (1.1%, 1.7% and 1.4%, respectively, p=0.8). Similarly, patients had a low risk of disabling stroke (0.4%, 1.3%, 0%, p=0.8). Rates of post-procedural permanent pacemaker were also similar (21%, 27%, 26%, p=0.5). At least moderate aortic regurgitation occurred in 9% of patients at discharge with no significant differences between groups. CONCLUSIONS: In this large Australian multicentre cohort of TAVI patients, 30-day mortality, and post-procedural outcomes were excellent and similar across the patient-risk spectrum. Our study offers further support for the safety of TAVI in low-risk populations and demonstrates the limitations of the STS score.

A polymorphism in the noradrenaline transporter gene is associated with increased blood pressure in patients with resistant hypertension.

OBJECTIVES: Noradrenaline released from sympathetic nerves is rapidly inactivated via the action of the noradrenaline transporter (NET). We aimed to determine whether a single nucleotide polymorphism (SNP) in the NET gene, rs7194256, was associated with blood pressure and plasma noradrenaline concentration in patients with resistant hypertension. METHODS: Ninety-two consecutive patients with resistant hypertension participated in this study (age 62 ±â€Š1.3 years, BMI 32 ±â€Š0.6 kg/m, mean ±â€ŠSEM). Blood pressure was assessed using 24-h ambulatory blood pressure monitoring. Genotyping of rs7194256 (C/T) was performed using a predeveloped TaqMan SNP Genotyping Assay. Plasma catecholamines were analyzed using high-performance liquid chromatography. RESULTS: There were no differences in anthropometric measures between those carrying a T allele or the CC genotype. Patients carrying a T allele had significantly higher SBP: 24-h mean 148 ±â€Š2.6 vs. 140 ±â€Š2.4; 24-h max 189 ±â€Š3.2 vs. 179 ±â€Š2.6; 24-h min 114 ±â€Š3.0 vs. 105 ±â€Š2.3; night mean 141 ±â€Š3.0 vs. 131 ±â€Š2.5; night max 170 ±â€Š3.6 vs. 159 ±â€Š3.1; night min 118 ±â€Š3.4 vs. 109 ±â€Š2.4 (all P < 0.05). T-allele carriers had a significantly higher arterial noradrenaline concentration: 573 ±â€Š53 vs. 377 ±â€Š35 pg/ml (P = 0.002) and lower ratio of the intraneuronal noradrenaline metabolite, 3,4-dihydroxyphenylglycol, to noradrenaline (3.01 ±â€Š0.4 vs. 4.08 ±â€Š0.3 pg/ml; P = 0.024). CONCLUSION: A SNP in the NET gene in patients with resistant hypertension is associated with higher plasma noradrenaline concentration and elevated SBP. Impaired NET function may be a contributor to the pronounced activation of the sympathetic nervous system characteristic of patients with resistant hypertension.

Ambulatory arterial stiffness index as a predictor of blood pressure response to renal denervation.

BACKGROUND: Renal denervation (RDN) can reduce blood pressure (BP) in patients with resistant hypertension, but less so in patients with isolated systolic hypertension. A possible explanation is that patients with stiffer arteries may have lesser neural contribution to their hypertension. METHOD: We hypothesized that arterial stiffness predicts the response to RDN. From ambulatory BP monitoring (ABPM), ambulatory arterial stiffness index (AASI) was calculated as 1 - the regression slope of DBP versus SBP. RESULTS: In 111 patients with resistant hypertension, RDN reduced office and 24-h SBP after 3, 6, and 12 months (by -11 ±â€Š22, -11 ±â€Š25, -14 ±â€Š21 mmHg for office, and -4 ±â€Š11, -5 ±â€Š12, -5 ±â€Š15 mmHg for 24-h SBP, respectively, P < 0.01). Patients with baseline AASI above the median (>0.51) showed no change in 24-h SBP at 6 months after RDN (-0.4 ±â€Š12.3 mmHg, P > 0.05), whereas an AASI below 0.51was associated with a marked reduction (-9.3 ±â€Š11.0 mmHg, P < 0.01). Across AASI quartiles, patients in the highest quartile (AASI ≥ 0.60) had lower muscle sympathetic nerve activity than the other three quartiles (39 ±â€Š13 versus 49 ±â€Š13 bursts/min, P = 0.035). The responder rate, defined as a 24-h SBP reduction of at least 5% was 58% in the lowest AASI quartile (<0.45) and 16% in the highest quartile (≥0.60). After adjustment for age, sex, BMI, office and 24-h SBP, an AASI less than 0.51predicted those who respond to RDN (odds ratio 3.46, P = 0.04). CONCLUSION: We conclude that in patients with resistant hypertension, a lower AASI is an independent predictor of the BP response to RDN, possibly explained by a more pronounced neurogenic rather than biomechanical contribution to their BP elevation.

The Effect of Renal Denervation on Plasma Adipokine Profile in Patients with Treatment Resistant Hypertension.

Background: We previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. A number of adipocyte-derived factors are implicated in BP control in obesity. Aim: The aim of this study was to examine whether RDN may have salutary effects on the adipokine profile in patients with resistant hypertension (RH). Methods: Fifty seven patients with RH undergoing RDN program have been included in this study (65% males, age 60.8 ± 1.5 years, BMI 32.6 ± 0.7 kg/m2, mean ± SEM). Throughout the study, the patients were on an average of 4.5 ± 2.7 antihypertensive drugs. Automated seated office BP measurements and plasma concentrations of leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were assessed at baseline and the 3 months after RDN. Results: There was a significant reduction in mean office systolic (168.75 ± 2.57 vs. 155.23 ± 3.17 mmHg, p < 0.001) and diastolic (90.68 ± 2.31 vs. 83.74 ± 2.36 mmHg, p < 0.001) BP 3 months after RDN. Body weight, plasma leptin and resistin levels and heart rate remained unchanged. Fasting insulin concentration significantly increased 3 months after the procedure (20.05 ± 1.46 vs. 29.70 ± 2.51 uU/ml, p = 0.002). There was a significant drop in circulating NEFA at follow up (1.01 ± 0.07 vs. 0.47 ± 0.04 mEq/l, p < 0.001). Adiponectin concentration was significantly higher after RDN (5,654 ± 800 vs. 6,644 ± 967 ng/ml, p = 0.024). Conclusions: This is the first study to demonstrate that RDN is associated with potentially beneficial effects on aspects of the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via an effect on metabolic pathways. Clinical Trial Registration Number: NCT00483808, NCT00888433.

Effect of renal denervation on kidney function in patients with chronic kidney disease.

AIMS: Renal denervation (RDN) can reduce blood pressure (BP) and slow the decline of renal function in chronic kidney disease (CKD) up to one year. Whether this effect is maintained beyond 12months and whether the magnitude of BP reduction affects estimated glomerular filtration rate (eGFR) is unknown. METHODS AND RESULTS: We examined eGFR in 46 CKD patients (baseline eGFR ≤60mL/min/1.73m2) on a yearly basis from 60months before to 3, 6, 12 and 24months after RDN. Ambulatory BP was measured before and after RDN. Linear mixed models analysis demonstrated a significant progressive decline in eGFR from months 60 to 12months (-15.47±1.98mL/min/1.73m2, P<0.0001) and from 12months to baseline prior to RDN (-3.41±1.64mL/min/1.73m2, P=0.038). Compared to baseline, RDN was associated with improved eGFR at 3months (+3.73±1.64mL/min/1.73m2, P=0.02) and no significant changes at 6 (+2.54±1.66mL/min/1.73m2, P=0.13), 12 (+1.78±1.64mL/min/1.73m2, P=0.28), and 24 (-0.24±2.24mL/min/1.73m2, P=0.91) months post procedure were observed. RDN significantly reduced daytime SBP from baseline to 24months post procedure (148±19 vs 136±17mmHg, P=0.03) for the entire cohort. Changes in SBP were unrelated to the eGFR changes at 6 (r=0.033, P=0.84), 12 (r=0.01, P=0.93) and 24months (r=-0.42, P=0.17) follow-up. CONCLUSION: RDN can slow further deterioration of renal function irrespective of BP lowering effects in CKD. RDN-induced inhibition of sympathetic outflow to the renal vascular bed may account for improved eGFR via alterations of intrarenal and glomerular hemodynamics.