Transcatheter Intervention for Inoperable Tricuspid Surgical Prosthesis Dysfunction: Minimally Invasive Approach to Mitigate Heart Failure.

What is the efficacy and safety of transcatheter tricuspid valve-in-valve implantation for patients with inoperable tricuspid surgical prosthesis dysfunction? Thirty-day mortality after greatly effective transcatheter treatment is 2 times less than the estimated surgical risk.

Diet and Lifestyle Intervention-Induced Pattern of Weight Loss Related to Reduction in Low-Attenuation Coronary Plaque Burden.

BACKGROUND: Despite extensive research on body weight and cardiovascular risk, the mechanistic relationship between weight loss and coronary plaque modification has not been adequately addressed. This study aimed to determine the association between body composition dynamics and low-attenuation coronary plaque (LAP) burden. METHODS: Eighty-nine participants (40% women, 60 ± 7.7 years) of the Dietary Intervention to Stop Coronary Atherosclerosis in Computed Tomography (DISCO-CT) study with non-obstructive atherosclerosis with nonobstructive atherosclerosis confirmed in computed tomography angiography (CCTA), a randomized (1:1), prospective, single-center study were included into the analysis. Patients were randomly assigned to either experimental arm (intensive diet and lifestyle intervention atop optimal medical therapy, n = 45) or control arm (optimal medical therapy alone, n = 44) over 66.8 ± 13.7 weeks. Changes (∆) in body mass (BM) and body composition parameters, including total body fat (TBF), skeletal muscle mass (SMM), and fat-to-muscle ratio (FMR), measured with bioimpedance analyzer were compared with CCTA-measured ∆LAP. Coronary plaque analysis was performed using the 2 × 192 dual-energy scanner (Somatom Force, Siemens, Germany), while quantitative coronary plaque measurements were performed using a semi-automated plaque analysis software system (QAngioCT v3.1.3.13, Medis Medical Imaging Systems, Leiden, The Netherlands). RESULTS: Significant intergroup differences were found for ∆BM (-3.6 ± 4.9 kg in the experimental vs. -1.4 ± 2.9 kg in the control group, p = 0.015), ∆TBF (-3.4 ± 4.8% in the experimental vs. 1.1 ± 5.5% in the control arm, p < 0.001), ∆SMM (1.9 ± 2.8% in the experimental vs. -0.7 ± 3.2% in the control arm, p < 0.001), and FMR [-12.9 (-21.2; -4.3)% in the experimental vs. 3.1 (-5.3; 10.7)% in the control arm, p < 0.001]. ∆LAP did not differ significantly between the study arms; however, in the whole study population, ∆LAP was positively correlated with ∆BM, ∆TBF, and ∆FMR (r = 0.45, p < 0.001; r = 0.300, p = 0.004; r = 0.233, p = 0.028, respectively), and negatively with ∆SMM (r = -0.285, p = 0.007). Multivariate linear regression analysis revealed the association of ∆LAP with ∆BM, ∆TBF, and ∆FMR. CONCLUSIONS: The study intervention resulted in BM reduction characterized by fat loss, skeletal muscle gain, and increased FMR. This weight loss pattern may lead to a reduction in high-risk coronary plaque. Compared to a simple weight control, tracking body composition changes over time can provide valuable information on adverse coronary plaque modification.

Strategy to optimize PeriproCeduraL AnticOagulation in structural transseptal interventions: Design and rationale of the STOP CLOT trial.

BACKGROUND: Both transcatheter edge-to-edge repair (TEER) of mitral regurgitation or left atrial appendage closure (LAAC) require periprocedural anticoagulation with unfractionated heparin (UFH) that is administered either before or immediately after transseptal puncture (TSP). The optimal timing of UFH administration (before or after TSP) is unknown. The Strategy To Optimize PeriproCeduraL AnticOagulation in Structural Transseptal Interventions trial (STOP CLOT Trial) was designed to determine if early anticoagulation is effective in reducing ischemic complications without increasing the risk of periprocedural bleeding. METHODS: The STOP CLOT trial is a multicenter, prospective, double-blind, placebo-controlled, randomized trial. A total of 410 patients scheduled for TEER or LAAC will be randomized 1:1 either early UFH administration (iv. bolus of 100 units/kg UFH or placebo, given after obtaining femoral vein access and at least 5 minutes prior to the start of the TSP) or late UFH administration (iv. bolus of 100 units/kg UFH or placebo given immediately after TSP). Prespecified preliminary statistical analysis will be performed after complete follow-up of the first 196 randomized subjects. To ensure blinding, a study nurse responsible for randomization and UFH/placebo preparation is not involved in the care of the patients enrolled into the study. The primary study endpoint is a composite of (1) major adverse cardiac and cerebrovascular events (death, stroke, TIA, myocardial infarction, or peripheral embolization) within 30 days post-procedure, (2) intraprocedural fresh thrombus formation in the right or left atrium as assessed with periprocedural transesophageal echocardiography, or (3) occurrence of new ischemic lesions (diameter ≥4 mm) on brain magnetic resonance imaging performed 2 to 5 days after the procedure. The safety endpoint is the occurrence of moderate or severe bleeding complications during the index hospitalization. CONCLUSIONS: Protocols of periprocedural anticoagulation administration during structural interventions have never been tested in a randomized clinical trial. The Stop Clot trial may help reach consensus on the optimal timing of initiation of periprocedural anticoagulation. CLINICAL TRIALS REGISTRATION NUMBER: The study protocol is registered at ClinicalTrials.gov, identifier NCT05305612.

Biomarkers in Peripartum Cardiomyopathy-What We Know and What Is Still to Be Found.

Peripartum cardiomyopathy (PPCM) is a form of heart failure, often severe, that occurs in previously healthy women at the end of their pregnancy or in the first few months after delivery. In PPCM, the recovery of heart function reaches 45-50%. However, the all-cause mortality in long-term observation remains high, reaching 20% irrespective of recovery status. The incidence of PPCM is increasing globally; therefore, effort is required to clarify the pathophysiological background of the disease, as well as to discover specific diagnostic and prognostic biomarkers. The etiology of the disease remains unclear, including oxidative stress; inflammation; hormonal disturbances; endothelial, microcirculatory, cardiomyocyte and extracellular matrix dysfunction; fibrosis; and genetic mutations. Currently, antiangiogenic 16-kDa prolactin (PRL), cleaved from standard 23-kDa PRL in the case of unbalanced oxidative stress, is recognized as the main trigger of the disease. In addition, 16-kDa PRL causes damage to cardiomyocytes, acting via microRNA-146a secreted from endothelial cells as a cause of the NF-κß pathway. Bromocriptine, which inhibits the secretion of PRL from the pituitary gland, is now the only specific treatment for PPCM. Many different phenotypes of the disease, as well as cases of non-responders to bromocriptine treatment, indicate other pathophysiological pathways that need further investigation. Biomarkers in PPCM are not well established. There is a deficiency in specific diagnostic biomarkers. Pro-brain-type natriuretic peptide (BNP) and N-terminal BNP are the best, however unspecific, diagnostic biomarkers of heart failure at the moment. Therefore, more efforts should be engaged in investigating more specific biomolecules of a diagnostic and prognostic manner such as 16-kDa PRL, galectin-3, myeloperoxidase, or soluble Fms-like tyrosine kinase-1/placental growth factor ratio. In this review, we present the current state of knowledge and future directions of exploring PPCM pathophysiology, including microRNA and heat shock proteins, which may improve diagnosis, treatment monitoring, and the development of specific treatment strategies, and consequently improve patients' prognosis and outcome.

Safety and efficacy of the Amplatzer™ Trevisio™ intravascular delivery system: Post-approval study results.

BACKGROUND: The Amplatzer™ Trevisio™ Intravascular Delivery System (Trevisio DS; Abbott Laboratories, Chicago, IL, USA) facilitates the delivery of Amplatzer™ Occluders and features an ultraflexible tip, which improves assessment of occluder position before release. AIMS: To assess the safety and efficacy of the Trevisio DS for transcatheter closure of patent foramen ovale and atrial septal defect. METHODS: The Amplatzer™ Trevisio™ Intravascular Delivery System Post-Approval Study was a prospective, postmarket, single-arm, multicentre, observational study of the Trevisio DS. Enrolled patients were indicated for transcatheter closure of patent foramen ovale or atrial septal defect. In all procedures, the Trevisio DS was used to deliver Amplatzer™ Occluders. Technical success was defined as successful deployment and release of at least one occluder. Device- or procedure-related serious adverse events were tracked until discharge or day 7, whichever occurred earlier. RESULTS: The study enrolled 144 patients with patent foramen ovale and 107 patients with atrial septal defect at 22 European sites; 53 patients with atrial septal defect (49.6%) were aged<18years. The rate of technical success was 98.4% (97.2% for atrial septal defect, 99.3% for patent foramen ovale). There was one serious adverse event (0.4%), an acute periprocedural device embolization that occurred after occluder release in a patient with atrial septal defect; the device was retrieved percutaneously. This was determined by the implanter to be unrelated to the performance of the Trevisio DS. CONCLUSIONS: The Trevisio DS exhibited a high rate of technical success and an excellent safety profile during transcatheter closure of patent foramen ovale and atrial septal defect.

Computed tomographic characteristics of congenital coronary artery fistulas in an adult population.

BACKGROUND: Coronary artery fistulas (CAFs) are usually congenital coronary artery anomalies of termination. AIMS: This study aimed to assess the prevalence, anatomic characteristics, and clinical significance of CAFs detected by computed tomography (CT) in an adult population. METHODS: We performed 45 817 CT examinations in 39 066 subjects between 2008 and 2020. The electronic database was manually checked using specific keywords to identify patients with CAFs. The CT characteristics of CAFs were evaluated. CAF was defined as clinically significant if it was the most plausible cause of myocardial infarction, infective endocarditis, heart failure, death during follow-up, hospitalization, or if it required either percutaneous or surgical intervention. RESULTS: Of 39 066 patients, 56 CAFs were detected in 42 subjects (20 men, 47.6%) with a prevalence of 0.11%. Most CAFs originated from the right coronary artery (RCA) (48.2%) and drained into the pulmonary artery (PA) (58.9%). CAFs terminating in the PA were more frequently multiple (P <0.001) and tortuous (P <0.001) as compared to CAFs without PA drainage. Clinically significant CAFs, identified in 7 of 42 patients, were more common in younger (P = 0.03) and male (P = 0.04) subjects and had larger lumen area and diameter at the site of origin (P = 0.03, P = 0.03, respectively). CONCLUSIONS: In the unselected adult population undergoing coronary CT angiography, the RCA and the PA are the most common sites of origin and termination of CAFs, respectively. CAFs draining into the PA are more often multiple and tortuous. Clinically meaningful CAFs are larger and most frequently detected in younger and male patients.

Identification of noncalcified coronary plaque characteristics using machine learning radiomic analysis of non-contrast high-resolution computed tomography.

BACKGROUND: Novel imaging and analysis techniques may offer the ability to detect noncalcified or high-risk coronary plaques on a non-contrast computer tomography (CT) scan, advancing cardiovascular diagnostics. AIMS: We aimed to explore whether machine learning (ML) radiomic analysis of low-dose high-resolution non-contrast electrocardiographically (ECG) gated cardiac CT scan allows for the identification of noncalcified coronary plaque characteristics. METHODS: We prospectively enrolled 125 patients with noncalcified plaques and adverse plaque characteristics (APC) and 25 controls without visible atherosclerosis on coronary CT angiography (CCTA). All patients underwent non-contrast CT exam before CCTA. Four hundred and nineteen radiomic features were calculated to identify the presence of any coronary artery disease (CAD), obstructive CAD (stenosis >50%), plaque with ≥2 APC, degree of calcification, and specific APCs. ML models were trained on a training set (917 segmentations) and tested (validation) on a separate set (292 segmentations). RESULTS: Among the radiomic features, 88.3% were associated with a plaque, 0.9% with obstructive CAD, and 76.4% with the presence of at least two APCs. Overall, 80.2%, 88.5%, and 36.5%, of features were associated with calcified, partially calcified, and noncalcified plaques, respectively. Regarding APCs, 61.1%, 61.8%, 84.2%, and 61.3% of features were associated with low attenuation (LAP), napkin-ring sign (NRS), spotty calcification (SC), and positive remodeling (PR), respectively. ML models outperformed conventional methods for the presence of plaque obstructive stenosis, and the presence of 2 APCs, as well as for noncalcified plaques and partially calcified plaques, but not for calcified plaques. ML models also significantly outperformed identification of LAP and PR, but neither NRS nor SC. CONCLUSION: Radiomic analysis of non-contrast cardiac CT exams may allow for the identification of specific noncalcified coronary plaque characteristics displaying the potential for future clinical applications.

Valve-in-valve transcatheter transfemoral mitral valve implantation (ViV-TMVI): Characteristics and early results from nationwide registry.

BACKGROUND: Valve-in-valve transcatheter transfemoral mitral valve implantation (ViV-TMVI) is an emerging treatment alternative to reoperation in high surgical risk patients with a failed mitral bioprostheses. AIM: To describe characteristics and evaluate 30-day outcomes of ViV-TMVI in the Polish population. METHODS: Nationwide registry was initiated to collect data of all patients with failed mitral bioprosthesis undergoing ViV-TMVI in Poland. This study presents 30-days clinical and echocardiographic follow-up. RESULTS: Overall, 27 ViV-TMVI were performed in 8 centers until May 2022 (85% since 2020). Mean (standard deviation [SD]) age was 73 (11.6) years with the median (interquartile range [IQR]) STS score of 5.3% (4.3%-14.3%). Mean (SD) time between surgical implantation and ViV-TMVI was 8.2 (3.2) years. Failed Hancock II (29%) and Perimount Magna (22%) were most frequently treated. Mechanisms of failure were equally often pure mitral regurgitation or stenosis (both 37%) with mixed etiology in 26%. Balloon-expandable Sapien 3/Ultra were used in all but 1 patient. Technical success was 96.3% (1 patient required additional prosthesis). Mean (SD) transvalvular mitral gradient reached 6.7 (2.2) mm Hg and mitral valve area was 1.8 (0.4) cm². None of the patients had moderate or severe mitral regurgitation with only 14.8% graded as mild. In 92.6% device success (2 patients had mean gradient ≥10 mm Hg) and in 85.6% procedural success was present. There were no deaths, cerebrovascular events or need for mitral valve surgery during 30-day follow-up. CONCLUSIONS: In short-term observation ViV-TMVI is safe and effective alternative for patients with failed mitral bioprosthesis at high surgical risk of re-operation. Longer observations on larger sample are warranted.

Benefits of the selective invasive strategy guided by CTA and CTA-derived fractional flow reserve in patients with coronary artery disease.

BACKGROUND: Coronary computed tomography angiography (CTA) has high diagnostic accuracy in ruling out significant stenosis of coronary arteries. The additional use of CTA- derived fractional flow reserve (FFR) further enhances diagnostic utility of coronary CTA. Some patients interrogated non-invasively have diseased coronary arteries and undergo further diagnostic testing, including invasive coronary angiography (ICA). Patients with one-vessel disease may benefit from invasive interrogation limited to the diseased vessel only. AIMS: We analyzed the impact of a "diseased-vessel-only" selective invasive diagnostic approach in 100 patients undergoing ICA following coronary CTA (and CT-FFR) as compared to the traditional "full ICA" approach. We aimed to compare contrast volume and radiation dose used during ICA in both scenarios, seeking potential benefits for the patient in reducing those values by the "dis-eased-vessel-only" approach. RESULTS: Sensitivity, specificity, positive predictive value, and negative predictive value of CTA in prediction of subsequent revascularization were 96%, 75%, 51%, and 99%, respectively, and for CT-FFR 90%, 90%, 69%, and 97%, respectively. Using CTA as a method to guide ICA would reduce contrast volume and estimated radiation dose (ED) by 35% and 42.0%, respectively (P <0.0001 for both). Taking into consideration CT-FFR results, contrast volume would be reduced by 57% and ED by 69% (P <0.0001 for both). CONCLUSION: These real-world data support the concept that vessels with <50% diameter stenosis on quantitative computed tomography and with hemodynamically insignificant CTA-derived FFR result may be omitted during ICA. Such an approach would result in substantial reductions in con-trast media volume used, as well as patients' exposure to radiation during ICA, while not leading to misdiagnoses.

High-density lipoprotein cholesterol, triglycerides, and characteristics of coronary atherosclerosis in patients with significant coronary artery disease newly diagnosed by computed tomography coronary angiography.

BACKGROUND: The Current European Society of Cardiology guidelines indicate specific target low-density lipoprotein cholesterol (LDL-C) levels for different cardiovascular risk categories in terms of prevention. However, the target for high-density lipoprotein cholesterol (HDL-C) and triglycerides has not been established. AIM: The study aims to investigate the associations betweenHDL-C,triglycerides, andcoronary plaque characteristics. METHODS: This was a prospective single-center study with enrolled consecutive patients with newly diagnosed significant (≥1stenosis ≥50%) CAD on computed tomography coronary angiography (CTCA). Patients had lipids andCTCA analysis, including high-risk plaque (HRP) features: low-attenuation plaque (LAP), napkin-ring sign (NRS), positive remodeling (PR), and spotty calcium (SC), type of the plaque (calcified, noncalcified, mixed), and their composition (calcified, fibrous, fibro-fatty, necrotic core). RESULTS: The study included 300 patients (191 men, 66 [8] years). Sixty-six percent of them had lipid-lowering therapy. HRPwas found in 208 patients. There was no association between LDL-C, plaque composition, and HRP presence. There was a negative correlation between HDL-C, fibro-fatty and necrotic core plaque components (P = 0.0002, P = 0.0009). There was a positive correlation between triglycerides and necrotic core (P = 0.038). There were differences in HDL-C and triglycerides in patients with and without NRS (47 vs. 53 mg/dl, P = 0.0002 and 128 vs. 109 mg/dl, P = 0.02). In logistic regression, HDL-C (odds ratio [OR], 0.95;95% confidence interval [CI], 0.93-0.98; P <0.001), triglycerides (OR, 1.00; 95% CI, 1.00-1.01; P = 0.02), and male sex (OR, 3.04; 95% CI, 1.41-6.52; P = 0.004) were NRS predictors. In multivariable regression, only HDL-C (OR, 0.96; 95% CI, 0.93-0.99; P = 0.02) was an independent predictor of NRS. CONCLUSION: Lower HDL-C and higher triglycerides were associated with NRS presence and more necrotic core plaque components in coronary plaques in patients with newly diagnosed CAD.

Computed Tomography Angiography-Derived Scores for Prediction of Chronic Total Occlusion Percutaneous Coronary Intervention Using the Hybrid Algorithm.

Whereas coronary computed tomography angiography (CCTA) exceeds invasive angiography for predicting the procedural outcome of chronic total occlusion (CTO) percutaneous coronary intervention (PCI), CCTA-derived scores have never been validated in the hybrid CTO PCI population. In this single-center, retrospective, observational study, we included 108 consecutive patients with 110 CTO lesions and preprocedural CCTA who underwent hybrid CTO PCI to assess the diagnostic accuracy of CCTA-derived scoring systems. Successful guidewire crossing within 30 min was set as the primary endpoint. The secondary endpoints were final procedural success and the need for using any non-antegrade wiring (AW) strategy within the hybrid algorithm. Time-efficient guidewire crossing and final procedural success were achieved in 53.6% and 89.1% of lesions, respectively, while in 36.4% of the procedures, any non-AW strategy was applied. The median J-CTO score was 1 (interquartile range (IQR): 0, 2), while the CT-RECTOR, KCCT, J-CTOCCTA, and RECHARGECCTA scores were 2 (IQR: 1, 3), 3 (IQR: 2, 5), 1 (IQR: 0, 3), and 2 (IQR: 1, 3), respectively. All scores were significantly higher in the lesions with failed versus successful time-efficient guidewire crossing. Although all of the CCTA-derived scores had numerically higher predictive values than the angiographic J-CTO score, no significant differences were noted between the scores in any of the analyzed study endpoints. High sensitivity of the CT-RECTOR and RECHARGECCTA scores (both 89.8%) for predicting successful guidewire crossing within 30 min, and high sensitivity (90.8%) of the KCCT score for predicting final procedural success, were noted. CCTA-derived scoring systems are accurate, noninvasive tools for the prediction of the procedural outcome of hybrid CTO PCI, and may aid in identifying the need for use of the hybrid algorithm.

Incidence and Predictors of Clinically Significant Bleedings after Transcatheter Left Atrial Appendage Closure.

BACKGROUND: Transcatheter left atrial appendage closure (LAAC) is performed in patients unsuitable for long-term anticoagulation, predominantly due to prior bleeding events. The study aimed to investigate the incidence and predictors of clinically significant bleeding (CSB) post-LAAC. METHODS: Consecutive patients after LAAC with an Amplatzer or WATCHMAN device were analyzed (05.2014-11.2019). Bleeding was classified as CSB when associated with at least one of the following: death, ≥2 g/dL hemoglobin drop, ≥2 blood units transfusion, critical anatomic site, or hospitalization/invasive procedure. RESULTS: Among 195 patients (age 74 (68-80), 43.1% females, HAS-BLED score 2.0 (2.0-3.0)), during median follow-up of 370 (IQR, 358-392) days, there were 15 nonprocedural CSBs in 14 (7.2%) patients. Of those, 9 (60.0%) occurred during postprocedural dual antiplatelet therapy (DAPT) (median 46 (IQR: 16-60) days post-LAAC) vs. 6 (40%) after DAPT discontinuation (median 124 (81-210) days post-LAAC), translating into annualized CSB rates of 14.0% (per patient-year on DAPT) vs. 4.6% (per patient-year without DAPT). In 92.9% (13/14) of patients, the post-LAAC nonprocedural CSB was a recurrence from the same site as bleeding pre-LAAC. In the multivariable model, admission systolic blood pressure (SBP) > 127 mmHg (HR = 10.73, 1.37-84.26, p = 0.024), epistaxis history (HR = 5.84, 1.32-25.89, p = 0.020), permanent atrial fibrillation (AF) (HR = 4.55, 1.20-17.20, p = 0.025), and prior gastrointestinal bleeding (HR = 3.35, 1.01-11.08, p = 0.048) predicted post-LAAC CSB. CONCLUSIONS: Nonprocedural CSBs after LAAC, with a similar origin as the pre-LAAC bleedings, were observed predominantly during postprocedural DAPT and predicted by elevated admission SBP, prior epistaxis, permanent AF, and gastrointestinal bleeding history. Whether a more reserved post-LAAC antiplatelet regimen and stringent blood pressure control may improve LAAC outcomes remains to be studied.

Guideline-Directed Medical Therapy Attainment and Outcomes in Dialysis-Requiring Versus Nondialysis Chronic Kidney Disease in the ISCHEMIA-CKD Trial.

BACKGROUND: Patients with chronic kidney disease (CKD) on dialysis (CKD G5D) have worse cardiovascular outcomes than patients with advanced nondialysis CKD (CKD G4-5: estimated glomerular filtration rate <30 mL/[min·1.73m2]). Our objective was to evaluate the relationship between achievement of cardiovascular guideline-directed medical therapy (GDMT) goals and clinical outcomes for CKD G5D versus CKD G4-5. METHODS: This was a subgroup analysis of ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) participants with CKD G4-5 or CKD G5D and moderate-to-severe myocardial ischemia on stress testing. Exposures included dialysis requirement at randomization and GDMT goal achievement during follow-up. The composite outcome was all-cause mortality or nonfatal myocardial infarction. Individual GDMT goal (smoking cessation, systolic blood pressure <140 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, statin use, aspirin use) trajectory was modeled. Percentage point difference was estimated for each GDMT goal at 24 months between CKD G5D and CKD G4-5, and for association with key predictors. Probability of survival free from all-cause mortality or nonfatal myocardial infarction by GDMT goal achieved was assessed for CKD G5D versus CKD G4-5. RESULTS: A total of 415 CKD G5D and 362 CKD G4-5 participants were randomized. Participants with CKD G5D were less likely to receive statin (-6.9% [95% CI, -10.3% to -3.7%]) and aspirin therapy (-3.0% [95% CI, -5.6% to -0.6%]), with no difference in other GDMT goal attainment. Cumulative exposure to GDMT achieved during follow-up was associated with reduction in all-cause mortality or nonfatal myocardial infarction (hazard ratio, 0.88 [95% CI, 0.87-0.90]; per each GDMT goal attained over 60 days), irrespective of dialysis status. CONCLUSIONS: CKD G5D participants received statin or aspirin therapy less often. Cumulative exposure to GDMT goals achieved was associated with lower incidence of all-cause mortality or nonfatal myocardial infarction in participants with advanced CKD and chronic coronary disease, regardless of dialysis status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01985360.