Exploring the landscape of academic retractions in medicine: a comprehensive umbrella review.

INTRODUCTION: The escalating trend of academic article retractions over the last decades raises concerns about scientific integrity, but heterogeneity in retractions and reasons for them pose a major challenge. We aimed to comprehensively overview systematic reviews focusing on retractions in the biomedical literature. EVIDENCE ACQUISITION: We abstracted salient features and bibliometric details from shortlisted articles. The Joanna Briggs Institute (JBI) Checklist for Systematic Reviews and Research Syntheses was used for validity appraisal. EVIDENCE SYNTHESIS: A total of 11 reviews were included, published between 2016 and 2023, and reporting on a total of 1851 retracted studies. Several major reasons for retractions were identified, spanning both misconduct (e.g., falsification, duplication, plagiarism) and non-misconduct issues (e.g., unreliable data, publishing problems). Correlates include author-related factors (number of authors, nationality) and journal-related factors (impact factor), with repeat offenders contributing significantly. Impacts of retractions is profound, affecting scholarly credibility, public trust, and resource utilization. CONCLUSIONS: In order to prevent retractions and amend their adverse effects, rigorous and transparent reporting standards, enhanced training in research ethics, strengthened peer review processes, and the establishment of collaborative and integrated research integrity offices are proposed.

Towards the Fifth Pillar for the Treatment of Heart Failure with Reduced Ejection Fraction: Vericiguat in Older and Complex Patients.

Heart failure with reduced ejection fraction (HFrEF) represents an emerging epidemic, particularly affecting frail, older, and multimorbid patients. Current therapy for the management of HFrEF includes four different classes of disease-modifying drugs, commonly referred to as 'four pillars', which target the neurohormonal system that is overactivated in HF and contributes to its progression. These classes of drugs include ß-blockers, inhibitors of the renin-angiotensin-aldosterone system, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. Unfortunately, these agents cannot be administered as frequently as needed to older patients because of poor tolerability and comorbidities. In addition, although these drugs have dramatically increased the survival expectations of patients with HF, their residual risk of rehospitalization and death at 5 years remains considerable. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, was reported to exert beneficial effects in patients with worsening HF, including older subjects, reducing the rate of both hospitalizations and deaths, with limited adverse effects and drug interaction. In this narrative review, we present the current state of art on vericiguat, with a particular focus on elderly and frail patients.

Management of Cardiovascular Complications in Antiphospholipid Syndrome: A Narrative Review with a Focus on Older Adults.

Antiphospholipid syndrome (APS), also known as Hughes syndrome, is an acquired autoimmune and procoagulant condition that predisposes individuals to recurrent thrombotic events and obstetric complications. Central is the role of three types of antiphospholipid antibodies that target phospholipid-binding proteins: lupus anticoagulant (LAC), anti-ß2-glycoprotein I (ß2-GPI-Ab), and anti-cardiolipin (aCL). Together with clinical data, these antibodies are the diagnostic standard. However, the diagnosis of APS in older adults may be challenging and, in the diagnostic workup of thromboembolic complications, it is an underestimated etiology. The therapeutic management of APS requires distinguishing two groups with differential risks of thromboembolic complications. The standard therapy is based on low-dose aspirin in the low-risk group and vitamin K antagonists in the high-risk group. The value of direct oral anticoagulants is currently controversial. The potential role of monoclonal antibodies is investigated. For example, rituximab is currently recommended in catastrophic antiphospholipid antibody syndrome. Research is ongoing on other monoclonal antibodies, such as daratumumab and obinutuzumab. This narrative review illustrates the pathophysiological mechanisms of APS, with a particular emphasis on cardiovascular complications and their impact in older adults. This article also highlights advancements in the diagnosis, risk stratification, and management of APS.

Acute normovolemic hemodilution in cardiac surgery: rationale and design of a multicenter randomized trial.

BACKGROUND: Minimizing the use of blood component can reduce known and unknown blood transfusion risks, preserve blood bank resources, and decrease healthcare costs. Red Blood Cell (RBC) transfusion is common after cardiac surgery and associated with adverse perioperative outcomes, including mortality. Acute normovolemic hemodilution (ANH) may reduce bleeding and the need for blood product transfusion after cardiac surgery. However, its blood-saving effect and impact on major outcomes remain uncertain. METHODS: This is a single-blinded, multinational, pragmatic, randomized controlled trial with a 1:1 allocation ratio conducted in Tertiary and University hospitals. The study is designed to enroll patients scheduled for elective cardiac surgery with planned cardiopulmonary bypass (CPB). Patients are randomized to receive ANH before CPB or the best available treatment without ANH. We identified an ANH volume of at least 650 ml as the critical threshold for clinically relevant benefits. Larger ANH volumes, however, are allowed and tailored to the patient's characteristics and clinical conditions. RESULTS: The primary outcome is the percentage of patients receiving RBCs transfusion from randomization until hospital discharge, which we hypothesize will be reduced from 35% to 28% with ANH. Secondary outcomes are all-cause 30-day mortality, acute kidney injury, bleeding complications, and ischemic complications. CONCLUSION: The trial is designed to determine whether ANH can safely reduce RBC transfusion after elective cardiac surgery with CPB. STUDY REGISTRATION: This trial was registered on ClinicalTrials.gov in April 2019 with the trial identification number NCT03913481.

Prediction of 30-day mortality after surgery for infective endocarditis using risk scores: Insights from a European multicenter comparative validation study.

BACKGROUND: It remains unclear today whether risk scores created specifically to predict early mortality after cardiac operations for infective endocarditis (IE) outperform or not the European System for Cardiac Operative Risk Evaluation II (EuroSCORE II). METHODS: Perioperative data and outcomes from a European multicenter series of patients undergoing surgery for definite IE were retrospectively reviewed. Only the cases with known pathogen and without missing values for all considered variables were retained for analyses. A comparative validation of EuroSCORE II and five specific risk scores for early mortality after surgery for IE - (1) STS-IE (Society of Thoracic Surgeons for IE); (2) PALSUSE (Prosthetic valve, Age ≥70, Large intra-cardiac destruction, Staphylococcus spp, Urgent surgery, Sex (female), EuroSCORE ≥10); (3) ANCLA (Anemia, New York Heart Association class IV, Critical state, Large intra-cardiac destruction, surgery on thoracic Aorta); (4) AEPEI II (Association pour l'Étude et la Prévention de l'Endocardite Infectieuse II); (5) APORTEI (Análisis de los factores PROnósticos en el Tratamiento quirúrgico de la Endocarditis Infecciosa) - was carried out using calibration plot and receiver-operating characteristic curve analysis. Areas under the curve (AUCs) were compared 1:1 according to the Hanley-McNeil's method. The agreement between APORTEI score and EuroSCORE II of the 30-day mortality prediction after surgery was also appraised. RESULTS: A total of 1,012 patients from five European university-affiliated centers underwent 1,036 cardiac operations, with a 30-day mortality after surgery of 9.7%. All IE-specific risk scores considered achieved better results than EuroSCORE II in terms of calibration; AEPEI II and APORTEI score showed the best performances. Despite poor calibration, EuroSCORE II overcame in discrimination every specific risk score (AUC, 0.751 vs. 0.693 or less, p=0.01 or less). For a higher/lesser than 20% expected mortality, the agreement of prediction between APORTEI score and EuroSCORE II was 86%. CONCLUSION: EuroSCORE II discrimination for 30-day mortality after surgery for IE was higher than five established IE-specific risk scores. AEPEI II and APORTEI score showed the best results in terms of calibration.

A 25-year-long journey into interventional cardiology: looking back, and rushing forward.

Cardiovascular disease remains decade after decade a leading cause of mortality, morbidity and resource use globally as well as locally. We have had the opportunity of being involved in several iterative breakthroughs in invasive cardiovascular procedures, ranging from the advent of coronary stents to transcatheter mitral valve repair. Building up such extensive clinical and research experience, we hereby present 25 years of cardiovascular interventions at Pineta Grande Hospital and Casa di Salute S. Lucia, respectively in Castel Volturno, and S. Giuseppe Vesuviano, both in the Italian Campania region, where the same team of interventional cardiologists has managed to adopt and master several cardiovascular innovations for the benefit of thousands of patients. Our experience showcases the evolution of invasive cardiology, especially in diagnostic and therapeutic practices. Key highlights include advancements in coronary procedures, with the introduction of bare-metal stents, drug-eluting stents and drug-coated balloons, despite the setback of bioresorbable vascular scaffolds, as well as transcatheter aortic valve implantation and innovative approaches to mitral regurgitation. Furthermore, this overview scrutinizes procedural challenges, patient outcomes, and quality of life improvements, providing a rich tapestry of clinical experiences and research insights. It serves as a testament to the dynamic nature of interventional cardiology, offering a forward-looking perspective on future trends and technologies. We hope that this overview will prove an informative and insightful read for those seeking to understand the intricate journey of invasive cardiovascular care over the past decades and its trajectory into the future.

Transcatheter Mitral Valve Repair With the MitraClip Device for Prior Mitral Valve Repair Failure: Insights From the GIOTTO-FAILS Study.

BACKGROUND: Minimally invasive mitral valve repair has a favorable risk-benefit profile in patients with significant de novo mitral regurgitation. Its role in patients with prior mitral valve repair is uncertain. We aimed to appraise the outcome of patients undergoing transcatheter edge-to-edge repair (TEER) with prior transcatheter or surgical mitral valve repair (SMVR). METHODS AND RESULTS: We queried the Italian multicenter registry on TEER with MitraClip, distinguishing naïve patients from those with prior TEER or (SMVR). Inhospital and long-term clinical/echocardiographic outcomes were appraised. The primary outcome was the occurrence of death or rehospitalization for heart failure. A total of 2238 patients were included, with 2169 (96.9%) who were naïve to any mitral intervention, 29 (1.3%) with prior TEER, and 40 (1.8%) with prior SMVR. Several significant differences were found in baseline clinical and imaging features. Respectively, device success was obtained in 2120 (97.7%), 28 (96.6%), and 38 (95.0%, P=0.261) patients; procedural success in 2080 (95.9%), 25 (86.2%), and 38 (95.0%; P=0.047); and inhospital death in 61 (2.8%), 1 (3.5%), and no (P=0.558) patients. Clinical follow-up after a mean of 14 months showed similar rates of death, cardiac death, rehospitalization, rehospitalization for heart failure, and their composite (all P>0.05). Propensity score-adjusted analysis confirmed unadjusted analysis, with lower procedural success for the prior TEER group (odds ratio, 0.28 [95% CI, 0.09-0.81]; P=0.019) but similar odds ratios and hazard ratios for all other outcomes in the naïve, TEER, and SMVR groups (all P>0.05). CONCLUSIONS: In carefully selected patients, TEER can be performed using the MitraClip device even after prior TEER or SMVR.

Comparative effects of different antiplatelet strategies in carriers of CYP2C19 loss-of-function alleles: a network meta-analysis.

BACKGROUND: Carriers of cytochrome 2C19 (CYP2C19) loss of function (LoF) alleles treated with clopidogrel have impaired drug metabolism resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored. METHODS: Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI) were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios (OR) and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR. Standard-dose of clopidogrel (75 mg daily) was used as reference treatment. RESULTS: A total of 12 RCTs testing 6 alternative strategies (i.e., clopidogrel 150 mg, prasugrel 3.75 mg, 5 mg, and 10 mg, ticagrelor 90 mg bid, and adjunctive cilostazol 100 mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10 mg (MD -127.91; 95% CI -141.04; -114.78) and ticagrelor 90 mg bid (MD -124.91; 95% CI -161.78; -88.04), followed by prasugrel 5 mg (MD -76.33; 95% CI -98.01; -54.65) and prasugrel 3.75 mg (MD -73.00; 95% CI -100.28; -45.72). Among other strategies, adjunctive cilostazol (MD-42.64; 95% CI -64.72; -20.57) and high-dose clopidogrel (MD -32.11; 95% CI -51.33; -12.90) were associated with a modest reduction in PRU compared with standard-dose clopidogrel. CONCLUSION: Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, while double-dose clopidogrel and additional cilostazol showed modest effects. Reduced-dose of prasugrel may represent a balanced strategy to overcome HPR without a significant increase in bleeding. The clinical implications of these pharmacodynamic findings warrant further investigation.

Transcatheter mitral valve repair with MitraClip: comparison of NT, NTr, and XTr Devices.

OBJECTIVES: Transcatheter edge-to-edge repair (TEER) has become an established minimally invasive treatment for significant mitral regurgitation. Ongoing refinements and the availability of different clipping devices have expanded the indications for and effectiveness of TEER, but comprehensive comparative data on this issue are lacking. In this study, we compared NT, NTr, and XTr MitraClip devices (Abbot) for TEER. METHODS: Details on patient, imaging, and procedural details, as well as short- and long-term outcomes, were sought from a national prospective clinical registry on TEER with MitraClip. The primary outcome of interest was discharge after procedural success without major clinical complications. RESULTS: A total of 2236 patients were included, 1228 (54.9%) in whom NT implantation only was attempted, 233 (10.4%) in whom NTr but not XTr implantation was attempted, and 775 (34.7%) in whom XTr implantation was attempted. Clinical and imaging features differed substantially across the groups, reflecting expanding indications with NTr and XTr devices. In-hospital outcomes were largely similar among the 3 groups, including death. Long-term unadjusted estimates of effect showed significant differences in several outcomes, including death, rehospitalization, and their composite, which demonstrated that NT was associated with more unfavorable outcomes compared with the other devices (all P less than .05). However, most differences depended on baseline features, as adjusted analysis showed no significant differences for early as well as long-term outcomes, including long-term death, rehospitalization, and their composite (all P greater than .05). CONCLUSIONS: New-generation MitraClip devices are associated with favorable procedural and clinical outcomes, despite being used in patients with more adverse features, when compared with patients treated with previous devices.

Intraprocedural continuous saline infusion lines significantly reduce the incidence of acute kidney injury during endovascular procedures for stroke and myocardial infarction: evidence from a systematic review and meta-regression.

BACKGROUND: Contrast media used in mechanical therapies for stroke and myocardial infarction represent a significant cause of acute kidney injury (AKI) in acute medical scenarios. Although the continuous saline infusion line (CSIL) is a standard procedure to prevent thrombus formation within the catheter during neurovascular interventions of mechanical thrombectomy (MT), it is not utilized in percutaneous coronary interventions (PCI). METHODS: A systematic review of the incidence of AKI after MT for stroke treatment was performed. These data were compared with those reported in the literature regarding the incidence of AKI after PCI for acute myocardial infarction. A random-effect model meta-regression was performed to explore the effects of CSIL on AKI incidence, using clinical details as covariates. RESULTS: A total of 18 and 33 studies on MT and PCI were included, respectively, with 69,464 patients (30,138 [43.4%] for MT and 39,326 [56.6%] for PCI). The mean age was 63.6 years±5.8 with male 66.6%±12.8. Chronic kidney disease ranged 2.0-50.3%. Diabetes prevalence spanned 11.1% to 53.0%. Smoking status had a prevalence of 7.5-72.0%. Incidence of AKI proved highly variable (I2=98%, Cochrane's Q 2985), and appeared significantly lower in the MT subgroup than in the PCI subgroups (respectively 8.3% [95% confidence interval: 4.7-11.9%] vs. 14.7 [12.6-16.8%], P<0.05). Meta-regression showed that CSIL was significantly associated with a decreased incidence of AKI (OR=0.93 [1.001-1.16]; P=0.03). CONCLUSIONS: Implementation of CSIL during endovascular procedures in acute settings was associated with a significant decrease in the risk of AKI, and its safety should be routinely considered in such interventions.

Comparative diagnostic accuracy of transcranial Doppler and contrast-enhanced transthoracic echocardiography for the diagnosis of patent foramen ovale and atrial septal defect.

BACKGROUND: Recognition of right-to-left shunt is crucial in the work-up of patients with suspected patent foramen ovale (PFO) or atrial septal defect (ASD). While transesophageal echocardiography (TEE) remains the gold standard diagnostic tool for the anatomic assessment of PFO/ASD, transcranial Doppler (TCD) and contrast-enhanced transthoracic echocardiogram (CE-TTE) hold the promise of providing minimally invasive yet accurate clinical details. Their comparative accuracy remains however debated. METHODS: We conducted a retrospective observational study leveraging our extensive institutional experience with systematic TCD and CE-TTE in patients with suspected PFO/ASD. Several measures of diagnostic test accuracy were computed, with point estimates and 95% confidence intervals, when applicable. RESULTS: A total of 1358 patients were included, with age 48±14 years and 772 (58%) women. Tests were performed for diagnostic purposes in 797 (58.6%) and during follow-up in 740 (54.5%). A PFO was eventually diagnosed in 1038 (77.9%) patients, and an ASD in 60 (4.5%). Agreement between TCD and CE-TTE occurred in 1309 (85.2%) cases, with TCD yielding worse findings than CE-TTE in 91 (5.9%) patients, and vice versa in 137 (8.9%), yielding a Cohen kappa of 78.6% (95% CI: 76.3-81.1%) and a highly significant P value at McNemar test (P<0.001). After dichotomization, and using TCD as benchmark, CE-TTE yielded sensitivity 96.9%, specificity 95.1%, area under the curve 92.1%, and P=0.249. Similar findings were obtained when focusing only on diagnostic tests or follow-up ones (Cohen kappa respectively 74.0% [70.2-77.1%], P<0.001 and 80.3% [76.4-84.3%], P<0.001). Notably, Valsalva was necessary to disclose the presence of shunt during TCD in 487 (31.7%) patients and during CE-TTE in 482 (31.4%) cases. Finally, performance of TCD and CE-TTE in a subset of patients eventually undergoing TTE was quite similar. CONCLUSIONS: The diagnostic accuracy of CE-TTE appears favorable, and this imaging test may identify patients who may be missed if only TCD is used to screen patients with suspected PFO/ASD. Accordingly, CE-TTE is recommended as an adjunct diagnostic modality for all patients with a high pre-test probability of PFO/ASD and right-to-left shunt.

A multicenter prospective observational study appraising the effectiveness of the Supera stent after subintimal recanalization of femoro-popliteal artery occlusion: The SUPERSUB II study.

BACKGROUND: Complex femoropopliteal artery disease represents a challenge. The Supera stent holds the promise of improving the results of endovascular therapy for complex femoropopliteal disease. AIMS: We aimed at appraising the early and long-term effectiveness of the Supera stent after successful subintimal angioplasty (SuperSUB strategy) for complex femoropopliteal lesions. METHODS: We conducted a multicenter, prospective, single-arm observational study including consecutive patients at participating centers in whom Supera was implanted after successful subintimal angioplasty for complex femoropopliteal lesions. RESULTS: A total of 92 patients were included Femoropopliteal arteries were the most common target, and lesion length was 261 ± 102 mm. Most procedures were technically demanding, with antegrade femoral access in 35 (38%) and retrograde distal access in 55 (60%). Supera stent length was 281 ± 111 mm, with 4, 5, and 6 mm devices being most commonly used: 32 (35%), 35 (38%), and 23 (25%), respectively. Technical success was achieved in 100% of subjects, as was clinical success (per subject), whereas procedural success (per subject) was obtained in 98%. At 24 months, freedom from clinically driven target lesion revascularization was 93%, whereas primary patency was 87%. When compared with a similar historical cohort, Supera stent use appeared to be associated with a reduction in resources. CONCLUSION: Use of Supera stent after successful subintimal recanalization of complex lower limb arterial lesions yields favorable procedural results, which are maintained over follow-up, and are associated also with a favorable resource use profile.

Safety and efficacy of drug-eluting stents for patients at high risk of bleedings: A network meta-analysis.

INTRODUCTION: Among different coronary stents implanted in High Bleeding Risk (HBR) patients with an indication for short antiplatelet therapy, no comparisons in terms of efficacy have been provided. METHODS: A Network Meta Analysis was performed including all randomized controlled trials comparing different coronary stents evaluated in HBR patients. Major Adverse Cardiovascular Events (MACEs) as defined by each included trial were the primary end point, whereas TLR (target lesion revascularization), TVR (target vessel revascularization), stent thrombosis and total and major (BARC3-5) bleedings were the secondary ones. RESULTS: A total of four studies (ONYX ONE, LEADERS FREE, SENIOR and HBR in BIO-RESORT) including 6637 patients were analyzed with different kind of stents and dual antiplatelet therapy (DAPT) length (1 or 6 months) on 12 months follow-up. About one-third of these patients were defined HBR due to indication for oral anticoagulation. All drug eluting stents (DESs) reduced risk of MACE compared to Bare Metal Stents (BMSs) when followed by a 1-month DAPT. At SUCRA analysis, Orsiro was the device with the highest probability of performing best. Rates of TLR and TVR were significantly lower when using Resolute Onyx, Synergy and BioFreedom stents in comparison to BMS when followed by 1-month DAPT, with Synergy ranking best. Synergy also showed a significantly lower number of stent thrombosis compared to BMS (RR 0.28, 95% CI 0.06-0.93), while Orsiro and Resolute Integrity showed the highest probability of performing best. CONCLUSION: In HBRs patients, all DESs were superior to BMSs in terms of efficacy and safety. Among DESs, Orsiro was the one with the highest ranking in terms of MACE, mainly driven by a reduced incidence of repeated revascularization and stent thrombosis.

Statistical primer: individual patient data meta-analysis and meta-analytic approaches in case of non-proportional hazards.

Individual patient data (IPD) meta-analyses build upon traditional (aggregate data) meta-analyses by collecting IPD from the individual studies rather than using aggregated summary data. Although both traditional and IPD meta-analyses produce a summary effect estimate, IPD meta-analyses allow for the analysis of data to be performed as a single dataset. This allows for standardization of exposure, outcomes, and analytic methods across individual studies. IPD meta-analyses also allow the utilization of statistical methods typically used in cohort studies, such as multivariable regression, survival analysis, propensity score matching, uniform subgroup and sensitivity analyses, better management of missing data, and incorporation of unpublished data. However, they are more time-intensive, costly, and subject to participation bias. A separate issue relates to the meta-analytic challenges when the proportional hazards assumption is violated. In these instances, alternative methods of reporting time-to-event estimates, such as restricted mean survival time should be used. This statistical primer summarizes key concepts in both scenarios and provides pertinent examples.

Mechanical Cardiopulmonary Resuscitation Devices: Evidence Synthesis with an Umbrella Review.

AIM: Sudden cardiac arrest is a significant cause of death worldwide. Good quality cardiopulmonary resuscitation increases patients' survival. Manual cardiopulmonary resuscitation is often ineffective as rescuers may experience physical and mental fatigue. Mechanical cardiopulmonary resuscitation devices are designed to address this issue, providing an automated approach for high-quality resuscitation. In the present comprehensive umbrella review we summarize current evidence on mechanical devices. METHODS: We searched systematic reviews on mechanical devices in MEDLINE/PubMed. Effect estimates were obtained from original reports, including 95% confidence intervals and p values, when applicable and available, focusing on return of spontaneous circulation, survival to discharge or 30 days, survival with good neurological outcome, and resuscitation-related injuries. RESULTS: From 21 potentially pertinent publications, we shortlisted 10 reviews, each including between 5 and 22 studies. AutoPulse, LUCAS, and LUCAS-2 were among the investigated devices. Most reviews concluded toward mechanical devices being similar or better than manual resuscitation for return of spontaneous circulation and 30-days survival. Regarding survival with good neurological function, some reviews lacked data, while the remaining ones reported similar results or worse outcomes in patients undergoing mechanical resuscitation. Focusing on resuscitation-related injuries, data were limited or conflicting with one review reporting higher rates of injuries with mechanical devices, and two others suggesting similar outcomes. CONCLUSIONS: Manual and mechanical cardiopulmonary resuscitation appear to be similar in terms of return of spontaneous circulation and short-term survival. Mechanical devices appear to be associated with higher resuscitation-related injuries, while there are conflicting data in terms of survival with good neurological outcomes. A comprehensive and large dedicated randomized trial is urgently needed.