Transesophageal Ultrasound-Guided Normothermic Regional Perfusion in Controlled Donors After Cardiocirculatory Determination of Death.

Programs of donation after cardiocirculatory determination of death (DCD) are increasingly established in many countries to increase the availability of organs for transplantation. The use of abdominal normothermic regional reperfusion (A-NRP), shortening total warm ischemia time (tWIT), has been recently recommended by the European Society for Organ Transplantation (ESOT) to decrease the risk potentially associated with transplantation of grafts from DCD donors. We aimed to describe our transesophageal ultrasound (TEU)-guided technique to implement A-NRP in controlled DCD (cDCD) donors through femorofemoral venoarterial extracorporeal support, preventing coronary and cerebral reperfusion occluding the aorta with a balloon. After assessment of the central vascular structures, the use of TEU in real time guides the insertion of the guidewires and the balloon. Moreover, TEU allows us to verify the proper positioning of a venous cannula and aortic balloon. The entire procedure may be performed without the need for fluoroscopic or radiographic evaluation, or limiting the need for fluoroscopic or radiology assistance to a selected scenario of difficult or expected difficult cannulation and/or balloon insertion. The distribution of interventions as antemortem and postmortem reflects the scenario imposed by Italian laws regulating organ procurement in DCD donors.

Using Transesophageal Echocardiography in Liver Transplantation with Veno-Venous Bypass Is a Tool with Many Applications: A Case Series from an Italian Transplant Center.

BACKGROUND: Hemodynamic instability (HDI) is common during liver transplantation (LT); veno-venous bypass (VVB) is a tool used in selected cases to ensure hemodynamic stability and for surgical needs. Transesophageal echocardiography (TEE) allows the transplant team to identify the causes of HDI and to guide therapies. We present a case series of four patients showing the valuable role of TEE during LT in VVB. METHODS: We report four explicative cases of TEE use in LT with VVB performed at IRCCS Azienda Ospedaliero-Universitaria di Bologna. Four transplants were performed between 2016 and 2022. RESULTS: Many authors have highlighted the diagnostic value of TEE during LT in the case of HDI. However, its specific role during LT with VVB is poorly described. This paper illustrates multiple potential uses of TEE in LT with VVB: TEE as a guide for catheterization and optimal cannula positioning, TEE as a tool for intraoperative Patent Foramen Ovale management, TEE as help for anticoagulation therapy and finally, TEE as support when evaluating bypass efficiency and correcting hypovolemia. CONCLUSION: TEE is a useful instrument during LT with VVB. However, further studies are needed to assess the suitable applications of TEE during LT in patients with HDI requiring VVB. TEE should be part of the anesthetist's cultural background.

Drug-Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review.

BACKGROUND: Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug-drug interactions (DDIs). Hepatitis C direct-acting antiviral agents (DAAs), via P-glycoprotein or CYP3A4 inhibition, may increase DOAC exposure with relevant bleeding risk. We performed a systematic review on DDIs between DOACs and DAAs. METHODS: Two reviewers independently identified studies through electronic databases, until 7 July 2020, supplementing the search by reviewing conference abstracts and the ClinicalTrials.gov website. RESULTS: Of 1386 identified references, four articles were finally included after applying the exclusion criteria. Three phase I clinical studies in healthy volunteers assessed interactions between dabigatran and glecaprevir/pibrentasvir, odalasvir/simeprevir, or sofosbuvir/velpatasvir/voxilaprevir, showing an increase in the dabigatran area under the concentration-time curve (AUC) by 138%, 103%, and 161%, respectively. CONCLUSIONS: DOACs and DAAs are under-investigated for DDI risk. Real-world studies are needed to assess the clinical relevance of the pharmacokinetic interactions with dabigatran and describe the actual spectrum of possible DDIs between DAAs and other DOACs.

Assessing the association between fluoroquinolones and emerging adverse drug reactions raised by regulatory agencies: An umbrella review.

BACKGROUND: Regulatory agencies warned against fluoroquinolones for the management of minor infections because of the risk of emerging adverse events (collagen-associated adverse events, neuropsychiatric toxicity and long-term disability). We aimed to assess quality and credibility of evidence as well as causality regarding these putative associations. METHODS: MEDLINE, Scopus, Web of Science and PROSPERO were searched, from inception to August 2019, for systematic reviews with meta-analyses investigating emerging adverse events. Two investigators extracted data to grade quality (through validated AMSTAR-2 tool), rank credibility of the evidence (convincing, highly suggestive, suggestive, weak) through adapted criteria including E-value calculation, and assess causality (Hill's criteria). RESULTS: Seven systematic reviews of observational studies providing 16 risk estimates [seven, five and four, respectively, for aortic aneurysm/dissection (AAD), retinal detachment (RD) and any tendon disorders (ATD)] met inclusion criteria. No systematic reviews with meta-analysis investigating the risk of neuropsychiatric toxicity or long-term disability were found. The associations between fluoroquinolones and AAD/ATD showed highly suggestive credibility and were supported by strong evidence of causality (double increased risk, especially within first 2 months of treatment). Conflicting data concerning the emergence of RD were retrieved, resulting in weak evidence of causality. Quality of the evidence ranged from high to low for AAD, from moderate to critically low for RD, and it was moderate for ATD. CONCLUSION: Our analysis supports credible, plausible and highly suggestive associations with AAD (rare occurrence but strong causality) and ATD. Limitations of both umbrella reviews and observational evidence should be considered.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants: Overview of Systematic Reviews.

Direct oral anticoagulants are now recommended by major guidelines as first-choice agents for both stroke prevention in non-valvular atrial fibrillation and treatment/prevention of venous thromboembolism in non-cancer patients. Although there are no published head-to-head trials comparing different direct oral anticoagulants, a growing body of evidence from indirect comparisons and observational studies is suggesting that each direct oral anticoagulant may have a specific risk profile. This review aims to (1) synthesize and critically assess the latest evidence in comparative effectiveness and safety research in the aforementioned consolidated therapeutic uses, by performing an overview of systematic reviews and (2) highlight current challenges, namely underexplored areas, where research should be directed, also considering ongoing unpublished studies. The evidence gathered so far on the risk-benefit profile of direct oral anticoagulants is appraised in the light of existing guidelines to discuss whether further implementation should be proposed.

How Safe is Performing Cholecystectomy in the Oldest Old? A 15-year Retrospective Study from a Single Institution.

BACKGROUND: Globally, the number of people aged 80 years or over, the "oldest old," is the fastest growing population group. Because of the strong association between age and gallstone disease, both prevalence and incidence of this disease are increasing. The feasibility of the cholecystectomy in octogenarians has been evaluated in several studies that confirmed the safety of the operation. However, the safety of this procedure in nonagenarians is still controversial. The aim of this study was to evaluate the safety of cholecystectomies in nonagenarians and identify related predictors for postoperative hospital length of stay (LOS) and in-hospital mortality up to 30 days postoperatively. METHODS: More than 500 cholecystectomies, both open and laparoscopic, were performed between January 2000 and September 2015 at our institution in patients 80 years and older. These statistics include both elective and emergent admissions. A retrospective review of charts over the last 15 years was conducted to compare mortality and length of postoperative stay among two patient groups: 319 octogenarians and 36 nonagenarians. Parameters evaluated include demographics, surgical presentation, American Society of Anesthesiologists (ASA) score, main diagnosis, comorbidities, type of surgery performed, LOS and in-hospital mortality. All data were analyzed with STATA (v.13) software, using a multivariate logistic regression after determining the statistically significant variables through a stepwise regression. CONCLUSIONS: We found out that being nonagenarian, compared to octogenarian, is not a significant risk factor in terms of LOS and in-hospital mortality within 30 days postoperatively. Despite that, the mortality rate among nonagenarians is still remarkably high as almost every patient was admitted in an emergent setting. The most remarkable predictor for mortality among the two groups was an "afternoon/night emergency" surgical presentation (OR 25.5, CI 1.53-42.35, p = 0.02). Thus, the surgical emergency management for gallbladder disease at our institution should be critically reevaluated. Performing the procedure in laparoscopy predicted a significant reduction (-5 days, CI -8.5 to -1.4, p = 0.006) of LOS, while presenting with "gallbladder and bile duct stones" (+6.3 days, CI 1.5-11.1, p = 0.01) or "acalculous cholecystitis" (+4.7 days, CI 0.4-9.2, p = 0.03) had the opposite effect. Despite the remarkable mortality rate of our series, being nonagenarian should not be considered as a reason to avoid gallbladder surgery in case of need. Our study suggests that nonagenarians are more suitable surgical candidates than may have previously expected.

Evolving cardiovascular uses of direct-acting oral anticoagulants: a paradigm shift on the horizon?

Direct-acting oral anticoagulants (DOACs), by virtue of pharmacological properties perceived as innovative, are changing the therapeutic scenario of patients requiring short- and long-term anticoagulation. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirms that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy, effectiveness and unequivocally documents a clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (AF) and venous thromboembolism. The following issues are attracting considerable clinical interest: (a) identifying specific subpopulations of patients with AF most likely to benefit from one of these agents (the so-called tailored therapy), and (b) expanding therapeutic indications in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk-benefit profile of DOACs, as compared to VKAs or heparins, is still incompletely characterized. In cardiology, the challenging task of selecting a suitable or even the most appropriate DOAC for patients with AF and a particular phenotype prompted experts to provide suggestions based on careful review of subgroups of patients from pivotal RCTs. However, in the past few months, variegated multicenter trials have been published (RE-CIRCUIT, PIONEER-AF-PCI, GEMINI-ACS-1), with potential influence on clinical practice. Therefore, this review aims to update the latest evidence on the evolving therapeutic uses of DOACs in the cardiovascular area, addressing potential impact for clinicians.

Emerging therapeutic uses of direct-acting oral anticoagulants: An evidence-based perspective.

Direct-acting oral anticoagulants (DOACs) were claimed to cause a potential paradigm shift in the therapeutic scenario of patients requiring short- and long-term anticoagulation, by virtue of their pharmacological properties, perceived as innovative. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirmed that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy and effectiveness and unequivocally documented a consistent and clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). Interestingly, two parallel paths can be identified in the current research scenario: A) in the aforementioned consolidated therapeutic indications, an innovative approach is directed towards tailored treatment strategies, to identify patients most likely to benefit from one of the different anticoagulant drugs, in particular subpopulations at increased risk of adverse events (e.g., bleeding); B) in unconventional settings, DOACs are gaining interest for potential use in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk-benefit profile of DOACs, as compared to VKAs or heparins, is less defined. The aim of this review is to critically assess the body of evidence underlying emerging therapeutic uses of DOACs (e.g., heparin-induced thrombocytopenia, anti-phospholipid antibody syndrome), including evolving issues in special populations (e.g., patients with VTE and cancer or cirrhosis). This will be achieved by analyzing the strength (i.e., systematic reviews, randomized clinical trials, observational studies, case report/series) and consistency (i.e., concordance) of both published and unpublished evidence registered in major public repositories.

Risk-Benefit Profile of Direct-Acting Oral Anticoagulants in Established Therapeutic Indications: An Overview of Systematic Reviews and Observational Studies.

Since 2008, the direct-acting oral anticoagulants (DOACs) have expanded the therapeutic options of cardiovascular diseases with recognized clinical and epidemiological impact, such as non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), and also in the preventive setting of orthopedic surgical patients. The large body of evidence, not only from pivotal clinical trials but also from 'real-world' postmarketing observational findings (e.g. analytical epidemiological studies and registry data) gathered to date allow for a first attempt at verifying a posteriori whether or not the pharmacological advantages of the DOACs actually translate into therapeutic innovation, with relevant implications for clinicians, regulators and patients. This review aims to synthesize the risk-benefit profile of DOACs in the aforementioned consolidated indications through an 'evidence summary' approach gathering the existent evidence-based data, particularly systematic reviews with meta-analyses of randomized controlled trials, as well as observational studies, comparing DOACs with vitamin K antagonists. Clinical evidence will be discussed and compared with major international guidelines to identify whether an update is needed. Controversial clinically relevant safety issues will be also examined in order to highlight current challenges and unsettled questions (e.g. actual bleeding risk in susceptible populations). It is anticipated that the large number of publications on NVAF or VTE (44 systematic reviews with meta-analyses and 12 observational studies retained in our analysis) suggests the potential existence of overlapping studies and calls for common criteria to qualitatively and quantitatively assess discordances, thus guiding future research.

Adverse events associated with the use of direct-acting oral anticoagulants in clinical practice: beyond bleeding complications.

Non-vitamin K oral anticoagulants, also known as direct oral anticoagulants (DOACs), have entered the market in 2008 with the expected breakthrough potential of circumventing limitations related to treatment with vitamin K antagonists (eg, warfarin) by virtue of their pharmacological properties. Although data derived from premarketing randomized clinical trials have largely demonstrated the clinical benefit of DOACs, especially in terms of reduced risk of intracranial bleeding, it is important to monitor the safety in the postmarketing phase, which better reflects real-world patients with comorbidities and polypharmacotherapy, in order to assess the actual risk-benefit profile. In this critical review, we aimed to evaluate the evidence on the latest debated safety issues. In the first section, we will discuss: 1) the need for pharmacovigilance (ie, the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems in the real-world setting), and 2) the importance of properly interpreting postmarketing data to avoid unnecessary alarm. In the second section, emerging and debated safety issues potentially associated with the use of DOACs in the postmarketing setting will be assessed: 1) the potential coronary risk (which emerged during the preapproval period); 2) the occurrence of liver injury (a risk undetected in clinical trials and highlighted by case reports or series); and 3) the potential for renal damage (a still unclear safety issue). It is anticipated that hepatic and renal issues still require dedicated postauthorization safety studies to ultimately assess causality.