[Non-inferiority trials]. / Gli studi di non-inferiorità.

Superiority trials are designed to test the hypothesis that a given diagnostic or therapeutic strategy is better than (i.e. "superior to") placebo or an active control. Conversely, non-inferiority trials test the hypothesis that a newer (i.e. alternative) strategy is not "unacceptably worse" than a control (i.e. "traditional", or "older") strategy. Non-inferiority trials are increasingly conducted in clinical medicine more often when a "newer" strategy is supposed to offer a relevant advantage in terms other than clinical efficacy (i.e. better tolerability, less cost, simpler regimen, etc.) versus a "gold standard" traditional strategy. The principle underlying non-inferiority trials is that the above advantage justifies the preferential use of the newer strategy in the clinical practice even if the clinical efficacy of the "new" appears to be a bit worse than that of the "old", albeit not unacceptably worse (i.e. not beyond a pre-specified value). The demonstration of non-inferiority requires that the confidence interval of the point estimate (e.g. the hazard ratio) does not cross a pre-specified limit. The definition of such pre-specified limit, the so called "non-inferiority margin", is a pivotal point when planning non-inferiority trials. It denotes the maximally tolerated worse effect of the alternative strategy, compared with the traditional one, required to conclude that an alternative strategy is non-inferior to the traditional "gold standard". The non-inferiority margin is derived from previous trials evaluating the efficacy of the traditional strategy vs placebo. We reviewed the principles and the practical aspects in the design and conduct of non-inferiority trials.

Electrical storm treatment by percutaneous stellate ganglion block: the STAR study.

BACKGROUND AND AIMS: An electrical storm (ES) is a clinical emergency with a paucity of established treatment options. Despite initial encouraging reports about the safety and effectiveness of percutaneous stellate ganglion block (PSGB), many questions remained unsettled and evidence from a prospective multicentre study was still lacking. For these purposes, the STAR study was designed. METHODS: This is a multicentre observational study enrolling patients suffering from an ES refractory to standard treatment from 1 July 2017 to 30 June 2023. The primary outcome was the reduction of treated arrhythmic events by at least 50% comparing the 12 h following PSGB with the 12 h before the procedure. STAR operators were specifically trained to both the anterior anatomical and the lateral ultrasound-guided approach. RESULTS: A total of 131 patients from 19 centres were enrolled and underwent 184 PSGBs. Patients were mainly male (83.2%) with a median age of 68 (63.8-69.2) years and a depressed left ventricular ejection fraction (25.0 ± 12.3%). The primary outcome was reached in 92% of patients, and the median reduction of arrhythmic episodes between 12 h before and after PSGB was 100% (interquartile range -100% to -92.3%). Arrhythmic episodes requiring treatment were significantly reduced comparing 12 h before the first PSGB with 12 h after the last procedure [six (3-15.8) vs. 0 (0-1), P < .0001] and comparing 1 h before with 1 h after each procedure [2 (0-6) vs. 0 (0-0), P < .001]. One major complication occurred (0.5%). CONCLUSIONS: The findings of this large, prospective, multicentre study provide evidence in favour of the effectiveness and safety of PSGB for the treatment of refractory ES.

Multimodality Imaging for Selecting Candidates for CRT: Do We Have a Single Alley to Increase Responders?

Cardiac resynchronization therapy has evolved in recent years to provide a reduction of morbidity and mortality for many patients with heart failure. Its application and optimization is an evolving field and its use requires a multidisciplinary approach for patient and device selection, technical preprocedural planning, and optimization. While echocardiography has always been considered the first line for the evaluation of patients, additional imaging techniques have gained increasing evidence in recent years. Today different details about heart anatomy, function, dissynchrony can be investigated by magnetic resonance, cardiac computed tomography, nuclear imaging, and more, with the aim of obtaining clues to reach a maximal response from the electrical therapy. The purpose of this review is to provide a practical analysis of the single and combined use of different imaging techniques in the preoperative and perioperative phases of cardiac resynchronization therapy, underlining their main advantages, limitations, and information provided.

Catheter-based renal artery denervation: facts and expectations.

Catheter-based renal artery denervation (RAD) is entering a new era. After the disappointing results of SYMPLICITY-HTN 3 trial in year 2014, several technical and methodological advancements led to execution of important SHAM-controlled randomized trials with promising results. Now, the 2023 ESH Guidelines give RAD a class of recommendation II with a Level of Evidence B. Currently, catheter-based RAD has two main areas of application: (a) Hypertensive patients who are still untreated, in whom RAD is a sort of a first-line treatment; (b) Difficult-to-control or true resistant hypertensive patients. Notably, randomized SHAM-controlled trials met their primary end-point in both these conditions. So far, we do not dispose of established predictors of the antihypertensive response to RAD. Some data suggest that younger patients with systo-diastolic hypertension, absence of diffuse atherosclerosis and evidence of sympathetic nervous system overactivity experience a better BP response to the procedure. We reviewed the available data on catheter-based RAD and included an updated meta-analysis of the results of the available SHAM-controlled trials. Overall, the reduction in 24-h systolic blood pressure (BP) after RAD exceeded that after SHAM by 4.58 mmHg (95% CI 3.07-6.10) in untreated patients, and by 3.82 mmHg (95% CI 2.46-5.18) in treated patients, without significant heterogeneity across trials, patient phenotype (untreated versus treated patients) and technique (radiofrequency versus ultrasound). There were no important safety signals related to the procedure. Notably, some data suggest that RAD could be an effective additional approach in patients with atrial fibrillation and other conditions characterized by sympathetic nervous system overactivity.

Therapy of Type 2 diabetes: more gliflozines and less metformin?

Metformin is a frequently used anti-diabetic drug. In addition to the well-known modulating properties on glyco-metabolic control, metformin reduces cardiovascular (CV) risk partly independently of its anti-hyperglycaemic effect. The use of 'new' anti-diabetic drugs, inhibitors of the renal Na-glucose co-transporter (SGLTs-I or 'gliflozines') and GLP-1 receptor agonists (GLP1-RAs), has further contributed to challenge the strictly 'gluco-centric' view of diabetic CV disease. Several controlled trials have demonstrated that the cardio-renal benefits of gliflozines and GLP1-RAs are present regardless of the presence of metformin as 'background' therapy. The impact on the 'cardio-renal continuum' exerted by SGLTs-I was also noted in non-diabetic patients with heart failure and reduced or preserved ventricular function and different levels of renal function. These drugs reduced re-hospitalization, CV mortality, and progression to end-stage renal disease. These clinical acquisitions, implemented by Scientific Societies, have led to a change in the therapeutic approach to diabetic cardio-renal disease. Although metformin still represents a valid therapeutic option to be offered particularly to 'naïve' diabetic patients without previous cardio-renal events, SGLTs-I and/or GLP1-RAs emerge as 'first-line' drugs in diabetic patients with previous CV events, or at high CV risk, without having to request 'on board' metformin therapy.

Cardiac complications of COVID-19 vaccination: now we know more.

The proliferation of good quality observational studies on the potential adverse effects of COVID-19 vaccination has greatly increased our knowledge on myocarditis and pericarditis, and also, more recently, on arterial hypertension. According to some recent studies, the incidence of a significant increase in blood pressure after COVID-19 vaccination is about 3.2% (95% CI: 1.62-6.21). The incidence of serious hypertensive emergencies or stage III hypertension has been reported as 0.6%. It is well known that the 'spike protein' of the Sars-CoV-2 virus, the synthesis of which is induced by vaccines, binds to ACE2 receptors, inducing their migration towards the inside of the cell. This would result in a lack of ACE2 activity on cell surfaces and therefore a relative deficiency of angiotensin1-7 with a relative excess of angiotensin II, which could explain, at least in part, the blood pressure increases. Regarding myo-pericarditis, there is evidence that the advantages of COVID-19 vaccination over non-vaccination remain preponderant in terms of prevented hospitalizations and serious complications of COVID-19, compared with the risk of developing myocarditis. In the age group most at risk of COVID-19 vaccine myocarditis (12-29 years), for every 100 000 vaccinated, compared to about four more cases of myocarditis we have 56 fewer hospitalizations, 13.8 admissions to intensive care and 0.6 fewer deaths. Several studies have shown that post vaccine myocarditis/pericarditis are generally short-lasting phenomena with favourable clinically course.

Inadvertent Lead Malposition in the Left Heart during Implantation of Cardiac Electric Devices: A Systematic Review.

BACKGROUND: The inadvertent lead malposition in the left heart (ILMLH) is an under-recognized event, which may complicate the implantation of cardiac electronic devices (CIEDs). METHODS: We investigated the clinical conditions associated with ILMLH and the treatment strategies in these patients. We made a systematic review of the literature and identified 132 studies which reported 157 patients with ILMLH. RESULTS: The mean age of patients was 68 years, and 83 were women. ILMLH was diagnosed, on average, 365 days after CIEDs implantation. Coexisting conditions were patent foramen ovale in 29% of patients, arterial puncture in 24%, perforation of the interatrial septum in 20%, atrial septal defect in 16% and perforation of the interventricular septum in 4%. At the time of diagnosis of ILMLH, 46% of patients were asymptomatic, 31% had acute TIA or stroke and 15% had overt heart failure. Overall, 14% of patients were receiving anticoagulants at the time of diagnosis of ILMLH. After diagnosis of ILMLH, percutaneous or surgical lead extraction was carried out in 93 patients (59%), whereas 43 (27%) received anticoagulation. During a mean 9-month follow-up after diagnosis of ILMLH, four patients experienced TIA or stroke (three on oral anticoagulant therapy and one after percutaneous lead extraction). CONCLUSION: ILMLH is a rare complication, which is usually diagnosed about one year after implantation of CIEDs. An early diagnosis of ILMLH is important. Lead extraction is a safe and effective alternative to anticoagulants.

Typical Atrial Flutter Mapping and Ablation.

Isthmus-dependent flutter represents a defeated arrhythmia. Possibly one of the most outstanding successes in terms of understanding the mechanism behind it has led to an effective, relatively simple, and safe targeted therapy. Technology, fulfilling a number of the clinical electrophysiologist's dreams, has linked diagnosis and therapy in computerized systems showing real-time imagines of the right atrium, the arrhythmia circuit, and the ablation target. The entire history of clinical electrophysiology is contained in its path and atrial flutter needs to be regarded with immense respect for a large amount of knowledge that its study always engenders."

Optimized radiofrequency lesions through local impedance guidance for effective CTI ablation in right atrial flutter.

BACKGROUND: Although radiofrequency (RF) catheter ablation of cavo-tricuspid isthmus (CTI) is an established treatment for typical right atrial flutter (RAFL), it remains to be established whether local tissue impedance (LI) is able to predict effective CTI ablation and what LI drop values during ablation should be used to judge a lesion as effective. We aimed to investigate the ability of LI to predict ablation efficacy in patients with RAFL. METHODS: RF delivery was guided by the DirectSense™ algorithm. Successful single RF application was defined according to a defragmentation of atrial potentials (DAP), reduction of voltage (RedV) by at least 80% or changes on unipolar electrogram (UPC). The ablation endpoint was the creation of bidirectional conduction block (BDB) across the isthmus. RESULTS: 392 point-by-point RF applications were analyzed in 48 consecutive RAFL patients. The mean baseline LI was 105.4 ± 12Ω prior to ablation and 92.0 ± 11Ω after ablation (p < 0.0001). According to validation criteria, absolute drops in impedance were larger at successful ablation sites than at ineffective ablation sites (DAP: 17.8 ± 6Ω vs. 8.7 ± 4Ω; RedV: 17.2 ± 6Ω vs. 7.8 ± 5Ω; UPC: 19.6 ± 6Ω vs. 10.1 ± 5Ω, all p < 0.0001). LI drop values significantly increased according to the number of criteria satisfied (ranging from 7.5Ω to 19.9). BDB was obtained in all cases. No procedure-related adverse events were reported. CONCLUSIONS: A LI-guided approach to CTI ablation was safe and effective in treating RAFL. The magnitude of LI drop was associated with effective lesion formation and BDB and could be used as a marker of ablation efficacy. CLINICAL TRIAL REGISTRATION: Catheter Ablation of Arrhythmias with a High-Density Mapping System in Real-World Practice (CHARISMA). URL: http://clinicaltrials.gov/ Identifier: NCT03793998.

Permanent His bundle pacing using a new tridimensional delivery sheath and a standard active fixation pacing lead: The telescopic technique.

INTRODUCTION: Permanent His bundle pacing (PHBP) preserves physiological ventricular activation but technical difficulties have limited its widespread use. We report the first experience of PHBP performed with a new specific delivery sheath (Selectra 3D, Biotronik, Berlin, Germany) and an extendable-retractable active screw, stylet-driven pacing lead (Solia S 60, Biotronik). METHODS AND RESULTS: Clinical, procedural, ECG, and electrical data from consecutive patients undergoing PHBP with this system were collected at implantation, and follow-up was performed after 1 month. Our cohort included 17 patients (71% males; mean age 76 ± 8 years) undergoing permanent pacing for sick sinus syndrome (59%) or atrioventricular block (41%). PHBP was successful in 15 (88%) procedures with mean procedure and fluoroscopy times of 63 ± 14 and 13 ± 5 min, respectively. The pacing threshold was 2.1 ± 1.1 V @1 ms and the sensed R-wave amplitude was 5.6 ± 3.5 mV; bipolar and unipolar pacing impedances were 526 ± 115 and 369 ± 109 Ω, respectively. At discharge, neither procedure-related complications nor lead dislodgement or pacing capture failures was reported. After 1 month, 14 (93%) patients still demonstrated His bundle stimulation and one (7%) lost His bundle capture but the lead revision was not necessary because the myocardial pacing threshold was stable. Follow-up threshold (2 ± 1.1 vs. 2.3 ± 1.2 V@1 ms, p = .239) and sensed R-wave amplitude (5.6 ± 3.4 vs. 6.4 ± 2.5, p = .403) was unchanged compared to the acute phase. CONCLUSION: PHBP performed with a standard active fixation pacing lead and a new delivery sheath for His pacing is feasible, safe and demonstrates clinically acceptable electric performance both at implantation and after 1 month.

Ventricular Preexcitation: An Anomalous Wave Interfering with the Ordered Ventricular Activation.

Ventricular preexcitation is a depolarization of the ventricles that occurs before the conventional sequence, and the electrocardiogram is the specific test for diagnosis. A Kent bundle is the paradigm of ventricular preexcitation, and it is associated with short PR, wide QRS and delta wave. This finding is not always very evident, as it can have different degrees of pre-eccitazione; therefore great diagnostic care must be taken in this field. If not properly identified, the pattern of ventricular preexcitation may lead to an incorrect diagnosis. The methodology of precision electrocardiology is able to confront all these aspects.

[Peri-myocarditis during urinary tract infection by Escherichia coli]. / Peri-miocardite durante infezione delle vie urinarie da Escherichia coli.

We report a case of acute myocarditis associated with pericarditis in a patient hospitalized for urinary tract infection due to Escherichia coli. To the best of our knowledge, there are no prior descriptions of acute myocarditis associated with pericarditis during Escherichia coli infections in the absence of sepsis. In our patient, myocardial damage has been accurately documented by electrocardiography, echocardiography and magnetic resonance imaging. Inclusion of magnetic resonance imaging allows detection of myocardial inflammatory lesions that otherwise would have remained undiagnosed. The basic mechanisms of myocardial damage during Escherichia coli infection are unclear. Endotoxins might cause inflammatory reactions in the myocardium leading to myocyte damage. After initiation of antibiotic therapy, there was a rapid improvement of contractile function, with concomitant normalization of clinical and biochemical abnormalities. We discussed our findings in the context of the limited information available from the literature.

Myocardial Perfusion Is Impaired and Relates to Cardiac Dysfunction in Patients With Atrial Fibrillation Both Before and After Successful Catheter Ablation.

Background Atrial fibrillation ( AF ) is associated with myocardial infarction, and patients with AF and no obstructive coronary artery disease can present with symptoms and evidence of cardiac ischemia. We hypothesized that microvascular coronary dysfunction underlies these observations. Methods and Results Myocardial blood flow ( MBF ) at baseline and during adenosine stress and left ventricular and left atrial function were evaluated by magnetic resonance in 49 patients with AF (25 paroxysmal, 24 persistent) with no history of epicardial coronary artery disease or diabetes mellitus, before and 6 to 9 months after ablation. Findings were compared with those obtained in matched controls in sinus rhythm (n=25). Before ablation, patients with AF had impaired left atrial function and left ventricular ejection fraction and strain indices (all P<0.05 versus controls). MBF was impaired in patients both under baseline conditions (1.21±0.24 mL/min per g·[mm Hg·bpm/104]-1 versus 1.34±0.28 mL/min per g·[mm Hg·bpm/104]-1 in controls, P=0.044) and during adenosine stress (2.29±0.48 mL/min per g versus 2.73±0.37 mL/min per g in controls, P<0.001). Under baseline conditions, MBF correlated with left ventricular strain and left atrial function (all P≤0.001), so that cardiac function was most impaired in patients with the lowest MBF . Baseline and stress MBF remained unchanged postablation (both P=ns), and baseline MBF showed similar correlations with functional indices to those present preablation (all P≤0.001). Conclusions Baseline and stress MBF are significantly impaired in patients with AF but no epicardial coronary artery disease. Reduction in MBF is proportional to severity of left ventricular and left atrial dysfunction, even after successful ablation. Coronary microvascular dysfunction may be a relevant pathophysiological mechanism in patients with a history of AF .

Bailout surgical explantation of a transcatheter valve-in-valve for subacute thrombosis: When there is no time for anticoagulation: Case report and literature review.

Trancatheter heart valve (THV) thrombosis is effectively treated with anticoagulation but alternative therapies are required when a faster gradient reduction is needed. Open heart surgery has been rarely performed due to the high perioperative mortality and only five cases have been described so far. Here we describe a case of emergent surgical explantation for THV thrombosis after a valve-in-valve. A 67years old man underwent transcatheter aortic valve implantation for a failed surgical bioprosthesis Epic 21mm (St. Jude Medical; St. Paul, Minnesota, US). A CoreValve 23mm (Medtronic, Minneapolis, Minnesota, US) was implanted through femoral access under conscious sedation without complications. Mean transvalvular gradient was effectively reduced (33mmHg vs 16mmHg) with no more than mild residual aortic regurgitation. After 8days the patient was discharged on dual antiplatelet therapy but was readmitted to the intensive care unit for pulmonary oedema 13days later. Echocardiography showed a raised transvalvular mean gradient (mean gradient change from discharge=15mmHg) without aortic regurgitation. Heart Team decided for emergent open heart surgery for the hemodynamic instability. On direct inspection THV was well positioned inside the surgical bioprosthesis but two cusps were covered by thrombus which markedly restricted their mobility. The THV and the former surgical valve were explanted and a new larger stented bioprosthesis was implanted. Thrombosis of the THV was confirmed on microscopic examination which showed no signs of inflammation or degeneration. The patient was discharged after 1month and the 3month follow up showed stable transvalvular gradients.

TAVI for Failed Valve-Sparing Operations: In-Hospital and Mid-Term Outcome.

BACKGROUND AND AIM OF THE STUDY: Although transcatheter aortic valve implantation (TAVI) is a steadily expanding treatment for the pathology of the aortic valve, its role in the replacement of native aortic valves following valve-sparing surgery has not been investigated. METHODS: Among 150 patients who underwent TAVI at the authors' institution, three (2%) had a failed valve-sparing operation. The in-hospital outcome, mid-term mortality, and valvular function of the three patients were evaluated retrospectively. These patients, who were deemed at high surgical risk by the heart team, underwent TAVI for predominant severe aortic stenosis (n = 2) or pure severe aortic regurgitation (AR) (n = 1). RESULTS: A self-expandable CoreValve prosthesis was inserted via femoral access in all three patients. Based on the Valve Academic Research Consortium 2 criteria (VARC-2), implantation was successful in all cases, with only one major access site complication and no more than mild residual AR. At a follow up of 13 ± 6 months there were no deaths and the mean transvalvular gradient remained low (7 ± 6 mmHg at discharge; 7 ± 4 mmHg at follow up), without any echocardiographic signs of valve deterioration. CONCLUSIONS: The results obtained with this small patient cohort demonstrated the feasibility, safety, and favorable mid-term outcomes of TAVI for failed valve-sparing operations in high surgical risk patients. However, these findings must be validated in larger cohorts before extending such treatment routinely to this subset of patients.