Coagulation Tests and Reversal Agents in Patients Treated with Oral Anticoagulants: The Challenging Scenarios of Life-Threatening Bleeding and Unplanned Invasive Procedures.

In clinical practice, the number of patients treated with direct oral anticoagulants (DOACs) has consistently increased over the years. Since anticoagulant therapy has been associated with an annual incidence of major bleeding (MB) events of approximately 2% to 3.5%, it is of paramount importance to understand how to manage anticoagulated patients with major or life-threatening bleeding. A considerable number of these patients' conditions necessitate hospitalization, and the administration of reversal agents may be imperative to manage and control bleeding episodes effectively. Importantly, effective strategies for reversing the anticoagulant effects of DOACs have been well recognized. Specifically, idarucizumab has obtained regulatory approval for the reversal of dabigatran, and andexanet alfa has recently been approved for reversing the effects of apixaban or rivaroxaban in patients experiencing life-threatening or uncontrolled bleeding events. Moreover, continuous endeavors are being made to develop supplementary reversal agents. In emergency scenarios where specific reversal agents might not be accessible, non-specific hemostatic agents such as prothrombin complex concentrate can be utilized to neutralize the anticoagulant effects of DOACs. However, it is paramount to emphasize that specific reversal agents, characterized by their efficacy and safety, should be the preferred choice when suitable. Moreover, it is worth noting that adherence to the guidelines for the reversal agents is poor, and there is a notable gap between international recommendations and actual clinical practices in this regard. This narrative review aims to provide physicians with a practical approach to managing specific reversal agents.

Italian Association of Hospital Cardiologists Position Paper 'Gender discrepancy: time to implement gender-based clinical management'.

It has been well assessed that women have been widely under-represented in cardiovascular clinical trials. Moreover, a significant discrepancy in pharmacological and interventional strategies has been reported. Therefore, poor outcomes and more significant mortality have been shown in many diseases. Pharmacokinetic and pharmacodynamic differences in drug metabolism have also been described so that effectiveness could be different according to sex. However, awareness about the gender gap remains too scarce. Consequently, gender-specific guidelines are lacking, and the need for a sex-specific approach has become more evident in the last few years. This paper aims to evaluate different therapeutic approaches to managing the most common women's diseases.

How to Manage Beta-Blockade in Older Heart Failure Patients: A Scoping Review.

Beta blockers (BBs) play a crucial role in enhancing the quality of life and extending the survival of patients with heart failure and reduced ejection fraction (HFrEF). Initiating the therapy at low doses and gradually titrating the dose upwards is recommended to ensure therapeutic efficacy while mitigating potential adverse effects. Vigilant monitoring for signs of drug intolerance is necessary, with dose adjustments as required. The management of older HF patients requires a case-centered approach, taking into account individual comorbidities, functional status, and frailty. Older adults, however, are often underrepresented in randomized clinical trials, leading to some uncertainty in management strategies as patients with HF in clinical practice are older than those enrolled in trials. The present article performs a scoping review of the past 25 years of published literature on BBs in older HF patients, focusing on age, outcomes, and tolerability. Twelve studies (eight randomized-controlled and four observational) encompassing 26,426 patients were reviewed. The results indicate that BBs represent a viable treatment for older HFrEF patients, offering benefits in symptom management, cardiac function, and overall outcomes. Their role in HF with preserved EF, however, remains uncertain. Further research is warranted to refine treatment strategies and address specific aspects in older adults, including proper dosing, therapeutic adherence, and tolerability.

Heart Failure with Preserved Ejection Fraction: How to Deal with This Chameleon.

Heart failure with preserved ejection fraction (HFpEF) is characterized by a notable heterogeneity in both phenotypic and pathophysiological features, with a growing incidence due to the increase in median age and comorbidities such as obesity, arterial hypertension, and cardiometabolic disease. In recent decades, the development of new pharmacological and non-pharmacological options has significantly impacted outcomes, improving clinical status and reducing mortality. Moreover, a more personalized and accurate therapeutic management has been demonstrated to enhance the quality of life, diminish hospitalizations, and improve overall survival. Therefore, assessing the peculiarities of patients with HFpEF is crucial in order to obtain a better understanding of this disorder. Importantly, comorbidities have been shown to influence symptoms and prognosis, and, consequently, they should be carefully addressed. In this sense, it is mandatory to join forces with a multidisciplinary team in order to achieve high-quality care. However, HFpEF remains largely under-recognized and under-treated in clinical practice, and the diagnostic and therapeutic management of these patients remains challenging. The aim of this paper is to articulate a pragmatic approach for patients with HFpEF focusing on the etiology, diagnosis, and treatment of HFpEF.

Anderson-Fabry Disease: Red Flags for Early Diagnosis of Cardiac Involvement.

Anderson-Fabry disease (AFD) is a lysosome storage disorder resulting from an X-linked inheritance of a mutation in the galactosidase A (GLA) gene encoding for the enzyme alpha-galactosidase A (α-GAL A). This mutation results in a deficiency or absence of α-GAL A activity, with a progressive intracellular deposition of glycosphingolipids leading to organ dysfunction and failure. Cardiac damage starts early in life, often occurring sub-clinically before overt cardiac symptoms. Left ventricular hypertrophy represents a common cardiac manifestation, albeit conduction system impairment, arrhythmias, and valvular abnormalities may also characterize AFD. Even in consideration of pleiotropic manifestation, diagnosis is often challenging. Thus, knowledge of cardiac and extracardiac diagnostic "red flags" is needed to guide a timely diagnosis. Indeed, considering its systemic involvement, a multidisciplinary approach may be helpful in discerning AFD-related cardiac disease. Beyond clinical pearls, a practical approach to assist clinicians in diagnosing AFD includes optimal management of biochemical tests, genetic tests, and cardiac biopsy. We extensively reviewed the current literature on AFD cardiomyopathy, focusing on cardiac "red flags" that may represent key diagnostic tools to establish a timely diagnosis. Furthermore, clinical findings to identify patients at higher risk of sudden death are also highlighted.

[Gender discrepancy: time to implement gender-based clinical management]. / Position paper ANMCO: Differenze di genere nell'approccio farmacologico cardiovascolare.

It is well established that gender strongly influences cardiovascular risk factors, playing a crucial role in cardiovascular prevention, clinical pathways, diagnostic approach and treatment. Beyond the sex, which is a biological factor, gender entails a socio-cultural condition that impacts access and quality of care due to structural and institutional barriers. However, despite its great importance, this issue has not been adequately covered. Indeed sex and gender differences scarcely impact the clinical approach, creating a lot of disparities in care and outcomes of patients. Therefore, it becomes essential to increase the awareness of the importance of sex and gender influences on cardiovascular diseases. Moreover, new strategies for reducing disparities should be developed. Importantly, these differences should be taken into account in guideline recommendations. In this regard, it is crucial to include a greater number of women in clinical trials, since they are currently underrepresented. Furthermore, more women should be involved as member of international boards in order to develop recommendations and guidelines with more attention to this important topic.The aim of this ANMCO position paper is to shed light on gender differences concerning many cardiovascular drugs in order to encourage a more personalized therapeutic approach.

[ANMCO Position paper: Ionizing radiation exposure and radioprotection in the cath-lab]. / Position paper ANMCO: Radioesposizione e radioprotezione nei laboratori di cardiologia interventistica.

In the last decades, because of the improvements in the percutaneous treatment of coronary heart disease, valvular heart disease, congenital heart defects, and the increasing number of cardiac resynchronization therapy and cardioverter-defibrillator implantations, the interventional cardiologists' radio-exposure has importantly risen, causing concerns for ionizing radiation-associated diseases such as cancer and neurodegenerative disorders. Consequently, the radiation exposure issue importantly affects operators' safety. However, our knowledge of this field is poor and most operators are unaware to be at risk, especially because of the absence of effective preventive measures. The aim of this ANMCO position paper is to improve the awareness of operators and identify new ways of reducing operator ionizing radiation dose and minimizing the risk.

Management of Patients Treated with Direct Oral Anticoagulants in Clinical Practice and Challenging Scenarios.

It is well established that direct oral anticoagulants (DOACs) are the cornerstone of anticoagulant strategy in atrial fibrillation (AF) and venous thromboembolism (VTE) and should be preferred over vitamin K antagonists (VKAs) since they are superior or non-inferior to VKAs in reducing thromboembolic risk and are associated with a lower risk of intracranial hemorrhage (IH). In addition, many factors, such as fewer pharmacokinetic interactions and less need for monitoring, contribute to the favor of this therapeutic strategy. Although DOACs represent a more suitable option, several issues should be considered in clinical practice, including drug-drug interactions (DDIs), switching to other antithrombotic therapies, preprocedural and postprocedural periods, and the use in patients with chronic renal and liver failure and in those with cancer. Furthermore, adherence to DOACs appears to remain suboptimal. This narrative review aims to provide a practical guide for DOAC prescription and address challenging scenarios.

Management of Residual Risk in Chronic Coronary Syndromes. Clinical Pathways for a Quality-Based Secondary Prevention.

Chronic coronary syndrome (CCS), which encompasses a broad spectrum of clinical presentations of coronary artery disease (CAD), is the leading cause of morbidity and mortality worldwide. Recent guidelines for the management of CCS emphasize the dynamic nature of the CAD process, replacing the term "stable" with "chronic", as this disease is never truly "stable". Despite significant advances in the treatment of CAD, patients with CCS remain at an elevated risk of major cardiovascular events (MACE) due to the so-called residual cardiovascular risk. Several pathogenetic pathways (thrombotic, inflammatory, metabolic, and procedural) may distinctly contribute to the residual risk in individual patients and represent a potential target for newer preventive treatments. Identifying the level and type of residual cardiovascular risk is essential for selecting the most appropriate diagnostic tests and follow-up procedures. In addition, new management strategies and healthcare models could further support available treatments and lead to important prognostic benefits. This review aims to provide an overview of the diagnostic and therapeutic challenges in the management of patients with CCS and to promote more effective multidisciplinary care.

Appropriateness of Dyslipidemia Management Strategies in Post-Acute Coronary Syndrome: A 2023 Update.

It has been consistently demonstrated that circulating lipids and particularly low-density lipoprotein cholesterol (LDL-C) play a significant role in the development of coronary artery disease (CAD). Several trials have been focused on the reduction of LDL-C values in order to interfere with atherothrombotic progression. Importantly, for patients who experience acute coronary syndrome (ACS), there is a 20% likelihood of cardiovascular (CV) event recurrence within the two years following the index event. Moreover, the mortality within five years remains considerable, ranging between 19 and 22%. According to the latest guidelines, one of the main goals to achieve in ACS is an early improvement of the lipid profile. The evidence-based lipid pharmacological strategy after ACS has recently been enhanced. Although novel lipid-lowering drugs have different targets, the result is always the overexpression of LDL receptors (LDL-R), increased uptake of LDL-C, and lower LDL-C plasmatic levels. Statins, ezetimibe, and PCSK9 inhibitors have been shown to be safe and effective in the post-ACS setting, providing a consistent decrease in ischemic event recurrence. However, these drugs remain largely underprescribed, and the consistent discrepancy between real-world data and guideline recommendations in terms of achieved LDL-C levels represents a leading issue in secondary prevention. Although the cost-effectiveness of these new therapeutic advancements has been clearly demonstrated, many concerns about the cost of some newer agents continue to limit their use, affecting the outcome of patients who experienced ACS. In spite of the fact that according to the current recommendations, a stepwise lipid-lowering approach should be adopted, several more recent data suggest a "strike early and strike strong" strategy, based on the immediate use of statins and, eventually, a dual lipid-lowering therapy, reducing as much as possible the changes in lipid-lowering drugs after ACS. This review aims to discuss the possible lipid-lowering strategies in post-ACS and to identify those patients who might benefit most from more powerful treatments and up-to-date management.

[ANMCO Position paper: Choosing Wisely - ANMCO proposals for 2023]. / Position paper ANMCO: Choosing Wisely ­ le proposte dell'ANMCO nel 2023.

Nowadays, a progressive and exponential increase in the use of invasive and non-invasive instrumental diagnostics and therapeutic services has been shown. Although unnecessary, instrumental examinations are often largely prescribed, replacing clinical evaluation. Their correct use, on the contrary, would address precise epidemiological and clinical contexts. Therefore identifying whether a test or procedure is appropriate or not plays a crucial role in clinical practice. Several documents from scientific societies and expert groups indicate the most appropriate cardiovascular diagnostic and therapeutic procedures. The international Choosing Wisely campaign invited the main scientific societies to identify five techniques or treatments used in their field that are often unnecessary and may potentially damage patients. The Italian Association of Hospital Cardiologists (ANMCO) joined the project identifying the five cardiological practices in our country at greater risk of inappropriateness in 2014. This list has recently been updated. Moreover, possible solutions to this problem have been proposed.

Management of oral anticoagulant therapy after intracranial hemorrhage in patients with atrial fibrillation.

Intracranial hemorrhage (ICH) is considered a potentially severe complication of oral anticoagulants (OACs) and antiplatelet therapy (APT). Patients with atrial fibrillation (AF) who survived ICH present both an increased ischemic and bleeding risk. Due to its lethality, initiating or reinitiating OACs in ICH survivors with AF is challenging. Since ICH recurrence may be life-threatening, patients who experience an ICH are often not treated with OACs, and thus remain at a higher risk of thromboembolic events. It is worthy of mention that subjects with a recent ICH and AF have been scarcely enrolled in randomized controlled trials (RCTs) on ischemic stroke risk management in AF. Nevertheless, in observational studies, stroke incidence and mortality of patients with AF who survived ICH had been shown to be significantly reduced among those treated with OACs. However, the risk of hemorrhagic events, including recurrent ICH, was not necessarily increased, especially in patients with post-traumatic ICH. The optimal timing of anticoagulation initiation or restarting after an ICH in AF patients is also largely debated. Finally, the left atrial appendage occlusion option should be evaluated in AF patients with a very high risk of recurrent ICH. Overall, an interdisciplinary unit consisting of cardiologists, neurologists, neuroradiologists, neurosurgeons, patients, and their families should be involved in management decisions. According to available evidence, this review outlines the most appropriate anticoagulation strategies after an ICH that should be adopted to treat this neglected subset of patients.

Congenital Ventricular Diverticulum.

Herein, we describe a 54-year-old patient with a congenital ventricular diverticulum (CVD), referred to our emergency department for presyncope episodes and multiple re-entrant ventricular tachycardias (VT). Significantly, echocardiographic findings were not clear, and the diagnosis was made by cardiac magnetic resonance imaging (CMRI), which showed the presence of an apical accessory cavity connected to the ventricle and contracting synchronously. CMRI allowed the differential diagnosis with other outpouching cardiac defects. The patient underwent a subcutaneous implantable cardioverter defibrillator (S-ICD) implant and was referred for heart transplantation (HT). The diagnosis, treatment, and main findings of the CVD are discussed in this case report.

Late-onset fabry disease due to the p.Phe113Leu variant: the first italian cluster of five families.

BACKGROUND: The GLA c.337T > C (p.Phe113Leu) is a known pathogenic variant associated to late-onset Fabry disease phenotype with predominant cardiac manifestations. A founder effect was demonstrated in a large cohort in the Portuguese region of Guimarães. Herein we report an in-depth phenotype description of a cluster of five Southern Italy families. METHODS: Family pedigrees of five index males with the p.Phe113Leu variant were obtained and all at-risk relatives underwent biochemical and genetical screening test. Carriers of GLA p.Phe113Leu variant underwent subsequent multidisciplinary clinical and instrumental evaluation. RESULTS: Thirty-one (16 M, 15 F) individuals with p.Phe113Leu pathogenic variant were identified. Sixteen out of 31 patients (51.6%) had cardiac manifestations. Notably, myocardial fibrosis was found in 7/8 patients, of whom 2 were under 40 years. Stroke occurred in 4 patients. White matter lesions were detected in 12/19 patients and occurred in 2/10 of subjects under 40 years. Seven females complained of acroparesthesias. Renal involvement occurred in 10 patients. Angiokeratomas were evident in 9 subjects. Eyes, ear, gastrointestinal and pulmonary involvement occurred in the minority of subjects. CONCLUSION: This study demonstrates that a cluster of subjects with p.Phe113Leu pathogenic variant is also present in Southern Italy. Disease manifestations are frequent in both sexes and may occur early in life. Cardiac involvement represents the core manifestation, but neurological and renal involvement is also frequent, suggesting that extra-cardiac complications deserve clinical attention.

Superiority of Direct Oral Anticoagulants over Vitamin K Antagonists in Oncological Patients with Atrial Fibrillation: Analysis of Efficacy and Safety Outcomes.

Background and aim. Cancer and atrial fibrillation (AF) may be associated, and anticoagulation, either with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), is necessary to prevent thromboembolic events by reducing the risk of bleeding. The log incidence rate ratio (IRR) and 95% confidence interval were used as index statistics. Higgin's I2 test was adopted to assess statistical inconsistencies by considering interstudy variations, defined by values ranging from 0 to 100%. I2 values of less than 40% are associated with very low heterogeneity among the studies; values between 40% and 75% indicate moderate heterogeneity, and those greater than 75% suggest severe heterogeneity. The aim of this meta-analysis was to compare the safety and efficacy of VKAs and DOACs in oncologic patients with AF. Methods. A meta-analysis was conducted comparing VKAs to DOACs in terms of thromboembolic events and bleeding. A meta-regression was conducted to investigate the differences in efficacy and safety between four different DOACs. Moreover, a sub-analysis on active-cancer-only patients was conducted. Results. A total of eight papers were included. The log incidence rate ratio (IRR) for thromboembolic events between the two groups was −0.69 (p < 0.005). The meta-regression did not reveal significant differences between the types of DOACs (p > 0.9). The Log IRR was −0.38 (p = 0.008) for ischemic stroke, −0.43 (p = 0.02) for myocardial infarction, −0.39 (p = 0.45) for arterial embolism, and −1.04 (p = 0.003) for venous thromboembolism. The log IRR for bleeding events was −0.43 (p < 0.005), and the meta-regression revealed no statistical difference (p = 0.7). The log IRR of hemorrhagic stroke, major bleeding, and clinically relevant non-major bleeding between the VKA and DOAC groups was −0.51 (p < 0.0001), −0.45 (p = 0.03), and 0.0045 (p = 0.97), respectively. Similar results were found in active-cancer patients for all the endpoints except for clinically-relevant non-major bleedings. Conclusions. DOACs showed better efficacy and safety outcomes than VKAs. No difference was found between types of DOACs.

Late-onset Fabry disease due to a new (p.Pro380Leu) pathogenic variant of GLA Gene.

Fabry disease is a rare X-linked lysosomal storage disorder due to pathogenic variants of the galactosidase alpha (GLA) gene, leading to a deficiency of alpha-galactosidase A. The inadequate enzymatic activity leads to progressive glycosphingolipids accumulation within tissues and subsequent multi-systemic dysfunction, with predominant involvement of heart, kidney, and nervous system. Two subtypes are recognized: the classic type and the late-onset type. We here describe the clinical characteristics of a patient with late-onset Fabry disease carrying a not previously identified GLA gene variant. This 50-year-old man came to hospital because of an acute ischemic stroke. He also complained of acroparesthesia and had angiokeratomas in the nape and the back. Blood alpha-galactosidase A activity was low, plasmatic lyso-Gb3 level was borderline, cardiac MRI showed cardiac fibrosis, brain MRI documented cerebrovascular disease, and skin biopsy revealed small fiber neuropathy without globotriaosylceramide-3 skin deposits. Genetic study by means of targeted next-generation sequencing analysis disclosed a missense substitution c.1139C>T (p.Pro380Leu) in the GLA gene. We suggest that this novel variant should be considered as pathogenic and associated with a late-onset variant of Fabry disease with a predominant neurological phenotype.

Management of Acute Coronary Syndrome in Cancer Patients: It's High Time We Dealt with It.

Cancer patients have an increased risk of cardiovascular disease and, notably, a significant prevalence of acute coronary syndrome (ACS). It has been shown that an elevated presence of cardiovascular risk factors in this setting leads to an interaction between these two conditions, influencing their therapeutic strategies and contributing to higher mortality. Nonetheless, cancer patients have generally not been evaluated in ACS trials, so that the treatment in these cases is still not fully known. We reviewed the current literature and discussed the best management for these very high-risk patients. The treatment strategy must be tailored based on the cancer type and stage, balancing thrombotic and bleeding risks. When the prognosis is longer than six months, especially if a clinical instability coexists, patients with ACS and cancer should be referred for percutaneous coronary intervention (PCI) as soon as possible. Moreover, an invasive strategy should be preferred in STEMI patients as well as in NSTEMI patients who are considered as high risk. On the contrary, in clinically stable NSTEMI patients, a conservative non-invasive strategy could be adopted, especially in cases of a poor life expectancy and/or of high risk of bleeding. Drug-Eluting-Stents (DES) should be the first choice if an invasive strategy is adopted. Conservative therapy could instead be considered in cancer patients with more stable CAD at an increased risk of major bleeding complications. However, the duration of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is recommended, but it should be as short as possible, whereas triple antithrombotic therapy is non-advised because it significantly increases the risk of bleeding. ACS management among cancer patients should be based on an accurate evaluation of the risk of thrombosis and bleeding. Future studies focused on choosing optimal strategies in tumor patients with ACS should be performed to treat this subset of patients better.

Update on Management of Cardiovascular Diseases in Women.

Cardiovascular diseases (CVD) have a lower prevalence in women than men; although, a higher mortality rate and a poorer prognosis are more common in women. However, there is a misperception of CVD female risk since women have commonly been considered more protected so that the real threat is vastly underestimated. Consequently, female patients are more likely to be treated less aggressively, and a lower rate of diagnostic and interventional procedures is performed in women than in men. In addition, there are substantial sex differences in CVD, so different strategies are needed. This review aims to evaluate the main gender-specific approaches in CVD.

Obstructive Sleep Apnea and Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia, increasing with age and comorbidities. Obstructive sleep apnea (OSA) is a chronic sleep disorder more common in older men. It has been shown that OSA is linked to AF. Nonetheless, the prevalence of OSA in patients with AF remains unknown because OSA is significantly underdiagnosed. This review, including 54,271 patients, carried out a meta-analysis to investigate the association between OSA and AF. We also performed a meta-regression to explore cofactors influencing this correlation. A strong link was found between these two disorders. The incidence of AF is 88% higher in patients with OSA. Age and hypertension independently strengthened this association, indicating that OSA treatment could help reduce AF recurrence. Further research is needed to confirm these findings. Atrial Fibrillation (AF) is the most common arrhythmia, increasing with age and comorbidities. Obstructive sleep apnea (OSA) is a regulatory respiratory disorder of partial or complete collapse of the upper airways during sleep leading to recurrent pauses in breathing. OSA is more common in older men. Evidence exists that OSA is linked to AF. Nonetheless, the prevalence of OSA in patients with AF remains unknown because OSA is underdiagnosed. In order to investigate the incidence of AF in OSA patients, we carried out a meta-analysis including 20 scientific studies with a total of 54,271 subjects. AF was present in 4801 patients of whom 2203 (45.9%) had OSA and 2598 (54.1%) did not. Of a total of 21,074 patients with OSA, 2203 (10.5%) had AF and 18,871 (89.5%) did not. The incidence of AF was 88% higher in patients with OSA. We performed a meta-regression to explore interacting factors potentially influencing the occurrence of AF in OSA. Older age and hypertension independently strengthened this association. The clinical significance of our results is that patients with OSA should be referred early to the cardiologist. Further research is needed for the definition of the mechanisms of association between AF and OSA.