Major adverse cardiovascular events associated with VEGF-targeted anticancer tyrosine kinase inhibitors: a real-life study and proposed algorithm for proactive management.

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment and burdened by cardiovascular toxicity. The majority of data come from clinical trials, thus in selected populations. The aim of our study is to evaluate the cardiotoxicity profile of VEGFR-targeted TKIs and the impact of cardiovascular risk factors in a real-life population. PATIENTS AND METHODS: In this cohort, population-based study, patients treated with VEGFR-targeted TKIs, bevacizumab and trastuzumab between 2009 and 2014 were analyzed. A multi-source strategy for data retrieval through hospital, pharmaceutical and administrative databases of the Lombardy region, Italy, has been adopted. The primary endpoint was to determine the incidence and type of major adverse cardiovascular events (MACEs) along with their temporal trend. The secondary endpoint was to define the impact of cardiovascular risk factors in the occurrence of MACEs. RESULTS: A total of 829 patients were treated with VEGFR-targeted TKIs. Eighty-one MACEs occurred in the first year of follow-up [crude cumulative incidence (CCI): 9.79%] mainly consisting of arterial thrombotic events (ATEs, 31 events, CCI: 3.99%), followed by rhythm disorders (22 events, CCI: 2.66%), pulmonary embolisms and heart failures (13 events each, CCI: 1.57%). While the incidence of most MACEs showed a plateau after 6 months, ATEs kept increasing along the year of follow-up. Hypertension and dyslipidemia were associated with an increase in risk of ATEs [relative risk difference (RRD) +209.8% and +156.2%, respectively], while the presence of previous MACEs correlated with a higher risk of all MACEs in multivariate analysis (RRD 151.1%, 95% confidence interval 53.6% to 310.3%, P < 0.001). CONCLUSIONS: MACEs occur in a clinically significant proportion of patients treated with VEGFR-targeted TKIs, with ATEs being predominant, mainly associated with hypertension and dyslipidemia. A clinical algorithm for effective proactive management of these patients is warranted.

What are the Characteristics of Patients Experiencing Adverse Drug Reactions to Oral Anticogulants and How Can Such Reactions be Prevented?

INTRODUCTION: Oral anticoagulants, including vitamin K inhibitors (VKAs) and direct anticoagulants (DOACs) are important for preventing and treating thromboembolic diseases. However, they are not recommended for use in all patients due to negative side effects and adverse drug reactions (ADRs). Currently, there is a paucity of information about their use in real life. Therefore, the aim of this pilot study is to report on the rate of serious ADRs in oral anticoagulant users, determine patient characteristics associated with increased risk of ADRs, and identify possible management strategies for reducing risk of ADRs within a hospital setting. METHODS: Patients admitted to the Internal Medicine Department of the Vimercate Hospital were recruited between November 1, 2015 and October 31, 2016. All patients reporting an ADR associated with anticoagulant use were selected. Demographic, clinical, and observational data were extracted from electronic hospital records, in particular, by the hospital discharge letters and other clinical records. The main outcome of the study was to evaluate the incidence of anticoagulants serious adverse drug reactions conditioning hospital admission, the percentage of preventable reactions, and the determinants of those. RESULTS AND DISCUSSION: Of the 2,064 admissions, 102 (4.9%) eligible patients were identified. Age ranged from 60-95 years (mean = 81.9, standard deviation = 6,59) and 47.1% (n=48) were female. Of the 102 cases, 68 used VKAs and 34 used DOACs. The most common admission diagnosis was heart failure following anemia or hemorrhage (56 cases), followed by acute hemorrhage (with or without anemia; 29 cases), and anemia not associated with evident hemorrhage (17cases). The majority of VKA users (n=65, 95.6%) had a high risk of major bleeding. ADRs were found to be preventable in 96% of VKA users and 68% of DOACs users. CONCLUSION: This study highlights the large percentage of ADRs from oral anticoagulants that can be avoided with more careful patient management. Periodic check-up of cardiac and renal function, as well as blood count, may be useful for reducing the risk of ADRs, especially in older DOACs users. Further research is needed to get new data to improve the patients monitoring system.

Allergy and the gastrointestinal system.

The gastrointestinal system plays a central role in immune system homeostasis. It is the main route of contact with the external environment and is overloaded every day with external stimuli, sometimes dangerous as pathogens (bacteria, protozoa, fungi, viruses) or toxic substances, in other cases very useful as food or commensal flora. The crucial position of the gastrointestinal system is testified by the huge amount of immune cells that reside within it. Indeed, gut-associated lymphoid tissue (GALT) is the prominent part of mucosal-associated lymphoid tissue (MALT) and represents almost 70% of the entire immune system; moreover, about 80% of plasma cells [mainly immunoglobulin A (IgA)-bearing cells] reside in GALT. GALT interacts strictly with gastrointestinal functions in a dynamic manner; for instance, by increasing intestinal permeability in replay to particular stimulations, or orientating the immune response towards luminal content, allowing either tolerance or elimination/degradation of luminal antigens, or sometimes provoking damage to the intestinal mucosa, such as in coeliac disease or food allergy. The immune mechanisms implicated in these actions are very complex and belong to both innate and adaptive immunity; innate immunity supplies an immediate non-specific response that is indispensable before specific adaptive immunity, which needs 7-10 days to be efficacious, takes place. The results of their interactions depend upon different contexts in which contact with external agents occurs and may change according to different genetic settings of the hosts.