Oral anticoagulation for atrial fibrillation in the era of non-vitamin K antagonist anticoagulants. Focus on very elderly patients

Introduction. Atrial fibrillation is the most common cardiac arrhythmia, characterized by irregular heart rhythm and associated with left atrial and left appendage thrombi formation that may cause ischemic stroke. Oral anticoagulant therapy has been shown to reduce the incidence of ischemic stroke in these patients by about two thirds, at the expense of an increase in bleeding. In the elderly, atrial fibrillation is particularly frequent, but anticoagulant therapy often encounter several issues: in fact, although ischemic risk increases with age, haemorrhagic risk is also high and often doctors prefers not to prescribe or discontinue oral anticoagulant therapy in fear of complications. The elderly patient, moreover, is often affected by multiple diseases, takes several drugs with potential risk of interactions and may have lower adherence to therapy. Aim. To evaluate the impact of anticoagulation in the elderly patient, focusing on the subgroup of very elderly patients (i.e. 80 years of age) who are often not included in major clinical trials. VENPAF. We initially conducted a retrospective "inception cohort" study involving all patients 80 years of age referred to the local Thrombosis Centre to start anticoagulant therapy with warfarin for atrial fibrillation (VENPAF study). From data analysis, we found that major haemorrhages rate is very high and tends to increase considerably over 85 years of age. Nevertheless, net clinical benefit appears to be maintained, as the calculated incidence of thromboembolism in the absence of anticoagulant therapy was higher in both age classes compared to the observed incidence of major haemorrhages. About 20% of these patients had discontinued warfarin and this was often decided by the general practitioner or the specialist; main reasons for discontinuation were low life expectancy, fragility and excessive haemorrhagic risk. We found that therapy discontinuation was not associated with an improvement in prognosis, but indeed these patients faced high rates of mortality, ischemic and haemorrhagic events, regardless of persistence or discontinuation of anticoagulant therapy. Analysing only patients who experienced a major bleeding event during anticoagulant therapy, we could highlight how the cumulative incidence of ischemic and haemorrhagic events was significantly higher in patients who suspended therapy than those who resumed it after the index event.control study. A case-control study was set to analyse which factors may possibly be associated with the development of intracranial haemorrhage with warfarin (the most serious complication of oral anticoagulant therapy). All patients followed by our Thrombosis Centre who developed intracranial bleeding in anticoagulant therapy were included; control group was created from anticoagulated patients paired for age, sex, and exposure to therapy in a 1:4 ratio. No variable was associated with the development of bleeding. We also could evaluate ischemic risk for each patient using HAS-BLED, ATRIA and ORBIT haemorrhage scores; these scores showed a predisposing capacity for particularly poor intracranial haemorrhage (c-statistic around 0.55 for all three scores). Veneto Region Registry. After the analysis of cerebral bleedings during warfarin therapy, we focused on the use of non-vitamin K oral anticoagulants (NOAC), which demonstrated to halve cerebral bleeding as compared with warfarin in clinical trials. Using Veneto Region registries of pharmacological prescriptions, exemptions, and department discharge diagnoses, we were able to select patients who started oral anticoagulant therapy because of non-valvular atrial fibrillation and compared patients who started warfarin therapy versus those who started a NOAC. Results were broadly consistent with the literature, with similar efficacy and safety but a sharp reduction in intracranial bleedings and a mild reduction in mortality with NOAC, despite the good quality of warfarin anticoagulation achieved thanks to the thrombosis centers of our regions. Moreover, we found that patients treated with NOAC in Veneto region are on average older and at higher ischemic risk than patients treated with warfarin. Finally, we analysed the subset of patients ≥80 years old and found a marked increase in gastrointestinal bleeding, especially from the lower tract, in patients treated with NOAC. However, ischemic stroke and total major bleedings rates were similar among the two groups and NOAC patients showed a lower risk of intracranial haemorrhage. Conclusions. The present work analysed the effects of anticoagulant therapy in elderly patients with 80 years or more. Based on the different studies we conducted, it was possible to conclude that, despite the high risk of haemorrhage, clinical benefit for the prevention of stroke is in favour for the use of these drugs in this subset of patients. In fact, patients who suspended anticoagulant treatment had a worse prognosis than patients who persisted. Intracranial hemorrhage is the most fearful side effect of anticoagulant treatment, being related to very high rates of mortality and disability; from our findings, these events are more frequent in the elderly and are not predictable by common cardiovascular risk factors or good anticoagulation quality. Data on NOAC users, on the other hand, seem to confirm that the risk of intracranial bleeding is inferior to warfarin even in the very elderly, despite a significant increase in the risk of gastrointestinal haemorrhage. Overall, therefore, our data confirms NOAC as the preferred anticoagulant therapy in very elderly patients with non-valvular atrial fibrillation

Oral anticoagulation for atrial fibrillation in the era of non-vitamin K antagonist anticoagulants. Focus on very elderly patients

Introduction. Atrial fibrillation is the most common cardiac arrhythmia, characterized by irregular heart rhythm and associated with left atrial and left appendage thrombi formation that may cause ischemic stroke. Oral anticoagulant therapy has been shown to reduce the incidence of ischemic stroke in these patients by about two thirds, at the expense of an increase in bleeding. In the elderly, atrial fibrillation is particularly frequent, but anticoagulant therapy often encounter several issues: in fact, although ischemic risk increases with age, haemorrhagic risk is also high and often doctors prefers not to prescribe or discontinue oral anticoagulant therapy in fear of complications. The elderly patient, moreover, is often affected by multiple diseases, takes several drugs with potential risk of interactions and may have lower adherence to therapy. Aim. To evaluate the impact of anticoagulation in the elderly patient, focusing on the subgroup of very elderly patients (i.e. 80 years of age) who are often not included in major clinical trials. VENPAF. We initially conducted a retrospective "inception cohort" study involving all patients 80 years of age referred to the local Thrombosis Centre to start anticoagulant therapy with warfarin for atrial fibrillation (VENPAF study). From data analysis, we found that major haemorrhages rate is very high and tends to increase considerably over 85 years of age. Nevertheless, net clinical benefit appears to be maintained, as the calculated incidence of thromboembolism in the absence of anticoagulant therapy was higher in both age classes compared to the observed incidence of major haemorrhages. About 20% of these patients had discontinued warfarin and this was often decided by the general practitioner or the specialist; main reasons for discontinuation were low life expectancy, fragility and excessive haemorrhagic risk. We found that therapy discontinuation was not associated with an improvement in prognosis, but indeed these patients faced high rates of mortality, ischemic and haemorrhagic events, regardless of persistence or discontinuation of anticoagulant therapy. Analysing only patients who experienced a major bleeding event during anticoagulant therapy, we could highlight how the cumulative incidence of ischemic and haemorrhagic events was significantly higher in patients who suspended therapy than those who resumed it after the index event.control study. A case-control study was set to analyse which factors may possibly be associated with the development of intracranial haemorrhage with warfarin (the most serious complication of oral anticoagulant therapy). All patients followed by our Thrombosis Centre who developed intracranial bleeding in anticoagulant therapy were included; control group was created from anticoagulated patients paired for age, sex, and exposure to therapy in a 1:4 ratio. No variable was associated with the development of bleeding. We also could evaluate ischemic risk for each patient using HAS-BLED, ATRIA and ORBIT haemorrhage scores; these scores showed a predisposing capacity for particularly poor intracranial haemorrhage (c-statistic around 0.55 for all three scores). Veneto Region Registry. After the analysis of cerebral bleedings during warfarin therapy, we focused on the use of non-vitamin K oral anticoagulants (NOAC), which demonstrated to halve cerebral bleeding as compared with warfarin in clinical trials. Using Veneto Region registries of pharmacological prescriptions, exemptions, and department discharge diagnoses, we were able to select patients who started oral anticoagulant therapy because of non-valvular atrial fibrillation and compared patients who started warfarin therapy versus those who started a NOAC. Results were broadly consistent with the literature, with similar efficacy and safety but a sharp reduction in intracranial bleedings and a mild reduction in mortality with NOAC, despite the good quality of warfarin anticoagulation achieved thanks to the thrombosis centers of our regions. Moreover, we found that patients treated with NOAC in Veneto region are on average older and at higher ischemic risk than patients treated with warfarin. Finally, we analysed the subset of patients ≥80 years old and found a marked increase in gastrointestinal bleeding, especially from the lower tract, in patients treated with NOAC. However, ischemic stroke and total major bleedings rates were similar among the two groups and NOAC patients showed a lower risk of intracranial haemorrhage. Conclusions. The present work analysed the effects of anticoagulant therapy in elderly patients with 80 years or more. Based on the different studies we conducted, it was possible to conclude that, despite the high risk of haemorrhage, clinical benefit for the prevention of stroke is in favour for the use of these drugs in this subset of patients. In fact, patients who suspended anticoagulant treatment had a worse prognosis than patients who persisted. Intracranial hemorrhage is the most fearful side effect of anticoagulant treatment, being related to very high rates of mortality and disability; from our findings, these events are more frequent in the elderly and are not predictable by common cardiovascular risk factors or good anticoagulation quality. Data on NOAC users, on the other hand, seem to confirm that the risk of intracranial bleeding is inferior to warfarin even in the very elderly, despite a significant increase in the risk of gastrointestinal haemorrhage. Overall, therefore, our data confirms NOAC as the preferred anticoagulant therapy in very elderly patients with non-valvular atrial fibrillation.Introduzione. La fibrillazione atriale è l’aritmia cardiaca più comune, caratterizzata da un ritmo cardiaco irregolare, spesso ad alta frequenza, e associato alla formazione di trombi in atrio e auricola sinistra che possono causare l’ictus ischemico cardioembolico. La terapia anticoagulante orale ha dimostrato di ridurre l’incidenza di ictus ischemico in questI pazienti di circa due terzi, alle spese però di un’aumentata incidenza dei sanguinamenti. Nell’anziano la fibrillazione atriale è particolarmente frequente ma il suo trattamento presenta delle difficoltà: infatti, sebbene il rischio ischemico aumenti con l’età, anche il rischio emorragico è maggiore. ln questi pazienti il medico spesso preferisce non prescrivere o interrompere la terapia anticoagulante orale nel timore di complicanze. Il paziente anziano, inoltre, può essere portatore di più patologie, assumere diversi farmaci con potenziale rischio di interazioni farmacologiche e presentare una ridotta aderenza alla assunzione della terapia. Scopo della tesi. Valutare l’impatto dell’anticoagulazione nel paziente anziano, con focus nel sottogruppo di pazienti con età 80 anni, che raramente vengono reclutati nei grandi trial clinici. VENPAF. Abbiamo inizialmente condotto uno studio retrospettivo “inception cohort” includendo tutti i pazienti con età 80 anni in terapia con warfarin presso il locale Centro Trombosi (studio VENPAF). Dall’analisi è emersa un’incidenza di emorragie maggiori molto alta, che tende ad aumentare sensibilmente sopra gli 85 anni di età; nonostante ciò, il beneficio clinico netto della terapia appare comunque mantenuto, in quanto l’incidenza calcolata di trombo-embolismo in assenza di anticoagulazione è risultata maggiore, in entrambe le classi di età, rispetto all’incidenza osservata di emorragie maggiori. Circa il 20% dei pazienti inclusi ha sospeso la terapia e questo è stato principalmente dovuto ad una decisione del medico di medicina generale o dello specialista; le ragioni addotte per la sospensione sono state la scarsa aspettativa di vita, la fragilità del paziente e l’eccessivo rischio emorragico. Abbiamo però constatato che la sospensione della terapia non era associata ad un miglioramento della prognosi ma anzi questi pazienti erano gravati da alti tassi di mortalità, eventi ischemici ed emorragici. Restringendo l’analisi ai pazienti che avevano sperimentato un evento emorragico in corso di terapia anticoagulante, abbiamo potuto evidenziare come l’incidenza cumulativa di eventi ischemici ed emorragiciera significativamente più alta nei pazienti che dopo tale evento sospendevano la terapia rispetto a quelli che la riprendevano. Studio caso-controllo. Per analizzare i fattori di rischio associati allo sviluppo di emorragia cerebrale in warfarin, abbiamo eseguito uno studio caso-controllo includendo tutti i pazienti seguiti per fibrillazione atriale presso il nostro Centro Trombosi. Abbiamo confrontato 51 pazienti con emorragia intracranica con 204 pazienti di controllo, appaiati per età, sesso ed esposizione alla terapia. Nessuna variabile analizzata è risultata associata allo sviluppo dell’emorragia. Abbiamo inoltre valutato il rischio emorragico per ogni paziente usando gli score HAS-BLED, ATRIA e ORBIT; tali score hanno presentato una capacità predittiva nei confronti dell’emorragia intracranica particolarmente scarsa o nulla (“c-statistic” minore 0.56 per tutti gli score utilizzati). Registro Regione Veneto. Dallo studio VENPAF e dallo studio caso-controllo è emersa da una parte una forte tendenza al sanguinamento intracranico nel paziente anziano, dall’ altra l’impossibilità di individuare specifici fattori predittivi di tale sanguinamento. È quindi con grande interesse che abbiamo guardato all’utilizzo clinico dei nuovi anticoagulanti orali (NAO), farmaci che dagli studi registrativi sembrano essere in grado di dimezzare questa grave complicanza rispetto al warfarin. Analizzando i dati della Regione Veneto attraverso il registro regionale delle prescrizioni farmacologiche, delle esenzioni e delle diagnosi di dimissione dai reparti, abbiamo potuto selezionare i pazienti che iniziavano una terapia anticoagulante orale perché affetti da fibrillazione atriale non valvolare. In confronto a warfarin, i NAO si sono dimostrati ugualmente efficaci e sicuri. Si è rilevata comunque una netta riduzione delle emorragie intracraniche e una lieve riduzione della mortalità rispetto alla terapia convenzionale, nonostante l’ottima qualità dell’anticoagulazione con warfarin raggiunta grazie ai centri trombosi veneti. In particolare, abbiamo riscontrato che nel Veneto i pazienti in terapia con NAO sono in media più anziani e a più alto rischio ischemico rispetto ai pazienti trattati con warfarin. Abbiamo infine analizzato la popolazione di età 80 anni e riscontrato un deciso aumento delle emorragie gastrointestinali, soprattutto dal tratto inferiore, nei pazienti in terapia con NAO. Tale incremento, però, non ha modificato il profilo di sicurezza di questi farmaci, che presentano comunque un rischiocomplessivo di emorragie maggiori e di ictus ischemici sovrapponibili al warfarin, con riduzione del rischio di emorragie intracraniche. Conclusioni. Il presente lavoro di ricerca ha cercato di esplorare gli effetti della terapia anticoagulante nel paziente grande anziano con 80 anni o più. Dall’insieme degli studi condotti è stato possibile concludere che, nonostante l’elevato rischio di emorragia, il beneficio clinico per la prevenzione dell’ictus è a favore dell’uso di questi farmaci; andando infatti a considerare i pazienti che sospendevano il farmaco, abbiamo constatato una prognosi peggiore rispetto ai pazienti che rimanevano in terapia. Una parte non trascurabile delle emorragie in warfarin è dovuta ai sanguinamenti intracranici che sono spesso fatali o gravemente invalidanti; dai nostri dati tali eventi sono più frequenti nell’anziano e non sono prevedibili dai comuni fattori di rischio cardiovascolare, né da una buona qualità dell’anticoagulazione. I NAO sembrano invece mantenere anche nell’anziano un rischio di emorragie intracraniche inferiore al warfarin, nonostante un significativo aumento del rischio di emorragie gastrointestinali. Nel complesso, quindi, i nostri dati confermano i NAO come la terapia anticoagulante da preferire nella fibrillazione atriale non valvolare anche nel paziente molto anziano

Fibroblast growth factor 23 and the bone-vascular axis: lessons learned from animal studies.

Calcification of arteries and cardiac valves is observed commonly in dialysis patients and represents a major determinant of the heightened cardiovascular risk observed during chronic kidney disease (CKD) progression. Recent advances from clinical and basic science studies suggest that vascular calcification should be considered a systemic disease in which pathologic processes occurring in the bone and kidney contribute to calcium deposition in the vasculature. Among the factors potentially involved in the vascular-bone axis dysregulation associated with CKD, there now is increasing interest in the role of the phosphaturic hormone fibroblast growth factor 23 (FGF-23). Increased FGF-23 plasma levels are observed with a decrease in kidney function and predict the risk of future cardiovascular mortality. However, clinical data are still unclear about whether a direct pathogenetic effect of FGF-23 on vascular/kidney/bone health exists. In the last few years, a series of basic science studies, performed using engineered mice, have contributed important pathophysiologic information about FGF-23 activities. This review summarizes findings from these studies and discusses the potential role of FGF-23 during the pathologic interplay between kidney, vessels, and bone in CKD

Antiphospholipid syndrome and the heart: A case series and literature review

Antiphospholipid syndrome is a rare autoimmune disease characterised by a high tendency of developing thrombotic events. It is diagnosed in the presence of specific laboratory criteria (positivity for lupus anticoagulant, and the presence of anticardiolipin and a\u3b22GPI antibodies) and clinical criteria such as thrombosis in any district (arterial or venous) and pregnancy morbidity. Being a multisystem disease, heart is commonly affected by direct (autoimmune mediated action) or indirect (thrombosis) pathological mechanisms. Heart valve lesions are the most frequent manifestations; however, the haemodynamic significance is quite uncommon but when it occurs it may require surgery that further complicates the picture due to the high risk of thrombosis. Coronary arteries and myocardium are also affected leading to ischaemic heart disease and left ventricular dysfunction. Other findings include chronic thromboembolic pulmonary hypertension and accelerated atherosclerosis. The consequences of heart involvement may be significant in overt disease. The treatment of cardiac complications is challenging and requires an in depth knowledge of the disease

Laboratory Diagnostics of Antiphospholipid Syndrome

Diagnosis of antiphospholipid syndrome (APS) lies in the recognition of antiphospholipid antibodies (aPL). As standardization of tests for the detection of aPL is far from being optimal and reference material is not available, inappropriate diagnoses of APS are not unusual. In the last few years, the concept of triple test positivity has emerged as a useful tool to identify patients with APS. Clinical studies on patients and carriers of triple positivity clearly show that these individuals are at high risk of thromboembolic events and pregnancy loss. Moreover, triple positivity arises from a single (probably pathogenic) antibody directed to domain 1 of \u3b22-glycoprotein I, a protein whose function is still unknown. Studies on homogenous group of patients with single or double positivity are scant, and uncertainties arise on their association with clinical events. Promising but undetermined results come also from the determination of antibodies directed to phosphatidylserine/prothrombin complex. Interpretation of laboratory profile in APS is challenging, and the collaboration between clinical pathologists and clinicians is highly desirable

Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial

Background New oral anticoagulants may simplify long-term therapy in conditions requiring anticoagulation. Rivaroxaban is a direct factor Xa inhibitor that has been extensively studied and is now approved for the prevention and therapy of a number of thromboembolic conditions. Objective and methods This is a multicentre, randomized, open-label, study that will evaluate if Rivaroxaban 20 mg od (or 15 mg od in patients with moderate renal insufficiency) is non-inferior to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and death in high risk (triple positive) patients with antiphospholipid syndrome. Secondary endpoints will assess the incidence of any individual component of the composite end point. An external adjudication committee will evaluate all suspected outcome events. This will be a unique trial, as it will enrol the biggest homogenous cohort of high risk APS individuals. Conclusion The methods and the study design should be appropriate to achieve study results that are both scientifically valid and relevant to clinical practice. </jats:sec

Minimizing the risk of hemorrhagic stroke during anticoagulant therapy for atrial fibrillation

none7Introduction: Oral anticoagulation (OAC) is given for ischemic stroke prevention in patients with nonvalvular atrial fibrillation. OAC’s most serious complications are major bleeding and, in particular, hemorrhagic stroke. Together with vitamin K antagonists (VKAs), direct oral anticoagulants (DOAC) are now available which have a more rapid onset/offset of action and more predictable anticoagulant effect. The advent of DOAC has given to the clinician an opportunity to tailor OAC therapy in order to maximize advantages and minimize complications. Areas covered: This review covers data published in literature regarding the risk of hemorrhagic stroke in patients taking OAC. Bleeding risk assessment is discussed and different bleeding risk factors are presented. The paper will also review clinical studies comparing DOAC against standard anticoagulation, in regard to the risk of hemorrhagic stroke. Expert opinion: Bleeding assessment is mandatory in order to select patients at high hemorrhagic risk who will benefit the most from close monitoring. Blood pressure, alcohol intake, concomitant medication and comorbidities should be constantly evaluated and treated accordingly. During VKA therapy, adherence and intensity of anticoagulation must be strictly monitored. DOAC are associated with lower risk of hemorrhagic stroke than VKA. However, periodic hepatic and renal checks as well as careful evaluation of time adherence are necessary to reduce the risk of bleeding.noneGiacomo Zoppellaro;Serena Granziera;Seena Padayattil Jose;Gentian Denas;Alessia Bracco;Sabino Iliceto;Vittorio PengoZoppellaro, Giacomo; Granziera, Serena; PADAYATTIL JOSE, Seena; Denas, Gentian; Bracco, Alessia; Iliceto, Sabino; Pengo, Vittori