Marco Proietti

Asymptomatic versus symptomatic atrial fibrillation: A systematic review of age/gender differences and cardiovascular outcomes

Up to 40% of atrial fibrillation (AF) patients are asymptomatic. Despite this, scarce data are available about asymptomatic AF, with regard to its clinical profile and relationship to cerebrovascular and cardiovascular risks. Our objective was to conduct a systematic review and meta-analysis was to study the relationship between age and gender with asymptomatic AF and to establish whether patients with asymptomatic AF have a higher risk of death (all-cause and cardiovascular) and stroke/systemic thromboembolism, when compared to symptomatic AF patients. After a comprehensive search, 6 studies (2 randomized clinical trials and 4 observational studies) were entered in the meta-analysis. Despite significant heterogeneity, our data show that the prevalence of females amongst asymptomatic AF group was significantly less compared to the symptomatic AF group (RR, 0.57; 95% CI: 0.52-0.64). No difference in age between asymptomatic and symptomatic AF patients (P=0.72) was seen. No differences were found in all-cause death between patients with asymptomatic and symptomatic AF (RR, 1.38; 95% CI: 0.82-2.17), nor in cardiovascular death (RR, 0.85; 95% CI: 0.53-1.36) or stroke/thromboembolism (RR, 1.72 95% CI: 0.59-5.08). Asymptomatic AF is more associated with male sex, irrespective of age. Both general and cardiovascular death risks as well as thromboembolic risk do not seem to be affected by the asymptomatic clinical status. Symptomatic status should not determine our approach to stroke prevention and other cardiovascular prevention therapies, amongst patients with AF.

Simple decision-making between a vitamin K antagonist and a non-vitamin K antagonist oral anticoagulant: using the SAMe-TT2R2 score

Stroke prevention with oral anticoagulation (OAC) is central to the modern management of atrial fibrillation (AF) patients.1 For many years, vitamin K antagonists (VKAs, e.g. warfarin) have been the default class of OAC, but we now recognize that it is not simply prescribing VKA but very close attention to quality of anticoagulation control is necessary, as reflected by the individual time in therapeutic range (TTR).2 An average individual TTR of >70% is recommended to maximize efficacy and safety of the VKAs.2,3 Nonetheless, the VKAs have significant inter- and intra-patient variability, partly from diet and drug interactions, thus necessitating regular international normalised ratio (INR) monitoring.2 More recently, we have had the non-VKA oral anticoagulants (NOACs, previously referred to as new or novel OACs4) available, which offer efficacy, safety, and relative convenience compared with the VKAs, for stroke prevention in AF. Due to cost considerations, some healthcare systems mandate a ‘trial of warfarin’ (sometimes called a ‘warfarin stress test’) for the initial 6 months, to determine whether a patient can do well on a VKA—and only if the TTR is suboptimal (e.g. <60%) is an NOAC then ‘authorized’ to be prescribed. When … [↵][1]*Corresponding author. Tel: +44 121 507 5080, Fax: +44 121 554 4083, Email: g.y.h.lip{at}bham.ac.uk [1]: #xref-corresp-1-1

Prevalence of Peripheral Artery Disease by Abnormal Ankle-Brachial Index in Atrial Fibrillation: Implications for Risk and Therapy

To the Editor: Nonvalvular atrial fibrillation (NVAF) is the most common sustained arrhythmia encountered in clinical practice and is associated with a 5-fold increased risk for stroke [(1)][1]. Moreover, patients with NVAF often suffer from atherosclerotic complications such as acute myocardial

Platelet Isoprostane Overproduction in Diabetic Patients Treated With Aspirin

Aspirin modestly influences cardiovascular events in patients with type 2 diabetes mellitus (T2DM), but the reason is unclear. The aim of the study was to determine whether in T2DM patients aspirin enhances platelet isoprostanes, which are eicosanoids with proaggregating properties derived from arachidonic acid oxidation by platelet NOX2, the catalytic subunit of reduced NAD phosphate oxidase. A cross-sectional study was performed comparing T2DM patients, treated (n = 50) or not treated (n = 50) with 100 mg/day aspirin, with 100 nondiabetic patients, matched for age, sex, atherosclerosis risk factors, and aspirin treatment. A short-term (7 days) treatment with 100 mg/day aspirin also was performed in 36 aspirin-free diabetic and nondiabetic patients. Higher platelet recruitment, platelet isoprostane, and NOX2 activation was found in diabetic versus nondiabetic patients and in aspirin-treated diabetic patients versus nontreated patients (P < 0.001). Platelet thromboxane (Tx) A2 (P < 0.001) was inhibited in all aspirin-treated patients. In the interventional study, aspirin similarly inhibited platelet TxA2 in diabetic and nondiabetic patients (P < 0.001). Platelet recruitment, isoprostane levels, and NOX2 activation showed a parallel increase in diabetic patients (P < 0.001) and no changes in nondiabetic patients. These findings suggest that in aspirin-treated diabetic patients, oxidative stress–mediated platelet isoprostane overproduction is associated with enhanced platelet recruitment, an effect that mitigates aspirin-mediated TxA2 inhibition.

Major Bleeding in Patients with Non-Valvular Atrial Fibrillation: Impact of Time in Therapeutic Range on Contemporary Bleeding Risk Scores

Bleeding risk represents a major concern in anticoagulated patients with atrial fibrillation (AF). Several bleeding prediction scores have been described: HAS-BLED, ATRIA, HEMORR2HAGES and ORBIT. Of these, only HAS-BLED considers quality of anticoagulation control amongst vitamin K antagonist (VKA) users. We hypothesised that predictive value of bleeding risk scores other than HAS-BLED could be improved incorporating time in therapeutic range (TTR) in warfarin-treated patients. Of the 127 adjudicated major bleeding events, 21.3% of events occurred in ‘low-risk’ HAS-BLED category (1.8 per 100 patient-years), compared to higher proportions (≥50% of events; ~2.5 per 100 patient-years) in ‘low-risk’ categories for other scores. Only the ‘low-risk’ HAS-BLED category was associated with the absence of investigator-defined major bleeding events (OR: 1.46;95% CI: 1.00–2.15). ‘High’ or ‘medium/high’ risk categories for the HAS-BLED (p = 0.023) or ORBIT (p = 0.022) scores, respectively, conferred significant risk for adjudicated major bleeding events. On Cox regression analysis, adjudicated major bleeding was associated only with HAS-BLED (HR: 1.62;95% CI: 1.06–2.48) and ORBIT (HR: 1.83;95% CI: 1.08–3.09) ‘high-risk’ categories. Adding ‘labile INR’ (TTR < 65%) to ORBIT, ATRIA and HEMORR2HAGES significantly improved their reclassification and discriminatory performances. In conclusion, HAS-BLED categorised adjudicated major bleeding events in low-risk and high-risk patients appropriately, whilst ORBIT and ATRIA categorised most major bleeds into their ‘low-risk’ patient categories. Adding TTR to ORBIT, ATRIA and HEMORR2HAGES led to improved predictive performance for major bleeding.

Ankle-Brachial Index and cardiovascular events in atrial fibrillation: The ARAPACIS study

Atrial fibrillation (AF) patients are at high risk for thrombotic and vascular events related to their cardiac arrhythmia and underlying systemic atherosclerosis. Ankle-Brachial Index (ABI) is a non-invasive tool in evaluating systemic atherosclerosis, useful in predicting cardiovascular events in general population; no data are available in AF patients. ARAPACIS is a prospective multicentre observational study performed by the Italian Society of Internal Medicine, analysing association between low ABI (≤ 0.90) and vascular events in NVAF out- or in-patients, enrolled in 136 Italian centres. A total of 2,027 non-valvular AF (NVAF) patients aged > 18 years from both sexes followed for a median time of 34.7 (interquartile range: 22.0-36.0) months, yielding a total of 4,614 patient-years of observation. Mean age was 73 ± 10 years old with 55 % male patients. A total of 176 patients (8.7 %) experienced a vascular event, with a cumulative incidence of 3.81 %/patient-year. ABI≤ 0.90 was more prevalent in patients with a vascular event compared with patients free of vascular events (32.2 vs 20.2 %, p< 0.05). On Cox proportional hazard analysis, ABI≤ 0.90 was an independent predictor of vascular events (hazard ratio (HR): 1.394, 95 % confidence interval (CI): 1.042-1.866; p=0.02), vascular death (HR: 2.047, 95 % CI: 1.255-3.338; p=0.004) and MI (HR: 2.709, 95 % CI: 1.485-5.083; p=0.001). This latter association was also confirmed after excluding patients with previous MI (HR: 2.901, 95 % CI: 1.408-5.990, p=0.004). No association was observed between low ABI and stroke/transient ischaemic attack (p=0.91). In conclusion, low ABI is useful to predict MI and vascular death in NVAF patients and may independently facilitate cardiovascular risk assessment in NVAF patients.

Chronic Kidney Disease, Time in Therapeutic Range and Adverse Clinical Outcomes in Anticoagulated Patients with Non-valvular Atrial Fibrillation: Observations from the SPORTIF Trials

Background Chronic kidney disease (CKD) is highly prevalent in atrial fibrillation (AF) patients and associated with an increased risk of adverse outcomes. Our objectives were to study clinical features associated with CKD in AF patients and the impact of CKD on anticoagulation control, as reflected by time in therapeutic range (TTR). We also determined the impact of CKD and TTR in predicting adverse outcomes. Methods and Results We analysed pooled datasets from SPORTIF III and V trials, including 3646 patients assigned to warfarin with data on renal function. CKD (creatinine clearance < 60 ml/min) was present in 952 (26%) patients. TTR was higher in patients with normal renal function compared to those with CKD (p < 0.001). On logistic analysis, chronic AF and male sex were associated with TTR > 70%, whilst diabetes mellitus, aspirin use and CKD were inversely associated with TTR > 70%. On Cox regression analysis, CKD was an independent predictor for stroke (p = 0.006) and death (p < 0.001). TTR > 70% was independently associated with a lower risk of stroke (p = 0.024), death (p = 0.001) and major bleeding (p = 0.001). Conclusions CKD is highly prevalent amongst AF patients and a risk factor for stroke and death. Adjusting for CKD, good quality anticoagulation control (TTR > 70%) was an independent predictor for lower risks of stroke, death and major bleeding.

Relation of female sex to left atrial diameter and cardiovascular death in atrial fibrillation: The AFFIRM Trial.

BACKGROUND Female sex is associated with thromboembolism related to atrial fibrillation (AF). Left atrial (LA) diameter independently predicted incident cardiovascular (CV) major events in the general population. In AF patients, LA enlargement is associated to AF occurrence and recurrence. No data have previously been reported on the relationship between LA enlargement, sex and CV death in AF patients. METHODS AND RESULTS All patients enrolled in the AFFIRM Trial with available data about LA dimension were included in this post-hoc analysis. Of the 2615 eligible for the present analysis, LA enlargement was recorded in 67.0%, more commonly in women than in men (p=0.032). Patients with LA enlargement had higher body mass index (BMI), and were more frequently hypertensive, diabetic, and diagnosed with a structural heart disease, prior coronary artery disease (CAD) and heart failure (HF). BMI, left ventricular mass, female sex and mitral valve insufficiency (p<0.001) were associated with LA enlargement. AF female patients with LA enlargement had a higher risk for CV death (p=0.011). LA diameter showed a significant association with CV death (p<0.001). Cox regression analysis demonstrated that LA diameter was an independent predictor of CV death in female AF patients (p=0.003). CONCLUSIONS LA diameter enlargement is associated with female sex, and carries a higher risk for CV death, particularly in females. LA diameter was an independent predictor of CV death in female AF patients.

VEGF-A gene promoter polymorphisms and microvascular complications in patients with essential hypertension

OBJECTIVES We investigated the possible involvement of vascular endothelial growth factor (VEGF-A) gene promoter polymorphisms in essential hypertension (EH). DESIGN AND METHODS 1225bp of the VEGF-A gene promoter were screened for polymorphisms using PCR amplification and direct DNA sequence analysis in 62 EH and 62 normotensive (HS) individuals. Circulating VEGF-A levels were determined by immunoassay. RESULTS -152G/A (p=0.009) and -116G/A (p=0.016) polymorphisms were correlated to hypertension (p<0.05). Median platelet VEGF-A load in EH was 2.10fg/plt. Patients with microvascular complications (MC) had higher platelet VEGF-A load than those without (p=0.005). Multivariate analyses showed that -116 A allele was an independent predictor of microalbuminuria (p=0.014) and increased platelet VEGF-A load (p=0.009) in EH. Platelet VEGF-A load independently predicted MC (p=0.049) in addition to -116G/A polymorphism (p=0.035). CONCLUSIONS Abnormal regulation of VEGF-A due to polymorphism at position -116 might represent a genetic factor for increased VEGF-A production and MC in EH.

Impact of chronic obstructive pulmonary disease on prognosis in atrial fibrillation: A report from the EURObservational Research Programme Pilot Survey on Atrial Fibrillation (EORP-AF) General Registry

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a common chronic disease, being associated with both high rates of morbidity and mortality. Similarly, atrial fibrillation (AF) is associated with a higher risk of both cardiovascular (CV) events and overall mortality. The AF and COPD often coexist, but the impact of COPD on prognosis in European AF patients is unknown. METHODS We evaluated COPD prevalence in patients enrolled in the EURObservational Research Programme Pilot Survey on Atrial Fibrillation Registry Pilot Phase. Clinical factors associated with COPD and adverse outcomes at 1-year follow-up were determined. RESULTS In the overall cohort, a diagnosis of COPD was recorded in 339 (11.0%) of AF patients. The AF patients with COPD were more burdened with risk factors and comorbidities, including diabetes mellitus (P < .0001) and chronic heart failure (P < .0001). β-Blockers were less likely to be prescribed to patients with COPD (P = .0007). On follow-up, AF patients with COPD had a higher risk of both CV death and all-cause death (both P < .0001), as well as for the composite outcome of any thromboembolic event/bleeding /CV death (P = .0003). Cox regression analysis found that COPD was independently associated with an increase in all-cause death (hazard ratio, 1.55; 95% CI 1.05-2.28; P = .0269). CONCLUSIONS Chronic obstructive pulmonary disease is highly prevalent in European AF patients, and is associated with higher rates of CV death, all-cause death, and the composite outcome of any thromboembolic event/bleeding/CV death. The presence of COPD in AF patients was independently associated with all-cause death in AF patients.