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1.
Direct oral anticoagulants and vitamin K antagonists are linked to differential profiles of cardiac function and lipid metabolism.
Eggebrecht, L, Prochaska, JH, Tröbs, SO, Schwuchow-Thonke, S, Göbel, S, Diestelmeier, S, Schulz, A, Arnold, N, Panova-Noeva, M, Koeck, T, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2019;(7):787-796
Abstract
BACKGROUND Experimental data indicate that direct acting oral anticoagulants (DOAC) and vitamin K antagonists (VKA) may exert differential effects on cardiovascular disease. METHODS Data from the prospective, observational, single-center MyoVasc Study were used to examine associations of DOAC as compared to VKA with subclinical markers of cardiovascular disease, cardiac function, and humoral biomarkers in heart failure (HF). RESULTS Multivariable analysis adjusted for age, sex, traditional cardiovascular risk factors, comorbidities, and medications with correction for multiple testing demonstrated that DOAC therapy was among all investigated parameters an independent significant predictor of better diastolic function (E/E': β - 0.24 [- 0.36/- 0.12]; P < 0.0001) and higher levels of ApoA1 (β + 0.11 g/L [0.036/0.18]; P = 0.0038) compared to VKA therapy. In propensity score-weighted analyses, the most pronounced differences between DOAC and VKA-based therapy were also observed for E/E' (∆ - 2.36) and ApoA1 (∆ + 0.06 g/L). Sensitivity analyses in more homogeneous subsamples of (i) individuals with AF and (ii) individuals with asymptomatic HF confirmed the consistency and robustness of these findings. In the comparison of factor IIa and Xa-directed oral anticoagulation, no differences were observed regarding cardiac function (E/E' ratio: βIIa inhibitor - 0.22 [- 0.36/- 0.08] vs. βXa inhibitor - 0.24 [- 0.37/- 0.11]) and lipid metabolism (ApoA1: βIIa inhibitor 0.10 [0.01/0.18] vs. βXa inhibitor 0.12 [0.04/0.20]) compared to VKA therapy. CONCLUSION This study provides the first evidence for differential, non-conventional associations of oral anticoagulants on cardiac function and lipid metabolism in humans. The potentially beneficial effect of DOACs in the highly vulnerable population of HF individuals needs to be further elucidated and may have implications for individually tailored anticoagulation therapy.
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2.
Stroke prevention in atrial fibrillation: State of the art.
Li, YG, Lip, GYH
International journal of cardiology. 2019;:201-209
Abstract
Stroke prevention is the cornerstone of the management of patients with atrial fibrillation (AF). Individual stroke risk stratification is generally the first step of deciding whether oral anticoagulation (OAC) will benefit patients with AF. Given that existing approaches to the prediction of 'high-risk' subjects are of limited value, the initial focus should be the identification of 'low-risk' patients who do not need antithrombotic therapy. For this, the CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥ 75 [2 points], diabetes mellitus, previous stroke/transient ischemic attack [2 points], vascular disease, age 65-74, female sex) performs well in identifying really low-risk patients (score of 0 in males or 1 in females), for whom OAC can be omitted. The approach to AF management has changed, with the non-vitamin K antagonist oral anticoagulants (NOACs) providing relatively better efficacy, safety and convenience compared with the traditional vitamin K antagonists (VKAs). The latter drugs are performing well, if attention is directed towards good quality anticoagulation control, as reflected by a time in therapeutic range (TTR) >70%. Nevertheless, OAC use remains suboptimal especially in some regions, such as Asia and Africa. Long-term adherence and quality of OAC use need to be maintained for better outcomes in patients with AF.
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3.
Heart Failure and Atrial Fibrillation, Like Fire and Fury.
Carlisle, MA, Fudim, M, DeVore, AD, Piccini, JP
JACC. Heart failure. 2019;(6):447-456
Abstract
Heart failure and atrial fibrillation are 2 common cardiovascular disorders that frequently complicate one another and exert a significant detrimental effect on cardiovascular health and well-being. Both heart failure and atrial fibrillation continue to increase in prevalence as the risk factors underlying each condition become more common. This review encompasses what is currently known about the epidemiology and pathophysiology of these comorbidities along with incorporation of landmark trials that have contributed to current guidelines. The focus is on clinically relevant considerations, including the contribution of inflammation in the pathophysiology of atrial fibrillation and heart failure. We explore the emerging role of catheter ablation relative to medical therapy in the management of heart failure with reduced ejection fraction, along with indications for biventricular pacing modalities in cardiac resynchronization therapy. We discuss current guideline-directed therapies and how practice models and national recommendations will likely change based on the most recent randomized controlled trials.
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Anticoagulation in Venous Thromboembolism Prophylaxis in Medically Ill Patients: Potential Impact of NOACs.
Knotts, TL, Mousa, SA
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2019;(4):365-376
Abstract
While substantial evidence supports the use of standard-duration injectable anticoagulants for venous thromboembolism (VTE) prophylaxis, consensus is mixed about which agents may be preferred in acutely ill patients with ongoing need of VTE prophylaxis past the first 10-day duration of hospital stay and post-discharge. Non-vitamin K antagonist oral anticoagulants (NOACs) provide Factor Xa inhibition to prevent the thrombin generation essential in thromboembolism development, but evidence for the efficacy and safety of most NOACs is conflicting regarding extended-duration prophylaxis. Enoxaparin, a preferred injectable anticoagulant in standard-duration VTE prophylaxis, has shown an increased risk of major bleeding events when used in extended-duration prophylaxis, which outweighs its benefit. Rivaroxaban has demonstrated efficacy in extended-duration prophylaxis, but both rivaroxaban and apixaban have shown increased risks of major bleeding. Betrixaban remains the only NOAC approved in the USA for extended-duration VTE prophylaxis, and it demonstrates efficacy, with fewer adverse effects than other NOACs. This review evaluates the appropriateness of different NOAC agents compared with current therapies for the extended-duration VTE prophylaxis setting in medically ill populations.
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Endothelial damage and thromboembolic risk after pulmonary vein isolation using the latest ablation technologies: a comparison of the second-generation cryoballoon vs. contact force-sensing radiofrequency ablation.
Hisazaki, K, Hasegawa, K, Kaseno, K, Miyazaki, S, Amaya, N, Shiomi, Y, Tama, N, Ikeda, H, Fukuoka, Y, Morishita, T, et al
Heart and vessels. 2019;(3):509-516
Abstract
Experimental data suggest that cryoenergy is associated with less endothelial damage and thrombus formation than radiofrequency energy. This study aimed to compare the impact of pulmonary vein isolation (PVI) on the endothelial damage, myocardial damage, inflammatory response, and prothrombotic state between the two latest technologies, second-generation cryoballoon (CB2) and contact force-sensing radiofrequency catheter (CFRF) ablation. Eighty-six paroxysmal atrial fibrillation (AF) patients (55 men; 65 ± 12 years) underwent PVI with either the CB2 (n = 64) or CFRF (n = 22). Markers of the endothelial damage (L-arginine/asymmetric dimethylarginine [ADMA]), myocardial injury (creatine kinase-MB [CK-MB], troponin-T, and troponin-I), inflammatory response (high-sensitive C-reactive protein), and prothrombotic state (D-dimer, soluble fibrin monomer complex, and thrombin-antithrombin complex) were determined before and up to 24-h post-procedure. The total application time was shorter (1,460 ± 287 vs. 2,395 ± 571 [sec], p < 0.01) and total procedure time tended to be shorter (199 ± 37 vs. 218 ± 38 [min], p = 0.06) with CB2 than CFRF ablation. The amount of myocardial injury was greater (CK-MB: 45 ± 17 vs. 11 ± 3 [IU/l], p < 0.01) with CB2 than CFRF ablation. The L-arginine/ADMA ratio was lower (160 ± 51 vs. 194 ± 38, p = 0.028) after CB2 than CFRF ablation. Inflammatory and all prothrombotic markers were significantly elevated post-ablation; however, the magnitude was similar between the two groups. During a mean follow-up of 20 ± 6 months, the single-procedure AF freedom was similar between the CB2 and CFRF groups (60/64 vs. 20/22, p = 0.82). CB2-PVI produces significantly lesser endothelial damage with greater myocardial injury than CFRF-PVI; however, similar anticoagulant regimens are required during the peri-procedural periods in both technologies.
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6.
United States Pharmacopeia Safety Review of Willow Bark.
Oketch-Rabah, HA, Marles, RJ, Jordan, SA, Low Dog, T
Planta medica. 2019;(16):1192-1202
Abstract
Willow bark (Salix spp.) is an ingredient in some dietary supplements. No serious adverse effects were reported from trials of willow bark extracts delivering 120 - 240 mg salicin (the purported active constituent) daily for up to 8 weeks. All studies involved adults only; none involved special subpopulations such as pregnant or breastfeeding women, or children. The most common adverse effects associated with willow bark are gastrointestinal; a few allergic reactions were also reported. Some publications advise caution when taking willow bark. There is a risk of increased bleeding in vulnerable individuals, salicylates cross the placenta and are eliminated slowly in newborns, some persons are sensitive or allergic to aspirin, and children are at risk of Reye syndrome. Concurrent use with other salicylate-containing medicines increases these risks. Metabolism of 240 mg salicin from willow bark could yield 113 mg of salicylic acid, yet dietary supplement products are not required to be labeled with warnings. In contrast, over-the-counter low-dose aspirin (81 mg strength), which delivers 62 mg salicylic acid, is required by law to include cautions, warnings, and contraindications related to its use in pregnant and nursing women, children, and other vulnerable subpopulations, e.g., those using anticoagulants. In the interest of protecting public health, the United States Pharmacopeia has included a cautionary labeling statement in the United States Pharmacopeia Salix Species monograph as follows: "Dosage forms prepared with this article should bear the following statement: 'Not for use in children, women who are pregnant or nursing, or by persons with known sensitivity to aspirin.'".
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7.
Non-vitamin K antagonist oral anticoagulants with amiodarone, P-glycoprotein inhibitors, or polypharmacy in patients with atrial fibrillation: Systematic review and meta-analysis.
Kim, IS, Kim, HJ, Yu, HT, Kim, TH, Uhm, JS, Kim, JY, Joung, B, Lee, MH, Pak, HN
Journal of cardiology. 2019;(6):515-521
Abstract
BACKGROUND Amiodarone, which inhibits CYP2C9 and P-glycoprotein, is commonly prescribed with non-vitamin K antagonist oral anticoagulants (NOACs) and polypharmacy in high-risk atrial fibrillation (AF) patients. We studied efficacy and safety of NOACs in AF patients receiving amiodarone, P-glycoprotein inhibitor, or polypharmacy. METHODS After a systematic database search (Medline, EMBASE, CENTRAL, SCOPUS, and Web of Science), four phase-III randomized trials comparing NOACs and warfarin in "with/without amiodarone," "with/without P-glycoprotein inhibitors," or "with/without multiple (≥5, polypharmacy) concomitant drugs" subgroups were included. The outcomes were pooled using a random-effects model to determine the relative risks (RRs) for stroke/systemic thromboembolism (SSTE), major bleeding (MB), intracranial hemorrhage (ICH), and all-cause mortality. RESULTS Among patients taking amiodarone, superiority of NOACs over warfarin in non-amiodarone users disappeared in terms of SSTE (p=0.11), MB (p=0.95), ICH (p=0.26), and mortality (p=0.32). No safety benefit (MB) of NOACs compared to warfarin was shown in patients taking P-glycoprotein inhibitors (p=0.47), but SSTE prevention was still superior with NOACs compared to warfarin in the same patient group [RR=0.78 (0.61-0.99), p=0.04, I2=11%]. In AF patients with polypharmacy, NOACs showed a lower risk of SSTE [RR=0.82 (0.71-0.96), p=0.01, I2=0%] and mortality [RR=0.91 (0.83-0.99), p=0.04, I2=0%], but not MB (p=0.81) compared to warfarin. CONCLUSIONS NOACs were equivalent to warfarin among AF patients with concomitant amiodarone use in terms of efficacy, safety, and mortality. There was no safety benefit of NOACs over warfarin in patients using polypharmacy or P-glycoprotein inhibitors. SYSTEMATIC REVIEW REGISTRATION The protocol of this meta-analysis was registered on PROSPERO under CRD42018104808 (https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42018104808).
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Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation.
Seiffge, DJ, Werring, DJ, Paciaroni, M, Dawson, J, Warach, S, Milling, TJ, Engelter, ST, Fischer, U, Norrving, B
The Lancet. Neurology. 2019;(1):117-126
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Abstract
BACKGROUND About 13-26% of all acute ischaemic strokes are related to non-valvular atrial fibrillation, the most common cardiac arrhythmia globally. Deciding when to initiate oral anticoagulation in patients with non-valvular atrial fibrillation is a longstanding, common, and unresolved clinical challenge. Although the risk of early recurrent ischaemic stroke is high in this population, early oral anticoagulation is suspected to increase the risk of potentially harmful intracranial haemorrhage, including haemorrhagic transformation of the infarct. This assumption, and current treatment guidelines, are based on historical, mostly observational data from patients with ischaemic stroke and atrial fibrillation treated with heparins, heparinoids, or vitamin K antagonists (VKAs) to prevent recurrent ischaemic stroke. Randomised controlled trials have subsequently shown that direct oral anticoagulants (DOACs; ie, apixaban, dabigatran, edoxaban, and rivaroxaban) are at least as effective as VKAs in primary and secondary prevention of atrial fibrillation-related ischaemic stroke, with around half the risk of intracranial haemorrhage. However, none of these DOAC trials included patients who had experienced ischaemic stroke recently (within the first few weeks). Clinicians therefore remain uncertain regarding when to commence DOAC administration after acute ischaemic stroke in patients with atrial fibrillation. RECENT DEVELOPMENTS Prospective observational studies and two small randomised trials have investigated the risks and benefits of early DOAC-administration initiation (most with a median delay of 3-5 days) in mild-to-moderate atrial fibrillation-associated ischaemic stroke. These studies reported that early DOAC treatment was associated with a low frequency of clinically symptomatic intracranial haemorrhage or surrogate haemorrhagic lesions on MRI scans, whereas later DOAC-administration initiation (ie, >7 days or >14 days after index stroke) was associated with an increased frequency of recurrent ischaemic stroke. WHERE NEXT?: Adequately powered randomised controlled trials comparing early to later oral anticoagulation with DOACs in ischaemic stroke associated with atrial fibrillation are justified to confirm the acceptable safety and efficacy of this strategy. Four such randomised controlled trials (collectively planned to include around 9000 participants) are underway, either using single cutoff timepoints for early versus late DOAC-administration initiation, or selecting DOAC-administration timing according to the severity and imaging features of the ischaemic stroke. The results of these trials should help to establish the optimal timing to initiate DOAC administration after recent ischaemic stroke and whether the timing should differ according to stroke severity. Results of these trials are expected from 2021.
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Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention.
Paciaroni, M, Agnelli, G, Caso, V, Silvestrelli, G, Seiffge, DJ, Engelter, S, De Marchis, GM, Polymeris, A, Zedde, ML, Yaghi, S, et al
Stroke. 2019;(8):2168-2174
Abstract
Background and Purpose- Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non-vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods- Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results- Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95-5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63-9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83-3.16), and CHA2DS2-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHA2DS2-VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33-0.61). Conclusions- In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA2DS2-VASc score were associated with increased risk of cerebrovascular events.
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Non-vitamin K antagonist oral anticoagulants in elderly patients with atrial fibrillation: A systematic review with meta-analysis and trial sequential analysis.
Caldeira, D, Nunes-Ferreira, A, Rodrigues, R, Vicente, E, Pinto, FJ, Ferreira, JJ
Archives of gerontology and geriatrics. 2019;:209-214
Abstract
BACKGROUND Elderly population is known to be associated with polymedication, comorbidities and altered drug pharmacokinetics. However, the most adequate oral anticoagulant, attending to its relative efficacy and safety, remains unclear. METHODS We searched for phase III randomized controlled trials (MEDLINE, Cochrane Library, SciELO collection and Web of Science) comparing novel non-vitamin K antagonist oral anticoagulants (NOACs) with Vitamin K antagonists (VKA) in the elderly population (≥75 years-old) in atrial fibrillation (AF). Risk ratios (RR) were calculated using a random effects model. Trial sequential analysis (TSA) was performed in statistically significant results to evaluate whether cumulative sample size was powered. RESULTS Four trials rendered data about elderly (≥75 years-old) and younger patients (<75 years-old) with AF. NOACs demonstrated a 30% significant risk reduction (RR 0.70, 95% CI: 0.61 to 0.80) in elderly patients compared to VKA, without heterogeneity across studies (I2 = 0%). The TSA showed that cumulative evidence of this subgroup exceeded the minimum information size required for the risk reduction. In younger patients, VKA and NOACs shared a similar risk of stroke and systemic embolism (RR 0.97, 95% CI: 0.79 to 1.18). Regarding major bleeding risk in the elderly, the overall comparative risk of NOACs was not different from VKA (RR 0.91, 95% CI: 0.72 to 1.16; I2 = 86%). CONCLUSIONS NOACs reduce significantly the risk of stroke and systemic embolism in elderly patients without increasing major bleeding events. The dimension of stroke risk reduction was significantly higher in the elderly than in younger adults.