Very Elderly Patients With Atrial Fibrillation Treated With Edoxaban: Impact of Frailty on Outcomes.

Background: Age and frailty are associated with underuse of anticoagulation in elderly patients with atrial fibrillation (AF). Objectives: This study aimed at assessing major clinical outcomes in very elderly patients with AF treated with recommended dose edoxaban and look for a possible relation with frailty measured by a validated score. Methods: This prospective multicenter cohort study enrolled consecutive very elderly (age ≥80 years) anticoagulation-naïve patients starting recommended doses of edoxaban. Upon entry into the study, patients were categorized into nonfrail, prefrail and frail with the SHARE-FI (Survey of Health, Ageing, and Retirement in Europe-Frailty Index) score. The primary outcome was a composite incidence of stroke/systemic embolism, major bleeding, clinically relevant nonmajor bleeding, and death between frail and fitter patients over 2 years follow-up. Secondary outcomes were frailty-related incidence of the individual components part of the composite outcome. Results: Of the 180 screened patients, 176 were enrolled in the study. Of these, 58 (32.9%) were frail, 35 (19.8%) prefrail, and 83 (47.2%) nonfrail. The composite outcome occurred in 49 patients (18.9% per patient-year). No difference in the primary endpoint between frail and fitter patients (incidence rate ratio: 1.2; 95% CI: 0.6-2.2) was observed. On multivariable analysis, anemia was significantly related to the primary outcome (HR: 3.6; 95% CI: 1.8-7.3; P < 0.001), while frailty was not (frail vs nonfrail HR: 0.9; 95% CI: 0.5-1.8). No difference across frailty categories of the individual components of composite events was observed, except for death. Conclusions: Anticoagulation with recommended dose edoxaban is feasible in very elderly patients with AF even if frail. (ESCAPE [Edoxaban and Frailty in Senior Individuals]; NCT03524924).

Cardiac and Cerebral Arterial Complications of Lemierre Syndrome: Results from a Systematic Review and Individual Patient Data Meta-analysis.

BACKGROUND: Lemierre syndrome is a potentially life-threatening disease, which affects otherwise healthy young adults and adolescents. It is characterized by acute neck vein thrombosis and septic embolism, usually complicating a bacterial infection. Data on the syndrome are sparse, particularly concerning arterial complications. METHODS: We evaluated the frequency and patterns of cerebral arterial and cardiac involvement ("arterial complications") in an individual patient level cohort of 712 patients, representing all cases described over the past 20 years in the medical literature who fulfilled the criteria: (1) bacterial infection in the neck/head site and (2) objectively confirmed thrombotic complication or septic embolism. The study outcomes were defined as all-cause in-hospital deaths and the occurrence of clinical sequelae at discharge or in the postdischarge period. RESULTS: A total of 55 (7.7%) patients had an arterial complication. The most frequent arterial complications were carotid involvement (52.7%), stroke (38.2%), and pericardial complications (20%). Patients with an arterial involvement were more likely to be treated with a greater number of antibiotics (23 vs. 10%) and to receive anticoagulation. In addition, patients with arterial complications had a greater risk of all-cause death (n = 20/600, 3.3% vs. n = 6/52, 12%; odds ratio [OR]: 3.8; 95% confidence interval [CI]: 1.5-9.9) and late clinical sequelae (n = 49/580, 9.0% vs. n = 15/46, 35%; OR: 5.2; 95% CI: 2.65-10.37). CONCLUSIONS: While Lemierre syndrome is known to be primarily characterized by venous thromboembolic events, our results suggest that local or distant arterial complications may occur in approximately one-tenth of patients and may be associated with a greater risk of long-term sequelae and death.

Nordic Walking and Walking in Parkinson's disease: a randomized single-blind controlled trial.

INTRODUCTION: Non-pharmacological interventions are increasingly being acknowledged as valuable options to overcome or reduce functional problems in patients with Parkinson's disease. In the last decades, Nordic Walking was employed and investigated by rehabilitation specialists. Clinical trials on the effect of Nordic Walking on motor and non-motor Parkinson's disease symptoms are few, small, and heterogeneous for inclusion criteria and intervention protocols. As a result, Nordic Walking training cannot be recommended as a standard rehabilitative tool in Parkinson's disease patients. METHODS: This randomized controlled single-blind trial recruited Parkinson's disease patients at a Hoehn and Yahr stage between 2 and 3 assigned to a Nordic Walking vs. Walking group. Subjects were extensively assessed for motor and non-motor symptoms at baseline and after 8 weeks of intervention period. To study the effects of intervention on the overall sample, paired-sample t test and Wilcoxon signed rank test were used, while differences between groups were estimated with general linear models repeated-measure and Mann-Whitney U test. RESULTS: Among 32 patients who ended the study period, improvements were observed in the following assessments: global motor outcome (p 0.001), dynamic and static balance ability (p 0.005; p 0.002), global non-motor symptoms outcome (p 0.003), fatigue (p 0.016), anxiety (p 0.043), and quality of life (p 0.003). The treatment group (Nordic Walking) failed to show any difference compared to the control group (Walking) in all considered outcomes. CONCLUSION: Nordic Walking was not superior compared to Walking in the studied population. Moderate intensity outdoor group activities like Nordic Walking and Walking seem to improve motor and non-motor symptoms parameters in patients with Parkinson's disease.

Determinants of the Quality of Warfarin Control after Venous Thromboembolism and Validation of the SAMe-TT2-R2 Score: An Analysis of Hokusai-VTE.

BACKGROUND: Time in therapeutic range (TTR) measures the quality of vitamin K antagonist (VKA) anticoagulation. In patients with atrial fibrillation, the dichotomized SAMe-TT2-R2 score (≥2 vs. < 2 points) can predict if adequate TTR is unlikely to be achieved. AIMS: We validated the SAMe-TT2-R2 score in patients with venous thromboembolism (VTE) randomized to the warfarin arm of the Hokusai-VTE trial. PATIENTS AND METHODS: A total of 3,874 patients were included in the primary analysis (day 31-180 from randomization). The efficacy and safety outcomes were symptomatic recurrent VTE and major or clinically relevant non-major bleeding. RESULTS: The rates of recurrent VTE and bleeding events were higher in patients with a TTR below the median (< 66% vs. ≥66%) resulting in an absolute risk difference (ARD) of +0.5% (95% confidence interval: 0%, +1.1%) and +2.2% (0.9%, +3.5%), respectively. Patients with high SAMe-TT2-R2 score were 76% of total and had lower median TTR (64.7% vs. 70.7%). The SAMe-TT2-R2 score exhibited low negative (0.59) and positive (0.52) predictive value (TTR threshold 66%), and poor discrimination (c-statistic, 0.58). ARD between patients with high and low score was 0% (-0.6%, +0.7%) for recurrence and +1.3% (-0.1%, +2.7%) for bleeding. Results were confirmed in sensitivity analyses focusing on the whole study period (day 1-365). CONCLUSION: In VTE patients, the SAMe-TT2-R2 score showed unsatisfactory discrimination and predictive value for individual TTR and did not correlate well with clinical outcomes. The choice of starting a patient on VKA cannot be based on this parameter and its routine use after VTE may not translate into clinical usefulness.

Lemierre Syndrome: Clinical Update and Protocol for a Systematic Review and Individual Patient Data Meta-analysis.

Lemierre syndrome usually affects otherwise healthy adolescents or young adults and occurs at an overall rate of 1 to 10 cases per million person-years with an estimated fatality rate of 4 to 9%. Diagnostic criteria remain debated and include acute neck/head bacterial infection (often tonsillitis caused by anaerobes at high potential for sepsis and vascular invasion, notably Fusobacterium necrophorum) complicated by local vein thrombosis, usually involving the internal jugular vein, and systemic septic embolism. Medical treatment is based on antibiotic therapy with anaerobic coverage, anticoagulant drugs and supportive care in case of sepsis. Surgical procedures can be required, including drainage of the abscesses, tissue debridement and jugular vein ligation. Evidence for clinical management is extremely poor in the absence of any adequately sized study with clinical outcomes. In this article, we illustrate two cases of Lemierre syndrome not caused by Fusobacterium necrophorum and provide a clinically oriented discussion on the main issues on epidemiology, pathophysiology and management strategies of this disorder. Finally, we summarize the study protocol of a proposed systematic review and individual patient data meta-analysis of the literature. Our ongoing work aims to investigate the risk of new thromboembolic events, major bleeding or death in patients diagnosed with Lemierre syndrome, and to better elucidate the role of anticoagulant therapy in this setting. This effort represents the starting point for an evidence-based treatment of Lemierre syndrome built on multinational interdisciplinary collaborative studies.

Primary thromboembolic prevention in multiple myeloma patients: An exploratory meta-analysis on aspirin use.

BACKGROUND: Multiple myeloma (MM) is a common hematological disorder, often complicated by venous thromboembolism, especially during treatment with immunomodulatory drugs. Acetylsalicylic acid (ASA) has been extensively used as thromboprophylaxis but its rationale is unclear and the efficacy versus low-molecular weight heparins (LMWH) is still matter of debate. European and American guidelines suggest different approaches and the optimal antithrombotic strategy is yet to be established. METHODS: We conducted an exploratory metanalysis and a systematic review on studies comparing ASA versus other interventions for thromboprophylaxis (no intervention or LMWH) in patients with MM. RESULTS: Ten studies were included (2 randomized controlled trials, 6 longitudinal and 2 retrospective studies) with 1,964 participants (1,257 treated with ASA, 640 with LMWH and 67 with no thromboprophylaxis). Patients treated with ASA had a significantly lower risk of VTE compared to no intervention (OR=0.20; 95%CI: 0.07-0.61, p=0.005; I2=41%). The use of ASA was associated with a higher VTE risk compared to LMWH in longitudinal studies (OR=2.60; 95%CI: 1.08-6.25; p=0.03; I2=0%), however no differences have been showed in randomized controlled trials. CONCLUSIONS: ASA demonstrated a good efficacy compared to no intervention; data are insufficient to confirm superiority of LMWH over ASA as thromboprophylaxis in MM patients. Large and well powered trials are warranted.

The Novel Oral Anticoagulants for Acute Venous Thromboembolism: Is Warfarin Dead?

The direct oral anticoagulants (DOACs) have been compared with parenteral anticoagulants and vitamin K antagonists (VKAs) for the treatment of venous thromboembolism (VTE) in several robust studies. DOACs have shown similar efficacy in preventing recurrent VTE and significant reductions in critical site (intracranial) bleeding, fatal bleeding, major and nonmajor bleeding. Warfarin and other VKAs are not dead as treatment modalities for VTE. A better way to describe the current situation is to use a boxing expression, "down but not out." VKAs and parenteral anticoagulants still have a role to play in the management of VTE in several clinical settings. In indications where DOACs can be used, VKAs should not, as the safety profile of VKAs is considerably worse than DOACs. Hence, guidelines are now recommending DOACs in preference to VKAs. In this article, we consider where DOACs are indicated, where there is growing evidence for use, where we have little evidence for use, and finally where there is no evidence for use and where they, thus, should not be used. We have included recommendations and examples of our own practice which may not be applicable to all settings.

Direct Oral Anticoagulants and Their Use in Treatment and Secondary Prevention of Acute Symptomatic Venous Thromboembolism.

Direct oral anticoagulants (DOACs) have been compared with standard therapy in large phase III studies to assess their safety and efficacy in the treatment of deep vein thrombosis and/or pulmonary embolism and in the secondary prevention of recurrent venous thromboembolism. Although the mean population age and the gross inclusion and exclusion criteria were similar across these studies, they differed in other aspects such as overall study design and acute treatment strategies. The 4 DOACs examined in phase III trials (apixaban, edoxaban, rivaroxaban, and dabigatran) showed noninferiority compared with standard therapy for the treatment of deep vein thrombosis and/or pulmonary embolism and for the prevention of recurrent venous thromboembolism. Furthermore, these DOACs exhibited a similar safety profile to standard therapy, with the risk of major bleeding significantly reduced in some of these studies. Rivaroxaban and apixaban were tested as a single-drug approach, whereas in the dabigatran and edoxaban studies, initial bridging with parenteral agents was employed. The purpose of this review is to compare the phase III studies of DOACs in this indication, to highlight the differences, and to discuss a series of clinically relevant issues, including the management of key patient subgroups (eg, fragile patients, those with cancer or renal impairment), extended treatment, use of comedications, heparin pretreatment versus a single-drug approach, and the bleeding profiles of the DOACs.

Monitoring Plasma Levels of Donepezil, 5-O-Desmethyl-Donepezil, 6-O-Desmethyl-Donepezil, and Donepezil-N-Oxide by a Novel HPLC Method in Patients With Alzheimer Disease.

BACKGROUND: In humans, donepezil (D) is metabolized to 5-O-desmethyl-donepezil (5DD), 6-O-desmethyl-donepezil (6DD), and donepezil-N-oxide (DNox). Although 6DD and DNox are pharmacologically active, the activity of 5DD is unknown. At present, no routine methods are available to detect D and its 3 metabolites simultaneously. In this study, a novel high-performance liquid chromatography method was developed and applied to a population of patients with Alzheimer disease on stable treatment with the drug. METHODS: Liquid-liquid extraction from plasma was accomplished by means of a solvent mixture of n-hexane/dichloromethane/ethylacetate (45:40:15) after sample alkalinization. Disopyramide was the internal standard. After evaporation, the residue was reconstituted in 200 µL of mobile phase (acetonitrile 85%:1% acetic acid 15%) and 50 µL was injected into the high-performance liquid chromatography column (X-Terra, RP8; flow: 1 mL/min). Photometric and fluorimetric detectors were used in tandem, to maximize the sensitivity of fluorescent compounds (D, 5DD, and DNox) and also to reveal nonfluorescent compounds (6DD and internal standard). RESULTS: The method was linear in the 10-100 ng/mL concentration range. Imprecision (coefficient of variation) varied between 3.2% and 12.6% and inaccuracy (% mean absolute error) between 1.3% and 13.3%, depending on the compound, concentration, and detection mode. The quantitation limits were 0.1-0.3 ng/mL for fluorescent compounds and 1.2-4.3 ng/mL for photometric compounds. D, 5DD, 6DD, and DNox through concentrations were measured in 54 patients with Alzheimer disease on treatment with D (10 mg q.d.). No interfering peaks by endogenous compounds or coadministered drugs were noted. Plasma concentrations were quite variable among patients (D: 10-106 ng/mL; 5DD: 0.07-2.8 ng/mL; 6DD: 1.2-36 ng/mL; DNox: 0.5-45.4 ng/mL). Of note, in 6 patients, the plasma concentrations of the 2 active metabolites (6DD and DNox) were higher than those of the parent drug. CONCLUSIONS: The above method proved to be suitable for therapeutic drug monitoring and may be useful in ascertaining the real contribution of metabolites to the therapeutic effects of donepezil.

Increasing incidence of non-valvular atrial fibrillation in the UK from 2001 to 2013.

OBJECTIVE: To determine whether the incidence of atrial fibrillation (AF) is static or rising in the UK. DESIGN: Among the cohort of all individuals aged ≥45 years in the UK Clinical Practice Research Datalink (CPRD) (linked to hospital discharges) we identified incident non-valvular AF cases between 2001 and 2013. Overall and annual AF incidence rates were calculated and standardised to the UK population. RESULTS: The cohort of 2.23 million individuals included 91,707 patients with incident AF. The overall standardised AF incidence rate was 6.7 (95% CI 6.7 to 6.8) per 1000 person-years, increasing exponentially with age and higher in men of all ages. There was a small increase in the standardised incidence of AF in the last decade from 5.9 (5.8 to 6.1)/1000 person-years in 2001 to 6.9 (6.8 to 7.1)/1000 person-years in 2013, mostly attributable to subjects aged >80 years with a non-primary hospital discharge diagnosis of AF. Standardised incidence rates of AF among white patients was 8.1 (8.1 to 8.2)/1000 person-years, compared with 5.4 (4.6 to 6.3) for Asians and 4.6 (4.0 to 5.3) for black patients. AF diagnosis was first made in general practice in 39% of incident AF. CONCLUSIONS: The incidence of AF in the UK has increased gradually in the last decade, with more than 200 000 first-ever non-valvular AF cases expected in 2015. This increase is only partly due to population ageing, though the principal increase has been in the elderly hospitalised for a reason other than AF.

To treat or not to treat very elderly naïve patients with atrial fibrillation with vitamin K antagonists (VKA): results from the VENPAF cohort.

Despite the recommendations in the guidelines, physicians still underuse warfarin in very elderly patients with non-valvular atrial fibrillation (NVAF). The risks of stroke and major bleeding both increase with age, but it is still not clear whether the beneficial effects of vitamin K antagonists (VKA) in preventing stroke outweigh the related bleeding risks in fragile, very elderly patients. The bleeding rates reported in real-world observational studies differ considerably. The aim of this study was to retrospectively assess the incidence of major bleeding in VKA-naïve patients over 80 years old with NVAF at a large anticoagulation clinic. Significant predictors of major bleeding were also investigated. Sixty-five major bleeding events (3.4 per 100 patient-years) and 25 thromboembolic events (1.3 per 100 patient-years) were recorded in a sample of 798 patients with a median follow-up of 2.2 years. Patients over 85 years old had significantly more major bleeding events than the 80- to 84-year olds (4.7 vs. 2.6 per 100 patient-years, p 0.014). Spontaneous bleeding was also significantly more common (3.0 vs. 1.3 per 100 patient-years, p 0.008) in the very elderly group. Age and diabetes were the only independent risk factor for bleeding on multivariate Cox analysis (Age HR 1.80, 95% CI 1.10-2.93; diabetes HR 1.76, 95% CI 1.00-3.09). These data show a sharp increase in major bleeding episodes among the very elderly with atrial fibrillation. Further studies are warranted with a view to identifying patients at risk.

VTE primary prevention, including hospitalised medical and orthopaedic surgical patients.

Primary prevention is the key to managing a significant proportion of the burden of venous thromboembolism (VTE), defined as deep venous thrombosis (DVT) or pulmonary embolism (PE). This is because VTE may lead to sudden death or are often misdiagnosed and therefore treatment is not feasible. Primary prevention usually commences in hospital as VTE following hospitalisation adds to the significant disease burden worldwide. Numerous medical, surgical and other risk factors have been recognised and studied as indications for prophylaxis. The risk of VTE continues following admission to hospital with a medical or surgical condition, usually long after discharge and therefore prolonged primary prophylaxis is often recommended. Clinical and observational studies in surgical patients show this risk extends for months and perhaps more than one year, for medical patients the risk extends for at least several weeks. For the specific groups of patients at higher risk of developing VTE primary prevention, either pharmaceutical or mechanical, is recommended. The aim of this review is to describe the population at risk, the main related risk factors and the approach to thromboprophylaxis in different populations.

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

INTRODUCTION: 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.

Thromboembolic prevention in frail elderly patients with atrial fibrillation: a practical algorithm.

Atrial fibrillation is a common condition in the elderly, and the incidence of thromboembolic events secondary to atrial fibrillation increases with age. Antithrombotic therapy effectively prevents stroke and systemic embolism but also exposes patients to the risk of bleeding. Because the risk of bleeding also increases with age, clinicians tend to withhold anticoagulation in the elderly. Anticoagulation is particularly complex in the frail elderly patient, who presents additional risk factors affecting both efficacy and safety of thromboembolic prevention. The main clinical trials rarely include frail elderly patients and, consequently, the guidelines do not provide guidance for their management. In the absence of clear indications for this class of patients, we identified some areas that should be taken into account both before starting and when discontinuing anticoagulation: comorbidities, polypharmacotherapy, adherence, cognitive impairment, mobility and monitoring barriers, nutritional status and swallowing disorders, risk of falls, and reduced life expectancy. We also suggest a multidimensional algorithm covering both a standard ischemic and bleeding risk assessment and an additional anticoagulation-focused frailty assessment. This is of particular relevance given the recent introduction of the oral direct inhibitors, as they are likely to widen the treatment options for the frail elderly. Depending on which aspect of frailty is present, anticoagulation can now be tailored accordingly.

Full penetrance of Morgagni-Stewart-Morel syndrome in a 75-year-old woman: case report and review of the literature.

CONTEXT: Morgagni-Stewart-Morel syndrome is defined as the presence of hyperostosis frontalis interna, variably associated with metabolic, endocrine, and neuropsychiatric disorders. The possible cause-effect relationship of these associations remains uncertain. CASE PRESENTATION: A 75-year-old woman presented with severe frontal headache and a history of psychotic disorders. On instrumental examination she was found to have extensive frontal hyperostosis and cortical atrophy. These findings, associated to the metabolic and neuropsychiatric pattern of the patient, are consistent with a high penetrance of Morgagni-Stewart-Morel syndrome. EVIDENCE ACQUISITION AND SYNTHESIS: In this clinical case seminar, we summarize the current understanding of the association between hyperostosis frontalis interna and Morgagni-Stewart-Morel, based on a MEDLINE search (case reports, original articles, and reviews published between 1928 and 2011) on this topic. Possible pathophysiological mechanisms underlying both the headache and the hyperostosis frontalis interna are discussed. CONCLUSION: A case of full penetrance of Morgagni-Stewart-Morel syndrome is reported, presenting many of the clinical features described in the literature. Metabolic and endocrine dysfunctions should be interpreted not only as isolated components of the syndrome, but also as the reason behind its pathogenesis. Endocrine or nutritional disorders may have led to an altered bone metabolism with frontal bone apposition. On the other hand, the severity of our patient's neurological and psychiatric symptoms correlates well with the severity of her hyperostosis frontalis interna and the cortical atrophy.