2,697 publications from this institution
Thromboembolic diseases are leading cause of mortality accounting for an estimated 1 in 4 deaths all over the world. Anticoagulation remains the mainstay of prevention and treatment of venous thromboembolic disorders. Conventional anticoagulants have been efficiently used over the last decades, but their clinical use encounters safety and convenience issues. To overcome these limitations, research have focused on development of new targets for anticoagulation leading to a relatively new class of drugs, non-vitamin K antagonist oral anticoagulants, specifically targeting activated factor X and thrombin. However, the search for more potent anticoagulant agents with reduced bleeding risk is still continuing. Areas covered: In this review, we provide an overview on emerging investigational anticoagulant drugs targeting factor XI in the coagulation cascade. We review data about the role of intrinsic pathway in thrombosis and haemostasis and the rationale of different pharmacodynamic approaches targeting factor XI. Expert opinion: Recent evidence suggests that the contact pathway plays a significant role in thrombosis by thrombus stabilization and growth without perturbing haemostasis. Factor XI might be a promising drug target to develop highly effective antithrombotic therapy with safety bleeding profile. Most of these investigational agents are in early development phases, only few have reached early phase clinical trials.
Abstract
Malignant hypertension (MHT) has traditionally been clinically diagnosed as the presence of severe blood pressure (BP) in association with hypertensive retinopathy changes of haemorrhages and exudates with or without papilledema. The pathophysiological hallmark in MHT is the presence of fibrinoid necrosis, which can involve multiple target organs. Thus, there is the view that the term MHT is obsolete and should be replaced by alternative terms, including hypertension with multi-organ damage [1]. A recent position document on hypertensive emergencies from the European Society of Cardiology (ESC) Council on Hypertension reflects this view [2]. In the current issue of the Journal of Hypertension, Rubin et al.[3] report a detailed evaluation of the target organs damage found in patients with MHT at the time of clinical presentation. The authors also report updated data on the 5-year survival status in these patients. The main novelty of the study was perhaps the inclusion of a systematic evaluation of brain target organ damage, using MRI scanning, in all patients, irrespective of their neurological symptoms. They found that target organ damage in the brain was very highly prevalent, in 93% of all examined patients. Second, the group used a universal treatment protocol, for BP lowering during the acute phase, on all their MHT patients from the Bordeaux cohort. A major increase in systemic and cerebral perfusion pressure, as occur in MHT, disturbs the autoregulation of the cerebral circulation, leading to the failure of autoregulatory cerebral vasoconstriction with focal or generalized dilatation of small arteries and arterioles [4]. This results in cerebral blood volume overload, impairment of blood–brain barrier function and, in extreme cases, development of brain oedema. Of importance, these cerebral abnormalities occur in parallel to the systemic impairment of macrovascular and microvascular function [5], thus limiting the ability to provide appropriate adjustment in peripheral vascular tone. The first signs and symptoms of the brain involvement are usually sudden onset of headache, nausea and vomiting. This may be followed by development of different visual signs and visual field loss, which in some cases may be accompanied by fluctuating neurological symptoms (restlessness, confusion and, in extreme, seizures and coma) [4,6]. In the MHT cohort from Bordeaux [3] only 20% of patients were admitted to the hospital due to high BP, and 10% due to the heart failure. The majority (70%) required hospital admission due to some degree of neurological problems. Although a substantial proportion of these patients had presented with headache and dizziness, but without obvious neurological damage, a quarter of the assessed population was found to have visual impairment and one in five developed a stroke. These data highlight the fact that despite the availability of various antihypertensive treatments symptomatic patients in acute phase of MHT are at risk of hypertensive encephalopathy, a life-threatening condition that requires hospital admission. The Bordeaux cohort [3] suggests that brain imaging can be helpful in the assessment of MHT patients. MRI usually shows evidence of white matter lesions, more often located in the posteriors brain regions [4,7]. Computed tomography or MRI scanning is also advisable to exclude cerebral haemorrhage, or infarction. In cases of hypertensive encephalopathy alone, white matter lesions are completely reversible after patient stabilization. Indeed, the study by Rubin et al.[3], following systematic evaluation of the brain by MRI, found that the white matter lesions were more prevalent in the posterior regions, with 51% of included patients affected. Other locations of white matter lesions were found in 27% of the tested population from the Bordeaux region. Analysis of the US data from the largest all-payer Nationwide Inpatient Sample database of national discharges found an increasing trend for hospital admissions of patients with either hypertensive encephalopathy or MHT over the last decade despite no increase in overall morbidity [8]. Also, increasing awareness of hypertension, changes in coding practices and subsequent increase in the costs from insurance, were suggested as reasons for these trends. White matter lesions, in the posterior part of the brain, are also evident in other conditions with microvascular dysfunction (e.g. antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome) and this mandates a holistic approach to patient assessment. MHT is a hypertensive emergency and the ESC position document on the management of hypertensive emergencies recommends use of intravenous BP lowering medications in patients with acute presentations [2]. However, the position document acknowledges that any recommendations are made based on consensus from clinical experience, given the lack of randomized controlled trials on different treatment strategies. Use of the angiotensin-converting enzyme (ACE) inhibitors at the acute phase must be commenced at a very much lower dose, as they could result in a rapid and dangerous fall in BP in some patients. One of the reasons for profound BP drop is volume depletion, secondary to pressure natriuresis. Intravenous saline infusion is recommended to be started together with the oral low-dose ACE inhibitors to correct the circulating volume. In the current report by Rubin et al.[3], very low oral dose of renin–angiotensin system blockers was carefully titrated over 48 h. The treatment was well tolerated and efficient in all patients, with no complications reported. Nevertheless, one of the study limitations was the use of a changed MHT definition during the data collection period. But it only applies to 15 patients who did not show signs of MHT retinopathy, although in others, three target organs were affected. The main cardiovascular risk factors at the time of the MHT diagnosis were not different in these patients compared with the rest of the cohort. In conclusion, MHT is the most severe and one of most challenging forms of the hypertension, affecting multiple organs, including the brain. MHT is not quite an obsolete diagnosis yet, but perhaps evolution of the definition may be needed in the twenty-first century reflecting contemporary practice [2]. Otherwise the principles of early diagnosis, detailed systematic evaluation (including modern brain imaging) and effective treatment remain key factors for a longer event free survival. Further data are clearly needed to assess the clinical significance of brain damage and the relation to patient survival and optimal long-term management. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
In this observational study of anticoagulated NVAF patients with polypharmacy, effectiveness and safety profiles are more favourable for NOACs vs. warfarin. Our observations are hypothesis generating and may help inform future clinical trials regarding appropriate OAC treatment selection in polypharmacy patients.
Abstract Background Patients with atrial fibrillation (AF) and severe liver cirrhosis were excluded from the pivotal randomized trials comparing direct oral anticoagulants (DOACs) and warfarin. In the present study, we compared the effectiveness and safety of DOACs and warfarin among AF patients with liver cirrhosis. Method A total of 3,691 AF patients with liver cirrhosis having a CHA2DS2-VASc score ≥1 for males and ≥2 for females and received oral anticoagulants (DOACs in 2,548 and warfarin in 1,143) were identified from the Taiwan National Health Insurance Research Database. The effectiveness and safety were compared between DOACs and warfarin groups. Results There was a trend suggesting a lower risk of ischemic stroke with DOACs compared to warfarin (2.91%/yr vs 3.41%/yr; HR 0.743, p=0.060). The risks of bleeding events were lower with DOACs compared to warfarin with a HR (95% CI) of 0.718 (0.573–0.899, p=0.004) for major bleeding and 0.509 (0.292–0.889, p=0.018) for ICH. The risk of mortality was also lower in patients treated with DOACs (HR=0.483; 95% CI: 0.424–0.551, p<0.001). The cumulative incidence curves of each events for 2 groups are shown in Figure. The results were essentially similar after the propensity matching analysis of 2 groups. Conclusion Compared to warfarin, DOACs were associated with a lower risk of ICH, major bleeding and mortality among AF patient with liver cirrhosis.
