February Issue - Extending the clinical utility of novel oral anticoagulants
Professor A John Camm
John Camm is Professor of Clinical Cardiology at St George’s, University of London and Imperial College London. He is an internationally renowned expert in atrial fibrillation (AF). He has published more than 1000 articles, including chairing the committee responsible for the development of the European Society of Cardiology guidelines for the management of AF, first published in 2010 and updated in 2012. He has received numerous prestigious awards for services to cardiology, including the European Society of Cardiology Gold Medal and the British Cardiovascular Society Mackenzie Medal.
Welcome to the February 2015 edition of the Thrombosis Adviser newsletter.
Dear Thrombosis Adviser user,
Globally, cardiovascular disease due to atherosclerosis is a major cause of mortality and a major healthcare burden. Atherosclerotic lesions predispose patients to thrombus formation through platelet activation and thrombin generation. Symptoms can manifest as coronary artery disease (CAD), peripheral artery disease (PAD) or cerebrovascular disease (CVD), and most commonly result in death due to myocardial infarction, stroke or heart failure (HF). Given the burden of these diseases, considerable attention is being devoted to expanding the use of the novel oral anticoagulants (OACs) in this setting, because these drugs have the potential to fulfil considerable unmet medical needs.
Data from the World Health Organization show that ischaemic heart disease and stroke are the leading causes of death worldwide, accounting for approximately one in four deaths. Estimates based on data from the Framingham Heart study suggest that one in three 40-year-old women and one in two 40-year-old men are expected to develop manifestations of CAD during their lifetime. PAD, although often overlooked in comparison with CAD and CVD, is an important marker of the extent of atherosclerotic disease. Recent epidemiological modelling estimated that the prevalence of PAD has increased by nearly one-quarter in the first decade of this millennium, largely owing to the increased life expectancy of the world’s population, and there are now likely to be at least 202 million cases worldwide.
The current European Society of Cardiology (ESC) guidelines recommend single antiplatelet therapy with acetylsalicylic acid (ASA), or clopidogrel as an alternative in cases of ASA intolerance, for the prevention of cardiovascular events in patients with stable CAD, and single antiplatelet therapy in patients with PAD. Even with antiplatelet therapy, up to 10% of patients with stable CAD or PAD will experience a major cardiovascular event per year. Therefore, a dual-pathway approach with both anticoagulant and antiplatelet agents may provide better protection against recurrent events in these patients. However, the combination of a vitamin K antagonist and an antiplatelet agent has been reported to be no more effective than antiplatelet therapy alone in patients with PAD. Moreover, in patients with CAD, a reduced incidence of recurrent ischaemic events is offset by an increase in the risk of major bleeding. The potential of the novel OACs to prevent recurrent atherothrombotic events while maintaining an acceptable benefit–risk profile in patients with established vascular disease has been demonstrated in the results of the ATLAS ACS 2 TIMI 51 trial, in which rivaroxaban in combination with standard antiplatelet therapy was given to patients with a recent acute coronary syndrome.
Several clinical trials testing novel OACs in the setting of stable CAD and/or PAD are ongoing. The most common approach being tested is dual-pathway treatment with a novel OAC plus single antiplatelet therapy versus standard antiplatelet therapy alone, although novel OAC monotherapy is also being directly compared to antiplatelet therapy. If successful, these studies will significantly extend the clinical utility of novel OACs and may challenge the established monopoly regarding the use of antiplatelet agents in this setting. The largest ongoing phase III study, COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS – clinicaltrials.gov NCT01776424), is testing the efficacy and safety of rivaroxaban (alone and in combination with ASA) versus ASA alone for the prevention of major cardiovascular events in patients with stable CAD or PAD. In patients with PAD alone, ePAD (edoxaban in Peripheral Artery Disease – NCT01802775) is an ongoing phase II study assessing the efficacy and safety of edoxaban in addition to ASA after femoropopliteal endovascular intervention, with or without stent placement, relative to current standard treatment with clopidogrel and ASA. A phase III study of rivaroxaban (VOYAGER) in patients with PAD undergoing peripheral artery intervention is also planned, and will include a minimum of 5000 patients from 20 countries.
In high-income countries, declining rates of mortality due to stroke and CAD have been offset by an increase in the prevalence of chronic HF. This trend is predicted to continue owing to the ageing population and the increased survival of patients who develop left ventricular dysfunction as a result of chronic CAD – projections estimate that the prevalence of HF will increase by nearly 23% in the next 20 years (US data). HF is associated with significant mortality (approximately half of patients with HF will die within 5 years of diagnosis) and morbidity, which place a significant burden on healthcare systems; in the US, more elderly individuals (≥65 years old) are hospitalized for HF than for any other medical condition. Thrombotic complications play a major role in the poor prognosis of these patients, and thus, patients with HF may benefit from antithrombotic therapy.
Because HF and atrial fibrillation (AF) often co-exist, patients with HF were included in the major phase III clinical trials of the novel OACs for stroke prevention in patients with AF. Available data from these studies suggest that the efficacy of novel OACs is maintained in this patient population. However, the question remains as to whether adjunctive anticoagulation therapy may be of benefit in patients with HF in sinus rhythm. Trials conducted to date, which compared vitamin K antagonists with antiplatelet agents, have indicated that anticoagulants may reduce the incidence of ischaemic stroke and other secondary outcomes, such as hospitalization, but this is offset by an increase in the risk of major bleeding, translating into a lack of mortality benefit. A better balance of benefits versus risks may be achieved with the novel OACs. Rivaroxaban is currently the only novel OAC being tested in this indication in the ongoing phase III COMMANDER HF trial (NCT01877915). Given the significant unmet need and burden of HF, the US Food and Drug Administration (FDA) has granted a fast-track designation for this study to help facilitate the development process and expedite the review of rivaroxaban in this indication.
Traditionally, strokes that occur without the presence of AF or occlusive CVD have been termed ‘cryptogenic strokes’ (i.e. of unknown cause), and are thought to account for approximately one-quarter of ischaemic strokes in Western populations. However, it is now thought that most of these cryptogenic strokes arise owing to thromboembolism, and thus a new terminology has been proposed – embolic stroke of undetermined source (ESUS). The thrombus associated with an ESUS is proposed to originate from minor-risk or covert cardiac sources (e.g. diseased valves, left heart dysfunction, non-AF arrhythmia or covert paroxysmal AF), non-stenotic atherosclerotic plaques located between the aortic arch and cerebral arteries, or even the venous system as a consequence of patent foramen ovale (so-called ‘paradoxical embolism’). Owing to its proposed thromboembolic aetiology, it is hypothesized that anticoagulants may provide better protection than antiplatelet agents against recurrent events in patients with ESUS. Indeed, in the Warfarin-Aspirin Recurrent Stroke Study (WARSS), although no benefit was seen with warfarin compared with ASA in the entire study population, a greater reduction in recurrent ischaemic stroke with warfarin was observed in select cryptogenic subgroups. In light of this evidence, and the proven efficacy of the novel OACs for the prevention of stroke in patients with AF (a major cardioembolic source), clinical trials are underway (or planned) that investigate the efficacy of dabigatran (RE-SPECT ESUS – NCT02239120) and rivaroxaban (NAVIGATE-ESUS), in comparison with ASA, for preventing the recurrence of ischaemic stroke in patients with ESUS.
Arterial thromboembolic disease remains a major healthcare burden, and current antiplatelet therapies, although effective, leave a significant number of patients at risk of major cardiovascular events. The ongoing studies of rivaroxaban and edoxaban in patients with established vascular disease and HF will shed light on the utility of the novel OACs in these settings, and will, if successful, provide important new therapeutic options to improve the long-term prognosis of this large patient population.