March Issue - Anticoagulants for Treatment of PE and DVT
Comparing the expanding anticoagulant treatment options for deep vein thrombosis and pulmonary embolism
Alexander (Ander) Cohen, MBBS, MSc, MD, FRACP
Ander Cohen is a vascular physician and epidemiologist specializing in the prevention of cardiovascular disease, stroke and coronary artery disease, and prophylaxis and treatment of venous thromboembolism. He has written or co-authored over 350 papers and abstracts on thrombosis, and is on international steering committees for several multicentre trials. Dr Cohen was trained at the Royal Australasian College of Physicians (FRACP) and the London School of Hygiene and Tropical Medicine, University of London (MSc in Epidemiology). He is a member of several international societies and committees, an advisor on numerous UK Government Health boards, and is involved in several educational charities.
Welcome to the March 2015 edition of the Thrombosis Adviser newsletter.
Dear Ladies and Gentlemen
Over the past few years, the number of oral anticoagulants (OACs) available for the treatment of several thromboembolic indications has increased. Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), has traditionally been treated with a vitamin K antagonist (VKA) overlapping with and following an initial period of parenteral anticoagulation, usually low molecular weight heparin. After being developed to overcome several limitations associated with VKA therapy, the non-VKA OACs rivaroxaban, dabigatran and apixaban have now received approval in Europe and North America for the treatment of DVT/PE and the secondary prevention of recurrent venous thromboembolic events. Edoxaban is approved for use in Japan and is expected to receive wider approval in the near future. Recently, the updated European Society of Cardiology (ESC) guidelines recommended rivaroxaban, dabigatran, apixaban and edoxaban (pending European approval) as alternatives to parenteral/VKA anticoagulation for acute-phase treatment and secondary prevention of patients at an intermediate or low risk of early mortality from PE (Class I, Level B). Rivaroxaban, dabigatran and apixaban are also recommended as alternatives to conventional therapy for patients who require extended anticoagulation (>3 months) (Class IIa, Level B).
The non-VKA OACs have been tested against conventional therapy in large phase III studies for the treatment of VTE: EINSTEIN DVT and EINSTEIN PE for rivaroxaban, RE-COVER and RE-COVER II for dabigatran, AMPLIFY for apixaban and Hokusai-VTE for edoxaban. Across these studies, non-VKA OACs (administered following initial heparin therapy in the case of dabigatran and edoxaban) were shown to be at least as effective as VKAs for preventing primary efficacy endpoint events (recurrent VTE and VTE-related death for all studies), and demonstrated a similar or reduced incidence of the principal safety outcome event of bleeding, compared with conventional treatment. The efficacy and safety of non-VKA OAC use for the extended secondary prevention of VTE following DVT/PE has been evaluated in placebo-controlled studies: EINSTEIN EXT for rivaroxaban, RE-SONATE for dabigatran and AMPLIFY-EXT for apixaban. These studies enrolled patients who had already received a period of anticoagulation for the treatment of the initial venous thromboembolic event. All three non-VKA OACs demonstrated superior efficacy compared with placebo for preventing recurrent VTE and VTE-related death, with small but non-significant differences in the incidence of major bleeding. Dabigatran was also compared with warfarin for extended VTE treatment in the RE-MEDY study, in which dabigatran was associated with non-inferior efficacy and similar rates of major bleeding. These studies are difficult to compare directly owing to variations in study design; therefore, in the absence of head-to-head comparison trials, there is no direct evidence to support the use of one non-VKA OAC over another. Nonetheless, knowledge of some of the key differences between the clinical studies of the available non-VKA OACs may aid therapeutic decision making.
One difference is the variation in DVT/PE status of the study populations in the phase III trials. Approximately one-third of patients with VTE in RE-COVER and AMPLIFY, and 40% of patients in Hokusai-VTE, had an index PE (with or without DVT), whereas the remaining patients presented with DVT. The EINSTEIN programme had two separate trials for PE (with or without DVT) and DVT (without PE). Although DVT and PE are both manifestations of VTE, they are also separate conditions with distinct management strategies. Analysis of independently randomized DVT and PE populations may, therefore, allow for a greater exploration of disease-specific outcomes, e.g. in relation to the location of a DVT or the extent of a pulmonary occlusion in PE and analysis of clot regression with anticoagulation. Prespecified pooling of data from EINSTEIN DVT and EINSTEIN PE was used to increase the statistical power of endpoint analysis, particularly for the small groups of challenging-to-treat patients included in these studies. Patients with an initial unprovoked DVT and/or PE are at higher risk of recurrent VTE compared with patients with VTE following a transient risk factor, such as surgery. Both unprovoked and provoked VTE patient populations were well represented in the EINSTEIN programme and Hokusai-VTE, with approximate split of 60–65% unprovoked versus 30–35% provoked events. AMPLIFY enrolled an even higher-risk population, with the proportion of patients with unprovoked VTE accounting for ~90% of the study population. The numbers of patients with unprovoked versus provoked VTE in the RE-COVER studies was not reported.
The phase III trials of the non-VKA OACs also differed in their use of ‘blind’ or ‘open’ randomization: RE-COVER, AMPLIFY and Hokusai-VTE were double blind, whereas EINSTEIN DVT and EINSTEIN PE were open label. Different trial designs introduce different risks of bias. Double-blind studies increase the internal validity of results by lowering the risk of investigator and patient bias from knowledge of treatment allocation. Open-label studies increase the external validity of results because both the patient and investigators are aware of the assigned treatment group, more closely resembling the situation seen in routine clinical care.
The differences between the approved dosing regimens of the non-VKA OACs have sparked much debate, including the perceived benefits and drawbacks of initial parenteral therapy [HD1] versus an oral single-drug approach and once- versus twice-daily dosing. Similar to the traditional VKA dosing regimen, dabigatran is initiated following at least 5 days of initial parenteral therapy. Some clinicians may feel more familiar with this dosing regimen because it fits with the established practice of administering parenteral therapy for a suspected VTE while awaiting results from diagnostics. However, like parenteral anticoagulants, all non-VKA OACs have a fast onset of action, providing rapid protection against further thromboembolic events. Rivaroxaban and apixaban were tested and approved as single-drug therapies, averting the need for sometimes painful and often inconvenient subcutaneous injections. Both agents are initiated with an intense period of twice-daily anticoagulation (21 days for rivaroxaban and 7 days for apixaban), after which the patient switches to a less-intense dosing regimen for long-term protection against recurrent VTE. In a subanalysis of EINSTEIN PE involving 347 patients, the 21-day rivaroxaban twice-daily dosing regimen was shown to be as effective as standard therapy for reducing thrombus burden, with 88% of patients in the overall safety population achieving complete or partial thrombus regression. Whereas rivaroxaban is dosed once daily for long-term VTE treatment, apixaban and dabigatran are administered twice daily. Non-VKA OACs have short half-lives, and it has been suggested that twice-daily dosing provides a greater consistency of plasma drug levels compared with once-daily dosing. However, dosing regimens cannot be based solely on pharmacological data, which do not reliably predict clinical efficacy and safety outcomes. Once-daily dosing regimens (particularly in chronic indications) have been shown to be associated with improved convenience, patient treatment satisfaction and adherence, which may have positive effects on clinical outcomes.
In the era of multiple non-VKA OAC options for VTE treatment, a physician can now choose an anticoagulant that he/she believes best suits an individual patient’s needs. All non-VKA OACs have proven to be at least as effective as conventional therapy for acute VTE treatment, with favourable safety profiles. In the absence of head-to-head comparison trials, a patient’s clinical characteristics; convenience of the dosing regimen; and the agent’s impact on patient quality of life, healthcare resource utilization and adherence, are important factors that may influence treatment decision making.