Practice-changing evidence from academic trials in VTE: COBRRA, RENOVE, and API-CAT

Free AccessEditorialPractice-changing evidence from academic trials in VTE: COBRRA, RENOVE, and API-CATStefano Barco, Tobias Tritschler, and Marc BlondonStefano BarcoStefano Barco, MD, Universitätsspital Zürich, Raemistrasse 100, RAE C04, 8091 Zürich, Switzerland[email protected] Department of Vascular Medicine, University Hospital Zurich, Switzerland Center for Thrombosis and Hemostasis, Johannes Gutenberg University Mainz, Germany , Tobias Tritschler Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland , and Marc Blondon Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland Published Online:September 26, 2025https://doi.org/10.1024/0301-1526/a001231PDF ToolsAdd to favoritesTrack Citations Cite ShareShare onFacebookXLinkedInRedditE-Mail SectionsMore The first half of 2025 brought several and partly unexpected advances in VTE management, thanks to three phase 3 trials evaluating different anticoagulation strategies and drug agents for VTE. For the first time since DOAC approval via pharma-sponsored trials, we now have high-quality, head-to-head data from academically sponsored investigator-initiated investigations. Let's review these findings in detail. The COBRRA trial [1, 2] directly compared the safety of rivaroxaban and apixaban during the acute treatment phase of VTE. This investigator-initiated, randomized, open-label trial with blinded endpoint adjudication enrolled 2,760 patients with acute symptomatic pulmonary embolism and/or proximal deep vein thrombosis. Patients received either rivaroxaban (15 mg twice daily for 21 days followed by 20 mg once daily) or apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily) for 3 months. The primary outcome – "clinically relevant bleeding" encompassing major and clinically relevant non-major bleeding – was significantly reduced with apixaban (3.3%) than with rivaroxaban (7.2%) (odds ratio, 0.44; 95% CI, 0.31 to 0.63; P<.0001). Rates of recurrent symptomatic VTE and all-cause mortality were low and similar between groups. The results are applicable to both unprovoked and provoked VTE, but not to cancer-associated VTE which was excluded. The number needed to treat with apixaban, instead of rivaroxaban, to avoid a clinically relevant bleeding is 26, and to avoid a major bleeding is 53 [2]. It is worth emphasizing that the results of the COBRRA trial led by Dr. L. Castellucci are truly unique. This is the first randomized study to directly compare two different anticoagulant therapies of the same class – factor Xa inhibitors – for any indication. Similar direct randomized comparative data exist neither for VTE prevention in medical or postoperative patients, nor for stroke and systemic embolism prevention in patients with atrial fibrillation. Broadening the scope even further, no such clinical data are available comparing different low molecular weight heparins or different vitamin K antagonists. The RENOVE study [3] was designed as a non-inferiority, multicenter, randomized, investigator-initiated, blinded trial. It enrolled patients with VTE who had already completed 6 to 24 months of anticoagulant therapy, randomizing them to receive either a reduced-dose DOAC – apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily – or a therapeutic (full) dose DOAC – apixaban 5 mg twice daily or rivaroxaban 20 mg once daily, as a secondary VTE prevention. A major innovation of this study is the inclusion of patients at high risk of recurrent VTE, including those with a first unprovoked VTE (i.e., without identifiable risk factors), those with a history of recurrent VTE, or patients with persistent risk factors (but not active cancer). A total of 2,768 patients were randomized in a 1:1 ratio. Although the pre-planned threshold to show non-inferiority was not met, the primary results of the study show that the 5-year risk of recurrent VTE was similar between the two groups: 2.2% in the reduced-dose group versus 1.8% in the full-dose group for an adjusted HR of 1.32 (95% CI 0.67 to 2.60; P=.23 for non-inferiority). However, the incidence of major or clinically relevant non-major bleeding was significantly lower in the reduced-dose group (9.9%) compared to the full-dose group (15.2%); adjusted HR 0.61 (95% CI 0.48 to 0.79). The API-CAT study [4] was a randomized, double-blind, investigator-initiated, non-inferiority trial evaluating extended anticoagulation with apixaban in patients with active cancer who had completed at least 6 months of therapy following a proximal deep vein thrombosis or pulmonary embolism. A total of 1,766 patients were randomized to receive either a reduced dose of apixaban (2.5 mg twice daily) or the standard full dose (5 mg twice daily) for 12 additional months. The primary efficacy outcome – recurrent fatal or nonfatal VTE – occurred in 2.1% of patients in the reduced-dose group and 2.8% in the full-dose group (adjusted subHR 0.76; 95% CI, 0.41 to 1.41; P=.001 for non-inferiority). Clinically relevant bleeding was significantly lower in the reduced-dose group (12.1%) compared to the full-dose group (15.6%) (adjusted subHR 0.75; 95% CI, 0.58 to 0.97; P=.03). What can we learn from these studies showing differential safety and efficacy of oral factor Xa inhibitors, and how will they influence clinical practice? In the acute phase of treatment, it is expected that apixaban will be preferred over rivaroxaban in most patients, due to its more favourable safety profile in COBRRA [2], which fully confirmed the safety outcomes observed in the original registration trials [5]. In the AMPLIFY [6] and EINSTEIN [7] trials, the cumulative incidence of clinically relevant bleeding with apixaban and rivaroxaban were 3.8% and 8.1%, respectively. This may lead to the reasonable question: should all patients with acute VTE now be treated with apixaban instead of rivaroxaban? Probably not, given certain specific scenarios where rivaroxaban retains potential advantages. For example, in patients with an extremely low bleeding risk – such as young or physically active individuals – rivaroxaban may still be preferred due to its once-daily dosing, which can be more convenient for athletes or highly active patients. The type of differential bleeding in COBRRA has not been released yet and will be critical to examine to understand specific subgroups, for instance with respect to menstrual bleeding: it remains unclear whether young women have similar bleeding profiles with the two factor Xa inhibitors [8]. Additionally, rivaroxaban's pharmacokinetic profile might still offer some advantages in selected populations. In obese patients (patients >120 kg were excluded from COBRRA), its high protein-binding rate (>95%) makes its pharmacokinetics less influenced by body weight [9]. In rare cases of short bowel syndrome [10, 11], rivaroxaban is theoretically more reliably absorbed, since its primary absorption site is in the stomach, whereas apixaban is absorbed more distally, beginning in the duodenum [12]. Interactions with specific drug classes may also influence the choice of treatment. Finally, it is unknown if apixaban is superior to rivaroxaban for the prevention of post-thrombotic syndrome in patients with deep vein thrombosis [13]. With regard to secondary VTE prevention after an initial therapeutic anticoagulation of at least six months, the RENOVE [3] and API-CAT [4] trials provide strong parallel confirmation that extended treatment with reduced-dose apixaban or rivaroxaban is safer than full-dose anticoagulation, while maintaining similar efficacy. These findings support the routine use of reduced-dose therapy in most patients with a history of acute VTE, except in those with contraindications to DOAC therapy – such as patients with thrombotic antiphospholipid syndrome or severe renal impairment, and specific subgroups, such as those with obesity in whom full-dose anticoagulation might be safer [14]. It should be emphasized that there is a growing number of generic drugs available for both agents, which will help reduce the economic burden on patients and healthcare systems. An open question remains: should also secondary prevention of VTE be influenced from these results with respect to the use of a specific factor Xa inhibitor? It is important to note that in the RENOVE [3] trial – where both apixaban and rivaroxaban were permitted – the overall rate of bleeding events was low across both treatment groups. Indeed, the study was not designed to directly compare the two drugs, but rather to evaluate two anticoagulation strategies (reduced-dose vs. full-dose for secondary prevention). That said, the investigators conducted a pre-specified subgroup analysis which showed that, at reduced doses, the risk-benefit profile (balancing thrombotic and bleeding events) was similar for apixaban and rivaroxaban. At five years, recurrent VTE occurred in 7 of 575 (1.2%) patients treated with low-dose apixaban and 12 of 674 (1.8%) patients treated with low-dose rivaroxaban. The slight reduction in recurrent event was counterbalanced by clinically relevant bleedings: 48 of 580 (8.3%) patients on low-dose apixaban and 48 of 674 (7.1%) patients on low-dose rivaroxaban. These non-randomized data suggest a comparable profile for both agents in the reduced-dose setting, although, it's important to emphasize again that the study was not powered for direct comparison. Moreover, the findings may be confounded by indication, namely by the clinical decision to select one drug over another in the acute VTE phase (prior to trial enrolment) or at the time of the dose reduction (at trial enrolment). Another relevant consideration is the current and future role of a third factor Xa inhibitor: edoxaban. Whether this agent will be preferred in future strategies remains to be seen; however, it is worth recalling that the edoxaban approval trial, Hokusai-VTE [15], remains the largest study to date on the treatment of acute VTE, enrolling over 8,000 patients. In our opinion, several pharmacokinetic and pharmacodynamic characteristics of edoxaban, which is given once daily, deserve attention: its lower potential for drug–drug interaction profile may be more favourable in patients on some immunosuppressants or chemotherapy [16]. It also allows for dose reduction during the first months of acute treatment based on predefined clinical criteria (i.e., low body weight, renal function, concomitant P-gp inhibitors) [15] – a flexibility not offered by apixaban or rivaroxaban. Moreover, it may have a better safety profile in terms of gastrointestinal bleeding compared to the other once-daily anti-Xa inhibitor rivaroxaban [17, 18]. These features could support a more individualized approach in specific patient populations where standard dosing of the other agents may be seen as suboptimal. The results of the COBRRA study [2] may also have implications for patients with atrial fibrillation. It is well known that, compared to patients with VTE, AF patients are on average about 10 years older at the time of anticoagulation initiation. Moreover, they tend to have a higher baseline bleeding risk, not only due to advanced age but also due to a higher burden of comorbidities and more frequent use of concomitant antithrombotic therapies. This raises the question of whether the findings of COBRRA [2] can be extrapolated to the population with atrial fibrillation, where indirect evidence from phase 3 trials and real-world data suggest that apixaban may have a more favourable safety profile than rivaroxaban [19, 20, 21]. The COmparison of Bleeding Risk Between Rivaroxaban and Apixaban in Patients With Atrial Fibrillation (COBRRA-AF; NCT04642430) is being conducted to answer this question. Another related question is how best to interpret the results of the AZALEA trial [22], which compared safety outcomes in atrial fibrillation patients randomized to receive the factor XI monoclonal antibody abelacimab (administered subcutaneously) versus standard-dose oral rivaroxaban. While abelacimab was associated with a 62% reduction in bleeding events, one could argue that a similar reduction might have been achievable with apixaban in this setting, assuming the results of COBRRA [2] are applicable. That said, a key potential advantage of the novel factor XI inhibitor therapy lies in its ease of administration – with subcutaneous injections given only once per month. Finally, we would like to highlight that it is indeed possible to successfully conduct ambitious, long-term studies, even when they are investigator-initiated and academically sponsored. These efforts deserve recognition, along with the institutions and networks that make them possible. The RENOVE study [3] was sponsored by the CHRU of the University of Brest, with support from the French InnoVTE Network. The API-CAT study [4] was sponsored by the Assistance Publique–Hôpitaux de Paris (AP-HP). The COBRRA study [1] was sponsored by the Ottawa Hospital Research Institute (OHRI), with organizational and network support from CanVECTOR and the INVENT-VTE Network.References1 Ottawa Hospital Research Institute. Comparison of bleeding risk between rivaroxaban and apixaban for the treatment of acute venous thromboembolism (COBRRA) [Internet]. ClinicalTrials.gov; 2017 Aug 10. Available from: https://clinicaltrials.gov/study/NCT03266783. 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