Less Is More: Low-Dose Direct Oral Anticoagulants for Extended Venous Thromboembolism Prophylaxis in Higher-Risk Patients Free

Primary treatment for venous thromboembolism (VTE) involves a minimum of three months of therapeutic anticoagulation.¹  For individuals requiring extended prophylaxis, determining the optimal dose and duration of anticoagulation after primary treatment can be challenging. Providers must weigh the risk of recurrent VTE, bleeding, and other patient-specific factors in determining the optimal course of therapy.

Until recently, only two landmark clinical trials had evaluated reduced-dose anticoagulation strategies for extended VTE prophylaxis following primary treatment.^2,3  These trials enrolled patients who had completed six to 12 months of therapeutic anticoagulation and for whom there was equipoise regarding whether to continue or stop anticoagulation. The AMPLIFY-EXT trial randomized patients to full-dose apixaban, reduced-dose apixaban, or placebo,²  while the EINSTEIN CHOICE trial randomized patients to full-dose rivaroxaban, reduced-dose rivaroxaban, or aspirin.³  Together, these trials highlight three important findings: (1) factor Xa-inhibiting direct oral anticoagulants (DOACs) at both full and reduced doses were more effective than placebo or aspirin in preventing VTE recurrence; (2) reduced-dose DOACs were comparable to full-dose DOACs in preventing VTE recurrence; and (3) compared to full-dose DOACs, reduced-dose DOACs had the potential for less bleeding complications, although the trials were not powered for this important endpoint.

Despite both trials’ requirement for equipoise with respect to extended VTE prophylaxis, unprovoked VTE was the index event for 41% of patients in EINSTEIN CHOICE and 92% in AMPLIFY-EXT. The inclusion of this higher-risk population has led to the more common use of reduced-dose DOACs for extended VTE prophylaxis, not only in intermediate-risk patients where there is equipoise regarding long-term anticoagulation, but also in patients at higher risk of VTE recurrence, even without a confirmatory trial.

Because EINSTEIN CHOICE and AMPLIFY-EXT were not designed to evaluate patients with VTE and higher risk of recurrence, an important question remains: Is there a similar role for reduced-dose DOACs in place of full-dose regimens in patients with higher risk of VTE recurrence? The RENOVE and API-CAT trials sought to answer this question, examining patients without and with cancer, respectively.

The RENOVE trial was a multicenter, open-label, randomized study comparing reduced-dose versus full-dose rivaroxaban or apixaban in patients at high risk of VTE recurrence with established indications for extended anticoagulation, such as an unprovoked initial event or persistent risk factors. The primary aim was to assess noninferiority of reduced-dose DOACs in preventing symptomatic recurrent VTE. The secondary aim was to assess the superiority of reduced-dose DOACs with respect to bleeding risk and net clinical benefit (a composite of recurrent VTE and clinically relevant bleeding). Eligible participants had completed six to 24 months of full-dose anticoagulation for primary therapy prior to randomization to either reduced-dose or full-dose apixaban or rivaroxaban. DOAC selection was determined based on patient or provider preference. Patients with active cancer were excluded.

The reduced-dose group included 1,383 patients, with 625 (45.2%) receiving apixaban and 758 (54.8%) receiving rivaroxaban. The full-dose group included 1,385 patients, with 630 (45.5%) receiving apixaban and 755 (54.5%) receiving rivaroxaban. Five-year cumulative incidence for recurrent VTE was 2.2% in the reduced-dose group (95% CI 1.1-3.3) versus 1.8% in the full-dose group (95% CI 0.8-2.7), after a median follow-up of 37.1 months. The adjusted hazard ratio (aHR) was 1.32 (95% CI 0.67-2.60; p=0.23 for noninferiority), not meeting the HR noninferiority threshold of 1.7. This threshold was based on prior VTE studies with double the VTE recurrence rates (approximately 4% five-year cumulative incidence), likely leading to the inability to establish noninferiority in the reduced-dose group. Nevertheless, the low VTE event rates in this high-risk group support either dose strategy. Notably, key secondary analyses in this trial suggest that reduced-dose DOACs are safer than full-dose DOACs with respect to clinically relevant non-major bleeding (aHR 0.61, 95% CI 0.48-0.79) and net clinical benefit (aHR 0.67, 95% CI 0.53-0.86). Stratified analyses to separately evaluate apixaban and rivaroxaban for the primary and key secondary endpoints were included in the supplementary appendix, and while the study was not designed to draw meaningful conclusions from these subgroup analyses, there are similar trends in efficacy and safety for both DOACs at reduced doses.

For cancer-associated VTE — a key exclusion from RENOVE — the API-CAT was a multicenter, double-blinded, randomized controlled trial evaluating the efficacy and safety of reduced-dose versus full-dose apixaban for 12 months in patients with active cancer and VTE. The primary aim was to assess noninferiority of reduced-dose apixaban in preventing symptomatic or incidental VTE recurrence. The secondary aim was to assess superiority of reduced-dose apixaban with respect to clinically relevant bleeding. Eligible participants with active cancer and VTE had completed at least six months of therapeutic anticoagulation prior to randomization to reduced-dose or full-dose apixaban.

Twelve-month cumulative incidence for recurrent VTE was 2.1% in the reduced-dose group versus 2.8% in the full-dose group, with an adjusted subhazard ratio (aSHR) of 0.76 (95% CI 0.41-1.41; p=0.001 for noninferiority), confirming that extended therapy with reduced-dose apixaban was noninferior to full-dose apixaban in preventing recurrent VTE among cancer patients. Similar to RENOVE, reduced-dose apixaban was superior to full-dose apixaban with regard to clinically relevant non-major bleeding (aSHR 0.75, 95% CI 0.58-0.97; p=0.03 for superiority).

These trials, summarized in the Table below, demonstrate that for both cancer and non-cancer patients at increased risk of recurrent VTE who have completed at least six months of therapeutic (i.e. full-dose) anticoagulation, reduced-dose DOACs provide similar protective efficacy with lower bleeding risks compared to full-dose DOACs.

We highlight an important limitation of these studies relevant to the clinician: neither trial addresses efficacy and safety of reduced-dose DOACs for patients with severely elevated body weight or body mass index (BMI), such as a BMI greater than 40 kg/m² — an increasingly common risk factor for VTE recurrence. While the RENOVE trial provides subgroup analyses of patients with a BMI of less than 30 versus a BMI of 30 or greater and the API-CAT trial provides subgroup analysis across BMI categories (≤18.5, 19-29, 30-34, and ≥35), we do not know whether dose reduction in patients with more severe obesity is appropriate given the likely limited number of participants with a BMI greater than 40 kg/m² in these trials. More comprehensive secondary analyses or future meta-analyses could provide valuable insights regarding the generalizability of these findings to this important patient population.

Two landmark clinical trials, RENOVE and API-CAT, evaluated reduced-dose versus full-dose DOACs (apixaban and rivaroxaban) in patients who completed at least six months of primary treatment for VTE and required extended prophylaxis. RENOVE evaluated non-cancer patients at higher risk of recurrent VTE, while API-CAT evaluated patients with cancer-associated VTE.

These impactful, practice-changing trials confirm that DOACs maintain low VTE recurrence rates, with reduced-dose DOACs providing similar efficacy to full-dose regimens with fewer bleeding complications. These findings support the transition of higher-risk VTE patients, including those with cancer-associated VTE, to reduced-dose DOACs after completing at least six months of full-dose anticoagulation.

The authors indicated no relevant conflicts of interest.

Dr. Superdock’s work is supported by a Ruth L. Kirschstein National Research Service Award (T32 CA244125) from the National Cancer Institute, part of the National Institutes of Health.