Post-TVP prophylaxis: AOD full dose or half-dose? | The doctor’s daily life

CONTEXT

Whether in the form of pulmonary embolism (EP) or proximal venous thrombosis of the lower limbs (or both), deep vein thrombosis (TVP) symptomatic are a serious pathology exposing to significant morbimortality (1.2). Anticoagulants are the crucial treatment of these pathologies whether heparin, followed (or not) of antivitamins K (AVK) or direct oral anticoagulants (AOD). The latter are more often prescribed for reasons of better convenience of employment and less risk of serious hemorrhage compared to AVK (3). If AODs have shown that they were better tolerated than AVK (3) the probability of TVP recurrence under treatment is real (around 2 % per year). As a result, clinicians tend to prolong the treatment with low -dose AOD, especially since Apixaban and Rivaroxaban have demonstrated their preventive effectiveness of PVTs (Versus placebo or aspirin) to a lower dosage than that indicated for the acute phase of the disease (4.5), and that they obtained a market permit (AMM) to this dosage and in this indication.

However, these trials were randomized versus placebo (or aspirin) and not versus AVK or the same AOD in the middle of the dose. In addition, in placebo or aspirin control groups, the two trials recruited patients for whom the need for prolonged anticoagulation was uncertain.

OBJECTIVE

Prove that a treatment with AOD in Demi-Dose as a preventive title of recurrence of a DVT is not lower than the same AOD with a full curative dose.

METHOD

Randomized trial of open-inferiority in 47 French hospitals and funded by the Ministry of Health. The main inclusion criterion was the elderly patients ≥ 18 years, victims of a symptomatic VVP considered at high risk of recurrence (not caused or recurrent DVT) having received anticoagulants at curative dose for 6 to 24 months and eligible for their extension (6). They were randomized to receive either a reduced dose of Apixaban (5 mg/d) or Rivaroxaban (10 mg/d) in the half-dose group or apixaban (10 mg/d) or Rivaroxaban (20 mg/d) with healing dosage in the full dose group.

The main judgment criterion (CJP) was the appearance of a new fatal symptomatic TVP or not. There were also two key secondary judgment criteria (hierarchical statistical analysis). The first was major or clinically relevant hemorrhages defined according to l’International Society of Thrombosis and Haemostasis (7). The second called “net profit” was made up of TVP recurrences and serious and clinically relevant hemorrhages. All events have been validated by a group of independent experts (Steering Committee) Unbeknown to the allocated group.

Given the results of the AOD tests previously published and the specific characteristics of high -risk patients included in Renove, the hypothesis was to observe 4 % of the main criterion events in the 2 groups in 2 years of follow -up. Non-inferiority was defined by a higher bound of the 95 % confidence interval (IC95) of the difference between the two groups <1.70 (in other words, the CJP rate in the half-dose group should not be> 70 % of that of the full dose group). To demonstrate non-inferiority with a power of 90 % it was necessary to include 1,030 patients in each group followed for 2 years. This power was also sufficient to show a significant difference in favor of the half-dose group on the two main criteria for secondary judgment. Statistical analysis (laminate on AOD received) was made up of dealing and per protocol (Population of analysis more relevant for an essay on non-inferiority).

RESULTS

Between November 2, 2017 and July 6, 2022, 2,768 patients were included: 1,383 in the half-dose group and 1,385 in the full dose group. During the first 12 months of follow -up there were only 0.75 % of CPJ events in the entire population included (1.5 % at 2 years much lower than 4 % expected). As a result, an amendment to the Steering Committee (unwittingly of randomization) increased the size of the workforce and the monitoring time to 36 months in order to maintain the initial power of the test.

In inclusion, the demographic and clinical characteristics of patients were similar in the 2 groups. The average age was 62.6 years (± 14.3) and 64.6 % were men. The average BMI was 25.6 kg/m2 and 65 % of patients had creatinine clearance ≥ 80 ml/min. 85.4 %of them had at least one history of symptomatic pulmonary embolism with (45.5 %) or without (40.0 %) deep venous thrombosis of the associated lower limbs. In addition, 60.8 % had a single history of DVT and 33.5 % had at least 2. Finally, the median duration of anticoagulation before randomization was 8.1 months (mini-max = 6.4-12.3); 48.9 % of the inclusive had only received AODs, the others having received heparin (in different forms) followed or not of an AVK.

During a median follow-up of 35.7 months in the 2 groups, there were 19 (2.2 %) CJP events in the half-dose group and 15 (1.8 %) in the full dose group: Hazard Ratio (HR) = 1.32; CI95 = 0.67-2.60, p of non-inferiority = 0.23.

Although the result on the main criterion is not significant, the authors have provided results on the two key secondary criteria, but without giving (rightly) the value of p. On serious or clinically relevant hemorrhages (9.9 % vs 15.2 %): HR = 0.61; IC95 = 0.48-0.79, in favor of the half-dose group. On the composite criterion “net profit”: HR = 0.67; CI95 = 0.53-0.86, in favor of the same group.

Comments

It is very rare that an exclusively French test is published in The Lancet. The main reasons for this unusual (and negative) publication in such a prestigious journal are: the high methodological quality of renovations, the size of the workforce included, the duration of follow-up, and especially the relevant clinical question to which it wished to answer (efficiency, tolerance, dosage and duration of a secondary preventive treatment of TVP by AOD at half dose).

Faced with the failure of the demonstration of non-inferiority on TVP recurrence it is logical to question its causes, while Renovely has been rigorously designed and particularly well conducted. The answer is in the very low impact observed in TVP recurrences in 3 years (≈ 2 % versus 6 % expected) which did not allow to demonstrate a significant non-inferiority. Probably (and legitimately) a little disappointed with this result, the authors still provided in the article the favorable results of the half-dose on the secondary hierarchical criteria (which can be considered by some as a “crime” of lese-metatistical). Therefore, these last results are to be considered as exploratory, because in a hierarchical analysis, it is theoretically compulsory to interrupt the approach as soon as the result of a previous analysis stage has been not significant (which was the case of the CJP in Renove).

In practice, if the clinical situation (TVP at high risk of recurrence) means that a practitioner wonders about the preventive interest of prolonged treatment by AOD, taking into account the results of this trial, it seems preferable (for the moment) to continue to prescribe the AOD with curative dosage rather than half a dose even if the tolerance and the net profit of the half-dose seem better without being really demonstrated. For the authors, the low recurrence rates in the two groups and the reduction of clinically relevant bleeding with the reduced dose could justify this therapeutic scheme. Additional research is necessary to identify the subgroups in which the AOD dose should not be reduced.

An exception concerns patients with cancer with a history of DVT as demonstrated in another French article published in the New England Journal of Medicine Almost at the same time (8). The latter establishes the non-inferiority of a half-dose of Apixaban compared to the full dose in terms of efficiency associated with a significant reduction in serious and clinically relevant hemorrhages. The incidence of TVP recurrence in the full dose group was 2.8 % in 11.8 months, which was much higher than that observed in the publication of Lancet.

Bibliography

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