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MSH Trial: Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia

MSH Trial: 1995, Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia. Source: NEJM

HERCULES Trial (2019): Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura

Source: NEJM

TITAN Trial (2016): Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura

Source: NEJM

TRAPS Trial (2018): Rivaroxaban vs. warfarin in antiphospholipid syndrome

Source: Blood

AVERT Trial: Apixaban to Prevent VTE in Patients with Cancer

AVERT trial Apixaban

2018, Apixaban to Prevent Venous Thromboembolism in Patients with Cancer, NEJM

The AVERT trial evaluated the use of apixaban for preventing venous thromboemboli such as deep venous thrombosis and pulmonary embolism in patients with cancer who were scheduled to start chemotherapy. These patients were at high risk of VTE based on the Khorana score.

The point that differentiated AVERT trial from other similar trials of using drugs for prevention of VTE in cancer patients was that it enrolled patients who did not have a history of VTE and the primary target was to lower the first incidence of VTE. In comparison, the CLOT and Hokusai VTE trials studied the use of LMWH for secondary prevention of VTE.

The study did show benefits of apixaban in preventing the first episode of VTE but this was countered by significant increase in bleeding risk. Currently based on guidelines, LMWH are preferred agents of choice for secondary prevention of VTE in patients with cancer. The 2012 CHEST guidelines on antithrombotic therapy recommend:

In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B). In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2B).


MOPETT: Low-dose tPA for submassive PE

2013, Low-dose tPA for submassive PE, AJC

EINSTEIN PE: Rivaroxaban for Acute PE

2012, Rivaroxaban for Acute Pulmonary embolism, NEJM

AMPLIFY Trial: Oral apixaban for VTE

amplify trial visual abstract, oral apixaban use in venous thromboembolism
Use of novel oral anticoagulation agents for VTE was established after a series of non-inferior trials that compared NAOCs with conventional therapy of LMWH and warfarin. The AMPLIFY trial was a randomized non-inferior trial that studied the usefulness of apixaban in preventing the recurrence of VTE after initial episode compared to conventional therapy of warfarin. The trial not only successfully established the efficacy of apixaban but also indicated its safety profile in terms of bleeding risk. Based on this trial, the 2016 CHEST guidelines for long term anticoagulation for VTE recommended NOAC over vitamin K antagonist (VKA) therapy. (all Grade 2B)

ANNEXA Trial: Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity

Source: NEJM

PROPPR Trial: Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs 1:1:2 Ratio and Mortality in Patients With Severe Trauma

Source: JAMA

Contribution by Sagar Dave
PGY2, Emergency Medicine
UConn Health

PREPIC 2 Trial: Effect of a Retrievable IVC Filter Plus Anticoagulation vs Anticoagulation Alone on Risk of Recurrent Pulmonary Embolism

Source: JAMA

ADJUST-PE study: Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism

Source: JAMA

Hokusai VTE Cancer Trial: Edoxaban for Cancer-Associated VTE

edoxaban, hokusai VTE cancer trial visual abstract

Let’s talk methodology…

In this randomized, open-label, non-inferiority trial, the authors analyze a primary composite outcome that includes recurrent VTE and major bleeding in cancer patients taking edoxaban, a factor X inhibitor developed by the study sponsor, Daiichi-Sankyo. They conclude that when compared with LMWH, edoxaban is non-inferior for the aforementioned composite outcome. Because composites occur more often than its components, using composites increase the study efficiency by decreasing the study time and sample size with subsequent costs reduction.

Non-inferiority trials are a useful tool when it is unethical to compare a new drug with placebo because a standard of care is available or because the trial involves serious outcomes such as mortality or in this case recurrence of VTE. Non-inferiority trials are usually confused with equivalence trials but these are different. Equivalence is applied mainly for comparison of generic versus marketed drug preparations to assess for pharmacokinetic differences. Otherwise, equivalence is impossible to be achieved between 2 drugs with different mechanisms of action such as edoxaban and LMWH. A non-inferiority approach may be used when the new treatment – edoxaban – seems to offer advantages such as better compliance, cost or availability over the standard of care – LMWH. Importantly, several considerations need to be accounted for when non-inferiority is part of the study design:

  1. As equivalence cannot be determined, a margin of non-inferiority should be established a-priori. This is defined as an acceptable margin of non-inferiority based on clinical judgment and statistical reasoning and it could be guided by previous trials that compared the control drug (LMWH) with placebo. In this case, the margin was a hazard ratio of 1.5 based on the unmet need for an alternative to parenteral LMWH and the advantages of oral therapy, allowing non-inferiority if the edoxaban population presented the composite outcome at 1.5 times the rate per unit time as the LMWH population or 50% the hazard.
  2. Importantly, the hazard ratio must be interpreted conjointly with time-to-event analysis or Kaplan-Meier curves. In this study, the curves cross for the composite primary outcome indicating non-inferiority, however, when interpretation is performed for each component, edoxaban appears to have less recurrent VTE but more major bleeding events when compared to LMWH. Once these 2 opposing components are combined into a composite, there is a sense of compensation.
  3. Intention-to-treat (ITT) analysis is indicated in superiority trials to preserve randomization – similar characteristics in both groups – avoiding attrition bias, however, including dropouts in non-inferiority trials can lead to bias towards equivalence. For this reason, in non-inferiority trials, it is recommended to perform both ITT and per-protocol analysis and both should demonstrate non-inferiority for it to be concluded. It this study a modified ITT analysis was performed including all patients who underwent randomization and received at least one dose of the assigned drug. These results were confirmed by sensitivity analysis of the primary outcome with a per-protocol approach.

In conclusion, non-inferiority trials should be cautiously executed and interpreted. Further studies with diverse factor X inhibitors are needed to validate these results and physicians must discuss risks and benefits of oral versus subcutaneous anticoagulation in cancer patients for whom quality of life might be the decisive variable.

Daniela Guerrero Vinsard MD.
Internal Medicine Resident at the University of Connecticut Health Center.

Source: NEJM

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