Assessing Novel Treatments to Reduce Thrombosis in PV, ET Requires New Approaches

Thrombosis is a major contributor to morbidity and mortality in patients with polycythemia vera (PV) and essential thrombocytopenia (ET) but there are challenges with accurately assessing a novel therapy’s effectiveness at reducing thrombotic events. A recent report offers guidance for future research.

According to the authors, few treatments have been able to reduce the thrombotic burden in patients with PV and ET, and progress on this front has been hindered by a lack of studies designed to assess a treatment’s impact on thrombotic events. In studies that are designed as primary prevention trials of thrombosis-related endpoints in the 2 diseases, they are met with several challenges, including low accrual and lack of feasibility to further accrue.

“Despite thrombosis accounting for the majority of morbidity and mortality in PV and ET, clinical research up to this point has been largely unregimented when it comes to evaluating the impact of therapeutic strategies on thrombosis,” explained the researchers, adding, “While many disease-specific limitations exist to account for the lack of attention toward thrombosis reduction, we believe these obstacles can be overcome with surrogate endpoint and biomarker validation studies, in addition to uniform clinical trial design.”

A surrogate endpoint touted by the researchers is hematocrit control <45%, based on a study that assessed 3 different aspirin regiments in ET. The study’s primary endpoint was TxA2, an unproven endpoint. According to the researchers, the approach highlighted measurable differences at 2 weeks rather than the traditional years it would normally take for outcomes such as thrombosis to occur.

The researchers note that there is difficulty in knowing if a surrogate endpoint is meaningful in all populations, and as a result, they urge that the relationship between a surrogate endpoint and the endpoint of interest should be well-established.

“Future studies should be aimed at validating surrogate endpoints for predicting thrombosis. One such method is trial-level validation, where the change in an endpoint is plotted against the change in a well-defined endpoint (i.e. thrombosis),” suggested the researchers. “The strength of this association is then measured by regression analysis. This strategy requires multiple trials that measure the same biomarker and endpoints.”

Non-inferiority trial designs also may play a potential role, say the researchers, who note that this type of design requires the consideration of the chosen non-inferiority margin that is sensitive to the assumed effects of a novel treatment relative to past effectiveness of the comparator treatment.

Reference

Tremblay D, Kosiorek, Dueck A, Hoffman R. Evaluation of therapeutic strategies to reduce the number of thrombotic events in patients with polycythemia vera and essential thrombocythemia. Front Oncol. Published online February 16, 2021. doi:10.3389/fonc.2020.636675