15-05-2025
Seeking a Perfect Risk-Benefit Balance in Treating VTE
At the dawn of the 21st century, venous thromboembolism (VTE) treatment remained in the dark ages. Backed by an MD and a legacy of paternalistic practice, we convinced patients to do what now seems unthinkable. Unfractionated heparin may come from pigs and cattle, but we infused it like snake oil. Patients spent 5 (or more) days in the hospital chasing partial thromboplastin times and enduring stops and starts with repeated blood draws. Finally, we discharged them on the only drug awful enough to require an eponymous nursing position and clinic.
Our approach to balancing risk-benefit was equally primitive. Patients diagnosed with their first VTE were given the proverbial 'trial of life.' They generally received 3-6 months of anticoagulation before being advised to stop, with guidance as blithe as it was vague: 'If you feel short of breath, go to the emergency room.' It mattered not whether their initial clot was a pulmonary embolism or a deep vein thrombosis. Or whether there was comorbid cardiopulmonary disease. If they had a second VTE, assuming they survived it, the initial treatment regimen (including the hospitalization) was repeated.
By 2008, our guidelines had incorporated data showing that for unprovoked events, fixed courses of anticoagulation provided less mitigation than delay. This pushed risk-benefit analysis to the forefront of all things VTE. Physicians, and patients, were forced to balance VTE recurrence with bleeding risk and decide whether to stop treatment after 3 months or continue it indefinitely. Shortly thereafter, the novel blood thinners hit the market, making indefinite anticoagulation slightly more palatable.
Meanwhile, the field continued to refine risk calculations. D-dimer testing had its moment in the sun before being knocked down a notch by the 2016 CHEST VTE guidelines. Lower-extremity ultrasound also helped, but it wasn't quite clear where and how it fit into overall risk after accounting for other factors. Both have given way to more complicated models that perform well in particular situations. There are even online risk calculators to help battle the viscous time scarcity epidemic afflicting all 21st century medicine clinics.
The latest breakthrough reduces bleeding more than VTE recurrence risk. In 2013, the AMPLIFY-EXT trial showed that after 6 months of full-dose treatment, a half dose of apixaban reduced bleeding without increasing recurrence risk. Not to be outdone, these findings were replicated using rivaroxaban in the EINSTEIN CHOICE study. Taken together, AMPLIFY-EXT and EINSTEIN CHOICE provide strong evidence that for those with a first episode of VTE with clinical equipoise (defined as uncertainty as to whether risk-benefit favored continued treatment) after 6 months of full-dose anticoagulation, reduced doses of apixaban or rivaroxaban are excellent options. The most recent iteration of the CHEST VTE Treatment Guidelines endorses this practice.
Because AMPLIFY-EXT and EINSTEIN CHOICE had the "clinical equipoise" proviso in their inclusion criteria, cancer patients were largely excluded. There's generally not equipoise for them; VTE recurrence risk is expected to remain indefinitely high, requiring indefinite protection. So, the practice of reduced dosing could not be generalized to cancer-related VTE — until now.
The API-CAT investigators very recently published reduced-dose data for cancer patients. Turns out, it works! As the accompanying editorial points out, advances in cancer treatment have led to increased survival times. Longer survival with active cancer translates to more cancer-related VTE. The API-CAT data are a critical addition to the literature. The sooner they're incorporated, the better.
