Therapeutic angiogenesis for patients with chronic limb-threatening ischemia: promising or hoax?

Chronic limb-threatening ischemia (CLTI) is a critical end-stage disease that leads to high amputation rates. Over the past few decades, therapeutic angiogenesis has attracted a lot of attention as a means to reduce the necessity for amputations. Especially gene- and cell therapy are regarded to as possible treatment modalities to restore the hampered blood flow. So far, early-phase clinical trials often fail to prove a significant clinical improvement in mortality, amputation rate, and ulcer healing but still conclude that therapeutic angiogenesis might be promising as therapy. The subsequent phase III clinical trials based on these indecisive early trials fail consistently to demonstrate clinical benefits leaving the promising early results unvalidated. In this review we will illustrate that designing good trials for CLTI patients is challenging, not in the last place since patients are often not eligible due to strict inclusion criteria. Moreover, in this review, we advocate that clinical trials should be conducted with a low risk of bias and that it is of utmost importance to publish results, regardless of the outcome. It is definitely very concerning that many studies of a lower quality (due to small group size or high chance for bias) reporting positive outcomes are published while good quality trials (often with larger group sizes) are stopped prematurely due to lack of effects and remain unpublished. This keeps the 'promising but not yet proven' image of these therapeutic neovascularization studies alive, with still new groups starting similar trials.