A Systematic Review of Clinical Trials in Patients With Critical Limb-Threatening Ischemia

Methodological Considerations Around RCTs

RCTs have been the foundation of evaluating treatment strategies. They serve as the most robust approach in determining whether a cause-and-effect relationship truly exists between a given treatment and its associated outcome. Typically, RCTs consist of multiple arms that involve comparison between certain treatments, regardless of whether or not the patients received the allotted treatment (intention-to-treat analysis). The analysis is focused on assessing the magnitude of the difference in predefined outcomes between intervention groups.²³ When designing and conducting a RCT, some considerations must be taken into account to ensure that the final result will be methodologically robust (ie, valid) and clinically relevant (ie, generalizable). Generally speaking, while internal validity of RCTs is high (provided they are well-designed and well-executed), external validity and general applicability of RCTs remain problematic.

The issue of trial population not representing real-world patients has been a concern for a significant number of clinicians, as randomized patients in trials tend to have a controlled set of variables. Experiments are designed and conducted to answer specific questions and avoid any unforeseen bias. Consequently, this has brought about concern regarding the applicability of these trial findings to the overall patient population.  

Lesion Characteristics in Registries and Retrospective Analyses

The complicated anatomical nature of disease distribution within the peripheral vessels makes comparison between trials nearly impossible; therefore, registries are more representative of real-world patients. Regarding lesion length, in the Peripheral RegIstry of Endovascular OutcoMEs (PRIME) registry, the overall average lesion length was 16 cm with an average of 1.5 lesions treated per intervention.²⁴ Similarly, the mean lesion length was 12 cm in the IN.PACT Global registry²⁵ and approximately 9 cm in the BIOLUX P-III registry (Table 2).²⁶ In the Tibiopedal Artery Minimally Invasive (TAMI) retrograde revascularization trial, complex lesions ranged in length between 200 mm and 300 mm.²⁷ However, in other analysis, such as the Chronic Total Occlusion Approach Based on Plaque Cap Morphology (CTOP) trial, the average chronic total occlusion (CTO) length ranged from 240 mm to 260 mm.²⁸ In another recent real-world CTO registry of 1516 consecutive patients from Germany, mean lesion length was shown to be 240 mm, similar to the real-world trials mentioned above.²⁹ It is important to note that an analysis was performed on different types of CTOs that were enrolled within the PRIME registry, where the authors confirmed an average lesion length of 200 mm. Morbidity is noted to worsen with longer lesions, as more distal disease suggests involvement of the tibial arteries and extension of the CTO across multiple vascular beds.³⁰

Device Characteristics

Most trials that have evaluated DCB or drug-eluting stents have mainly enrolled patients with claudication rather than CLTI (as a matter of fact, only subgroup analyses of patients with CLTI from these trials are available thus far), thereby calling into question whether potentially limb-saving drug-eluting technology should be avoided in the setting of CLTI. Most RCTs were initially designed to determine technical endpoints, such as target lesion revascularization or primary patency, rather than mortality. Contemporary trials comparing surgical and endovascular approaches in the treatment of patients with CLTI demonstrate conflicting results. In the Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia (BEST-CLI) study, it was shown that venous bypass appears to be superior to endovascular therapy in patients with femoral-popliteal lesions who were ineligible for surgical treatment due to multilevel CTOs. However, this was not the case for synthetic conduit bypass.²² Yet, in the vein bypass first vs a best endovascular treatment first revascularization strategy for patients with CLTI who required an infrapopliteal bypass, with or without an additional more proximal infrainguinal revascularization procedure to restore limb perfusion (BASIL-2) trial, it was shown that an endovascular approach demonstrated a significant reduction in mortality compared to a surgical approach.¹⁰ The difference observed in the primary combined endpoint was primarily driven by the reduction in mortality. Unlike the BEST-CLI trial, BASIL-2 did not require patients to have an adequate autologous vein conduit or to be good surgical candidates, which may have influenced the applicability of its findings. In addition, these trials do not report real-world concerns such as patient quality of life and wound healing, which are often the goal of treating CLTI.

Outcomes

The recent COMPASS and VOYAGER trials have introduced a new powerful combination to reduce intervention and cardiovascular related risk(s) in PAD patients, but their external validity has been questionable.^31,32 In the French COPART registry, it was observed that, among hospitalized patients with symptomatic lower extremity arterial disease, the low-dose rivaroxaban plus aspirin combination used in these trials could not be implemented in many cases due to various practical limitations.³³ As a result, those who were eligible may potentially experience greater absolute benefit because these patients are deemed higher risk than those enrolled in the trials. This leads to questions regarding outcomes of revascularization in patients with CTLI in the hospital vs outpatient setting,³⁴ with a provider base demonstrating variable experience. These RCTs did not include a control arm that is consistent with contemporary best medical practices and therapy, were funded by industry, and measured a primary outcome that was a composite not based upon the views or experiences of the patients. In addition, in most RCTs patients are only enrolled after successful lesion crossing. As a result, the true failure rate of endovascular attempts is often underreported. Similarly, observational registries typically enroll patients only after successful treatment, further contributing to selection bias and limiting generalizability.

Patients With Critical Limb-Threatening Ischemia in RCTs vs Real-World Patient Populations 

RCTs carry the burden of tackling very complex disease processes such as PAD but often exclude the most complex patients and lesions. For example, although the BEST-CLI study demonstrated that venous bypasses and conduits are superior to endovascular therapies, it is important to consider that it is not uncommon for patients to have undergone previous coronary artery bypass grafting where saphenous vein was already harvested.³⁵

Patients with CLTI carry high levels of morbidity and mortality. The complex nature of these patients extends from their clinical history, which includes CAD, cerebrovascular disease, diabetes, heart failure, and CKD, especially those with ESRD on hemodialysis, that will certainly limit patient inclusion in research trials. Several groups have utilized fewer selected data from large administrative registries to confirm or confute controversial claims. It has become increasingly important to analyze inherent selection bias in trials that may become clinically relevant. For instance, it is well-known that RCTs tend to enroll fewer women when compared with observational registries.²⁰ This highlights the ongoing need to address selection bias and improve the generalizability of trial findings to better reflect real-world patient populations.