Considering the distinct cardiovascular risk in patients presenting with CLI, the INCORPORATE trial sought to determine whether a proactive approach with default CA and ischemia-targeted revascularization is superior to a conventional conservative approach in terms of spontaneous MI and overall survival at 12 months. The trial was prematurely halted due to COVID-19-related burdens, and therefore, it failed to show significant differences between the outcomes of two groups. Nevertheless, there was a signal of trends towards an unfavorable outcome in conservatively treated patients, especially for the combined secondary endpoint of MACCE (Table 4).

Given the results of recent trials like ORBITA, ISCHEMIA, and REVIVED, there is a rising debate about the necessity of coronary revascularization in chronic coronary syndrome [12,13,14]. Contrarily, other studies have demonstrated that when revascularization is limited to patients with extensive ischemia and to lesions which are responsible for it, then beneficial outcomes can be expected compared to pure optimal medical therapy [15, 16]. Even more importantly, patients with significant non-revascularized coronary artery disease were exposed to a greater long-term risk of death or myocardial infarction, even though they presented with no or only mild symptoms at baseline [17].

Actually, the patient population investigated in the INCORPORATE trial shares many similarities with this latter cohort: these patients bear a significant atherosclerotic burden in the peripheral vasculature, which is in itself associated with a higher incidence of coronary atherosclerosis and pronounced cardiovascular risk [18, 19]. This aligns with our findings as well, where almost two-thirds of the patients in the invasive group did indeed have one or more functionally relevant coronary artery stenoses with FFR as low as 0.65 ± 0.12. Notably, the incidence of left main stem and left anterior descending artery stenosis was as high as 45%.

Still, clinical symptoms such as angina or shortness of breath during exercise might remain concealed, which can be explained by the minimal exercise capacity of these patients due to their primary disease. Patients, recruited in the trial, were suffering from Rutherford 4 or more symptoms, suggesting severe claudication or even rest pain in the lower extremities. This suggests that in daily life, these patients rarely engage in exercise intense enough to reach the ischemic threshold of their myocardium. In line with this, we found that fewer than one-tenth of the patients experienced CCS II or worse angina, and only one-quarter had a NYHA II or worse symptomatic status. However, the applicability and interpretability of the CCS and NYHA classification systems for these patients may be questionable. It is important to emphasize, while these patients have minimal or no symptoms, and probably no myocardial perfusion deficiency at baseline, this condition might change dramatically once patients undergo successful peripheral revascularization, releasing the former exercise capacity burden. As exercise capacity becomes less limited by peripheral vascular conditions, the myocardium faces an increase in workload that coronary perfusion potentially cannot comply with. In the best-case scenario, this situation leads to progressive stable symptoms only. However, this might also explain the high incidence of early myocardial infarction and cardiac mortality as the first presentation in patients who underwent treatment for CLI [1, 20,21,22].

This mechanism suggests that careful cardiologic assessment towards existing CAD might be reasonable for patients, who underwent treatment of CLI. The decision whether to begin with non-invasive tests or to proceed directly with invasive CA remains a topic of open discussion. This choice may also be influenced by local logistical factors. Systematic non-invasive testing as a gatekeeper could have its strategic importance. However, modalities such as ergometry, myocardial scintigraphy, and coronary computed tomography have their own limitations, either in sensitivity or specificity, when dealing with this potentially complex CAD population [23]. However, and as highlighted in a recent consensus paper, particularly with the latest generation of CT scanners, CCTA may possess the capability to not only diagnose but also guide the treatment of CAD, including multi-vessel disease [24]. Stress echocardiography or stress magnetic resonance tomography could offer a more conclusive approach, especially in experienced hands. The results can even guide revascularization, once indicated. On the other hand, one could argue that the threshold for invasive CA could be kept low, considering the inherently high pretest probability. Still, the cornerstone of revascularization strategies has to remain the functional confirmation of lesion significance. This can probably be done equally well by either angiogram-based or wire-based technologies. In the INCORPORATE trial, we specifically avoided non-invasive functional assessments in this high-risk cohort for several reasons. As detailed in the design paper [10], patients with CLI present unique challenges: (1) the inability of exercise testing due to limited physical capacity, (2) frequent occurrence of balanced ischemia, and (3) widespread coronary calcification that limits the diagnostic accuracy of non-invasive tests. Balanced ischemia occurs when there is diffuse and symmetric reduction in blood flow to the myocardium, making it difficult for non-invasive imaging tests to detect regional differences in perfusion. These limitations justify, in our opinion, the use of invasive coronary angiography and FFR measurement to obtain precise functional information on coronary lesions. This approach aligns with the ESC guidelines’ recommendation that when non-invasive tests are not available or inconclusive, invasive measures such as FFR are warranted to guide revascularization decisions. According to the 2019 ESC guidelines, these techniques are recommended for initial diagnosis, especially in patients with lower probabilities of significant CAD. However, invasive coronary angiography remains the gold standard for definitive diagnosis, particularly in high-risk patients with inconclusive non-invasive test results [8].

It is also important to note that since the inception of the INCORPORATE trial, there have been significant advancements in high-quality CT technology and CT-derived fractional flow reserve (CT-FFR). These advancements may warrant consideration in future studies or clinical practice for similar patient cohorts.

While the INCORPORATE trial did not specifically address the impact of routine coronary angiography prior to PAD surgery on surgical risk, it is important to note that existing evidence suggests no significant benefit in this context [25]. Previous studies have indicated that routine coronary angiography before PAD surgery does not reduce surgical risk or improve outcomes. This underscores the need for careful patient selection and highlights the distinct approach of our study, which focuses on FFR-guided revascularization in patients who have already undergone successful peripheral revascularization.

It is noteworthy that only 75% of patients in the intervention group, despite being high-risk, were on statin therapy. This suboptimal use of statins highlights the need for improved adherence to guideline-recommended therapies in high-risk populations, ensuring that all eligible patients receive appropriate lipid-lowering treatment could potentially enhance clinical outcomes. Patients treated invasively were more frequently smokers compared to those in the control group. Smoking is a known risk factor for adverse cardiovascular events, which can influence outcomes. This disparity could have mitigated the potential benefits of revascularization, despite the intervention.

The study has limitations to be declared. The COVID-19 pandemic significantly impacted the execution of the study: It posed substantial challenges in patient recruitment and maintaining protocol adherence for individuals, particularly when rapid discharge was a general policy due to limited hospital capacities. This primarily resulted in a certain rate of crossover, which ultimately exceeded the initially expected rate. Secondly, these issues prompted us to terminate the trial early because of a drastic slowdown in patient recruitment, making it unrealistic to complete the trial within a reasonable timeframe. Thirdly, even if this patient cohort suffers dramatically bad cardiovascular outcome, we observed markedly lower event rate than expected from former literature. Still, we are convinced that the data, which has been generated, despite their limitations, are valuable for enhancing our understanding of this extremely vulnerable patient cohort.

As highlighted in the “Results” section, the observed event rate in the conservative group was notably lower than anticipated, at 11% compared to the expected 20%. This, coupled with the reduced enrollment of only 185 patients, which is 28% of our initial target, has substantially affected our trial’s power. Recalculations indicate that the power to detect a significant difference between groups under these new conditions is approximately 5.57%, markedly lower than the intended 90%. Moreover, the required sample size to achieve the original power, given the observed event rate, would be estimated to be around 39,476 patients, far exceeding our initial projection of 650. This significant disparity highlights the challenges in detecting true differences with such a reduced sample and altered event rates. However, the smaller sample size does raise concerns about the variability and accuracy of the observed event rate. These factors underscore the need for a cautious interpretation of our results. Additional data or studies would be necessary to validate these findings and better understand the true event rates in a larger and more diverse population.