Based on this review of post-endovascular antiplatelet and anticoagulant treatment regimens for patients with CLI, patients should receive antiplatelet therapy, particularly DAPT. This regimen showed no increase in major bleeding incidences compared to MAPT, and reduced post-surgical restenosis, TLR, and amputations for diabetic patients [28, 31]. Also, the combination of antiplatelet and anticoagulant was shown to have overall superior efficacy, with no difference in bleeding incidences, compared to antiplatelet alone. The effects were significant for restenosis , limb salvage, survival rates, and cumulative rates of above ankle amputation or death . In addition, patients who undergo infra-popliteal endovascular intervention or with arterial injury > 10 cm might benefit the most from treatment with AP + AC . However, the antithrombotic regimen is best determined based on an individual basis.
Guidelines for antithrombotic therapy in patients with PAD and CLI are variable and inconclusive [1, 19, 41, 42]. The European Society of Cardiology (ESC) recommends the use of MAPT (aspirin) for angioplasty (class I recommendations) [19, 42]. The American College of Chest Physicians recommends the use of MAPT (aspirin or clopidogrel) after angioplasty (grade 1A) [16, 19]. The Society for Vascular Surgery recommends a minimum of 30 days of aspirin and clopidogrel following infrainguinal endovascular procedures (grade 2B) [19, 41]. The consensus across the majority of the studies, however, is that there is a lack of evidence to support one specific treatment regimen [19,20,21,22, 26, 27].
DAPT with aspirin and clopidogrel was suggested for at least 1 month following stent implantation, regardless of stent type, or with aspirin and ticagrelor in PAD patients with previous myocardial infarction . We found that treatment with DAPT following endovascular intervention seems superior to MAPT treatment for the prevention of restenosis in femoropopliteal segments in CLI , but not in infra-popliteal segments , suggesting that DAPT effects in CLI might be influenced by arterial segment as well as follow-up duration. We also found that TLR was lower in DAPT-treated groups compared to MAPT-treated groups [28, 31]. However, in contrast to the superior effects of aspirin plus clopidogrel over aspirin in the context of TLR when treated for 6 months , this advantage disappeared at 1 year after intervention when clopidogrel was discontinued at 6 months , suggesting the need to treat patients with DAPT for a longer duration than 6 months after endovascular intervention. However, there have been no follow-up studies to address this issue, and further investigations are warranted to determine appropriate treatment duration.
Studies investigating anticoagulation therapy for endovascular intervention for PAD, whether alone or in combination with antiplatelet therapy, are limited. The combination of rivaroxaban and aspirin reduced the risk of (CV) death, stroke, MI, acute limb ischemia, vascular amputation, and mortality compared to aspirin alone in patients with established vascular diseases . Although the rivaroxaban and aspirin increased bleeding relative to aspirin alone, there was no significant excess of severe bleeding. These results agree with studies regarding the combination of antiplatelet and anticoagulant following endovascular intervention for CLI [33, 34]. The development of restenosis, which leads to increased amputation rates following endovascular procedures, might be attributed to the development of both short-term (via elastic recoil) and long-term (via arterial remolding) changes in the treated vasculature [19, 36,37,38, 45]. The disturbance of blood flow may result from the use of a stent, leading to endothelial injury, which promotes platelet aggregation and disturbs the production of anti-thrombotic factors and vasodilatory factors as well as the activation of coagulation cascade, all of which lead to thrombus formation, proliferation of vascular smooth muscle, and consequently stenosis [19, 38,39,40]. These substances may also cause reduced lumen diameter because they promote proliferation of vascular smooth muscle, and their migration into the intima causes reduction in lumen diameter. Additionally, activation of the coagulation cascade at the site of endothelial injury promotes thrombus formation and may contribute directly to intimal hyperplasia and stenosis [19, 39, 40]. Thus, treatment with antiplatelet/anticoagulant can interfere with the progression of this pathophysiology and protect from the development of long-term complications such as restenosis and reocclusion following endovascular intervention by inhibiting platelet aggregation and activation and disrupting tissue factor stimulation of the coagulation cascade.
Prothrombotic derangement with reduced fibrinolysis and platelet hyperactivity is particularly prominent in CLI, likely because atherosclerosis is the most common cause of CLI. These events may extend to affect the outcome of the postoperative (endovascular or surgical bypass) treatment with antithrombotic drugs . This phenomenon might partly explain the low incidence rate of bleeding in the studies included in this report, although further studies are needed to confirm this finding. Nonetheless, AP + AC can interfere with the progression of this pathophysiology and protect from the development of long-term restenosis and re-occlusion following endovascular intervention via inhibiting platelet aggregation and activation as well as disrupting tissue factor stimulation of the coagulation cascade. The AP + AC treatment regimen seems promising for CLI cases undergoing endovascular procedures and warrant further investigation, particularly for infra-popliteal endovascular intervention or with arterial injury > 10 cm .
CLI-specific antiplatelet/anticoagulant therapy is mainly extrapolated from studies of patients with asymptomatic PAD or claudication [27, 47]. Azarbal et al. suggested the extrapolation of PAD to CLI is reasonable since the studies contain both PAD and CLI patients ; however, there are challenges with this extrapolation. For instance, the efficacy of aspirin in patients with CLI remains elusive and may be related to underrepresentation of CLI in clinical trials of PAD, inefficient aspirin metabolism (i.e., aspirin resistance), and inappropriate dosing [27, 48]. Additionally, aspirin resistance may be a consequence of more rapid recovery of platelet aggregability following each dose of aspirin in PAD, with accelerated platelet turnover . Similarly, although dual antiplatelet therapy with aspirin and clopidogrel is frequently used in patients with CLI after endovascular or surgical revascularization, there is little evidence for the efficacy of this strategy. Importantly, endovascular and surgical intervention for CLI seem to cause a prothrombotic derangement with reduced fibrinolysis and platelet hyperactivity . Also, studies addressing the role of antithrombotic treatment for CLI and PAD have many weaknesses preventing proper recommendations based on solid evidence [19, 27]. Issues that need to be addressed in future studies include the lack of standardization and harmonization of data collection, heterogeneity of patient demographics, underpowered statistical analyses, and non-consistent reporting of bleeding incidences, and also the lack of proper subgroup analyses for diseases, presence or absence of stents, injured arterial segments, and injury lengths. In this review, the values of subgroup analyses were shown for artery segment  and disease (diabetes) . However, the most striking evidence for the value of subgroup analyses was the study showing no difference between aspirin alone and aspirin plus dalteparin on occlusion rates for PAD, but the subgroup analysis for CLI showed significantly better occlusion outcomes for aspirin plus dalteparin . These results suggest the necessity of exclusively evaluating the antithrombotic effect in CLI patients after endovascular intervention, or at least stratifying data for CLI in PAD studies, since antithrombotic treatment after endovascular intervention for PAD might not necessarily be effective for CLI and vice versa. These limitations preclude the development of recommendations for antithrombotic therapy after endovascular intervention.
The study has some limitations. This review included both randomized trials and retrospective studies. Different combinations of drugs and follow-up durations within each treatment group were used across studies. The number of studies, number of patients, endovascular procedure, and follow-up duration varied across groups. Statistical methods varied across the studies and subgroup analyses were not consistently performed. The review included data on studies published over a period of over 10 years, so various aspects of these surgical procedures may have evolved during this time, thereby affecting outcomes. However, we believe that this study will be of great value for practitioners treating patients with CLI as the studies used in this review were mostly specific for CLI patients. This review also underscores the potential differences in antithrombotic treatment outcomes for PAD versus CLI, necessitating the need to develop studies exclusively investigating strategies to treat CLI patients.