The degree of damage caused by smoking is directly related to the amount of tobacco consumed. When CLI is identified in a critical clinical setting, smoking cessation is an important modifiable behavior that may impact subsequent vascular or endovascular interventions. Patients with CLI must refrain from smoking. Smoking cessation improves walking distance, doubles the 5-year survival rate [3], and reduces the incidence of postoperative complications [4]. More than 75 % of patients presenting with CLI have tried and failed to quit smoking. Up to 25 % of patients will try to follow clinical advice to stop smoking, but more than 75 % of them will fail in less than 3 months [5]. With medical advice alone, approximately 5 % of patients will have long-term success in quitting. However, the urgency of management for CLI prevents smoking cessation from having time to take effect.

Increasing concentrations of each of the lipid components—cholesterol, low-density lipoprotein (LDL), triglyceride, and lipoprotein (a)—have shown to be independent factors for acceleration of CLI [6]. So treatment with statins helps to prevent plaque instability and thrombosis due to their pleiotropic effects, such as improvement of endothelial function, reduction of inflammation, and stabilization of atherosclerotic plaques [7]. In a retrospective review for CLI patients undergoing endovascular interventions (highlighted below), statin use was associated with significantly higher rates of patency, limb salvage, and overall survival [8]. Perioperative statin treatment in statin-naive patients reduces atrial fibrillation, MI, and duration of hospital stay [9].

This is a retrospective review of 646 patients, 319 receiving statin therapy and 327 without, who underwent an endovascular intervention for CLI. The statin group had significantly higher rates of DM, coronary artery disease (CAD), congestive heart failure (CHF), previous myocardial infarction (MI), and coronary artery bypass grafting (CABG) (P < 0.05). The two groups had similar lesion length, location, lesion type, TransAtlantic Inter-Society Consensus (TASC) classification, and primary procedure. At 24 months, the statin-treated group had higher rates of primary patency (43 % vs 33 %; P = 0.007), secondary patency (66 % vs 51 %; P = 0.001), limb salvage (83 % vs 62 %; P = 0.001), and overall survival (77 % vs 62 %; P = 0.038). Therefore, statin therapy was proven to be beneficial with improved limb salvage and mortality in patients undergoing endovascular intervention for CLI [8].

Control of blood pressure remains an important intervention for cardiovascular (CV) primary prevention and also has been established as one of the principal improvements in stroke and PAD reduction. Current HTN guidelines advocate aggressive treatment in patients with atherosclerosis. The angiotensin-converting enzyme inhibitor (ACEI) ramipril (10 mg/day) has been shown to increase pain-free walking distance, maximum walking time, and Walking Improvement Questionnaire scores in a small randomized placebo-controlled study [9]. This has been replicated in a larger study where ramipril 10 mg/day increased the mean of pain-free walking time by 92 % (87 s) and the maximum walking time by 139 % (193 s) [10]. Calcium channel blockers are protective against all-cause, CV, and cerebrovascular disease mortality [11].

There is currently no evidence that beta-blockers (BB) adversely affect walking distance in patients with CLI. Two meta-analyses of studies involving patients with mild and moderate lower-limb ischemia did not confirm that BBs were associated with exacerbation of PAD symptoms [12, 13]. As a result of these trials, beta-1-specific BBs are now commonly prescribed for the treatment of HTN in PAD patients. The clinical value of administering perioperative beta-blockers was shown to be associated with significant reductions of perioperative myocardial ischemia and infarction in various surgical settings [14, 15]. In patients undergoing vascular surgery or major amputation, with low to intermediate cardiac risk, preoperative targeted beta-blockade alone is more effective in preventing cardiac morbidity than selective cardiac stress testing and non-targeted beta-blockade [16].

DM is independently associated with the development of PAD and its progression to CLI. DM has also been shown to be an independent risk factor for amputation and increased complications in CLI patients. In the STENO-2 study, 160 diabetics were randomly assigned to either intensified or conventional therapy (i.e., control of blood glucose, statins, antithrombotic therapy, blood pressure control). On follow-up, intensive therapy was associated with significantly reduced risks of all-cause death and CV death [17]. In the United Kingdom Prospective Diabetes Study, therapy was associated with risk reductions for microvascular disease, MI, and death from any cause as well as for any diabetes-related endpoint [18]. On the contrary, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, the rates of microvascular complications were improved by intensive diabetes therapy during a follow-up of 5 years [19]. However, this treatment did not lower macrovascular complications or cardiovascular deaths. The benefits of tight diabetes control on functional lower-limb outcomes such as limb salvage or freedom from repeated revascularization in CLI patients has not been determined.

There is a direct clinical benefit of antiplatelet therapy for primary CV prevention; however, there is currently no convincing data showing a delay or reduction of the progression in lower-limb disease. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events trial (CAPRIE) confirmed that the combined risk of death from vascular causes, MI, and stroke was significantly lower with clopidogrel (75 mg/day) than compared with aspirin (325 mg/day). These benefits were most pronounced in patients with PAD [20]. The Antithrombotic Trialists’ Collaboration meta-analysis found a 23 % reduction in serious vascular events within 42 trials [21]. However, there was no significant reduction of CV events in patients with PAD. In a subsequent analysis, which included study data on various antiplatelet drugs such as aspirin, clopidogrel, ticlopidine, and dipyridamole, the group reported a 23 % risk reduction of CV events in patients with PAD [22]. Low-dose aspirin (75–325 mg) is similarly effective as a higher dose in PAD patients. However, higher doses of aspirin will result in increased bleeding rates and very low doses (<75 mg) are not effective. The daily dose of clopidogrel for secondary prevention in PAD patients is 75 mg. Compared to aspirin alone, dual antiplatelet therapy (DAT) was associated with a lower rate of a composite of index graft occlusion or revascularization, above-ankle amputation of the affected limb, or death, without increasing bleeding risks [23].

Two RCTs analyzed whether or not antiplatelet therapy may improve patency rates subsequent to lower-limb endovascular therapy. In the first study, a total of 199 patients undergoing angioplasty of the femoropopliteal segment were randomized to three groups: dipyridamole (75 mg) plus aspirin (330 mg), dipyridamole (75 mg) plus aspirin (100 mg), or placebo. Patients from both dipyridamole arms showed higher patency rates as compared to those on placebo [24]. In the second study, of patients randomized to placebo or aspirin (50 mg) plus dipyridamole (400 mg) after peripheral vascular angioplasty, there were no significant differences in primary patency [25]. The Coronary Artery Spasm in Patients with Acute Coronary Syndrome (CASPAR) study randomized a total of 425 patients undergoing below-the-knee bypass grafting to either aspirin (75–100 mg/day) alone or aspirin (75–100 mg/day) plus clopidogrel (75 mg/day) [26]. Unfortunately, the combination of clopidogrel plus aspirin did not improve lower-limb or systemic outcomes.

Evidence of the effects of warfarin in patients with atherosclerosis comes mainly from trials of patients with coronary artery disease (CAD). Two meta-analyses demonstrated that warfarin at both moderate- and high-intensity levels reduces the risk of death, MI, or stroke, but this is counteracted by an increased rate of bleeding [27, 28]. In a study comparing the efficacy of warfarin (with a target international normalized ratio of 3.0–4.5) with aspirin (80 mg) on infra-inguinal graft patency in patients with PAD, a similar number of graft occlusions occurred in each group [29]. On the other hand, the risk of bleeding was almost doubled in the oral anticoagulation group. A Cochrane systematic review examined the use of heparin products for intermittent claudication [30]. The use of heparins was not associated with a significant difference in CV events compared with placebo. Therefore, the use of warfarin and heparin is not recommended in patients with intermittent claudication.

Antiplatelet agents have a beneficial effect on graft or stent patency. The relative risk of infra-inguinal graft occlusion in patients treated with aspirin was 0.78 in one meta-analysis [31].

A recent Cochrane review demonstrated that antiplatelet agents improved graft patency rates to a greater extent in patients with prosthetic grafts compared to those with venous grafts [32]. From the same review, it was also concluded that there was no statistically significant improvement in survival or CV events in those treated with aspirin following bypass surgery. Henceforth, aspirin is recommended for patients undergoing lower-limb angioplasty. Belch et al. [22] investigated the use of adjuvant combination clopidogrel and aspirin therapy following below-knee bypass graft surgery. They found that, in the population as a whole, the combination did not show an improvement in the composite primary endpoint of index graft occlusion or revascularization, above-ankle amputation, or death compared with aspirin alone. However, the combination did improve outcome in a subgroup analysis of patients with prosthetic grafts, without significantly increasing major bleeding rates. The evidence for use of adjuvant anticoagulation has been summarized in a recent Cochrane review [33]. It was concluded that patients undergoing infra-inguinal venous grafts are more likely to benefit from vitamin K antagonists such as warfarin than platelet inhibitors; this difference is not seen in those with artificial grafts.

Prostanoids act by preventing platelet and leukocyte activation and protect the vascular endothelium. A recent systematic review and meta-analysis of the use of prostanoids for CLI included 20 RCTs with a total of 2724 participants [34]. The trials investigated intravenous prostaglandin (PG) E1, intra-arterial PGE1, intravenous iloprost, low-dose iloprost infusion, oral iloprost, intravenous prostacyclin (PGI2), lipoecraprost, and ciprostene. The comparators were placebo and other pharmacological agents. The findings of the meta-analysis showed that prostanoids when compared with placebo appeared to have some efficacy for treating rest pain (RR 1.32, 95 % CI 1.10–1.57) and ulcer healing (RR 1.54, 95 % CI 1.22–1.96). There was no statistically significant effect on the number of amputations and mortality when prostanoids were examined as a group, but iloprost showed favorable results in reducing major (above-/below-knee) amputations (RR 0.69, 95 % CI 0.52–0.93). Therefore, there is no conclusive evidence based on a high-quality meta-analysis of homogeneous long-term RCTs, regarding efficacy and safety of different prostanoids in patients with CLI, and further high-quality trials are required.

It has been reported that pentoxifylline (Trental, Sanofi, Paris France) improves blood flow by increasing blood cell deformity and decreasing viscosity. In one study, pentoxifylline 600 mg given intravenously twice daily to patients with CLI was associated with reduced pain scores [35]. However, no significant benefit was demonstrated in another study of the same dosing regimen [36]. Therefore, there is currently a lack of consistent evidence to recommend the use of pentoxifylline for the treatment of CLI.

Cilostazol (Pletal by Otsuka, Tokyo, Japan) is used to treat the symptoms of intermittent claudication, but its use for CLI is less well studied. In a small study of the effect of cilostazol treatment on skin perfusion pressure in severely ischemic limbs, it was found that the drug improved microvascular circulation [37]. However, there is no strong evidence that cilostazol improves clinical outcomes in patients with CLI. In a retrospective analysis of data from 618 patients who underwent endovascular stenting for CLI (356 of whom were treated with cilostazol at the discretion of the surgeon), 5-year outcomes were compared between those who were prescribed cilostazol and those who were not. Treatment with cilostazol was associated with higher rates of amputation-free survival and limb salvage but not overall survival or freedom from repeat revascularization [38]. In the absence of RCTs in patients with CLI, there is insufficient evidence to recommend the use of cilostazol in this patient group.