Of all CV risk factors, tobacco exposure through cigarette smoking is the most strongly associated with the development and progression of PAD and its complications: MACE such as MI, stroke, CV death, and MALE. There is a solid foundation of data supporting a variety of smoking cessation interventions. Smoking cessation can prevent PAD and reduce MACE and MALE when PAD becomes symptomatic. Aside from behavioural counselling, pharmacological therapy should be considered, from nicotine replacement therapy (NRT) such as gum and patches, tobupropion and varenicline. Nicotine-containing e-cigarettes (EC) should also be given consideration. Behavioural therapy supporting pharmacotherapy does augment the 6-month quitting rate, but the relative risk (RR) is only 1.05-1.20, translating to a 20% quit rate compared with 17% when patients receive no support.[25]<\/a><\/sup> Behavioural therapy effectiveness is immensely variable in the literature and has been extensively reviewed in a recent Cochrane review of 312 RCTs with 250,563 participants. The RR of smoking cessation at 6 months is 1.44, ranging from 1.22 to 1.70 with a 6% background rate of quitting.[25]<\/a><\/sup> Drug therapies are few and the data are limited mainly to bupropion and varenicline. Bupropion shows an effect on quitting with a RR of 1.64 (additional 6 quitters per 100 after 6 months compared with a nonpharmacological approach).[26]<\/a><\/sup> This effect seems less than with varenicline (RR of 0.71).[26]<\/a><\/sup> Psychiatric adverse events seem more frequent with bupropion than with placebo (RR, 1.25).[26]<\/a><\/sup> A combination of bupropion with NRT or with varenicline marginally appears to enhance the quitting rate but the RRs are respectively 1.19 and 1.21, which are not significant.[27]<\/a><\/sup> In a network meta-analysis of 267 trials with 101,804 participants, varenicline and combination NRT (ie, combining 2 types of NRT such as patches, tablets, sprays, lozenges, and inhalers) vs placebo were most effective of all drug interventions (varenicline vs placebo odds ratio [OR], 2.88 [95% CI, 2.40 3.47]), accepting nausea as a frequent side effect. This translates to 1 extra quitter for 11 treated people.[28]<\/a><\/sup> Varenicline is similar to combination NRT (OR, 1.06 [95% CI, 0.75-1.48]), and superior to bupropion or single-use NRT, although each of these were superior to placebo (OR for bupropion vs placebo, 1.82 [95% CI, 1.60-2.06]) and NRT vs placebo (OR, 1.84 [95% CI, 1.71-1.99]). More recently, nicotine EC have been advocated to reduce smoking addiction. The most recent Cochrane review that compared nicotine EC with NRT showed a positive effect of nicotine EC on quitting with a RR of 1.53 (95% CI, 1.21-1.93) resulting in additional 3 quitters per 100 after 6 months. This effect was higher when compared with behavioural support only\/no support, with a RR of 2.61 (95% CI, 1.44-4.74) resulting in additional 6 quitters per 100.[29]<\/a><\/sup> Among patients with PAD, a recent meta-analysis of 6 randomized trials involving 558 patients with PAD in which smoking interventions (behavioural counselling with or without NRT or a community intervention program promoting smoking reduction) were evaluated, suggested smoking cessation interventions increased the chance of quitting smoking (RR, 1.48 [95% CI, 0.84 2.61]),[30]<\/a><\/sup> although the wide CIs indicate a need for more RCTs. Furthermore, a high-quality trial of 124 patients with PAD included in this meta-analysis, in which intensive counselling with a minimum of 6 sessions was tested, was associated with a 2.97 (95% CI, 1.27-6.93) odds of smoking cessation, which was statistically significant.[31]<\/a><\/sup> Considering this, together with the positive effect of individual counselling, compared with usual care groups observed in a meta-analysis of smokers from the general population, which included 27 trials involving 11,100 people in which intensive counselling was effective at bringing about smoking cessation (RR, 1.57; 95% CI, 1.40-1.77), suggests this is an important and effective consideration for smoking cessation strategy for patients with PAD.[32]<\/a><\/sup><\/p>\n\n\n Recommendations<\/p> Values and Preferences<\/p> Smoking is one of the most potent risk factors for PAD and is associated with MACE and MALE complications. Studies were selected irrespective of whether the effect of smoking and smoking cessation were specifically focused on PAD patients but also CAD and cardiovascular disease patients or all of these regrouped subpopulations. High value was given to any intervention that led to a significant reduction or cessation of smoking, although the success rate of any given intervention was low compared with treatment of hypertension and dyslipidemia. The value of smoking cessation is considered high not only because of its effect on vascular disease, but also because of the profound effect on preventing many cancers and chronic obstructive pulmonary disease.<\/p>\n<\/div>\n\n\n Practical Tip<\/p> Inquire at every clinical visit about the patient\u2019s smoking status, even if abstinence has been achieved, and offer behavioural support, and present therapeutic options for smoking reduction, and how to access them to patients, because smoking is a major risk factor for CAD and PAD and smoking reduction decreases the risk of MACE and MALE.<\/p>\n<\/div>\n\n\n\n PICO 2.2a: Does tight glycemic control (hemoglobin A1c < 7%) reduce incidence of MALE or need for revascularization in patients with PAD?<\/em><\/p>\n\n\n\n Patients with concurrent diabetes and PAD have a three- to fourfold increase in mortality and have a rate of amputation that is 5 times higher than patients with PAD without diabetes.[33]<\/a>–[35]<\/a><\/sup> Although promising, no clear association between strict hemoglobin A1c control and reduction in MACE, MALE, or death in patients with PAD has been reported.<\/p>\n\n\n Recommendation<\/p> PICO 2.2b: Do antihyperglycemic agents result in a reduction in MALE, revascularization, amputation, or MACE, in patients with PAD and diabetes?<\/em><\/p>\n\n\n\n The choice of antihyperglycemic agents in patients with PAD should be individualized to the patient\u2019s wishes, preferences, and financial support\/drug coverage. However, diabetes medication should be chosen to provide the optimal CV protection and reduction in MALE.[36]<\/a><\/sup> Unfortunately, very few hypoglycemic medications have been studied in patients with PAD, although some have shown more promise than others. Incretin-based selective inhibitors of dipeptidyl peptidase 4 (DPP-4) medications used in diabetes have not shown a reduction in MACE or MALE in PAD patients. However, a large observational trial of 82,169 patients who started receiving DPP-4 medication did show a 16% reduction in the development of PAD in patients with type 2 diabetes, and a subsequent 35% reduction in amputations among those with established PAD and type 2 diabetes.[37]<\/a><\/sup> This vascular protection was only shown in patients receiving combination therapy with metformin. A recent observational study reported a reduction in adverse limb outcomes with glucagon-like peptide 1 (GLP-1) agonists or DPP-4 inhibitors.[38]<\/a><\/sup> There is now a large body of evidence to support the use of the sodium-glucose cotransporter 2 (SGLT-2) inhibitors in patients with PAD and diabetes, in reducing mortality and MACE, and also MALE. In D<\/strong>apagliflozin E<\/strong>ffect on C<\/strong>ardiovascular<\/strong> E<\/strong>vents-T<\/strong>hrombolysis i<\/strong>n M<\/strong>yocardial I<\/strong>nfarction (DECLARE-TIMI), the effects of dapagliflozin was examined in 17,160 patients with diabetes of whom 1025 had concurrent PAD. Patients with PAD and diabetes had higher baseline risk of MACE, hospitalization for heart failure, progression of renal disease, and MALE compared with patients without PAD. The benefit of dapagliflozin in reducing MACE, MALE, and death was consistent regardless of PAD diagnosis in this population. Furthermore, there was no increased risk of adverse limb outcomes in patients with PAD and diabetes randomized to dapagliflozin.[39]<\/a><\/sup> In the Can<\/strong>agliflozin Cardiov<\/strong>ascular A<\/strong>ssessment S<\/strong>tudy (CANVAS) trial, canagliflozin was associated with an increased risk of amputation among patients with diabetes and PAD, but this has not been observed with other SGLT-2 inhibitors such as empagliflozin and dapagliflozin. Two large meta-analyses reported no overall significant increased risk of amputation with SGLT-2 inhibitors as a class, with the only signal coming from canagliflozin but not the other agents (eg, empagliflozin, dapagliflozin).[40]<\/a>,[41]<\/a><\/sup><\/p>\n\n\n Recommendation<\/p> Recommendation<\/p> Practical Tip<\/p> Presently, there is no reason to suspect that empagliflozin or dapagliflozin increase the risk of PAD or lower limb amputations. The risk, or lack of risk, associated with canagliflozin remains to be established.<\/p>\n<\/div>\n\n\n\n PICO 2.3a: In patients with PAD, what is the role of cholesterol-lowering with statins, ezetimibe, niacin, or resins compared with placebo for the reduction of death, CV death, nonfatal MI, nonfatal stroke, or MALE?<\/em><\/p>\n\n\n\n PICO 2.3b: In patients with PAD, what is the role of PCSK-9 inhibitors compared with use of statins with or without ezetimibe for the reduction of death, CV death, nonfatal MI, nonfatal stroke, or MALE?<\/em><\/p>\n\n\n\n Patients with PAD constitute a very high-risk subset of patients with atherosclerotic vascular disease. There is strong and high-quality evidence supporting aggressive lipid-lowering with statins to reduce overall and CV mortality as well as major adverse CV and cerebrovascular events. There is also strong evidence to support this intervention for the purpose of avoiding MALE. There is moderate-quality evidence that aggressive lipid-lowering might improve patient outcomes such as pain-free walking time and overall ambulatory ability. See section 2.3 of the Supplementary Material for further evidence and explanation. PAD cohorts have been shown consistently to have high risk and high absolute event reductions with PCSK-9 inhibitors.[20]<\/a><\/sup> They benefit from significant event reductions, including adverse limb events, within 3 years, probably because of their far more substantial lipid-lowering compared with ezetimibe, and possibly because of additional benefit when lipoprotein(a) level is elevated. Patient outcomes such as pain-free walk time and overall ambulatory activity are not extensively studied but represent potential additional benefits that might promote acceptance and adherence to these lipid lowering therapies. Evidence for reduction of MALE or PAD patient-relevant outcomes is not yet available for icosapent ethyl. The additional use of this agent has been compared with placebo, not to additional use of ezetimibe or PCSK-9 inhibitors. Moreover, a decision to intensify lipid-lowering using the latter agents in patients receiving maximally tolerated statins might also affect triglycerides, thereby altering the criterion for consideration of icosapent ethyl, which is proven to reduce MACE in the absence of ezetimibe or PCSK-9 inhibitors. Accordingly, for the reduction of MACE, patient-physician decisions that accommodate patient preferences, priorities, and access issues will determine when it is appropriate to consider icosapent ethyl for the PAD patient. See section 2.3 of the Supplementary Material for further evidence and explanation.<\/p>\n\n\n Recommendation<\/p> Values and Preferences<\/p> Statin add-on therapy and icosapent ethyl present numerous challenges with respect to cost and access for many patients. They also contribute to the burden of medications and complexity of therapy. Any decision to implement them should be made through open patient-physician discussion. Although not specifically validated in clinical trials, it is reasonable to approach the recommendations for statin add-on therapy in sequence with consideration of ezetimibe followed by PCSK-9 inhibitors if lipid thresholds are not met. But, as emphasized in the 2021 CCS guidelines for the management of dyslipidemia, patients whose levels are significantly above threshold in whom the typical reduction of low-density lipoprotein cholesterol by ezetimibe is not likely to achieve cholesterol levels below threshold might be served more effectively and efficiently by use of a PCSK-9 inhibitor as the add-on of choice while reserving ezetimibe if needed as a third, lipid-lowering agent.[42]<\/a><\/sup><\/p>\n<\/div>\n\n\n\n PICO 2.4a: How should hypertension be diagnosed in patients with lower extremity PAD?<\/em><\/p>\n\n\n\n Because patients with PAD are at high risk of CV events, hypertension diagnosis and treatment is important as a risk reduction strategy. Most clinical studies that described the association between BP control and CV outcomes have used a 24-hour ambulatory BP monitoring (ABPM) assessment to establish a clinical diagnosis of hypertension.[43]<\/a>–[45]<\/a><\/sup> Sequential home BP monitoring (HBPM) spaced throughout the day can be used as an alternative. The greater the number of recordings, the more accurately this reflects the true BP when averaged over multiple assessments.[46]<\/a> <\/sup>Out-of-office BP measurements have a better prognostic value compared with office-based assessments.[43]<\/a>,[47]<\/a><\/sup> Moreover, 24-hour ABPM improves CV risk stratification compared with office-based BP assessments.[43]<\/a>,[48]<\/a><\/sup> Hence, the Hypertension Canada 2020 guidelines advocate for a standardized protocol in which BP is measured at 20 to 30 minute intervals throughout the day.[44]<\/a><\/sup> If ABPM monitoring is unavailable or not tolerated, HBPM can be used as an alternative. Hypertension can be diagnosed after multiple out-of-office assessments. Hypertension is diagnosed if the mean ambulatory daytime BP is 135\/85 mm Hg, or if the 24-hour mean BP is 130\/80 mm Hg (Fig. 3). Patients with PAD are at an elevated risk of future vascular events, and a target of 140\/90 mm Hg should be considered as the treatment threshold.[49]<\/a><\/sup><\/p>\n\n\n\n PICO 2.4b: In patients with PAD without an indication for a specific antihypertensive agent, what is the ideal BP target?<\/em><\/p>\n\n\n\n Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and CV death.[50]<\/a>,[51]<\/a><\/sup> There are no large-scale RCTs that specifically assessed BP targets in patients with lower extremity PAD. In a subgroup of patients with PAD from the S<\/strong>ystolic Blood Pr<\/strong>essure In<\/strong>tervention T<\/strong>rial (SPRINT),[52]<\/a><\/sup> intensive BP lowering to a systolic BP target < 120 mm Hg was associated with a reduction in the primary outcome of CV death and all-cause mortality. Because of the higher baseline risk among patients with PAD, the absolute risk reduction was larger in patients with PAD compared with those without PAD. However, intensive BP control also led to a greater absolute increased risk of adverse events in patients with PAD.<\/p>\n\n\n Recommendations<\/p> Practical Tip<\/p> In select patients, intensive systolic BP targets (< 120 mm Hg) might be considered. However, we suggest that caution be exercised if systolic BP is < 110 mm Hg because this is associated with an increase rate of adverse events (eg, MACE and MALE) in patients with PAD.<\/p>\n<\/div>\n\n\n\n PICO 2.4c: In patients with PAD without an indication for a specific antihypertensive agent, what is the preferred approach to achieve optimal BP control?<\/em> Diet, exercise, weight management, alcohol reduction, stress management, and self-monitoring play an important role in managing BP. See Supplemental Table S1 for targets.<\/p>\n\n\n\n Angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium antagonists, and diuretics are all suited for BP-lowering treatment in patients with PAD[53]<\/a>,[54]<\/a><\/sup>; see Figure 4, from Hypertension Canada. In the absence of contraindications, we recommend that patients with PAD and hypertension be treated with ACE inhibitors or ARBs as first choice agents. ACE inhibitors and ARBs have been shown to reduce MACE in patients with arterial peripheral vascular diseases.[55]<\/a><\/sup> ACE inhibitor or ARB use is also associated with reduced MACE among patients with critical limb ischemia.[56]<\/a> <\/sup>Most patients with hypertension require multiple agents for optimal BP control. Use of combination pills therapy improves adherence, BP, and CV outcomes compared with usual pharmacological care.[55]<\/a>,[57]<\/a><\/sup><\/p>\n\n\n\n Recommendation<\/p> As mentioned previously, in the SPRINT trial, aggressive BP control among patients with PAD was associated with an increased risk of the primary outcome, CV death, and all-cause mortality compared with patients without PAD. As such, the optimal target is likely between 120 mm Hg and 140 mm Hg. A theoretical risk exists with the use of b-blockers in patients with limb ischemia. Previous guidelines have suggested avoiding the use of b-blockers in those with severe PAD. However, large systematic reviews on the topic have not shown increased harm with the use of b-blockers among patients with PAD. As such, they are not contraindicated and might be useful in PAD patients with concomitant CV disorders, where they are indicated as a second-line option.[59]<\/a>,[60]<\/a><\/sup><\/p>\n\n\n\n A substantial amount of evidence has emerged since the 2005 Canadian Cardiovascular Congress Consensus Conference for the management of PAD. The advent of newer thienopyridines and direct oral anticoagulants (DOACs), as well as their investigation within atherosclerotic PAD, has vastly expanded the tools available to practitioners. This has come with a concomitant shift in the understanding of the pathophysiology of lower extremity PAD. A large proportion of severe vascular occlusions are mediated by thrombotic occlusive disease, even in the absence of major atherosclerotic lesions, reframing PAD as a condition of \u201cathero-thrombo-embolism\u201d and informing the choice of antithrombotics investigated and used clinically. Lower extremity PAD is continually appreciated as but 1 manifestation of systemic atherosclerosis. As such, the efficacy of antithrombotics in lower extremity PAD are evaluated ac- cording to MACE and MALE outcomes. The benefit of antithrombotics in lower extremity PAD in conferring global vascular protection must be weighed against the risk of major and\/or fatal bleeding.<\/p>\n\n\n\n PICO 2.5a: In adult patients with asymptomatic PAD does a single antiplatelet agent compared with placebo affect rates of MACE, MALE, or bleeding?<\/em><\/p>\n\n\n\n Patients with a low ABI, but without clinical limb symptoms or previous vascular intervention, are considered to have asymptomatic lower extremity PAD.<\/p>\n\n\n Recommendation<\/p> Practical Tips<\/p> PICO 2.5b: In adult patients with stable symptomatic lower extremity PAD (no recent or imminent revascularization), what is the optimal antithrombotic therapy considering the outcomes of MACE, MALE, or bleeding?<\/em><\/p>\n\n\n\n Patients with intermittent claudication, without recent (< 6 months) endovascular or surgical peripheral artery revascularization, and without acute symptoms of rest pain or tissue loss, are considered to have stable lower extremity PAD. Although single antiplatelet therapy has been the mainstay of antithrombotic therapy for symptomatic PAD patients,[61]<\/a>,[62]<\/a><\/sup> recent large trials that have tested low-dose DOACs together with aspirin have provided important new evidence.[63]<\/a>,[64]<\/a><\/sup><\/p>\n\n\n Recommendations<\/p> Values and Preferences<\/p> This recommendation places high value on the overall C<\/strong>ardiovascular O<\/strong>utcom<\/strong>es for P<\/strong>eople U<\/strong>sing A<\/strong>nticoagulation S<\/strong>trategies<\/strong> (COMPASS) trial findings, which showed a significant net clinical benefit with combination low-dose rivaroxaban and aspirin among a heterogenous patient population with PAD. Patients who place a high value on minimizing ischemic risk, such as MI, stroke, acute limb ischemia, or major vascular amputation, might opt for rivaroxaban 2.5 mg twice daily in combination with aspirin. Patients who place a high value on bleeding avoidance and minimizing pill burden might opt for single antiplatelet therapy alone.<\/p>\n<\/div>\n\n\n Practical Tips<\/p> Recommendation<\/p> Values and Preferences<\/p> This recommendation places a high value on the reduction of vascular events despite elevated bleeding risk. Patients at extremely high bleeding risk might not tolerate single antiplatelet therapy alone and might best be served by no antithrombotic therapy, particularly if vascular risk is low.<\/p>\n<\/div>\n\n\n Recommendations<\/p> Values and Preferences<\/p> This recommendation places greater weight on prevention of ischemic events (particularly coronary events) than on the risk of bleeding. The combination of ticagrelor and aspirin likely has greater ischemic benefit yet higher bleeding risk as contrasted with the combination of clopidogrel and aspirin, with choice of therapy directed by individual patient profile and preferences.<\/p>\n<\/div>\n\n\n Practical Tips<\/p> Patients with recent (< 1 year) coronary revascularization and stable lower extremity PAD should have the choice of antithrombotic therapy guided by the 2018 CCS\/Canadian Association of Interventional Cardiology focused update on the guidelines for the use of antiplatelet therapy,[67] although patients with symptomatic lower extremity PAD should merit particular consideration for ticagrelor and aspirin in combination.\n<\/p>\n<\/div>\n\n\n Recommendation<\/p> Practical Tips<\/p> PICO 2.5c: In adult patients who undergo elective endovascular revascularization for lower extremity PAD, what is the optimal antithrombotic therapy to prevent MACE, MALE, bleeding, or need for repeat intervention, in the early postoperative period (within 12 months)?<\/em><\/p>\n\n\n\n The Antithrombotic Trialists\u2019 Collaboration reported a numerical but not statistically significant reduction in MACE associated with single antiplatelet therapy vs placebo (odds reduction, 29%) after peripheral angioplasty.[69]<\/a><\/sup> A subsequent Cochrane review identified 2 small trials that compared aspirin and dipyridamole, respectively, vs placebo after endovascular revascularization, with pooled analysis showing a similar nonsignificant result for lesion patency at 6 months.[70]<\/a><\/sup> In the Management of Peripheral Arterial Interventions with Mono or Dual Antiplatelet Therapy (MIRROR) trial, DAPT using aspirin and clopidogrel was compared with aspirin alone in 80 patients after endovascular lower extremity revascularization. DAPT improved target lesion revascularization rates at 6 months (5% vs 8%; P 1\u20444 0.04) but not at 1 year.[25]<\/a><\/sup> Despite the lack of robust RCT data, DAPT after endovascular stenting is often extrapolated from the CV literature and mandated in trials investigating varying endovascular options.[71] <\/sup>Two small trials (n 1\u20444 160 and n 1\u20444 167, respectively) that compared full-dose oral anticoagulation with DAPT after endovascular revascularization showed no significant difference in lesion patency with increased bleeding events.\n
2.2 Glucose control, diabetes, and PAD<\/h2>\n\n\n\n
2.2.1 Glucose control and PAD<\/h3>\n\n\n\n
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2.2.2 Diabetes medications and PAD<\/h3>\n\n\n\n
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2.3 Lipid-lowering and PAD<\/h2>\n\n\n\n
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\na. Maximally tolerated dose of statin therapy
\nb. Statin add-on therapies (ezetimibe and\/or PCSK-9 inhibitors) if receiving maximally tolerated dose of statin therapy and the low-density lipoprotein cholesterol is 1.8 mmol\/L, non-high-density lipoprotein cholesterol 2.4 mmol\/L or apolipoprotein B100 0.7 mg\/dL.<\/li>\n2.4 Hypertension<\/h2>\n\n\n\n
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Optimal hypertension management requires a holistic approach. Lifestyle modifications and pharmacological agents are the mainstay of treatment.<\/p>\n\n\n\n2.4.1 Lifestyle modification<\/h3>\n\n\n\n
2.4.2 Pharmacological<\/h3>\n\n\n\n
![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/07\/Figure-3-PAD-1024x851.png\")
<\/figure>\n\n\n\n
2.4.3 Special considerations in PAD patients<\/h3>\n\n\n\n
2.5 Antithrombotic therapy<\/h2>\n\n\n\n
2.5.1. Asymptomatic lower extremity PAD<\/h3>\n\n\n\n
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2.5.2 Stable symptomatic lower extremity PAD<\/h3>\n\n\n\n
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2.5.3 Therapy after elective lower extremity revascularization<\/h3>\n\n\n\n
2.5.3.1 Endovascular revascularization<\/h4>\n\n\n\n