Contemporary Medical Management of Peripheral Artery Disease
Abstract
Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis. Modifiable risk factors including cigarette smoking, dyslipidemia, diabetes, poor diet quality, obesity, and physical inactivity, along with underlying genetic factors contribute to lower extremity atherosclerosis. Patients with PAD often have coexistent coronary or cerebrovascular disease, and increased likelihood of major adverse cardiovascular events, including myocardial infarction, stroke and cardiovascular death. Patients with PAD often have reduced walking capacity and are at risk of acute and chronic critical limb ischemia leading to major adverse limb events, such as peripheral revascularization or amputation. The presence of polyvascular disease identifies the highest risk patient group for major adverse cardiovascular events, and patients with prior critical limb ischemia, prior lower extremity revascularization, or amputation have a heightened risk of major adverse limb events. Medical therapies have demonstrated efficacy in reducing the risk of major adverse cardiovascular events and major adverse limb events, and improving function in patients with PAD by modulating key disease determining pathways including inflammation, vascular dysfunction, and metabolic disturbances. Treatment with guideline-recommended therapies, including smoking cessation, lipid lowering drugs, optimal glucose control, and antithrombotic medications lowers the incidence of major adverse cardiovascular events and major adverse limb events. Exercise training and cilostazol improve walking capacity. The heterogeneity of risk profile in patients with PAD supports a personalized approach, with consideration of treatment intensification in those at high risk of adverse events. This review highlights the medical therapies currently available to improve outcomes in patients with PAD.
Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis with common treatment approaches to reduce cardiovascular risk. Risk factors that drive atherogenesis in peripheral arteries overlap those associated with atherosclerosis in other circulations, including smoking, hyperlipidemia, hypertension, and diabetes.1 Thus, patients with PAD often have coexistent coronary or cerebrovascular disease, referred to as polyvascular disease, and are at heightened risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death. For example, in the EUCLID trial (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease trial), in the 13 855 patients with PAD: 44% had clinical atherosclerotic disease in other territories, including 19% with coronary artery disease (CAD), 15% with cerebrovascular disease, and 10% with atherosclerotic disease in all 3 territories.2 The presence of polyvascular disease identifies the highest risk patient group for MACE, and those most likely to derive the greatest benefit with effective therpies.3–5
Patients with PAD also have impaired walking capacity and symptoms of intermittent claudication and are at risk of critical limb ischemia leading to major adverse limb events (MALE), such as peripheral revascularization or amputation. In the patients with PAD participating in the REACH (The REduction of Atherothrombosis for Continued Health) Registry, there was a 22% risk of peripheral revascularization and a 6% risk of amputation over 4 years.6 Patients with PAD and prior peripheral revascularization or amputation are at increased risk for recurrent MALE relative to patients with PAD with no prior revascularization.7,8 It is well established that there is a decreased risk of MACE and MALE among patients with PAD who are treated with risk factor modifying and antithrombotic therapies. Unfortunately, patients with PAD remain undertreated compared with patients with CAD,9,10 underscoring the importance of raising the awareness among medical professionals of PAD. A key health goal important for health equity is the improved management of PAD to reduce the incidence of nontraumatic amputations.11 This review highlights the medical therapies currently available to improve outcomes in patients with PAD.
Pathophysiologic Drivers of Clinical PAD
Complex layers of underlying pathophysiologic processes drive the clinical manifestations of PAD as illustrated in Figure 1. Key modifiable risk factors including cigarette smoking, poor diet quality, obesity, and physical inactivity along with underlying genetic factors all contribute to lower extremity atherosclerosis.12 Arterial obstruction in the limb is a core feature of PAD leading to diminished blood flow and ischemia.13 However, the symptoms of PAD including claudication, functional limitation, and critical limb ischemia are not fully determined by reduced ankle brachial index (ABI).14 Vascular dysfunction with abnormal endothelium-mediated vasodilation impairs augmentation of blood supply during exercise and reduces functional capacity in patients with PAD.15–17 Inflammatory activation with increased circulating biomarkers relates to both incident disease and the rate of decline in walking distance in patients with PAD.18,19 Multiple risk factors for PAD including smoking, hypercholesterolemia, and diabetes induce oxidative stress that accelerates arterial damage and injury to skeletal muscle.20,21 Chronic ischemia produces alterations in the leg skeletal muscle that limit walking ability.22 The skeletal muscle myopathy of PAD is characterized by impaired oxygen metabolism, mitochondrial dysfunction, skeletal muscle fiber changes, and atrophy.
Severe chronic restriction in blood flow along with local factors in the foot contribute to the transition to critical limb ischemia. Microvascular disease synergizes with obstructive PAD to markedly increase amputation rates indicating the importance of targeting specific risk factors including chronic kidney disease and diabetes.23 Inadequate angiogenesis with reduced capillary density is associated with advanced PAD and highlights the potential for developing therapies that augment microvascular growth.24 Microembolization may also contribute to microvascular loss evidenced by small vessel thrombotic obstruction in amputated limbs from patients with critical limb ischemia.25 Acute limb ischemia is an important contributor to MALE, particularly in patients with prior revascularization, and seems to be largely driven by arterial thrombosis (in situ and artery to artery embolism).
Risk Modifying Therapies for PAD
Treatment with guideline-recommended therapies for PAD lowers the incidence of MACE and MALE though the residual risk remains elevated particularly in patients with polyvascular disease, indicating the importance of intensification of therapy.26–28 The foundation of risk reduction treatment in patients with PAD is lifestyle modification, including dietary modification, exercise, and smoking cessation.
Diet
Epidemiological studies connect adherence to healthy dietary patterns with lower incidence of clinical PAD. Specific factors include following recommendations for fiber and fruit and vegetable intake.29–31 The PREDIMED primary prevention trial reported a lower risk of PAD in the Mediterranean diet intervention group. Both patients with intermittent claudication and critical limb ischemia have a high prevalence of poor dietary quality that may reflect socioeconomic factors and limited food access. Malnutrition predicts adverse outcomes in critical limb ischemia and nutritional improvement may be a novel therapeutic avenue.32,33 Improving access to a high-quality diet is important for all patients with PAD.
Smoking Cessation
Tobacco smoking is a key modifiable risk factor for the development and clinical expression of PAD. It promotes thrombosis through effects on platelets, endothelial cells, and the coagulation system by inducing oxidative stress and lowering nitric oxide.34–36 In animal models, cigarette smoke impairs the lower extremity response to ischemia by oxidative stress. In humans, use of tobacco products impairs endothelial function and smoking cessation rapidly improves vasodilator ability. Cigarette smoke also drives plaque hemorrhage and systemic inflammation though the components responsible for cardiovascular risk remain poorly defined. Selected volatile organic compounds produced in cigarette smoke, such as acrolein, have been identified as inducers of endothelial damage.37–39 The impact of nicotine on vascular biology is increasingly recognized, including its effect on acceleration of plaque neovascularization, a process linked to atherogenesis.40,41 Importantly, electronic cigarette use leads to exposure to volatile organic compounds and nicotine raising the possibility of vascular injury.42,43 Marijuana use is increasingly common among patients with cardiovascular disease and is associated with an arteritis similar to Buergers disease, nonatherosclerotic peripheral artery disease; however, the impact on atherogenesis is less clear.44,45
In patients with symptomatic PAD, smoking cessation lowers the risk of critical limb ischemia, amputation, and death. Smoking cessation also reduces atherosclerosis progression in the limb shown by decreased decline in ABI over time.46 Only a third of patients with PAD who smoke receive cessation counseling or medications. The center at which a patient is treated is a major determinant of quit rate suggesting that system change to promote established cessation practices in PAD works. Current practice for smoking cessation includes the 5 A’s: Ask, Assess, Advise, Assist, and Arrange/Connect. At every visit, inquire about intensity of former and current tobacco product use (including cigarettes, cigar products, electronic cigarettes, hookah use). It is important to describe to patients the specific impacts of continued smoking, including risk of amputation and offer referral to a smoking cessation program, and to provide access to multiple approaches to increase the likelihood of successful quit attempts. There are multiple pharmacological therapies that are efficacious for smoking cessation, including varenicline, buproprion, and nicotine replacement therapy. In the EAGLES trial (Study Evaluating The Safety And Efficacy Of Varenicline and Bupropion For Smoking Cessation In Subjects With And Without A History Of Psychiatric Disorders trial), varenicline was superior to single nicotine replacement therapy and buproprion and earlier concerns regarding potential neuropsychiatric effects were resolved.47 Current American Thoracic Society guidelines recommend varenicline as first-line therapy with consideration of combining with nicotine patch whereas the American Cardiology of Cardiology recommends either varenicline or combination nicotine-replacement therapy in patients with cardiovascular disease.48,49 Behavioral support with counseling enhanced smoking abstinence in patients with PAD.50,51 The evidence regarding the efficacy of electronic cigarettes to assist with tobacco product cessation remains inconclusive as does the cardiovascular impact relative to combustible cigarettes. Thus, the medically proven approaches remain first-line therapies. It is also important to assess and reduce exposure to secondhand smoke that is known to have acute and chronic cardiovascular effects.
Lipid-Lowering Therapy
Lipid-lowering therapies stabilize atherosclerotic plaque progression in patients with PAD. Recent trials have demonstrated that LDL-C reduction is consistently associated with reductions in both MACE and MALE, supporting a strategy of even lower goals particularly for high-risk patients.52,53 Reduction of systemic inflammation, as measured by C reactive protein, also has been linked to the benefits of statins in patients with PAD.54,55 The Heart Protection Study was a placebo-controlled randomized study examining the efficacy of simvastatin on major adverse cardiovascular events in 20 536 patients with stable atherosclerosis, including those with CAD, cerebrovascular disease, or PAD as well as those with diabetes or treated hypertension.56 Among the group randomized to statin therapy, there was a 24% reduction in the risk of MACE, defined as major coronary events, strokes of any type, and coronary or noncoronary revascularizations. This beneficial effect of simvastatin extended to those 6748 patients enrolled with PAD, in whom there was a 22% reduction in the risk of MACE. Among patients randomized to simvastatin, there was a 16% reduction in the risk of a first acute peripheral vascular event, defined retrospectively as the first occurrence of a noncoronary revascularization, aneurysm repair, major amputation, or death from PAD.57
Observational studies have also found that statin therapy reduces the risk of MACE in patients with PAD. The REACH registry was an international registry of >68 000 outpatients aged ≥45 years with established cardiovascular diseases or ≥3 risk factors.58 Among the patients with PAD treated with a statin compared with those who were not, there was a significant reduction in MACE, as well as adverse limb events including worsening claudication or new critical limb ischemia, limb revascularization, and amputation.6 Similarly, among 107 999 patients with incident PAD in the National Veterans Affairs database, those taking a statin had lower mortality and amputation rates.59 Another study found that among patients with PAD referred for revascularization, high-intensity stain compared with low-moderate intensity statin was associated with lower mortality and decreased MACE.60 One observational study found that following revascularization, statin treatment was associated with both improved survival and improved limb salvage.61 A review of patients with critical limb ischemia or claudication who had undergone peripheral revascularization captured in a set of German insurance claims data found that statin initiation was associated with lower risk of all-cause mortality, major amputation, and, cardiovascular events.62 In a meta-analysis of patients with PAD and critical limb ischemia, statin therapy was associated with a 38% reduction in mortality, 50% reduction in MACE, and 25% reduction in amputation rates.63 Several studies have demonstrated that statin therapy improves walking distance in patients with PAD and intermittent claudication.64 Statins are also associated with less decline in walking capacity among patients with PAD.19,65
PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are effective at reducing LDL cholesterol and reducing the risk of MACE in patients with established atherosclerosis and those with acute coronary syndromes.52,53 PCSK9 inhibitors not only lower LDL levels, but in preclinical models blunt atherogenesis through limiting lesion inflammation and NF-ΚB activation.20–22 In clinical studies, PCSK9 inhibitors reduce lipoprotein(a) (LP(a)), an emerging biomarker of risk in PAD.66–69 Lp(a) promotes atherosclerosis through oxidative stress and recruitment of monocytes to the arterial wall.70
Two currently approved drugs in this class are evolocumab and alirocumab, both of which are monoclonal antibodies that inhibit PCSK9. In the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk trial), 27 564 patients with cardiovascular disease (prior myocardial infarction, ischemic stroke, or PAD) and LDL cholesterol levels of ≥ 70 mg/dL were randomized to either evolocumab or placebo. Evolocumab significantly reduced the risk of the primary composite end point of cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina or coronary revascularization by 15%. Among the 3642 patients with established PAD, evolocumab reduce the risk of cardiovascular death, myocardial infarction, or stroke by 27%.3 It also reduced the risk of MALE, a composite of acute limb ischemia, major amputation, or urgent revascularization, by 37%. In the ODYSSEY OUTCOMES trials (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab trials), 18 924 patients who had had an acute coronary syndrome 1 to 12 months earlier and LDL cholesterol levels of ≥70 mg/dL, were randomized to either alirocumab or placebo. Alirocumab significantly reduced the risk of the composite primary end point of death from CAD, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization by 15%. Alirocumab reduced risk of PAD events, defined as critical limb ischemia, limb revascularization, or unplanned amputation for ischemia by 31%.71 The reduction in limb events in ODYSSEY were associated with a reduction in Lp(a) reduction rather than LDL.
Inclisiran is a small interfering RNA that inhibits hepatic synthesis of PCSK9 to lower LDL cholesterol. It was studied in statin-treated patients with established cardiovascular disease or at high risk for cardiovascular disease.72 Inclisiran significantly lowered LDL cholesterol, the primary end point. In addition, there were fewer adverse cardiovascular events in patients treated with inclisiran, although this finding needs to be tested in an appropriately powered prospective trial.
Ezetimibe lowers LDL cholesterol by reducing absorption of cholesterol from the intestine via its inhibitory effect on NPC1L1 (Niemann–Pick C1–like 1) protein. IMPROVE-IT was a randomized, placebo-controlled trial that assessed the effect of ezetimibe added to statin therapy after acute coronary syndrome in 18 144 patients. The addition of ezetimibe resulted in an 8% reduction in the risk of the primary composite end point of cardiovascular death, a major coronary event or stroke.73 There was a consistent 8% relative risk reduction with ezetimibe for the primary end point among the patients in IMPROVE-IT who had concomitant polyvascular disease, which included 1005 patients with peripheral artery disease and 1071 with previous stroke or transient ischemic attack.4
Niacin lowers LDL cholesterol and triglycerides and increases HDL (high-density lipoprotein) cholesterol via a variety of mechanisms. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) study was a placebo-controlled trial that examined the effect of extended-release niacin in 3414 statin-treated patients with established cardiovascular disease, defined as stable CAD, cerebrovascular or carotid disease, or PAD.74 Niacin therapy increased HDL cholesterol and lowered triglyceride levels and LDL cholesterol but had no significant effect on the primary composite end point of death from CAD, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. A study using Mendelian randomization found that genetically elevated HDL did not lower the risk of myocardial infarction, supporting the negative findings in the AIM-HIGH trial.75 The ICPOP (Intermittent Claudication Proof of Principle) study examined the efficacy of the combination of extended release niacin (low and high dose) plus lovastatin versus a dietary intervention on walking capacity in patients with PAD and claudication.76 Compared with dietary intervention, extended release niacin plus lovastatin had no effect on peak walking time or claudication onset time.
Fibrates activates lipoprotein lipase via its effect on lipoprotein PPAR-α (peroxisome proliferator–activated receptor alpha) and lowers LDL cholesterol and triglycerides and increases HDL cholesterol. A meta-analysis of 18 trials including 45 058 participants found that fibrate therapy reduced the risk of coronary events by 10% but had no effect on cardiovascular or all-cause mortality.77 Few studies have specifically examined the effect of fibrates on MACE or MALE in patients with PAD. In one placebo-controlled trial of 1568 men with PAD, bezafibrate did not reduce the incidence of fatal and nonfatal CAD or stroke.78 The FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study found that fenofibrate did not reduce the risk of major amputations in patients with type 2 diabetes but did decrease the risk of minor amputations in those without known large-vessel disease.79
The REDUCE-IT trial was a placebo-controlled trial that assessed the efficacy of icosapent ethyl, a stable eicosapentaenoic acid ethyl ester, on adverse cardiovascular events in patients with established cardiovascular disease (including a subgroup with PAD) or with diabetes and other risk factors, and had elevated fasting triglycerides and were receiving statin therapy.80 Icosapent ethyl reduced the risk of adverse cardiovascular events by 25%; however, its efficacy in the subgroup of patients with PAD has not been reported.
ANGPTL3 (angiopoietin-like 3) inhibits lipoprotein and endothelial lipase. Evinacumab is a monoclonal antibody that inhibits ANGPTL3 and has been shown to decrease LDL cholesterol in patients with hypercholesterolemia.81,82 Its efficacy in improving cardiovascular outcomes in patients with clinical manifestations of atherosclerosis, including those with PAD, is not yet established.
Glucose-Lowering Therapy
Diabetes is a potent risk factor for the development of PAD. Diabetes accelerates the risk of PAD through the promotion of atherosclerosis, microvascular dysfunction, and endothelial injury. Patients with diabetes are at ~2-fold risk of major adverse cardiovascular risk relative to patients without diabetes.83 Moreover, the risk of adverse limb events, such as amputation, is not only heightened in patients with PAD and diabetes relative to patients with PAD but without diabetes, but also seems driven by multifactorial etiologies and particularly synergies between wound formation and delayed wound healing, disordered immune function, and propensity for infection and ischemia.77,78 The direct link between hyperglycemia and microvascular complications such as retinopathy and nephropathy and the benefit of glucose lowering for reducing the risk of these complications has been established.83 Therefore, it is intuitive to consider glucose lowering as a mechanism to reduce the risk of MACE and MALE. Trials to prove this hypothesis, however, are limited, with some even showing harm with strategies to achieve lower glucose targets particularly in patients with PAD.84 The arrival of novel target specific agents for the treatment of diabetes that demonstrate broad and robust benefits beyond those explained by glucose lowering alone has revolutionized medical therapy for patients with diabetes, including those with PAD.
The United Kingdom Prospective Diabetes Study evaluated dietary restriction versus intensive glucose lowering with medical therapy (sulfonyl-urea, insulin, or metformin) and showed benefit for microvascular disease but not MACE at 5-year follow-up, but a 15% relative risk reduction myocardial infarction at the 10-year follow-up.85 Both the ACCORD (Action to Control Cardiovascular Risk in Diabetes) and ADVANCE trials (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trials) investigated more versus less intensive glucose lowering in patients with diabetes, including subgroups with PAD, with neither demonstrating a benefit for the reduction of MACE over a median of 3.5 and 5 years, respectively and with increased risk of hypoglycemia in both and excess mortality in ACCORD.86 In the ACCORD trial, intensive glucose lowering was associated with lower rates of amputation.87
The peroxisome proliferator–activated receptor gamma agonist, pioglitazone, was effective in lowering glucose and was studied for outcomes in the PRO-active (Prospective Pioglitazone Clinical Trial in Macrovascular Events), a study which included 1043 patients with symptomatic PAD and followed patients for a mean of 34.5 months. The broad vascular composite end point including MACE, revascularization, and amputation was not significantly reduced; however, there were lower rates of the composite of cardiovascular death, myocardial infarction, or stroke with a 14% relative reduction that was statistically significant. A second class of therapies, the dipeptidyl peptidase 4 inhibitors, were studied in large cardiovascular outcomes trials and were shown to reduce glucose but have no effect (benefit or harm) on ischemic outcomes.
In this context, the profound benefits for MACE, heart failure, and cardiovascular mortality with the sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin observed in the EMPA-REG trial (Efficacy and Safety of Empagliflozin [BI 10773] in Type 2 Diabetes Patients on a Background of Pioglitazone Alone or With Metformin trial) represented an important step forward in risk reduction for patients with diabetes and vascular disease.88 The trial recruited patients largely with established vascular disease, including 600 patients with PAD, in which the benefits for MACE and mortality were consistent.89 Although the benefits for MACE were largely confirmed in the subsequent CANVAS trials (CANagliflozin cardioVascular Assessment Study trials), investigating canagliflozin, findings of an ≈2-fold risk of amputation, with the greatest absolute risk in those with PAD, created concerns for its use in patients with PAD.84,90,91 Work to elucidate the etiology of this risk did not reveal a specific mechanism; however, the CANVAS trials were not prospectively designed to assess amputation risk.92 The subsequent CREDENCE trial (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy trial), investigating the same agent in patients with diabetes and chronic kidney disease, did not confirm this risk although differences in trial design including enhanced foot hygiene, exclusion of patients at high risk for amputation and treatment cessation for high-risk conditions for amputation may have attenuated any risk if present.93 The DECLARE-TIMI 58 trial (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events trial) studied the agent dapagliflozin in a broad diabetes population including a large group of patients with diabetes and risk factors, but no established vascular disease.94 Findings confirmed the benefits of the class for heart failure and kidney complications and clarified that MACE benefits were largely confined to patients with established vascular disease and largely coronary disease. A dedicated analysis in patients with PAD focused on limb outcomes and amputation with prospective collection and categorization.95 Overall, patients with PAD were at heightened risk of major adverse limb events and amputation relative to those without PAD and the primary drivers of amputation were infection as well as ischemia. There was no increased risk of amputation, and no consistent pattern of risk in any specific subgroup. The benefits of dapagliflozin were consistent in patients with PAD with larger absolute benefits due to their higher risk profile, underscoring the importance of this class in high-risk patients with diabetes. The data overwhelming support the use of SGLT2i in patients with diabetes and PAD. Any risk for amputation, if present, is likely mitigated through careful foot hygiene and judicious use in patients with active conditions threatening amputation, such as critical limb threatening ischemia.
The GLP (glucagon-like protein)-1 receptor agonists lower glucose through a different mechanism. In cell models, liraglutide inhibits platelet aggregation and improves endothelial signaling. In preclinical models, GLP-1 agonists improve endothelial function by lowering the arterial expression of proinflammatory pathways, and inhibit platelet aggregation and atherosclerosis.96–100 Large clinical outcomes trials similarly observed a clear benefit for cardiovascular outcomes. The pattern of efficacy was distinct from the SGLT2i, with greater benefit for ischemic outcomes with the GLP-1 agonists relative to heart failure and kidney benefits observed with SGLT2i. The LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial) demonstrated benefits for both MACE and cardiovascular death in high-risk patients with diabetes treated with liraglutide.101 Findings were subsequently confirmed with the oral GLP-1 agonist, semaglutide. The systemic cardiovascular benefits were broadened by observations that liraglutide significantly reduced the risk of amputation by ~35%.102 Taken together, these observations suggest that GLP-1 agonists may have direct vascular benefits and be of particular benefit in patients with PAD and diabetes who are at high risk of amputation. Ongoing studies are evaluating whether such therapies have other vascular effects translating to improved function and exercise time in patients with symptomatic PAD and diabetes (NCT04560998).
Overall, the role of diabetes care in the patient with PAD has become of even greater importance as the risk of cardiovascular and limb complications is further elucidated, and the broad benefits of the SGLT2i and GLP-1 agonists are further demonstrated.103,104 Although glucose-lowering therapies with traditional agents have shown the greatest benefit for reductions in microvascular complications, SGLT2i and GLP-1 agonists significantly reduce cardiovascular mortality, heart failure, kidney complications, MACE, and amputation. Such observations support recent changes in guidelines to move these therapies earlier in the treatment of patients with diabetes, including those with PAD, and add urgency to achieving broader and more systematic use in this high-risk population.105
Antithrombotic Therapies
Accumulating evidence connects disruption of the hemostatic process and enhanced platelet activity with cardiovascular risk in PAD.106 In pathological specimens, lesions in patients with advanced PAD demonstrate both plaque thrombosis and microembolism, linking MALE to thrombus formation. Importantly, the prevalence of luminal occlusion by thrombus in the absence of obstructive atherosclerotic lesions is common in the lower extremity arteries suggesting a distinct role of atherothrombosis in PAD.25 One study of arteries from amputated limbs of patients with critical limb ischemia showed that ≈73% of femoral-popliteal arteries had both atherosclerosis and thrombosis contributing to luminal stenosis, but among infrapopliteal arteries, only 33% of arteries had thrombi associated with significant atherosclerosis, whereas 67% had thrombotic occlusion without atherosclerosis. It was suggested that the infrapopliteal thrombi may be embolic from proximal arteries where calcified nodules are present and may precipitate thrombus formation.107 Treatments targeted at thrombotic complications of atherosclerosis have shown substantial benefit and occupy a growing place in the management of PAD.108,109
Data for the use of antithrombotic therapies in PAD were historically derived from subgroups of broad atherosclerosis trials or meta-analyses evaluating therapies for the reduction of MACE and including subgroups with PAD.110–113 Recent trials, however, have greatly increase the understanding of the role of antithrombotic therapies in PAD by extending end points to include MALE including adjudicated acute limb ischemia (ALI) as key secondary outcomes or components of primary outcomes.2,114–116 In addition, trials focused on patients selected for PAD in both the chronic and postrevascularization setting have greatly elucidated the efficacy and safety in these populations and settings and have also helped to demonstrate differences in the effects of antithrombotic therapies in PAD populations relative to those observed in CAD.2,116 Such innovations hold promise for greater personalization of antithrombotic therapy in PAD where traditionally guidelines have advocated for a broad treatment approach.117,118
Aspirin Monotherapy
The benefit of aspirin in PAD is largely based on the Antithrombotic Trialists (ATT) Collaboration meta-analysis, which included 9000 patients with PAD.110,111 Overall, antiplatelet monotherapy was associated with a 22% reduction in MACE with a 60% excess in major bleeding including intracranial bleeding overall. Of note, the meta-analysis included wide variations in aspirin dosing as well as other antiplatelet therapies such as picotamide. Therefore, the ATT provides supportive evidence for antiplatelet monotherapy through a large and heterogenous meta-analysis but should not be interpreted as specifically supporting aspirin per se.119 Indeed, 2 dedicated trials of aspirin for MACE prevention in patients with no known vascular disease, but marginally low ABI found no benefit of aspirin compared with placebo. Both the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) and AAA (Aspirin for Asymptomatic Atherosclerosis) trials found no difference in cardiovascular outcomes with long-term aspirin in patients with an abnormal ABI, but no other symptoms of atherosclerosis.120,121 The high cut points for ABI used in these studies raise concerns regarding the generalizability of these findings to patients with symptomatic PAD, and therefore, guidelines have largely reconciled with the position that aspirin is efficacious for MACE reduction in symptomatic PAD (such as those in ATT) but of unclear benefit in asymptomatic marginally low ABI.117,118 Importantly, no study has definitively demonstrated benefits of aspirin for preventing MALE including ALI and amputation, and therefore application of aspirin monotherapy is solely for reducing MACE.
P2Y12 Monotherapy
Inhibitors of the P2Y12 receptor for ADP have been studied in prevention of MACE including in PAD populations. The STIMS (Swedish Ticlopidine Multicenter Study) evaluated ticlopidine, a first generation P2Y12 inhibitor, versus placebo in 687 patients with PAD and showed a 30% reduction in mortality, primarily fatal vascular events.122 Overall ticlopidine was not well tolerated with a 2.5-fold excess in drug discontinuation relative to placebo. Clopidogrel, a second generation and better tolerated agent, studied compared with aspirin in over 19 000 patients with chronic atherosclerosis in the CAPRIE trial (a randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events trial).112 Relative to aspirin, clopidogrel reduced MACE with a modest relative risk reduction of 8.7% but was well tolerated. Results were largely consistent in those with PAD with a suggestion of greater MACE benefit in a subgroup analysis versus those without PAD.112 There was no advantage with regard to MALE. Of note, both STIMS and CAPRIE were reported in 1996 and therefore may not reflect benefits in the context of current background therapy such as statin use. A third-generation agent, ticagrelor, was then studied as monotherapy relative to clopidogrel in over 12 000 patients selected on the basis of PAD and was found not to be superior; however, there appeared to be an interaction on the basis of prior coronary intervention with a lower associated rate of MACE in those with versus without a history of coronary procedures.2 There was no MALE benefit of ticagrelor versus clopidogrel as monotherapy.
More Intensive Antiplatelet Strategies
Combination of Aspirin and P2Y12 Inhibition
More intensive regimens have been evaluated in large atherosclerosis programs with PAD subgroups. The CHARISMA trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance trial) studied the combination of aspirin and the P2Y12 inhibitor clopidogrel (DAPT) in a broad population with stable atherosclerosis or risk factors and was overall neutral for the primary end point of MACE, but subsequent subgroup analyses raised the hypothesis of benefit in those with symptomatic atherosclerosis, most notably prior myocardial infarction.123 In patients with PAD, the primary end point was also neutral, and there was more moderate or severe bleeding overall.113,124 The PEGASUS-TIMI 54 trial (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin) evaluated DAPT with aspirin and ticagrelor versus aspirin alone in high-risk patients with prior myocardial infarction and demonstrated a significant reduction in MACE.125 In the subgroup with concomitant PAD (CAD+PAD), there was a greater absolute benefit (>5% absolute risk reduction at 3 years) and lower rates of cardiovascular and all-cause mortality.126 Of note, MALE was formally adjudicated and significantly reduced by ≈40% with ticagrelor versus placebo.126 The benefits of ticagrelor for MALE was confirmed in the (Effect of THEMIS trial Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study), which studied DAPT with ticagrelor in patients with diabetes and coronary disease.127 The combination of aspirin and ticagrelor reduced MACE with a consistent benefit in those with comorbid PAD (PAD+CAD) and showed an ≈50% reduction in MALE.
The TRA2P-TIMI 50 trial studied the combination of aspirin and/or clopidogrel and the novel thrombin receptor antagonist, vorapaxar, in a broad atherosclerosis population including over 3700 patients with symptomatic PAD.114 Vorapaxar significantly reduced MACE with consistent benefit in the PAD population and in addition reduced ALI by 42%.128 There was more GUSTO moderate or severe bleeding and excess risk of intracranial hemorrhage in patients with prior stroke but not in those with CAD or PAD without prior stroke. Vorapaxar was approved for use in CAD or in PAD on this basis.129 Subsequent analyses have shown greater benefit in those with polyvascular disease (PAD+CAD) or PAD with prior lower extremity revascularization.8
More Intensive Antithrombotic Strategies Combining Antiplatelet and Anticoagulant Therapy
An alternative approach to more-intensive antithrombotic therapy to DAPT is the combination of an aspirin and therapies targeted at either thrombin generation. The WAVE trial (Warfarin Antiplatelet Vascular Evaluation) evaluated the combination of therapeutic warfarin plus aspirin versus aspirin alone in a dedicated PAD population and found no benefit for MACE or limb outcomes but an intolerable safety profile with a ≈3-fold risk of life-threatening bleeding.130
An alternative approach to inhibiting thrombin generation was the use of a direct factor Xa inhibitor (FXa). Through the ATLAS TIMI 51 trial, the low dose of 2.5 mg twice daily of rivaroxaban (25% of the total daily dose for atrial fibrillation) was shown to be efficacious for the reduction of MACE in patients with acute coronary syndromes when added to aspirin or DAPT.131,132 This combination was subsequently studied in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), which recruited high-risk patients with CAD or PAD.115 Overall, the trial was stopped early for overwhelming efficacy of rivaroxaban 2.5 mg twice daily with aspirin versus aspirin alone including cardiovascular and all-cause mortality. Benefits were consistent in the over 7000 patients with PAD.108,133 Although there was a 70% excess in major bleeding, there was no excess in critical organ bleeding, intracranial bleeding, or fatal bleeding. In addition to the MACE benefits, there was a ≈45% reduction in MALE and a significant reduction in amputation.
Antithrombotic Therapy After Lower Extremity Revascularization
Although the risk profile of patients with PAD in the postrevascularization setting is known to be characterized by an extremely high risk of MALE and particularly ALI, there are few well-powered trials of medical therapies in this setting and fewer demonstrating benefit.134 The CASPAR trial studied the combination of aspirin and clopidogrel versus aspirin alone in over 800 patients after lower extremity bypass and showed no benefit for MACE, MALE, or mortality but more bleeding.135 An analogous trial in the endovascular setting called CAMPER terminated for inadequate enrollment. Thus, although DAPT is often used for variable durations in this setting, there are no prospective randomized data to support limb vascular efficacy or to characterize the safety of this approach.
Anticoagulation with warfarin is utilized in some cases to maintain patency after bypass surgery largely on the basis of observational studies. The Dutch Bypass Oral Anticoagulants or Aspirin Study formally evaluated this strategy in a randomized fashion and demonstrated no benefit for graft patency or limb outcomes and a ≈3 fold excess in hemorrhagic stroke.136
The VOYAGER PAD (Vascular Outcomes Study of Aspirin Along with Rivaroxaban in Endovascular or Surgical Limb Revascularizations for Peripheral Artery Disease) studied the addition of rivaroxaban 2.5 mg twice daily to aspirin and allowed concomitant clopidogrel in a broad population of patients with PAD undergoing surgical or endovascular revascularization.116 Overall, there was a significant reduction in the primary outcome composite of acute limb ischemia, major vascular amputation, myocardial infarction, or ischemic stroke. Risk overall and benefit of rivaroxaban were driven by limb outcomes. There was a number needed to treat for the primary outcome of 39 and although more bleeding, no excess in intracranial hemorrhage or fatal bleeding and a 6:1 benefit risk ratio. Overall, the favorable benefit risk ratio was consistent regardless of background clopidogrel use highlighting the potential utility of the strategy regardless of clopidogrel use.
Overall, selecting an antithrombotic therapy requires recognition of a patient’s risk of MACE and MALE (see risk stratification below). In addition, selection must be tailored to the setting including chronic symptomatic PAD and postrevascularization. A summary of antithrombotic therapy is shown in the Table.
| Monotherapy | Combination therapies | |||||
|---|---|---|---|---|---|---|
| Aspirin | Clopidogrel vs aspirin | Aspirin+vorapaxar vs aspirin* | Aspirin+ticagrelor 60 mg twice daily vs aspirin | Aspirin+rivaroxaban 2.5 mg twice daily vs aspirin | Aspirin+rivaroxaban 2.5 mg twice daily vs aspirin* | |
| Pivotal studies | ATT110,111 | CAPRIE112 | TRA2P-TIMI 508,114,129 | PEGASUS-TIMI 54125,126 | COMPASS108,115,133 | VOYAGER PAD116 |
| Population | Chronic atherosclerosis with symptomatic PAD subgroup | Chronic atherosclerosis with symptomatic PAD subgroup | Chronic atherosclerosis with symptomatic PAD subgroup | Prior MI with symptomatic PAD subgroup† | Chronic atherosclerosis with symptomatic PAD subgroup | Postrevascularization for symptomatic PAD |
| Effects for MACE | 22% relative risk reduction | 8.7% relative risk reduction | 20% relative risk reduction | 15% relative risk reduction | 24% relative risk reduction | 15% relative risk reduction in composite of MACE or MALE |
| Effects for MALE | No benefit described | No benefit described | 42% relative risk reduction | 35% relative risk reduction | 46% relative risk reduction | |
| Bleeding | 60% relative excess in major extracranial bleeding | No major differences in bleeding | 62% relative risk increase in GUSTO severe bleeding | 2.32-fold relative excess in TIMI major bleeding | 70% relative excess in ISTH major bleeding | 43% excess in TIMI major bleeding |
*
Clopidogrel allowed as part of background therapy.
†
Polyvascular disease, patients with PAD, and no MI not included.
Therapies to Improve Function
Impaired functional status in patients with PAD involves a complex interaction between arterial obstruction, vascular dysfunction, and altered skeletal muscle metabolism.137 Cilostazol is a phosphodiesterase 3 inhibitor, which is indicated for treatment of patients with PAD. Individual studies and meta-analyses of these studies have found that cilostazol increases both maximal and pain-free walking distance in patients with claudication by ≈15% over 24 weeks, corresponding to an average of about 40 and 30 meters, respectively.138–140 Cilostazol increases intracellular cAMP levels, which may in turn inhibit platelet aggregation and cause vasodilation; however, the exact mechanism through which cilostazol improves walking capacity is not known. Cilostazol has not been shown to increase mortality,141 but it is contraindicated in patients with congestive heart failure of any severity. This warning is based on its association with other phosphodiesterase 3 inhibitors, such as milrinone and vesnarinone, which have been reported to increase mortality in patients with heart failure.142,143 Observational studies have not suggested an increased risk of mortality in patients with heart failure prescribed cilostazol, emphasizing the need for shared decision-making with patients.144,145
Pentoxifylline is a theophylline derivate that is approved by the FDA for treatment of patients with PAD and intermittent claudication. Its proposed mechanisms of action are reducing blood viscosity and increasing deformability of erythrocytes and leukocytes, thereby improving blood flow to affected limbs.146 Placebo-controlled studies have variably reported small improvement or no improvement in walking time in patients treated with pentoxifylline.139,147,148 A pilot study of an antioxidant-rich cocoa therapy improved 6-minute walk along with increases in calf muscle perfusion and capillary density.149
Exercise Training
Exercise therapy is highly effective to preserve and restore walking ability in patients with PAD by inducing a diverse set of beneficial systemic and limb adaptations.137,150,151 Although exercise training does not alter severity of obstruction measure by ABI, there does seem to be a benefit on endothelium-dependent vasodilation and microvascular flow.152–154 Chronic ischemia disrupts skeletal muscle mitochondrial efficiency and exercise training using treadmill and resistance approaches may improve muscle characteristics and oxidative capacity.22,149 Inflammation may also be reduced by treadmill exercise programs in PAD that holds the potential for long-term plaque stabilization.155,156
Accordingly, supervised exercise training is an effective intervention to improve walking capacity in patients with PAD and intermittent claudication. Optimal exercise training sessions are 30 to 60 minutes for a minimum of 3 times per week for 3 to 6 months.157 Treadmill exercise is primary training modality, but other modalities such as a track may be used. Participants walk to near maximal claudication discomfort, rest to alleviate the discomfort, and then resume walking. Meta-analyses of studies that examined supervised exercise training found that exercise training improves pain-free walking distance, maximum walking distance, and quality of life in patients with intermittent claudication.158,159 This improvement in walking distance was not found in a meta-analysis of home-based exercise training.160 However, home-based exercise training supplemented by group-mediated cognitive behavioral intervention or quantified with a step activity monitor has been shown to improve walking distance.161,162 The LITE trial (Light Treatment Effectiveness Trial) compared a low-intensity to high-intensity home-based walking exercise intervention in patient with PAD and found a clinically significant increase in 6-minute walk distance in the high-intensity group, but no benefit of low-intensity exercise compared with the control group.163
Several trials have compared the efficacy of exercise training to revascularization in patients with intermittent claudication. In the CLEVER study (Claudication: Exercise Versus Endoluminal Revascularization Study), patients with aortoiliac disease and claudication were randomized to optimal medical care, which included cilostazol, optimal medical therapy with supervised exercise training, or optimal medical care plus endovascular stent revascularization.153 Patients randomized to either supervised exercise training or aorto iliac stenting achieved greater peak walking distance on a treadmill at 6 months compared with patients receiving optimal medical therapy alone. Peak walking distance was greater in those randomized to supervise exercise training than those treated with stenting. Quality of life measures, however, were greater in those who underwent stenting then and those treated with supervised exercise training. A meta-analysis of 5 studies comprising 345 patients compared endovascular revascularization with supervised exercise training, including the CLEVER trial, and showed no significant difference in maximal walking distance or pain-free walking distance between the 2 groups.164
The combination of supervised exercise training and endovascular revascularization improves walking capacity more than supervised exercise training alone. The Revascularization and Supervised Exercise (ERASE) randomized 212 patients with PAD characterized by aortoiliac or femoropopliteal artery stenoses, or both, to either supervised exercise training and stenting or supervised exercise training alone.165 The study found that combination treatment with endovascular revascularization plus supervised exercise training compared with exercise training increased maximum walking distance, pain-free walking distance, ABI, and quality of life at 3, 6, and 12 months. In a meta-analysis derived from 7 trials comprising 987 patients who underwent combined endovascular therapy and supervised exercise training, compared with those who underwent supervised exercise training alone, had significantly greater maximum walk distance, as well as a lower risk of revascularization or amputation over a median follow-up of 12.4 months.166
Risk Stratification and Personalization of Therapy
Subgroup analyses from trials of patients with medical therapy have helped to elucidate the heterogeneity of risk and response to therapies in patients with PAD. Although traditionally lumped on the basis of ABI and symptoms, there seem to be potent and consistent markers of higher risk subgroups for both MACE and MALE. Such risk stratification may be useful when personalizing the therapeutic approach to patients with PAD (Figure 2). Although therapies may be broadly efficacious, their absolute benefit is likely to be the greatest in those at higher risk and therefore risk stratification may enable clinicians to identify and target high risk populations as well as assist in staging of therapies in patients for whom multiple treatments are indicated.
Several studies have demonstrated that concomitant symptomatic CAD is associated with significantly increased MACE risk relative to symptomatic PAD patients without CAD, even after adjustment for baseline differences. Such populations seem to derive greater absolute benefits from intensive lipid lowering.5 In addition, the benefit of more potent antithrombotic strategies in PAD for MACE seem the greatest in those with PAD and CAD versus PAD and no known CAD. Subgroups of CAD trials with comorbid PAD also find similar greater benefits of more potent antithrombotic therapies for MACE.167
Observational data as well as subgroups of PAD cohorts have demonstrated that patients with prior lower extremity revascularization are at long-term heightened risk of MALE, particularly ALI.168 Reports describe a 4-fold long-term risk of ALI even after adjusting for other differences.126,169,170 In addition, benefits of more potent antithrombotic therapies for MALE reduction seem more robust in PAD subgroups with prior lower extremity revascularization.8
The recognition of comorbid diabetes in patients with PAD identifies higher MACE and amputation risk than in patients with PAD without diabetes. In addition, the adoption of targeted glucose-lowering therapies such as GLP1 agonists that reduce amputation may be favored early in the intensification of therapy, particularly in those at high risk of amputation such as those with prior amputation or more severe PAD.
Biomarkers of risk maybe useful in risk stratification. While LDL-C is a commonly utilized marker of risk with clear targets in PAD, other markers such as lipoprotein Lp(a) may inform further heightened risk and increased benefits of targeted therapies such as PCSK9 inhibition.5,71 Future studies are likely to elucidate additional biomarkers of risk including inflammatory markers, which may assist in personalization of therapies.
Finally, with regard to more potent antithrombotic therapies, excluding high bleeding risk patients from should be considered, and approaches to identifying patients at higher bleeding risk in patients with coronary disease may be useful.171 Generally, prior major bleeding, unexplained anemia, severe liver or kidney disease, and the need for therapeutic anticoagulation are reasonable considerations for bleeding risk.
Future Directions
Several studies have linked higher levels of Lp(a) to the incidence and progression PAD as well as limb amputation.69,172 In addition to induction of inflammation and vascular injury, Lp(a) promotes thrombosis by acting both in an antifibrinolytic and platelet activating fashion. Recent genetic association studies have described an association of loci in the Lp(a) coding gene with PAD.12 Newer therapies that specifically target Lp(a) are currently being evaluated in patients with atherosclerotic disease and may hold potential for PAD.173,174 Therapies targeted at reducing inflammation are actively being investigated as therapies for atherosclerotic disease. A small study showed an increase in walking time following treatment with the interleukin-1β inhibitor, canakinumab, in patients with symptomatic PAD and results from PAD subgroups in large clinical trials are anticipated.175,176
Conclusions
Patients with PAD are a highly vulnerable population for both MACE and MALE. The drivers of risk include diet and lifestyle including smoking with resulting risk driven by dyslipidemia, diabetes, and thrombosis. The risk profile of patients with PAD is heterogenous with those with polyvascular disease at heightened risk of MACE, those with prior amputation, critical limb ischemia, or revascularization at heightened risk of MALE, and those with comorbid diabetes at heightened risk of MACE, heart failure, kidney complications, and amputation. The therapeutic approach to prevention in PAD must start with lifestyle interventions including diet, exercise, and smoking cessation. Medical therapies have demonstrated efficacy in reducing the risk of MACE and MALE through treatment of pathways of risk (Figure 2) and improving function in patients with PAD. The growing number of therapies and evident heterogeneity of risk profile in PAD supports a personalized approach to treatment intensification. Despite these novel therapies, significant risk remains and opportunities exist for novel approaches and further treatment intensification to improve outcomes in this complex and growing population.
Footnote
Nonstandard Abbreviations and Acronyms
- AAA
- Aspirin for Asymptomatic Atherosclerosis
- ABI
- ankle-brachial index
- AIM-HIGH
- Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes
- ANGPTL3
- angiopoietin-like 3
- FIELD
- Fenofibrate Intervention and Event Lowering in Diabetes
- GLP
- glucagon-like protein
- HDL
- high-density lipoprotein
- ICPOP
- Intermittent Claudication Proof of Principle
- MACE
- major adverse cardiovascular event
- MALE
- major adverse limb event
- NPC1L1
- Niemann–Pick C1–like 1
- PAD
- peripheral artery disease
- PCSK9
- proprotein convertase subtilisin/kexin type 9
- PEGASUS-TIMI 54
- Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin
- POPADAD
- Prevention of Progression of Arterial Disease and Diabetes
- PPAR-α
- peroxisome proliferator–activated receptor alpha
- PRO-active
- Prospective Pioglitazone Clinical Trial in Macrovascular Event
- SGLT2i
- sodium-glucose transporter 2 inhibitor
- STIMS
- Swedish Ticlopidine Multicenter Study
- WAVE
- Warfarin Antiplatelet Vascular Evaluation
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Published online: 10 June 2021
Published in print: 11 June 2021
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Disclosures M.P. Bonaca discloses grant support to CPC from Amgen, AstraZeneca, Bayer, JanOne, Janssen, Merck, NovoNordisk, Sanafit, and Sanofi. M.P. Bonaca and M.A. Creager are supported by a Strategically Focused Vascular Disease Research Network grant from the American Heart Association (18SFRN33900147). N.M. Hamburg discloses consulting for Merck, Bayer, Novonordisk, and Sanifit, equity interest in Acceleron Pharma, and is supported by grants from the American Heart Association (AHA 20SFRN35120118 and AHA 20YVRN35500014) and by grants from the NHLBI (R01HL137771 and 2U54HL120163).
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