Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Medical Treatment of Peripheral Artery Disease
Medical treatment of patients with peripheral artery disease (PAD) is targeted at preventing adverse cardiovascular and limb outcomes and improving limb function. Atherothrombotic complications such as myocardial infarction (MI), ischemic stroke, and cardiovascular death are referred to as major adverse cardiovascular events (MACE), with risk related to the systemic nature of atherosclerosis (see Chapter 16 ). In addition, patients with PAD are at risk of major adverse limb events (MALE), including acute limb ischemia (ALI), chronic critical limb ischemia (CLI), and ischemic amputation ( Fig. 19.1 ).
Outcomes in patients with symptomatic peripheral artery disease at 4 years in the REACH registry (A) and the TRA2P-TIMI 50 trial (B).
(From Bonaca MP, Creager MA. Pharmacological treatment and current management of peripheral artery disease. Circ Res. 2015;116:1579–1598.)
Although all patients with PAD are at heightened risk of both MACE and MALE, there is growing appreciation of the heterogeneity of risk within the broad population of patients with PAD. Risk is related to the presence of concomitant symptomatic disease in other vascular beds (polyvascular disease), especially coronary artery disease (CAD), and also to the severity of disease in the limbs. The risk of MACE in patients with PAD is 60% to 80% greater than that in patients with history of MI or stroke without symptomatic PAD; however, the greatest risk is in those who have both symptomatic PAD and symptomatic CAD exceeding that of symptomatic PAD or CAD alone ( Fig. 19.2 ). The risk of MALE is highest in those with prior peripheral revascularization, followed by those with symptomatic PAD but no history of peripheral revascularization, and with relatively low risk in those without symptoms but with an ankle-brachial index (ABI) less than 0.9 ( Table 19.1 and Fig. 19.3 ). The therapeutic approach to patients with PAD therefore depends on the severity of symptoms and manifestation of disease in the lower extremities, the presence of concomitant symptomatic disease in other vascular territories, and the presence of comorbid disease such as diabetes. Preventive measures such as diet, smoking cessation, blood pressure control, and lipid optimization apply to all patients ( Fig. 19.4 ). Targeted therapies such as those for glucose lowering apply only to those with specific risk factors such as diabetes. The intensity of antithrombotic therapy must be balanced against the associated risk of bleeding, when considered for those with the highest risk of MACE (e.g., those with polyvascular disease) or MALE (e.g., those with prior peripheral revascularization). Similarly, although intensive low-density lipoprotein cholesterol (LDL-C) lowering may have the same relative benefits for all patients with PAD, expensive therapies with limited availability may first be considered in those patients at the highest absolute risk, who are likely to derive the greatest absolute risk reductions.
Outcomes in patients with symptomatic peripheral artery disease (PAD) randomized to placebo in the FOURIER trial and followed for 2.5 years. All patients with PAD are shown in orange (A) and then stratified by PAD only (yellow) or PAD with prior myocardial infarction (MI) and/or prior stroke ( red , B). BMI, Body mass index; CABG/PCI, coronary artery bypass grafting/percutaneous coronary intervention; CHF, congestive heart failure; CVD, cardiovascular death; eGFR, estimated glomerular filtration rate; HR, hazard ratio; TIA, transient ischemic attack.
(Data from Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial [Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk]. Circulation. 2018;137:338–350.)
Table 19.1
Independent Predictors of Acute Limb Ischemia in Peripheral Artery Disease Trials
| TRA2P-TIMI 50 | PEGASUS-TIMI 54 PAD | EUCLID | |
|---|---|---|---|
| Prior peripheral revascularization | HR 3.60 (2.10–6.18) P < .001 |
HR 3.76 (2.26–6.25) P < .001 |
HR 4.23 (2.86–6.25) P < .001 |
| ABI ≤ 0.50 | HR 2.86 (1.81–4.51) |
||
| ABI ≥ 1.30 | HR 2.71 (1.09–6.72) |
||
| Current smoking | HR 2.17 (1.01–4.67) P = .046 |
ABI, Ankle-brachial index; HR, hazard ratio.
The incidence of major adverse limb events (MALE) in patients with lower extremity peripheral artery disease randomized in the COMPASS trial and stratified by peripheral artery disease history. ABI, Ankle-brachial index.
(From Bonaca MP, Creager MA. Antithrombotic therapy and major adverse limb events in peripheral artery disease: a step forward. J Am Coll Cardiol. 2018;71:2316–2318.)
Markers of risk and goals of prevention in patients with peripheral artery disease (PAD) diagnosed by ankle-brachial index (ABI) and symptoms. MACE, Major adverse cardiovascular events; MALE, major adverse limb events.
This chapter reviews the evidence to support medical treatments to reduce the risk of MACE and MALE in patients with PAD, and the physical and medical therapies used to improve functional capacity in patients with intermittent claudication. Investigational therapies are briefly discussed. Catheter-based revascularization for PAD is reviewed in Chapter 20 , and surgical revascularization for PAD is reviewed in Chapter 21 . Multisocietal consensus guidelines for management of the patient with PAD are available and helpful for guiding clinical practice.
Interventions to reduce cardiovascular risk and adverse limb events
Prevention guidelines recommend lifestyle modification, such as a heart-healthy diet, regular exercise habits, and maintenance of a healthy weight. Specific diet recommendations include Mediterranean diets and the DASH (Dietary Approaches to Stop Hypertension) diet. PAD guidelines advocate for interdisciplinary care, including nutritionists/dieticians. Lifestyle modifications should be recommended for all patients with PAD regardless of the severity of disease or comorbidities. These interventions have little risk and low cost and have the potential to reduce risk of MACE, improve limb function, and improve quality of life.
Smoking Cessation
Tobacco smoking is associated strongly with the development and progression of PAD, and the risk of PAD among smokers is as high as threefold that of nonsmokers (see Chapter 16 ). Smoking cessation is a critical component of risk factor modification for patients with PAD.
Smoking cessation has salutary effects on claudication symptoms, exercise physiology, and limb-related outcomes in patients with symptomatic PAD. Patients with intermittent claudication who quit smoking have longer pain-free walking times and maximal walking times compared with patients who continue to smoke. Smoking cessation is also associated with improved clinical outcomes in patients with PAD. Continued smoking in patients with claudication is associated with higher rates of CLI, need for peripheral revascularization, and MACE. Similarly, in patients undergoing bypass surgery, continued smoking is associated with lower patency rates both for venous and prosthetic grafts. Ongoing smoking is also associated with development of MI and a trend toward decreased overall survival at 10 years of follow-up. In the Spanish Factores de Riesgo y ENfermedad Arterial (FRENA) Registry, patients with vascular disease (467 of the 1182 smokers had PAD) who stopped smoking had lower mortality over a mean of 14 months follow-up.
Despite the multiple benefits of smoking cessation in patients with PAD, it is an extremely difficult goal to accomplish and initial success rates are low. The efficacy of physician advice in achieving smoking cessation is less than 5%. The effectiveness of smoking cessation interventions in patients with PAD was evaluated in a randomized trial of 124 patients with PAD who were currently smoking. Patients randomized to a PAD-specific tailored counseling program had higher rates of abstinence at 6 months compared with those receiving minimal intervention (21.3% vs. 6.8%). Although the intervention was successful, almost 80% were no longer abstinent at 6 months, underscoring the need for more effective interventions.
Smoking cessation programs are more successful when coupled with pharmacologic therapy, including both nicotine and nonnicotine agents. The antidepressant bupropion has been demonstrated to improve tobacco abstinence rates at 12 months relative to placebo when used alone or in combination with the nicotine patch. Varenicline, a partial agonist of the nicotinic acetylcholine receptor (nAchR) α4β, improves tobacco abstinence rates among subjects with or without cardiovascular disease, including patients with PAD. Among those with cardiovascular disease, varenicline is associated with a threefold likelihood of abstinence at 1-year follow-up compared with placebo, although the absolute abstinence rate is only approximately 20%. Side effects of varenicline include sleep abnormalities, nausea, and flatulence. Both varenicline and bupropion are associated with an increased risk of neuropsychiatric side effects. Package labeling for both agents includes a black box warning recommending observation for changes in behavior or mood or development of suicidal ideation while receiving these agents for smoking cessation treatment.
Recommendations
Smoking cessation advice and encouragement of cessation efforts should be key components of each office visit. Although time intensive, achievement of smoking cessation is one of the most powerful interventions to reduce risk in patients with PAD. Evaluation using the “5 A” algorithm (Ask, Advise, Assess, Assist, and Arrange) may be useful. For patients motivated to quit smoking, treatment with nicotine replacement therapy, bupropion, or varenicline should be considered. These efforts may be incorporated into a formal smoking cessation program that includes longitudinal counseling on an individual basis or in a small group.
Blood Pressure Lowering
Optimizing blood pressure reduces cardiovascular risk, including stroke, MI, and congestive heart failure. A number of therapies are effective at reducing blood pressure, and large randomized trials have demonstrated the benefits of pharmacotherapy on outcomes, including mortality. The SPRINT trial demonstrated greater risk reduction with more intensive blood pressure lowering. The current American Heart Association/American College of Cardiology (AHA/ACC) blood pressure–lowering guidelines recommend treating patients with established cardiovascular disease, including patients with PAD, to a target of < 130/80 mm Hg. There are few studies of blood pressure lowering in patients with PAD and which focus either on specific drugs or optimal targets. No specific antihypertensive agent or class has been shown to improve limb vascular outcomes or symptoms of claudication, nor is convincing evidence for harm, specifically with β-blocker therapy. The Appropriate Blood Pressure Control in Diabetes (ABCD) study enrolled 950 patients, with 53 having symptomatic PAD. Patients were randomized to treatment with enalapril or nisoldipine (intensive treatment) or placebo (moderate control) and followed for 5 years. Although the number of events was modest, there appeared to be a significant reduction in risk reduction in MACE in those with PAD who received intensive treatment (achieving a mean of 128/75 mm Hg). Benefits appeared to be greater in patients with more severe disease as measured by ABI. These observations were further supported by the International Verapamil-SR/Trandolapril study. In a post hoc subgroup analysis of patients with PAD, treatment to a target < 130/80 mm Hg reduced the risk of MACE. Although a J-shaped relationship was seen overall, this was not seen in the PAD subgroup.
There are few trials comparing classes of agents for blood pressure lowering in patients with PAD. Several studies evaluating the benefits of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have reported consistent benefits in subgroups of patients with PAD. The Heart Outcomes Prevention Evaluation (HOPE) trial randomized patients with vascular disease or diabetes to ramipril 10 mg daily or placebo and followed them for 5 years. The trial showed a 22% reduction in MACE with ramipril with consistent benefits for components of the MACE end point. The HOPE trial included 4051 patients with PAD (44% of the overall trial), and benefits in this subgroup were similar to those observed in the overall trial. Of note is that the reductions in adverse outcomes were observed even though there was only a modest blood pressure–lowering effect overall (5 mm Hg at 1 month, 3 mm Hg at study completion). Similar benefits were observed in the EUROPA trial, which randomized 12,218 patients to the ACEI, perindopril, or placebo and observed a 20% reduction in MACE with consistent benefits in the subgroup of patients with PAD. These observations were extended to ARBs in the ON TARGET trial, which randomized more than 25,000 patients to telmisartan, ramipril, or the combination of both. Overall, telmisartan and ramipril showed similar efficacy with consistent findings in the approximately 3000 patients with PAD, supporting the use of ACEI or ARB therapy in this population.
The use of β-blockade may be indicated in patients with PAD in the comorbid setting of atrial fibrillation or CAD or as an additional class of drugs when multiagent therapy is needed for blood pressure lowering. Although there have been theoretic concerns about risk in patients with PAD stemming from reductions in cardiac output or resulting unopposed α-agonism potentially leading to adverse limb outcomes, these risks have not been observed in studies or meta-analyses; however, the number of patients included in these studies is small, and there are no large prospective trials of β-blockade in PAD patients evaluating limb outcomes. One study evaluated 177 patients with Fontaine stage II claudication who were randomized to nebivolol or hydrochlorothiazide for 24 weeks. Both therapies appeared to be well tolerated with no difference in adverse effects between agents.
Recommendations
Blood pressure control is an important component of cardiovascular risk reduction in all patients, including those with PAD. Recent AHA/ACC guidelines recommend treating to a target of < 130/80 mm Hg. It is reasonable to measure blood pressure in both upper extremities to exclude the possibility of occult subclavian stenosis leading to inaccurate blood pressure assessment in one of the arms. Although limited data exist comparing specific agents, the benefits of ACEI and ARB therapy have been shown, and these agents should be considered first line antihypertensive therapy in patients with PAD. In patients with another indication for β-blocker therapy, it can be safely used without an excess in limb risk.
Glucose-Lowering Therapies in Patients with Diabetes
Robust observational datasets show a clear association between diabetes mellitus and PAD, with associated risks of PAD 2 to 4 times that of patients without diabetes (see Chapter 16 ). Diabetes mellitus is associated with heightened risk of microvascular, as well as macrovascular complications. Elevated glucose is associated with lower patency rates after peripheral vascular intervention and higher risk of amputation. Independent risk factors for amputation include poor vision, neuropathy, and ABI ≤ 0.5, suggesting both microvascular and macrovascular etiologies to limb loss in this complex population. Tissue loss in the setting of chronic CLI may have a particularly complex pathobiology, with significant contributions of ischemia, microvascular disease, and infection. Therapies to lower glucose have shown consistent benefit for reduction of microvascular complications but mixed effects on macrovascular outcomes. For the latter, the specific mechanism of the therapy may be more important than the effect of the therapy on glucose levels.
Treating to Lower Glycemic Targets
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial investigated whether more intensive glucose-lowering control to achieve a lower glycated hemoglobin would reduce outcomes in patients with cardiovascular disease (35% with PAD) or risk factors. Patients in the intensive therapy arm achieved a glycated hemoglobin of 6.4% versus 7.5% in those randomized to standard therapy and at 3.5 years had higher rates of cardiovascular and all-cause mortality. The ADVANCE trial similarly showed no benefit among patients randomized to achieve a lower glycated hemoglobin target (6.5% vs. 7.3%) at 5 years of follow-up but did not show an excess in mortality. A third trial of more intensive glucose lowering in veterans, with a median follow-up of 5.6 years, also showed no benefit.
The Look AHEAD trial investigated whether intensive lifestyle intervention targeted at lowering glucose would be beneficial. Of the 5145 patients randomized, 714 had established cardiovascular disease. At 10 years the intensive intervention led to weight loss, improved fitness, and lower glycated hemoglobin; however, these benefits did not translate into lower rates of MACE. There was statistical heterogeneity with a trend toward benefit in those without established cardiovascular disease and a trend toward harm in those with cardiovascular disease.
Although data for the macrovascular benefits of glucose lowering are mixed, there are some data to suggest that benefits may emerge only over longer periods of time than that included in most clinical trial observation periods. For example, the United Kingdom Prospective Diabetes Study (UKPDS) randomized patients with newly diagnosed type II diabetes mellitus to either dietary restriction only or intensive medical therapy (with sulfonylurea, insulin, or metformin). At 5 years of follow-up, there were reductions in microvascular complications with intensive medical therapy relative to diet; however, there was no benefit for MACE. At 10 years a benefit for MACE became evident with a 15% relative risk reduction for MI and a 6% relative risk reduction in mortality. Taken together these studies suggest that macrovascular benefits attributable to glucose lowering may be present over long periods of time, largely in patients without evident cardiovascular disease.
Class Specific Glucose-Lowering Therapies
Several trials have investigated the effects of class glucose-lowering agents both for safety and efficacy in high-risk populations. Two large trials have evaluated dipeptidyl peptidase 4 (DPP-4) inhibitors in patients with diabetes at high risk for cardiovascular events. Neither agent (saxagliptin or alogliptin) reduced MACE risk over relatively short follow-up, but both had some microvascular benefits in the setting of modest glucose lowering and appeared safe. The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) trial randomized patients to the peroxisome proliferator–activated receptor gamma (PPAR-γ) agonist, pioglitazone, or placebo. Patients with established vascular disease, including 1043 with symptomatic PAD, were included. Over a mean follow-up of 34.5 months, there was no benefit for a broad macrovascular composite of MACE, revascularization, or amputation; however, there was a reduction in the key secondary end point of MACE, which included MI, stroke, and cardiovascular death. These data suggest that PPAR-γ may be a target that reduces cardiovascular risk in patients with diabetes and vascular disease.
Three agents targeting the sodium glucose cotransporter 2 (SGLT2) are currently available. Two have completed large outcomes trials, and a third trial of a third in this class is in progress. This class of drugs reduces plasma glucose by inducing glucosuria, with associated reductions in body weight and blood pressure and increased risk of urinary tract infections. The EMPA-REG trial enrolled approximately 7000 patients with diabetes mellitus and stable cardiovascular disease and randomized them to empagliflozin or matching placebo. The trial was designed to evaluate cardiovascular safety and was not powered for superiority; nonetheless, at the conclusion, empagliflozin significantly reduced the MACE composite of cardiovascular death, MI, or stroke by 14%. In addition to significant reductions in mortality and ischemic events, there was a reduction in hospitalizations for heart failure. Benefits observed were robust, leading to regulatory approval for cardiovascular risk reduction in patients with diabetes and vascular disease; however, the mechanism of benefit has not been clearly defined and is out of proportion to what would be expected based on glucose or blood pressure lowering alone. In addition to the macrovascular benefits, there were also improvements in renal outcomes.
The outcomes in EMPA-REG were evaluated in the subgroup of approximately 1400 patients with PAD at baseline. A consistent benefit was observed for MACE, with a significant 43% reduction in cardiovascular mortality and 38% reduction in all-cause mortality. There was no differential in the safety profile of empaglifozin among patients with PAD, including no increased risk of lower extremity amputation.
The CANVAS program evaluated the safety and efficacy of the SGLT2 inhibitor canagliflozin in a population of patients with either established cardiovascular disease or risk factors. Consistent with EMPA-REG, canagliflozin reduced MACE overall; however, the results were most notable in patients with established cardiovascular disease. CANVAS also showed similar benefits for the composite of cardiovascular death and heart failure, with consistent risk reductions in those with and without established cardiovascular disease. Observational analyses have also supported a class effect for cardiovascular benefit. The results of CANVAS confirmed the benefits observed in EMPA-REG and reinforced the notion that SGLT2 inhibition is an important mechanism for risk reduction in patients with diabetes. However, there was an approximately twofold excess in the risk of lower extremity amputation with canagliflozin compared with placebo. The risk was consistent for major and minor amputations in patients with or without PAD, but with the greatest absolute excess in patients with PAD, and particularly those with prior amputation. These findings, which also have been seen in observational analyses, led to a black box warning by the US Food and Drug Administration (FDA) for amputation.
A third SGLT2 inhibitor, dapagliflozin, is available for treating patients with diabetes. A large outcomes trial, DECLARE-TIMI 58, is currently evaluating the efficacy and safety of dapagliflozin in high-risk patients with established cardiovascular disease or risk factors. The study is powered for ischemic efficacy and will include well-characterized limb outcomes. Results are anticipated in late 2018.
Another target specific class of diabetes therapy are the glucagon-like peptide-1 (GLP-1) agonists. These, delivered parenterally by injection, induce weight loss and lower glucose levels. In two large outcomes trials, GLP-1 agonists have shown significant reductions in ischemic risk, largely in patients with established cardiovascular disease. GLP-1 agonists appear to have primary benefit in ischemic risk reduction, but there have been no signals for limb benefits or adverse limb events.
Recommendations
Diabetes mellitus is a risk factor for PAD and a common comorbid condition. Patients with diabetes and PAD are at high risk of MACE, microvascular complications, and complex limb events that are highly morbid. Glucose lowering remains a core aspect of medical management, with the primary goal of reducing microvascular complications with targets as outlined by professional society guidelines, with metformin being first line oral therapy. SGLT2 inhibitors reduce MACE; however, signals for amputation raise concerns for canagliflozin, particularly in PAD patients; this is not the case for empagliflozin. The mechanisms of benefit and harm with this class of glucose-lowering drugs are unclear. The GLP-1 agonists reduce ischemic risk. Because the benefits of SGLT2 inhibitors and GLP-1 agonists appear independent of their glucose-lowering effects, they should be considered in appropriate patients for macrovascular risk reduction. In patients on insulin or secretagogue therapy, addition of drugs from other classes may necessitate reductions in the intensity of therapy to avoid hypoglycemia.
Antiinflammatory Therapy
A growing body of evidence supports a causal role for inflammation in the pathogenesis of atherothrombosis. The recently completed Cardiovascular Risk Reduction Study (Reduction in Recurrent Major CV Disease Events) (CANTOS) trial evaluated the efficacy and safety of antiinflammatory therapy in patients with vascular disease. CANTOS randomized approximately 10,000 patients with prior MI and a high sensitivity C-reactive protein greater than 2 mg/dL to canakinumab, a monoclonal antibody targeting interleukin-1β (IL-1β) or placebo, and followed them for 48 months. Treatment with canakinumab reduced the risk of MACE by 17%, with broader benefits for reducing cancer deaths. However, there was an increased risk of fatal infections. MACE and MALE outcomes in the subgroup with PAD have not been reported. The CANTOS trial establishes the importance of inflammatory risk in atherothrombosis and the potential benefit of targeting IL-1β. Additional studies will be necessary to define the role of antiinflammatory therapies in patients with PAD.
Recommendations
Currently there is no established role for antiinflammatory therapy with canakinumab in patients with PAD. Future trials of therapies targeting inflammation are needed to establish the role of these therapies in patients with vascular disease.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here
