Overview
Drugs for Patients With Peripheral Artery Disease
Peripheral artery disease (PAD) is broadly defined as arterial occlusive disease outside of the coronary circulation and generally refers to atherosclerotic occlusive disease. While nonatherosclerotic occlusive disease including that related to fibromuscular dysplasia and vasculitis does exist, it is relatively uncommon relative to atherosclerotic disease, and the focus of the current chapter will be on the latter. The most common manifestation of PAD is in the lower extremities and in some contexts PAD as a term is used to specifically describe lower extremity atherosclerotic occlusive disease. Overall it is estimated that over 10 million people in the United States and over 200 million globally have lower extremity PAD (referred to as PAD going forward).
Patients with PAD are at heightened risk of atherothrombosis including systemic events, also referred to as major adverse cardiovascular events (MACE), such as myocardial infarction (MI), stroke, and cardiovascular death (CV death). In addition, by nature of atherosclerosis of the limbs, patients with PAD suffer significant morbidity related to limb ischemia. This morbidity spans from functional limitations due to impaired limb perfusion to limb threatening events such as chronic critical limb ischemia (CLI), acute limb ischemia (ALI), and related ischemic tissue loss, the latter two are commonly referred to as major adverse limb events or MALE ( Fig. 10.1 ).
Medical therapy for the patients with PAD therefore has three key goals: to reduce the risk of MACE, to reduce the risk of MALE, and to improve function ( Fig. 10.2 ). Because the risk of MACE and MALE are driven by atherothrombosis, preventive therapy overlaps with those for ischemic heart disease ( Chapter 1 ) and specifically with antihypertensive therapies ( Chapter 2 ), diabetes drugs ( Chapter 4 ), lipid-modifying drugs ( Chapter 6 ), and antithrombotic drugs ( Chapter 8 ). The efficacy and safety, however, in PAD particularly with regard to limb outcomes is unique to this population ( Fig. 10.3 ). In addition, two important risk factors for incident PAD and risk markers for adverse outcomes in PAD are smoking and diabetes, therefore medical therapy related to these issues is particularly important for prevention. It must also be noted that patients with PAD and concomitant coronary disease, described as polyvascular disease, may be particularly high risk and have greater absolute benefits of preventive therapies. Finally, a large body of data supports the efficacy of exercise to improve function in PAD and, as such, exercise receives a class I indication in clinical practice guidelines. Because this is not a medical therapy it will not be reviewed in this chapter; however, it should be a core aspect in the appropriate medical care of patients with PAD.
While there are a number of pharmacotherapies that have demonstrated efficacy in reducing rates of MACE and/or MALE in PAD, rates of utilization of these therapies remains low overall and especially when compared to patients with coronary artery disease (CAD). Efforts to improve guideline dissemination and implementation of preventive therapies are needed.
Drugs for Smoking Cessation
Smoking is strongly associated with the development of incident PAD. In addition, continued smoking in patients with PAD is associated with accelerated disease progression and poor outcomes. Smoking cessation in PAD is associated with improvement in function as measured by walking time as well as lower rates of the need for peripheral revascularization, CLI, and MACE. In spite of clear evidence of the harms of smoking, the success rate of a strategy of physician advice for cessation low and estimated to be in the range of 5%–7%. Randomized counseling interventions have increased success to ~ 20%; however, persistence is poor with almost 80% of those that quit returning to smoking by 6 months. The coupling of pharmacologic therapy with counseling holds promise for improved rates of smoking cessation
Drug Class Overview and Guidelines
Current guidelines give a class I recommendation for the assistance in developing a plan for quitting including pharmacotherapy. Three medication options include varenicline, bupropion, and/or nicotine replacement therapy.
Mechanisms of Action
Varenicline is a partial agonist of the nicontinic acetylcholine receptor (nAchR) α4β. Bupropion works by inhibiting the reuptake of selected neurotransmitters including dopamine, serotonin, and norepinephrine, and reduces the severity of withdrawal symptoms. Nicotine replacement is nicotine in noncigarette formulations and can come in several forms including gum and patches.
Data for Use
Bupropion has been studied both alone and in combination with a nicotine patch, with both strategies showing benefits relative to placebo. At 12 months, relative to placebo, bupropion increased the likelihood of quitting smoking by ~ 60% but with 20% remaining abstinent at 1 year. Varenicline has been shown to increase the likelihood of abstinence at 1 year relative to placebo by threefold in patients with cardiovascular disease. Overall it appears to be more efficacious than bupropion alone or in combination with nicotine replacement. Nicotine replacement appears to be efficacious with 50%–70% improvements in rates of quitting relative to placebo regardless of form (gum, transdermal patch, nasal spray, inhaler, oral).
Side Effects
Varenicline has a number of associated side effects including sleep disturbance, nausea, skin reactions, and flatulence. Both varenicline and bupropion are associated with neuropsychiatric side effects, and labels for both agents include black box warnings for observing changes in mood, behavior, and/or the development of suicidal ideations. Bupropion should not be used in patients with seizure disorders, some eating disorders, or in those at high risk of seizure (e.g., those stopping benzodiazepine or antiseizure medications.) Nicotine side effects in part depend on the mode of use, but common side effects described include local irritation, dizziness, headache, nausea, palpitations, and sleep disturbance.
Drug interactions
Bupropion should not be used within 14 days of stopping a MAO inhibitor, and there are interactions with a number of other drugs for depression or bipolar disorder. Varenicline may interact with ranolazine. Nicotine is a stimulant and therefore may interact with other stimulants, such as caffeine.
Antihypertensive Therapies
Antihypertensive therapies are covered in Chapter 2 in detail. The diagnosis and treatment of hypertension for patients with PAD mirrors general guidelines for hypertension including thresholds and selection of therapy. Current guidelines recommend treating patients with established cardiovascular disease, including patients with PAD, to a blood pressure target below 130/80 mmHg. The ESC guidelines note that in patients with PAD, an SBP below 110–120 mg may be associated with risk due to the J-shape relationship between SBP and CV events observed in PAD patients in the International Verapamil-SR/Trandolapril (INVEST). Although there is theoretic concern in reducing blood pressure to low targets in patients with marginal limb perfusion, other trials have demonstrated benefit with achieving such targets and with an acceptable safety profile. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial that randomized 950 patients with diabetes to enalapril or nislodipine observed a reduction in MACE in patients with PAD receiving intensive treatment (mean BP 128/75 mmHg), with greater benefits in those with more severe occlusive disease as represented by lower ankle brachial index (ABI). Similar findings were shown in the International Verapamil-SR/Trandolapril study, which observed a reduction in MACE with a target of < 130/80 mmHg in the subgroup with PAD.
With regard to specific agents, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are preferred in PAD (class II in guidelines) due to consistent benefits observed in large PAD subgroups in trials demonstrating benefits of these therapies. The benefits of these therapies for reducing MACE have been demonstrated robustly. In contrast, small studies describing improvements in function and limb outcomes have not been substantiated. The Heart Outcomes Prevention Evaluation Trial (HOPE) randomized patients to ramipril 10 mg daily or placebo and followed for 5 years observing significant reductions in MACE with the intervention arm. A large subgroup of ~ 4000 patients had PAD, and benefits were consistent in this subgroup. The EUROPA trial similarly observed benefits of perindopril versus placebo with consistent benefits in the subgroup with PAD. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) randomized patients to telmisartan, ramipril, or both and observed similar outcomes with either agent, including in a subgroup of 3000 patients with PAD.
Theoretic concerns regarding the risk of worsening limb outcomes in PAD with β-blockade therapy have been raised. Although not a first choice in PAD, these therapies may be indicated in patients with concomitant CAD or arrythmia such as atrial fibrillation. The concern for harm is based on the theoretical decrease in cardiac output and/or unopposed α-agonism with nonspecific agents that could lead to worsening limb malperfusion. In spite of these concerns, no harm in randomized studies or meta-analyses have been reported, and current guidelines do not recommend against their use.
A detailed description of mechanism of action, side effects, and drug interactions are included in Chapter 2 . Experimental therapies with blood pressure–lowering effects in PAD have been studied with the question of whether vasodilator therapy may improve limb symptoms and limb outcomes. There are no current data to support the use of vasodilator therapy for limb outcomes in PAD and ongoing trials are discussed under the section titled “Vasodilators.”
Antithrombotic Therapies
Antithrombotic drugs are covered in detail in Chapter 8 . The data supporting specific antithrombotic strategies in PAD will be discussed in this section. Current guidelines only assign single antiplatelet therapy (SAPT) a class I indication in symptomatic PAD. It is not recommended in asymptomatic PAD if identified through screening ABI. Since publication of the current guidelines there have been new data supporting the benefits of more intensive strategies in selected patients but with associated increased bleeding. These data will be incorporated into subsequent iterations of the guidelines.
Antiplatelet Monotherapy
Aspirin is an antiplatelet drug that works through irreversible inhibition of cyclooxygenase (COX)-1 through acetylation of the hydroxyl of a serine residue. The most robust dataset evaluating the efficacy and safety of aspirin in PAD is the Antithrombotic Trialists Collaborative (ATT) meta-analyses including patients with primary and secondary prevention including a subgroup of the later of ~ 9000 with PAD. Overall aspirin was associated with consistent benefits in secondary prevention with a 23% reduction in MACE in those with PAD at a cost of a 60% excess in major extracranial bleeding. Patients with PAD included in the ATT were symptomatic, including those with history of intervention. Subsequent studies have investigated broadening the use of aspirin to populations with no evidence vascular disease and marginally low ABI (called asymptomatic PAD). The prevention of Progression of Arterial Disease with Diabetes (POPADAD) trial randomized patients with diabetes and an ABI < 0.99 to aspirin 100 mg or placebo. At 7 years there was no benefit of aspirin in this population for MACE or limb outcomes. The Aspirin for Prevention of Cardiovascular Events in a General Population Screened for a low Ankle-Brachial Index (AAA) enrolled 3350 patients with an ABI ≤ 0.95 and randomized to aspirin or placebo. At ~ 8 years, event rates were low and there was no significant differences in MACE or MALE with aspirin versus placebo, but there was a ~ 70% excess in bleeding.
Inhibitors of the platelet P2Y 12 receptor have been studied in patients with PAD both as monotherapy and as an adjunct to other agents, primarily aspirin. One of the earliest trials to evaluate this class of therapies in PAD was the Swedish Ticlopidine Multicenter Study (STIMS) evaluating MACE with Ticlopidine versus placebo in 687 patients with claudication over approximately 5 years. Overall there was a 51% reduction in the need for lower extremity revascularization and a 30% reduction in all-cause mortality. Clopidogrel, a second-generation P2Y 12 inhibitor, was studied head to head against aspirin in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events trial (CAPRIE), which enrolled more than 19,000 patients with stable atherosclerosis for a primary outcome of MACE. Overall, clopidogrel was superior to aspirin with an 8.7% relative risk reduction; however, there was statistical heterogeneity of benefit based on qualifying disease state, with the 6452 patients with symptomatic PAD (ABI ≤ 0.85 and history of claudication or prior intervention for ischemia) deriving a greater (23.8%) benefit. Clopidogrel was subsequently tested directly against the third-generation agent, ticagrelor, in over 12,000 patients with symptomatic PAD (ABI ≤ 0.85 and history of claudication or prior intervention for ischemia) in the A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCILD) trial. Ticagrelor was not superior, and overall outcomes both for efficacy and safety appeared similar between treatment arms.
More Intensive Antiplatelet Therapy
Several more recent trials have studied more intensive antiplatelet therapy in patients with PAD. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) randomized 15,603 patients with stable atherosclerosis or risk factors to the addition of clopidogrel to aspirin (dual antiplatelet therapy or DAPT) versus aspirin alone and evaluated MACE over long-term therapy. Overall there was no statistically significant benefit of DAPT; however, in a post hoc analysis of those patients with atherosclerosis, similar to those randomized in the CAPRIE trial, there was a 17% lower rate of MACE with DAPT. In the 2383 patients with symptomatic PAD, there was no significant reduction in MACE; however, DAPT was associated with lower rates of hospitalization and MI, raising the hypothesis of potential benefits in this subgroup. The CASPAR trial tested the same comparison in 851 patients with PAD undergoing lower extremity bypass and showed no benefit. An analogous trial after endovascular intervention called CAMPER was launched but was terminated after failing to enroll enough participants. A novel mechanism for platelet inhibition through antagonism of the protease-activated receptor (PAR) for thrombin was tested in the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients with Atherosclerosis (TRA2 o P-TIMI 50). The agent vorapaxar, a PAR-1 antagonist, was tested against placebo on a background or aspirin and/or clopidogrel in patients with symptomatic atherosclerosis for the reduction of MACE. In the 26,449 patients randomized, including patients with symptomatic PAD, vorapaxar reduced MACE by 13% and increased GUSTO moderate or severe bleeding. There appeared to be heterogeneity for harm in terms of bleeding and intracranial hemorrhage, with a greater risk in patients with prior stroke. Consequently, the drug was approved for use in patients with a history of MI or symptomatic PAD. A novel aspect of this trial was the prospective definition, ascertainment, and adjudication of ALI as an endpoint. In patients with PAD (ABI ≤ 0.90 or prior revascularization for ischemia) there was a 15% reduction in MACE, a 30% reduction in MALE, and a 42% reduction in ALI with the greatest absolute benefit for MACE in those with concomitant CAD, and the greatest absolute benefit for MALE in those with prior lower extremity revascularization.
The use of DAPT (aspirin and a P2Y 12 inhibitor) has also been studied in patients with PAD and CAD, also called polyvascular disease. This population has been shown to be at higher risk of MACE than PAD or CAD alone. A subgroup analysis of the PEGASUS-TIMI 54 trial, which randomized more than 21,000 patients with prior MI to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo all on a background of aspirin, demonstrated that DAPT with ticagrelor reduced MACE as well as was associated with lower rates of cardiovascular death and all-cause mortality. In addition, ticagrelor reduced MALE by 35% with greater absolute benefits for both MACE and MALE in those with versus without PAD. Overall ticagrelor increased major bleeding by more than twofold, with the risk similar in those with and without PAD. Similar observations were published from the PRODIGY trial, which randomized patients after coronary intervention to shorter versus longer durations of DAPT with clopidogrel. In patients with concomitant PAD, longer DAPT was associated with reductions in MACE as well as lower rates of all-cause mortality with similar risks of bleeding regardless of PAD status. MALEs were not reported in PRODIGY. The Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus (THEMIS) trial compared DAPT with ticagrelor versus aspirin alone in patients with CAD and type 2 diabetes mellitus (T2DM) but no history of MI. Overall, ticagrelor reduced MACE but increased major bleeding, and the subgroup that appeared to derive the greatest benefit relative to risk was those with prior coronary revascularization. The composite of ALI or major amputation for vascular cause was defined as MALE, and there was a significant 54% reduction with ticagrelor relative to placebo.
Full Dose Anticoagulation
The use of anticoagulation as an adjunct to antiplatelet therapy has also been studied in PAD. The Warfarin Antiplatelet Vascular Evaluation (WAVE) trial randomized 2161 patents with PAD to warfarin, with an international normalized ratio (INR) target of 2–3 or placebo on a background of aspirin. Overall there was no benefit of warfarin for MACE or MALE, but there was a greater than three-fold increase in life-threatening bleeding. The Dutch Bypass Oral Anticoagulants or Aspirin (BOA) Study Group trial randomized 2690 patients with PAD undergoing lower extremity bypass to the same two arms and similarly observed no benefit for MACE or MALE but did observed a 3.48-fold hazard of hemorrhagic stroke and a two-fold increase in major bleeding.
Low-Dose Anticoagulation
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial evaluated regimens of rivaroxaban 2.5 mg twice daily added to aspirin and rivaroxaban 5 mg twice daily alone and compared them each to aspirin monotherapy in high-risk patients (polyvascular, at least two risk factors, or older age) with CAD and/or PAD for MACE. Overall the trial was terminated early for efficacy with a mean follow-up of 23 months. The rivaroxaban 2.5 mg twice daily plus aspirin arm was superior to aspirin alone for MACE, but rivaroxaban 5 mg twice daily alone was not. Overall this strategy significantly reduced MACE as well as the secondary outcomes of MALE and major amputation. Rates of cardiovascular death and all-cause mortality were lower with rivaroxaban 2.5 mg twice daily as well. Bleeding with the regimen was increased, including a 70% increase in ISTH major bleeding. Benefits were consistent in the 4129 with symptomatic lower extremity PAD; however, due to enrichment, approximately 70% had concomitant CAD. Subsequent analysis demonstrated that rivaroxaban 2.5 mg twice daily reduced MALE in patients with PAD (defined as ALI, urgent revascularization or amputation) by 46% with the greatest absolute benefit in patients with prior lower extremity revascularization. The Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities (VOYAGER PAD) trial is evaluating rivaroxaban 2.5 mg twice daily versus placebo on a background of aspirin 100 mg daily as well as clopidogrel at the discretion of the treating physician. Outcome from this trial will clarify the benefit and risk of this strategy in a dedicated PAD population, in the post-interventional period, and with regard to background P2Y 12 inhibition.
Summary: Antiplatelet monotherapy with either aspirin or clopidogrel remains the only antithrombotic therapy currently with a class I recommendation in PAD guidelines. Recent data demonstrate that more intensive regimens including the combination of aspirin and a P2Y 12 inhibitor, aspirin and/or clopidogrel with vorapaxar, and aspirin and rivaroxaban 2.5 mg twice daily reduce MACE in patients largely with PAD and CAD (polyvascular disease) as well as MACE and MALE in patients with prior revascularization. Full-dose anticoagulation with vitamin K antagonists have largely been harmful in this population, and there are no data to support other doses of factor Xa inhibitors. Ongoing trials will better define the optimal anti-thrombotic strategies after peripheral intervention. A personalized approach to antithrombotic therapy is recommended ( Table 10.1 ).
| Patient risk profiles in PAD | ||||
|---|---|---|---|---|
| Antithrombotic regimens studied in PAD | Low Risk for MACE and MALE | High risk for MALE and low risk for MACE | High risk for MACE and low risk for MALE | High risk for MACE and MALE |
| Monotherapy with aspirin or P2Y 12 inhibitor ( n.b. clopidogrel monotherapy FDA approved for PAD ) | Standard | Consider if high bleeding risk | Consider if high bleeding risk | Consider if high bleeding risk |
| Aspirin and P2Y 12 inhibitor ( n.b. DAPT with ticagrelor FDA approved for patients with prior MI or for CAD and diabetes mellitus including those with concomitant PAD ) | Consider in PAD patients with high MACE risk (e.g. prior MI) | Consider in PAD patients with high MACE risk (e.g. prior MI) with benefit for MALE reduction | ||
| Aspirin or clopidogrel + vorapaxar ( n.b. vorapaxar FDA approved in PAD added to aspirin or clopidogrel ) | Consider if at low bleeding risk | Consider if at low bleeding risk | Consider if at low bleeding risk | |
| Aspirin + rivaroxaban 2.5 mg twice daily | Consider if at low bleeding risk if approved in PAD | Consider if at low bleeding risk if approved in PAD | Consider if at low bleeding risk if approved in PAD | |
Lipid-Modifying Therapies
A full overview of lipid-modifying therapy is provided in Chapter 6 . The following section will focus on the evidence and indications in patients with peripheral artery disease. The epidemiologic data supporting the relationship of dyslipidemia to MACE is well established. Although relationships between several lipid parameters and outcomes have been described, the most robust literature for therapeutic intervention involves lowering low-density lipoprotein cholesterol (LDL-C). A number of large trials have established the benefits of LDL-C lowering through a variety of mechanisms in patients with atherosclerosis, with several showing consistency in patients with PAD. More recently, data describing the relationship of LDL-C and both the need for peripheral revascularization and MALE have been published, more clearly elucidating the role of LDL-C lowering in PAD. Finally, icosapent ethyl has been shown to be beneficial in terms of reducing MACE in patients with atherosclerosis and high triglycerides; however, the exact mechanisms are debated and the effect on MALE is not currently known.
Low-Density Lipoprotein Lowering
One of the first trials to robustly assess the effect of LDL-C lowering with statin therapy in patients with atherosclerosis, including PAD, was the Heart Protection Study (HPS), which randomized 20,536 patients to simvastatin or placebo and demonstrated a 24% reduction in MACE over a period of approximately 5 years. The HPS trial included 6748 patients with PAD, and in this subgroup the benefit of simvastatin was consistent (22% reduction). In addition, simvastatin was associated with a 20% reduction in the need for noncoronary revascularization; however, detailed data on the impact on MALE events was not described. Although several nonrandomized studies have observed lower rates of MACE and MALE with statin versus no statin or with high-versus low-intensity statins, there have been few other robustly powered randomized trials reporting outcomes in PAD.
Although some guidelines had previously focused on statin therapy for risk reduction, the Examining Outcomes in Subject With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) versus Simvastatin (IMPROVE-IT) trial demonstrated that further LDL-C lowering with the addition of the nonstatin therapy, ezetimibe, to statin therapy reduced the risk of MACE in patients with acute coronary syndromes (ACS). The subgroup with concomitant PAD and polyvascular disease was subsequently observed to have higher risk, particularly when combined with concomitant diabetes as well as greater absolute benefit with a number needed to treat (NNT) of 11 at 7 years in those with both features. The IMPROVE-IT trial demonstrated that LDL-C lowering, even with nonstatin therapies, reduced risk in patients with atherosclerosis with consistent relative risk reductions in those with PAD.
Another mechanism of lowering LDL-C is through inhibition of the proprotein convertase subtilisin kexin type 9 (PCSK9), which acts as a chaperone carrying the LDL receptor from the surface of the liver to its destruction, thereby reducing the ability of the liver to uptake LDL-C and resulting in higher LDL-C levels. Two antibodies, evolocumab and alirocumab, have demonstrated sustained reductions in LDL-C and resulting reductions in MACE in patients with stable atherosclerosis (evolocumab) and ACS (alirocumab).
Both the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial with evolocumab and the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY Outcomes) trial with alirocumab have reported data on patients with PAD and polyvascular disease. The FOURIER trial included 3642 patients with PAD and observed a consistent 60% reduction in LDL-C (from 92 mg/dL to 30 mg/dL) as well as a consistent relative risk reduction for MACE regardless of PAD status at baseline. Due to their higher risk, however, patients with PAD were observed to have a more robust absolute risk reduction (3.5% at 2.5 years, NNT 29). Similarly, in ODYSSEY OUTCOMES, patients with polyvascular disease were higher risk, and the absolute risk reductions were greater with each increment in symptomatic vascular bed (ARR 3 years 1.4% one vascular bed, 1.9% two vascular beds, 13.0% three vascular beds, ARR interaction 0.0006).
In patents with symptomatic PAD only (no prior MI or stroke), in FOURIER, the evolocumab for MACE were consistent; however, even without polyvascular disease, there was a robust risk reduction at 2.5 years (ARR 4.5%, NNT 21). A novel aspect of this trial was the formal assessment of MALE as defined as the composite of ALI, urgent revascularization, or major vascular amputation. Treatment with evolocumab reduced MALE by 42% overall, and when combined as a composite of MACE or MALE in PAD without prior MI stroke, there was a 6.3% absolute risk reduction at 2.5 years translating into an NNT of 16. The relationship of achieved LDL-C to risk of MALE as linear down to an LDL-C of less than 10 mg/dL ( Fig. 10.4 ).
Other Lipid-Modifying Agents
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial randomized patients with diabetes to fenofibrate or placebo. Although there was no significant reduction in MACE, there were lower rates of secondary endpoints including the need for peripheral revascularization. A subsequent analysis from this study also reported a 36% reduction in amputations. Ongoing studies of fibrate therapies are investigating their benefit in terms of reductions in MACE and limb outcomes.
Several studies have evaluated polyunsaturated fatty acids and outcomes in peripheral artery disease; however, no consistent benefit for function or symptoms was observed. The Japan EPA Lipid Intervention Study (JELIS) was an open-label randomized trial of eicosapentanoic acid (EPA) in 18,645 patients with coronary artery disease. A small subgroup (n = 223) had PAD at baseline and were observed to be at higher risk for MACE and to drive a benefit from EPA (HR 0.44, 95% CI 0.19-0.97, P = 0.041). A highly purified dose of EPA at 4 g daily was studied in the multicenter, randomized, double-blind, placebo-controlled study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin (REDUCE-IT) trial. The REDUCE-IT trial randomized 8179 patients with established cardiovascular disease or diabetes with other risk factors on statin therapy, and with fasting triglycerides of 135–499 mg/dL to EPA (4 g daily) or placebo. Overall there were significant reductions in MACE and cardiovascular death with benefits across the range of baseline triglycerides as well as for first and total events. Novel therapies using small interfering RNA (siRNA) to lower LDL-C as well as therapies targeting other lipoproteins (e.g., lipoprotein[a] or Lp[a]) are under investigation. Genetic studies have suggested that the latter may be associated specifically with both incident PAD and PAD outcomes.
Summary: Dyslipidemia, particularly LDL-C and Lp(a), are associated with incident PAD and higher risk of MACE and MALE in patients with PAD. Therapies to reduce LDL-C have demonstrated robust benefits in reducing both MACE and MALE in patients with PAD regardless of polyvascular disease. The risk and benefit of therapeutic intervention are reflected in current guidelines specifically identifying PAD as a high-risk condition for intensive lipid lowering. In addition, novel therapies such as icosapent ethyl, siRNA, and targeted therapies for Lp(a) hold promise for further risk reductions in PAD.
Glucose-Lowering Therapies
Drugs for diabetes are discussed in Chapter 4 in detail. The current section will focus on the evidence in patients with PAD including for limb outcomes.
Diabetes is a potent risk factor for the development of PAD. In addition, concomitant diabetes is associated with worse outcomes in PAD both for MACE and MALE. Diabetes and PAD are synergistic in their risk for outcomes such as amputation, as both macro- and microvascular disease independently contribute to risk.
Glycemic Targets in PAD
Data supporting the benefits of intensive glucose lowering for reducing macrovascular events in PAD are derived largely from broader trials of treatment in diabetes and cardiovascular disease and have been largely mixed. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial investigated more versus less intensive glucose lowering to achieve a lower glycated hemoglobin in patients with cardiovascular disease (~ 1/3 with PAD) or risk factors, and the more intensive strategy demonstrated higher cardiovascular risk. Similarly, the United Kingdom Prospective Diabetes Study (UKPDS) study randomized patients with T2DM to dietary restriction or intensive medical therapy, and while microvascular complications were reduced, there was no benefit for macrovascular outcomes. At 10-year follow-up, however, there appeared to be lower associated risks of MACE, suggesting that the benefits may only emerge after longer-term treatment. Guidelines regarding glucose lowering in patients with vascular disease, and specifically PAD, generally follow recommendations for other patients with established cardiovascular disease. Clinicians should, however, pay even greater attention to foot hygiene, as patients with PAD and T2DM are at higher risk of not only amputation but also limb infections compared to patients with T2DM and no PAD.
Target Specific Glucose-Lowering Therapies
There are currently two classes of drugs that were designed to lower blood glucose and have specific impact for patients with vascular disease. The first is the class of inhibitors for sodium glucose cotransporter 2 (SGLT-2). The second are agonists of the glucagon-like peptide-1 (GLP-1).
SGLT-2 Inhibitors
There are three SGLT-2 inhibitors commercially available for which there are data to support use in patients with established atherosclerotic vascular disease. The first with outcomes data, empagliflozin, was found in the EMPA-REG trial to reduce ischemic events (myocardial infarction, stroke, and cardiovascular death or MACE) by about 14%. In addition to benefits for MACE, there were robust reductions in hospitalization for heart failure and all-cause mortality. The population in EMPA-REG was characterized by known atherosclerotic vascular disease including peripheral artery disease. In the subgroup of ~ 1400 patients with PAD, the benefits of empagliflozin were consistent, including significant reductions in cardiovascular and all-cause mortality. Limb outcomes were not prospectively adjudicated, but subsequent exploratory analyses showed no benefit or harm for amputation.
The CANVAS program studied the agent canagliflozin in a broader population including those with atherosclerotic vascular disease and those with risk factors. Canagliflozin reduced MACE and the effects appeared most robust in those with cardiovascular disease versus those with risk factors only. An unexpected finding was a roughly twofold increase in amputations with canagliflozin with similar relative risks for major and minor amputation and for this with and without PAD; however, the greatest absolute risks were seen in patients with PAD and particularly those with prior amputation. The excess in amputation risk was not seen in the subsequent CREDENCE trial that evaluated canagliflozin in patients with diabetes and chronic kidney disease; however, patients at high risk for amputation were excluded, and if a condition that put a patient at risk developed during the study, the drug was to be interrupted. In addition, the protocol called for excellent foot hygiene. Whether the amputation risk with canagliflozin is a true finding or not, CREDENCE suggests that good foot hygiene and careful management in the small subset of patients at high risk for amputation would attenuate any such risk.
The third agent is dapagliflozin, which was studied in the DECLARE-TIMI 58 trial. Of the three outcomes trials this included the most patients with risk factors only and had coprimary endpoints of MACE and hospitalization for heart failure. The benefits for heart failure were statistically significant and consistent in those with and without atherosclerotic vascular disease, effectively expanding the benefits to a broader population. Limb outcomes and specifically amputations were prospectively collected and reviewed by a blinded vascular specialist, and overall no imbalance in amputations was seen with dapagliflozin.
GLP1 Agonists
The glucagon-like peptide-1 (GLP1) agonists are a second class of agents that have demonstrated cardiovascular benefits. As opposed to the SGLT-2i, which appear to have the greatest benefit in terms of reductions in heart failure and mortality, the GLP1 agonists appear to have their greatest benefits for reducing ischemic risk. Although early agents have been delivered parentally by injection, oral drugs are also available. The risks and benefits of this class are described in detail in Chapter 4 . Of particular interest in the care of patients with PAD are observations that this class of therapy may reduce the risk of amputations. Although confirmatory data are needed, lower rates of amputation have been observed in studies of at least one GLP1 agonist, and there have been no data to suggest any harm in terms of limb events.
Summary: Diabetes is a frequently comorbid condition with peripheral artery disease, and therefore diabetes management may be of particular interest for the vascular clinician. Glycemic control reduces the risk of microvascular complications such as neuropathy, which may predispose to lower extremity wounds and ultimately amputation. Both the SGLT-2 inhibitors and GLP1 agonists have shown consistent benefits in subgroups with PAD and should be considered in patients with PAD and diabetes. Deciding which to prioritize may be driven by comorbidities, with preference for SGLT-2i in patients with concomitant heart failure or at high risk of heart failure while GLP1 agonists may be preferred in patients at high ischemic risk and in those at high risk of amputation. Good foot hygiene is critical in patients with PAD and diabetes to reduce the risk of lower extremity infections and amputation.
Therapies for Symptoms
There are two approved pharmacotherapies for symptoms of claudication in patients with PAD. Both cilostazol and pentoxifylline are approved and available, although use overall is modest.
Cilostazol is an inhibitor of phosphodiesterase-3 (PD-3) and has been described as having effects on platelet aggregation, smooth muscle cell proliferation, and vasoactivity. The exact mechanism by which cilostazol improves function is not known, although all of these effects may alone or in part have benefits in PAD. Several trials have evaluated the efficacy of cilostazol. A meta-analysis including 1258 patients with claudication found that cilostazol significantly increased maximal walking distance relative to placebo (50.7% versus 24.3%) with an absolute increase in walking distance of approximately 42 meters. A subsequent meta-analysis of 3718 patients with claudication showed consistent benefits for claudicants. Benefits appear sustained even after endovascular intervention. Collectively these data demonstrate that cilostazol is superior to placebo at improving walking distance and delaying onset of pain in PAD.
There are, however, tolerability issues observed including gastrointestinal side effects, headache, and dizziness, which may limit or shorten use. Although cilostazol is used more than pentoxifylline for this indication, most PAD cohorts describe use at 10% or less of patients. In addition, due to safety issues with other phosphodiesterase inhibitors, cilostazol is contraindicated in patients with heart failure. This is not due to any harm observed with cilostazol, but rather due to a warning across the class of agents. Because patients with PAD have class I indications for antiplatelet therapy, and in the post-intervention setting DAPT is often used, the question of bleeding risk with cilostazol may be of concern to the physician treating the vascular patient. Cilostazol does have antiplatelet and antithrombotic effects, but large outcomes trials powered for ischemic and bleeding events have not been conducted. Therefore, the interaction between therapies is not well characterized. Large trials, however, of novel antithrombotics have not prohibited cilostazol and have not reported any heterogeneity in safety in those taking or not taking cilostazol. Therefore, a personalized approach should be taken, although cilostazol is generally not prohibited in patients on more potent antithrombotic regimens.
Cilostazol is prescribed at 100 mg twice daily. Patients may be started on 50 mg twice daily for 2–4 weeks to assess tolerability, with the dose titrated to 100 mg twice daily. In addition, patients taking drugs that are CYP3A4 or CYP2C19 inhibitors may reduce the dose to 50 mg twice daily. There is no dose adjustment recommended for patients with hepatic or renal impairment.
Pentoxifylline is a xanthine derivative that is a competitive nonselective phosphodiesterase inhibitor. It has several downstream effects including inhibition of adenosine 2 receptors, increases in cyclic AMP, inhibition of tumor necrosis factor, and leukotriene synthesis reducing inflammation. It has also been described that exposure to pentoxifylline improves blood cell deformability and reduces viscosity as well as having a modest antiplatelet effect. For the vascular patient, pentoxifylline may be used on label for claudication symptoms and is sometimes used off label for the healing of chronic venous leg ulcers.
The data supporting the efficacy of pentoxifylline in PAD is modest. Meta-analyses have found that the individual studies are of low quality and with large variability and have concluded that the role in claudication remains uncertain. A three-arm trial of cilostazol, pentoxifylline, and placebo was conducted and demonstrated that cilostazol improved function but pentoxifylline was similar to placebo. Overall studies of pentoxifylline have shown that it is well tolerated. Contraindications include hypersensitivity to xanthine derivatives or recent retinal or cerebral hemorrhage, and there are cautions for patients at high risk of bleeding. Dosing is generally 400 mg every 8 hours, but the dose can be decreased to twice daily if gastrointestinal or other side effects occur. Dose modification to twice daily is also recommended for patients with a creatinine clearance less than 30 mL/min.
Summary : Claudication, and related functional limitation, is a major morbidity in PAD. Cilostazol and pentoxifylline are available and should be offered to appropriate patients with limiting claudication. Of the two, data supporting the efficacy of cilostazol are stronger and it is preferred as a first choice by practice guidelines.
Experimental Therapies for Peripheral Artery Disease
Vasodilator Drugs
Although the notion that dilation of the conduit arteries of the legs would lead to improved perfusion and improved symptoms in PAD is attractive, there are little data to support efficacy in this population. The lack of efficacy stands in contrast to that seen for angina in patients with coronary disease. There have been several studies evaluating the efficacy and safety of prostaglandin therapy in patients with claudication or CLI. Therapies evaluated include prostaglandin E1 (PGE1), prostacycline (PGI2), betaprost, and iloprost. These agents have been investigated as delivered both intraarterially and intramuscular. Although there are ongoing trials, completed studies have not observed benefits for CLI or function with these agents. A review of 33 trials and over 4000 patients randomized to therapy or placebo showed no benefit for amputation and higher risk of adverse events. Trends suggesting small effects on rest pain and ulcer healing require validation in future studies.
Metabolic Drugs
Functional abnormalities in PAD are due to limitations in perfusion but also to maladaptation and metabolic dysfunction in affected muscle beds. Therefore, investigations into therapies that may improve metabolic efficiency and function have been conducted. Two such agents are L-carnitine and its derivative propionyl-L-carnitine. It has been hypothesized that by providing increased levels of carnitine, these agents will improve the Krebs cycle enhancing glucose and oxidative metabolism. Studies in claudicants, however, have shown no convincing benefit, and these agents remain largely investigational. The piperazine derivative ranolazine induces metabolic effects that improve the efficiency of oxygen use. Ranolazine is effective and available for reducing angina in patients with coronary artery disease. A single-center pilot study observed benefits in function versus placebo as measured by pain-free walking time. These findings require validation, and ranolazine is not currently approved for use in treating symptoms of claudication.
Angiogenic Growth Factors
Agents stimulating or promoting angiogenesis have been studied with the hypothesis that they may improve development of collateral vessels thereby improving overall perfusion. This improvement in perfusion may be beneficial for symptoms as well as treatment of CLI. This class includes vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and hypoxia-inducible factor 1 α (HIF-1α). Trials of these agents have not shown convincing benefit, although there have been promising signals for validation in smaller nonrandomized studies that require validation. A systematic review and meta-analysis found overall no benefit for gene therapy for angiogenesis for amputation, wound healing, or function PAD patients with claudication or CLI. Currently these therapies are not recommended in patients with PAD.
Drugs for Venous Thromboembolism
Anticoagulant drugs are covered in detail in Chapter 8 . The following chapter gives a focused review of their use in venous thromboembolism.
The mainstay of therapy for venous thromboembolism is anticoagulation. This can be delivered parenterally or orally. The strategy for initial treatment, switching, and long-term treatment is determined by the patient, comorbidities, and their risk in the acute and chronic settings.
Parenteral Anticoagulants
Heparins are commonly used anticoagulants and can be delivered as unfractionated heparin (UFH), a sulfated glycosaminoglycan obtained from pig mucosa, or low-molecular-weight heparin (LWMH). The latter is more specifically directed at factor Xa and has greater bioavailability, a more predictable dose response, and longer half-life, all of which make it suitable for subcutaneous administration even at therapeutic doses, while UFH requires intravenous administration and frequent monitoring. Patients with impaired renal function require dose adjustment with LMWH, and dosing may be complex in patients with morbid obesity. The utility of titrating LMWH dosing to anti-Xa levels remains uncertain. A further derivative is the pentasaccharide fondaparinux. This injectable is an effective anticoagulant and has been administered in patients at risk for heparin-induced thrombocytopenia (HIT), although such use is off label. Two parenteral direct thrombin inhibitors can be used, bivalirudin and argatroban, but, their use in this setting is generally reserved for patient with or at risk for HIT.
Oral Anticoagulants
As noted, these agents are covered in detail in Chapter 8. Available therapies include vitamin K antagonists (VKA) and the direct oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban ( Box 10.1 ). Of particular relevance in the patient with acute VTE is the timing of initiation and dosing regimen. Dabigatran, a direct thrombin inhibitor, has been studied in the acute setting after a 5-day course of a parenteral agent and has not been studied as initial therapy. Dosing for this indication after appropriate parenteral therapy is 150 mg twice daily, and it should not be used in patients with a creatinine clearance less than 30 mL per minute.
