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Vascular Medicine Drugs
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.
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