Medical treatment in patients with lower extremity artery disease (LEAD)

Control of modifiable risk factors

Smoking cessation

Rationale

Up to 80% of patients with LEAD are current or former smokers. Smoking is an established cause of multiple diseases and is responsible for 50% of all avoidable deaths, half of these due to cardiovascular disease (CVD). The risks associated with smoking show a dose–response relationship with no lower limit for deleterious effects. Duration also plays a role [1].In observational studies, smoking cessation lowers rates of cardiovascular ischaemic events and limb-related events in patients with LEAD and may increase walking distance. Inversely, tobacco persistence after revascularisation leads to a twofold to threefold increase of failure rates [1].Stopping smoking is the most cost-effective strategy for CVD prevention and its benefits greatly exceed any risks associated with pharmacologic treatment [2]. Quitting must be encouraged in all smokers at each visit. Passive smoking should also be assessed and prevented [3, 4].

Evidence-based drug interventions

• Nicotine replacement therapy (NRT) (chewing gum, tablets, transdermal patches, nasal spray…) is effective regardless of the setting.
• Bupropion is an antidepressant which aids long-term smoking cessation with a similar efficacy to NRT. Bupropion carries a known risk of seizures (1/1,000 users), but without increased risks of neuropsychiatric problems [5]. Overall, NRT and bupropion help 80% more people to quit than placebo [1].
• Varenicline is a partial nicotine receptor agonist which increases the chances of quitting more than twofold compared with placebo (14 trials, 6,166 people). Varenicline is more effective than nicotine patches and bupropion. Low-dose varenicline (four trials, 1,272 people) roughly doubles the chances of quitting and reduces the number and severity of side effects. Nausea is the main side effect, but this is usually moderate and subsides over time. Considering recent RCT results [5], the US Food and Drug Administration (FDA) recently removed the black-box warning for the psychiatric side effects of this drug.
• Electronic cigarettes (e-cigarettes) may help in smoking cessation but should be covered by the same marketing restrictions as cigarettes. No safety issues have been observed at two years, but more data are required to rule out adverse effects (particularly if dual use with cigarettes) [1, 6].

Which strategy?

Advice, agreement on a smoking cessation strategy (establishing a quit date), encouragement and motivational interventions are mandatory at each visit. In case of failure, or in addition to these strategies (eventually considering the addiction level by the Fagerstrom test [7]), drugs should be offered [1, 4]. Co-ordinated smoking cessation interventions, including non-pharmacological and pharmacological approaches, have the greatest efficacy (rates of smoking cessation increased to 21.3%, compared with 6.8% with standard advice) [8].

Diet

A healthy diet is recommended as a cornerstone of CVD prevention (grade I). Details and modalities are to be found in ESC guidelines [1]: replace saturated fatty acids by polyunsaturated ones, reduce salt intake (<5 g per day), favour fruit, vegetable, wholegrain fibre and fish consumption, limit alcoholic beverages and discourage sugar-sweetened soft drinks.

Exercise

Exercise plays a fundamental role in the treatment of peripheral artery disease (PAD). It will be discussed in more detail in a specific article.

Pharmacologic treatment of claudication symptoms 

The aim of these medications is to ameliorate claudication symptoms by increasing the pain-free walking distance (PFWD) and the maximal walking distance (MWD).

Statins

All patients with LEAD should be taking a statin, regardless of cholesterol levels, in order to reduce cardiovascular risk [2]. In addition, an improvement in claudication symptoms at six and 12 months compared with placebo has been shown by simvastatin in 69 patients [9] and atorvastatin in 354 patients [10]. In a Cochrane Collaboration analysis[11], statins vs. placebo were associated with a significant 89.76 m increase of PFWD (95% CI: 30.05-149.47, p=0.003) and 152 m increase of MWD (95% CI: 32.11 to 271.88, p=0.01) . ESC guidelines consider that, on top of general prevention, statins are indicated to improve walking distance (class IA) [3].

Cilostazol

Cilostazol is a vasodilator that inhibits vascular smooth muscle cell proliferation and prevents platelet aggregation. It is an effective therapy to increase walking distance in patients with claudication (American Heart Association [AHA] levelIa). In a Cochrane review (including 15 double-blind randomised controlled trials [RCT] – 3,718 participants), cilostazol was associated with improvement in claudication symptoms but no changes in cardiovascular deaths or quality of life (QoL) when compared with placebo [12]. It is more effective than pentoxifylline or placebo [13]. Side effects include headache, gastrointestinal complaints, dizziness, and palpitations. In one trial, 20% of patients discontinued cilostazol within three months [14]. It is contraindicated in patients with congestive heart failure.

Other agents

Some data report an efficacy of angiotensin-converting enzyme inhibitors (ACEI) over placebo in increasing PFWD [15] However, some other reports have recently been withdrawn because of unreliable data, and a meta-analysis of the remaining studies was inconclusive [16]

Pentoxifylline, naftidrofuryl, buflomedil and carnitine have all been evaluated, but most of the studies relied on low quality methodology. Their prescription has therefore been progressively reduced and, for most of them, reimbursement denied. Pentoxifylline, initially approved by the FDA in 1984, reduces viscosity and improves erythrocyte flexibility; it is generally well tolerated. Unfortunately, in a recent multicentre RCT of pentoxifylline, cilostazol, or placebo for patients with moderate-to-severe claudication, there was no difference between pentoxifylline and placebo in the primary endpoint of MWD [13].

Chelation therapy (e.g., ethylenediaminetetraacetic acid) was evaluated in a Cochrane review of five studies with 260 participants [17] which showed no significant difference in PFWD and MWD compared with placebo.

Pentoxifylline and chelation therapy are thus not recommended by the FDA for PAD patients (AHA levelIII) [4].

Limits 

Finally, the improvements in MWD observed are relatively modest [18]: 104 m for simvastatin, 56 m for atorvastatin, 69 m for cilostazol, 98 m for indobufen and 90 m for naftidrofuryl. European guidelines suggest an at least 30% increase from baseline in MWD to be significant. In patients with a baseline MWD at 200 m, an improvement of 100 m (50%) is considered meaningful to help maintain essential activities of daily living. Moreover, because treadmill testing results are associated with wide intra- and inter-individual variation, resulting from a great heterogenicity in the different protocols, walking distances are probably not fully comparable. Another concern is that, in terms of QoL, patients focus largely on pain and limitations in daily activities: an increase in walking distance, even if statistically significant, may not be subjectively appreciated. Finally, the clinician must be aware that patients with LEAD are often taking many medications aimed at reducing cardiovascular morbidity and mortality, and to treat comorbidities such as diabetes or hypertension; prescribing a huge number of medications may expose them to side effects and reduce adherence. For all these reasons, drugs to increase WD (except statins) are rarely prescribed and of limited value. Cilostazol may be proposed in case of insufficient results with medical management including an exercise programme, as an intermediate step before revascularisation [2].

Antithrombotic treatment in pad patients

LEAD patients present platelet hyperaggregability, increased platelet activation, enhanced thrombin generation, and a decreased fibrinolytic potential [19], emphasising the central role of antiplatelet and anticoagulant drugs. Therefore, the value of antithrombotic treatment has been largely evaluated, with data generally derived from subgroup analysis of PAD patients among large therapeutic trials on atherosclerotic disease.

Asymptomatic pad

Two major randomised trials have evaluated aspirin effects in asymptomatic LEAD.

 In the Aspirin for Asymptomatic Atherosclerosis (AAA) trial [20], 3,350 subjects with ankle-brachial index (ABI) <0.95 were randomised to 100 mg aspirin compared to placebo with a mean follow-up of eight years. The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) [21] trial compared aspirin to placebo in diabetic asymptomatic LEAD patients (ABI <0.99). A total of 1,276 patient were enrolled, with a median follow-up of 6.7 years. Neither of these trials found any benefit of aspirin regarding the rates of coronary events, strokes and peripheral revascularisations, or any difference in all-cause mortality. An increased risk of bleeding was observed in the AAA trial.

To date, antiplatelet therapy is not recommended in patients with isolated asymptomatic LEAD [3].

Symptomatic pad

Single antiplatelet therapy (SAPT)

Aspirin has been widely tested in LEAD patients. The Antithrombotic Trialists’ Collaboration [22], a meta-analysis of 287 studies of 135,000 patients with cardiovascular disease, included 9,214 patients with asymptomatic and symptomatic PAD and/or previous peripheral revascularisation. In the LEAD subgroup, there was a 23% odds reduction for serious vascular events. However, only 40% of the patients included were treated with aspirin. A more recent meta-analysis [23] focused on the role of aspirin. Of the 5,269 participants included, 1,516 patients received aspirin monotherapy. A non-significant difference was observed in MACE (8.2% vs. 9.6%, RR 0.75, 95% CI: 0.48-1.18), but a significant reduction in non-fatal stroke incidence was reported in the aspirin group (RR 0.64, 95% CI: 0.42-0.99).

• Other antiplatelet drugs have been evaluated as SAPT. Clopidogrel (75 mg) was compared to aspirin (50 to 325 mg) in 6,452 patients with symptomatic LEAD in a subgroup of CAPRIE [24] with a mean follow-up of 1.9 years. The rate of cardiovascular death, non-fatal MI, and non-fatal stroke was lower for clopidogrel (RR reduction of 23.8%, p=0.0028), associated with a lower risk for intracranial and gastrointestinal bleeding.
• The Ticagrelor versus Clopidogrel (EUCLID) trial [25] randomised 13,885 patients with symptomatic LEAD to receive ticagrelor (90 mg b.i.d.) or clopidogrel (75 mg o.d.). Patients with clopidogrel resistance were excluded. At 30 months, the rates of MACE and acute limb ischaemia (ALI) were similar in both groups; a lower incidence of ischaemic stroke in ticagrelor patients was the only noted difference (p=0.03). Ticagrelor was discontinued more often than clopidogrel because of dyspnoea and minor bleedings.

In symptomatic LEAD, SAPT, with either aspirin or clopidogrel, is recommended. Clopidogrel may be preferred over aspirin. Ticagrelor is not superior to clopidogrel [3].

Dual antiplatelet therapy (DAPT)

• DAPT with clopidogrel and aspirin in LEAD patients has been evaluated in a secondary analysis of 3,096 patients [26] included in the CHARISMA trial. The trial showed no benefit of DAPT in reducing the primary efficacy. DAPT was associated with increased bleeding (minor and major).
• DAPT with ticagrelor-aspirin has been compared to aspirin in the PAD subgroup from PEGASUS-TIMI 54 [27] which showed a strong absolute risk reduction in MACE and major acute limb events (MALE) by this combination. The clearest benefit occurred with the 60 mg dose of ticagrelor, with an absolute excess of major bleeding of 0.12%. Considering these results, DAPT with ticagrelor-aspirin may be proposed in LEAD subgroups with high ischaemic risk, such as those with a history of MI and no high bleeding risk [3].

Rivaroxaban on top of aspirin

The COMPASS trial [28] randomly assigned 27,395 participants with stable atherosclerotic vascular disease to rivaroxaban (2.5 mg b.i.d.) plus aspirin (100 mg, rivaroxaban alone (5 mg b.i.d.) or aspirin alone (100 mg daily); 4,966 patients (27%) presented stable PAD. The primary outcome (MACE) was lowered to 24% by the association of rivaroxaban with aspirin compared to aspirin alone (4.1% vs. 5.4%) with a 79% increase in major bleeding (3.1% vs. 1.9%), but without difference in the fatal or intracranial bleeding rates. Interestingly, ischaemic strokes were lowered by 49% and cardiovascular mortality by 22%. A subgroup study of COMPASS, looking at 6,391 patients with LEAD [29], confirmed that low doses of rivaroxaban combined with aspirin reduce MALE by 43%, amputations by 58% and fatal peripheral vascular outcomes by 24%. In spite of the increase in bleedings, this association should be considered in the future as an important therapy to improve prognosis among LEAD patients.

Vorapaxar

Vorapaxar has an antiplatelet effect associated with anti-inflammatory features. In the subgroup analysis of the TRA 2P – TIMI 50 trial, it significantly reduced the risk of peripheral limb ischaemia and peripheral revascularisation in patients with a history of PAD [30]. However, in landmark trials, vorapaxar significantly increased the risks of bleeding. Therefore, it should not be considered in patients with high bleeding risks (75 years of age or older, weight less than 60 kg, or history of stroke or TIA) unless benefit significantly outweighs the risks. Vorapaxar is approved in the USA as an additive therapy for symptomatic LEAD patients with a history of MI and who are at a low risk for bleeding (Level IIb in AHA-ACC guidelines). It is not approved by the European Union in case of PAD.

Endovascular procedures and peripheral arterial surgery [19]

In LEAD patients undergoing percutaneous peripheral interventions, at least four weeks of DAPT with aspirin and clopidogrel is recommended after infrainguinal stent implantation. Stenting below-the-knee arteries is often followed by a longer period of DAPT, but no specific evidence is available.Vitamin K antagonists may be considered after autologous vein infrainguinal bypass [31]; anticoagulants on top of antiplatelets increase the risk of life-threatening bleeding. Except for formal indications (e.g., atrial fibrillation), the use of oral anticoagulants is controversial after vascular surgery.

Conclusions

According to the 2017 ESC Guidelines [3], best medical therapy (BMT) includes (Class I):

• CV risk factor management, proposing pharmacological and non-pharmacological measures in order to obtain smoking cessation, healthy diet, weight loss and regular physical exercise.
• Statins for all LEAD patients, in order to reduce LDL-C to <70 mg/dL or decrease it by >_50% if baseline values are 70-135 mg/dL.
• Antiplatelets (SAPT) for symptomatic LEAD patients.
• Blood pressure must be controlled at <140/90 mmHg (ACEIs or ARBs as first-line drugs) and, in diabetic patients, strict glycaemic control is recommended.

Such an assessment, associated with exercise and, if needed, revascularisation, should give the patient an optimal control of symptoms and quality of life, and prevent cardiovascular events.

Unfortunately, little is known on the patterns of such recommendations in the “real world”. Data from a recent survey [32] over an eight-year period of 1,982 outpatient visits among patients with PAD showed that no antiplatelet therapy was offered in 35.7% and no statin in 33.1%. Among current smokers with PAD, smoking cessation counselling or medication was used in 35.8% of visits and exercise or diet counselling in only 22% of them.

This underuse of guideline-recommended therapies in patients with PAD highlights the necessity to improve the quality of care in these high-risk patients concerning lifestyle recommendations and secondary prevention. Better awareness and education represent the next priority goals for the whole vascular community.