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Title: Medical Management of Peripheral Artery Disease 11
Peripheral Artery Disease
Medical Management of Peripheral Artery Disease
Endorsed by: Prof. Dr. Varinder Singh Bedi, Senior Consultant, New Delhi
Background
Peripheral artery disease (PAD) is the narrowing of peripheral arteries due to chronic atherosclerosis and
may lead to severe limb-associated complications, amputation, or functional impairment. 1 In the Heart Protection Study Collaborative c) PCSK9 (proprotein convertase subtil-
Patients with PAD show an increased rate of ischemic stroke, myocardial infarction (MI), and mortality
with significant economic burden on patients and poor quality of life. 2-5
Despite the severity of this condition, patients with PAD are predominantly undertreated than their CAD
counterparts with comparatively few trials directly assessing the efficacy of pharmacotherapy. 6 effective in preventing limb loss than moderate
In a recent review, Bevan and Solaru have discussed various clinical evidences advocating the utility of
systematic medical management for patients with PAD. The recommended pharmacotherapy primarily
7
aims at cholesterol reduction, platelet inhibition, anticoagulation, peripheral vasodilatation, blood
pressure control, smoking cessation, and exercise therapy (Table 1). 7 PAD. 13,14
Table 1: Optimal medical management of peripheral artery disease 7
Antihypertensive
Anticoagulation
Cholesterol
Cholesterol Antiplatelet Anticoagulation Antihypertensive Peripheral Lifestyle
Peripheral
Antiplatelet
Lifestyle
lowering drugs vasodilators
lowering drugs drugs drugs vasodilators management
management
drugs
drugs
Statin Aspririn Warfarin Angiotensin-converting Cilostazol Supervised physical
enzyme inhibitors exercise
Ezetimibe Clopidogrel Rivaroxaban Angiotensin receptor Smoking cessation
blockers
PCSK9 inhibitors Ticagrelor
class II recommendation for ACE inhibitors or reduction in major adverse limb events along
ARBs or ARB for management of PAD. 22 with cardiovascular events. Thus, the novel
strategy of rivaroxaban and aspirin holds
5) Lifestyle modification promise to prevent thrombotic complications
and improve the quality of life of PAD patients.
a) Smoking cessation
Patients with PAD report smoking-related References
complications and increased mortality. Patients
1) Jones WS, Patel MR, Dai D, Vemulapalli S, Subherwal S,
with PAD who underwent angiography, Stafford J, Peterson ED. High mortality risks after major
lower extremity amputation in Medicare patients with
continuous smoking led to increased mortality peripheral artery disease. Am Heart J 2013;165:809–815,
(31% versus 14%; P<0.05) and higher amputation 815.e1. doi: 10.1016/j.ahj.2012.12.002
rate (40% versus 19%; P<0.05). Though clear 2) Ohman EM, Bhatt DL, Steg PG, Goto S, Hirsch AT, Liau
25
CS, Mas JL, Richard AJ, R ther J, Wilson PW; REACH
evidence is lacking for any direct association Registry Investigators. The Reduction of
between pharmacotherapy to manage smoking Atherothrombosis for Continued Health (REACH) registry:
an international, prospective, observational investigation
and PAD-related mortality, these interventions in subjects at risk for atherothrombotic events-study
design. Am Heart J 2006;151:786.e1–786.10. doi:
are included under class IA recommendations 10.1016/j.ahj.2005.11.004
for PAD patients for their overall health benefits. 22 3) Fowkes FGR, Murray GD, Butcher I, Heald CL, Lee RJ,
Chambless LE, Folsom AR, Hirsch AT, Dramaix M,
b) Physical exercise deBacker G, et al; Ankle Brachial Index Collaboration.
Ankle brachial index combined with framingham risk
Supervised exercise therapy programs aim to score to predict cardiovascular events and mortality: a
meta analysis. JAMA 2008;300:197–208. doi:
improve claudication symptoms related to PAD 10.1001/jama.300.2.197
and are highly effective. However, such 4) Murabito JM, Evans JC, Larson MG, Nieto K, Levy D,
26
interventions lack direct evidence on PAD related Wilson PW; Framingham Study. The ankle-brachial index
in the elderly and risk of stroke, coronary disease, and
mortality and amputation rates. death: the Framingham Study. Arch Intern Med
2003;163:1939–1942. doi: 10.1001/archinte.163.16.1939
Conclusion 5) Marrett E, DiBonaventura Md, Zhang Q. Burden of
peripheral arterial disease in Europe and the United
Recent advancements in therapeutic strategies States: a patient survey. Health Qual Life Outcomes
and improved application of available 2013;11:175. doi: 10.1186/1477-7525-11-175
pharmacotherapies for PAD management have 6) Berger JS, Ladapo JA. Underuse of prevention and
lifestyle counseling in patients with peripheral artery
demonstrated promising results and satisfactory disease. J Am Coll Cardiol 2017;69:2293–2300. doi:
clinical outcome. Antithrombotic therapy is the 10.1016/j.jacc.2017.02.064
mainstay of treatment of PAD. Dual antiplatelet 7) Bevan GH, Solaru KTW. Evidence-based medical
management of peripheral artery disease Arterioscler
therapy (clopidogrel and aspirin) showed Thromb Vasc Biol 2020;40:541–553. DOI:
reduction in MI, stroke, and other major adverse 10.1161/ATVBAHA.119.312142
cardiac events, while in patients with PAD, limb 8) Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK,
Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino
outcomes were not studied or reported. The J, Forman DE, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/
addition of oral anticoagulant rivaroxaban at ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on
the management of blood cholesterol: a report of the
vascular dose (2.5 mg bid) to aspirin resulted in American College of Cardiology/American Heart
Association task force on clinical practice guidelines. J
1) Cholesterol reduction patients including those with PAD to minimize 25% reduction in vascular death, nonfatal MI, or receiving combination aspirin and warfarin
12
19
According to ACC/AHA guidelines, high-intensity cardiovascular events. Thus, ezetimibe may cerebrovascular accident in subgroups of therapy alone. However, major bleeding events
statin is recommended for patients with prove to be an effective therapy when patients with atherosclerotic vascular disease and intracranial hemorrhage were significantly
symptomatic PAD (Target LDL-C of <70) with a co-administered with statin therapy. More (manifested as recent ischaemic stroke, increased. Further analysis reported poor
class I recommendation. 8 specific studies are required for patients with myocardial infarction, or symptomatic peripheral compliance and a 30% rate of discontinuation of
PAD. arterial disease). 6 warfarin at follow-up. Thus, poor adherence to
19
a) Statin therapy could be a possible reason for lack of
c) Dual anti-platelet therapy (DAPT) efficacy in study patients. 19
Group in PAD patients, treatment with isin/kexin type 9) inhibitors In the CHARISMA trial (Clopidogrel for High
moderate-intensity statin therapy, simvastatin In the FOURIER trial (Further Cardiovascular Atherothrombotic Risk and Ischemic b) Rivaroxaban
reduced peripheral vascular events by 17%. A Outcomes Research With PCSK9 Inhibition in Stabilization, Management, and Avoidance) The COMPASS trial (Cardiovascular Outcomes
9
recent observational study also demonstrated Subjects With Elevated Risk) patients with PAD DAPT was compared to single antiplatelet for People Using Anticoagulation Strategies)
that high-intensity statin therapy is more showed a 59% reduction in LDL-C with therapy and included patients with PAD. A demonstrated mortality reduction benifit with
17
evolocumab, resulting in a 3.5% absolute risk post-hoc sub-group analysis in PAD patients low-dose rivaroxaban in combination with aspirin
intensity therapy. Besides peripheral vascular reduction in cardiovascular events (MI, death, revealed that DAPT therapy led to non-significant for patients with PAD. 20, 21 Major adverse limb
10
complications, statin therapy also prevented stroke, hospitalization for unstable angina, and reduction in the primary endpoint (rate of CV events occurred less often in rivaroxaban and
systemic complications and reduced the rate of coronary revascularization) compared with a death, MI, or stroke) - 7.6% in the clopidogrel plus aspirin combination group than aspirin alone. 20, 21
all cardiovascular events : 1.6% absolute risk reduction in patients without aspirin group and 8.9% in the placebo plus There was no significant increase in fatal
9
Major adverse limb events were also aspirin group (hazard ratio, 0.85; 95% CI, bleeding or symptomatic intracranial bleeding
coronary revascularization (30% reduction)
reduced (acute limb ischemia, major amputation, 0.66–1.08; P = 0.18) between the two treatment groups (P=0.40). 20, 21
major coronary events (21% reduction)
or urgent peripheral revascularization for The Heart Protection Study found a 22% relative
ischemic stroke (26% reduction).
ischemia). 13 3) Anticoagulation risk reduction in the first major vascular event
CLI is the consequence of with moderate-intensity statin therapy while the
b) Ezetimibe 2) Antiplatelet therapy atherothromboembolism in the limbs. Clinical COMPASS trial showed a 28% relative risk
Ezetimibe selectively blocks Niemann-Pick evidence highlights that timely anticoagulation in reduction in the primary outcome with the use of
C1-like 1 protein (NPC1L1), that transports a) Aspirin
high risk patients may prevent limb-related low-dose rivaroxaban and aspirin. HPS and
cholesterol in the intestines and inhibits lipids Aspirin has been shown to be effective for
complications from PAD, as well as other COMPASS were different studies. Mentioned
absorption in the gastrointestinal tract. It is a symptomatic PAD. CLIPS (Critical Leg Ischemia cardiovascular morbidity and mortality. 18 RRR values are for information only, and not for
11
promising treatment option to treat Prevention Study) trial provides a direct evidence direct comparison. 20, 21
hypercholesterolemia as it selectively reduces regarding usefulness of low-dose aspirin (81 mg) a) Warfarin
low-density lipoprotein or LDL (“bad” cholesterol) in 366 patients with symptomatic and The WAVE trial (Warfarin Antiplatelet Vascular 4) Blood Pressure management
and triglycerides, without affecting the asymptomatic PAD and showed a 64% relative Evaluation) investigated the use of warfarin in Several prospective and retrospective studies
concentration of “good” cholesterol or high risk reduction in major vascular events [ischemic combination with aspirin for patients with have shown a reduction in mortality with
density lipoproteins (HDL). 11 stroke, MI, and vascular death (P=0.022)]. 15 symptomatic PAD (81.8% of the total trial Angiotensin-converting enzyme (ACE) inhibitors
population), subclavian disease, and carotid and Angiotensin receptor blockers (ARBs) over
The IMPROVE-IT trial (Improved Reduction of b) Clopidogrel disease. The trial found no significant difference other antihypertensive agents. 22, 23, 24 Based on
Outcomes: Vytorin Efficacy International Trial) The CAPRIE trial (Clopidogrel Versus Aspirin in in the occurrence of major adverse these findings, both European Society of
showed that ezetimibe benefits high-risk Patients at Risk for Ischemic Events) showed a cardiovascular events between patients Cardiology and ACC/AHA guidelines have given a
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