CASE CHALLENGE IN PAD: ROLE OF ANTITHROMBOTIC

PROTECTION

LITERATURE REVIEW

Atherothrombosis and Peripheral Arterial Disease

Patients with atherosclerotic cardiovascular (CV) diseases (ASCVDs), such as coronary artery disease
(CAD), cerebrovascular disease, and peripheral artery disease (PAD), have arteries that have become
narrow and hardened over time. Atherosclerosis occurs when the inside of an artery is damaged and the
body attempts to repair the artery by depositing cholesterol and other materials at the site of injury. 1
Secondary thrombotic events, such as myocardial infarction (MI), transient ischemic attack (TIA),
stroke, or CV death, occur when an atherosclerotic lesion is disrupted and a thrombus forms; known as
atherothrombosis, this is the leading cause of death in the industrialized world. 2; 3

Atherothrombosis poses an economic burden for individual patients and healthcare systems. The
international REduction of Atherothrombosis for Continued Health (REACH) Registry enrolled
outpatients ≥ 45 years old who had established CAD, cerebrovascular disease, PAD, or ≥ 3
atherothrombotic risk factors. Using data from the American participants in this study, researchers
found that annualized medication costs for patients ranged from $2401 to $2481. Mean annual
hospitalization costs per patient ranged from $1344 for patients with no affected arterial beds at
baseline to $8155 for patients with 3 affected beds at baseline. 4 Canadian researchers also used
REACH data to determine healthcare costs in their country. They found that costs increased
significantly with the number of arterial beds affected, and – after adjusting for other clinical factors –
they determined that having PAD at baseline was independently associated with increased
hospitalization costs. 5

It may be helpful for clinicians to think about CAD, cerebrovascular disease, and PAD as a single
disease that affects different areas of the vasculature. Patients with CAD experience angina that may
progress to an MI. Patients with cerebrovascular disease experience a TIA ("unstable angina" in the
brain) that may be followed by a stroke ("MI" in the brain), and patients with PAD experience
intermittent claudication ("unstable angina" of the lower limbs) followed by gangrene ("MI" of the
limbs). 2

REACH registry data have also provided information about the risk for secondary events and associated
risk factors. A 3-year analysis of 39,675 patients with symptomatic atherosclerosis found that 40.4% of
patients with PAD experienced at least 1 of the following: MI, stroke, vascular death, or
rehospitalization for a vascular event not attributed to MI, stroke, or death. Furthermore, even patients
treated with antithrombotic therapies for comorbid conditions experienced secondary thrombotic
events. The study identified the following risk factors as increasing the risk of recurrent ischemic
events: hypertension, hypercholesterolemia, type 2 diabetes, obesity, smoking, and prior history of an
ischemic event. 3

DIAGNOSIS

1
In PAD, atherosclerosis in the arteries leading to the extremities causes decreased blood flow to the
limbs, and this almost always occurs in the lower extremities. 6 Patients with PAD are considered to
have an equivalent CV risk to patients with a previous MI. Globally, PAD affects > 200 million adults,
and smokers have a 4-fold increased risk of developing PAD. Some patients may have no symptoms
because they are not physically active enough. 7 Patients with PAD who are active typically have muscle
pain or cramping in the hips, thighs, or calves while walking or exercising 8, a condition called
claudication; these symptoms are relieved by rest. Other symptoms that may indicate PAD include leg
numbness or weakness, a cold sensation in the lower leg or foot, changes in the color of the legs, slower
hair growth on the legs, slower toenail growth, weak pulses in the legs or feet, and erectile dysfunction
in men. In advanced cases, patients may have leg pain even at rest or while lying down. Lifestyle
measures that can improve the symptoms of PAD include quitting smoking, exercising, and consuming
a healthy diet. 9; 2

Moderate to severe PAD causes diminished or absent peripheral pulses, and when the foot is below the
level of the heart, it may be a dusky red color. In some cases, elevating the foot causes color loss and
pain. Edema is typically not present. Chronic PAD can cause thin, pale skin with thinning hair or hair
loss. The feet and legs may feel cool, or the affected leg may sweat excessively and become cyanotic.
As PAD progresses, patients may develop ulcers on the toes or heel, especially after local trauma. The
ulcers may be surrounded by black tissue (dry gangrene). It is common for these ulcers to become
infected (wet gangrene) and cause progressive cellulitis. 6

Patients with suspected PAD should have a thorough history taken, and routine laboratory testing can be
used to check cholesterol and triglycerides as well as serum glucose levels. Clinicians should investigate
the patient's lifestyle, diet, and physical activity, in addition to performing a thorough physical exam.
European Society of Cardiology (ESC) and European Society for Vascular Surgery (ESVS) guidelines
note that a physical exam also provides prognostic information. For example, patients with carotid
bruits are at twice the risk for MI and CV death, interarm blood pressure asymmetry (≥ 15 mm Hg) is a
marker for vascular disease, and a femoral bruit is an independent marker for ischemic cardiac events.
10

The ankle-brachial index (ABI) is a noninvasive test that can be used to diagnose and monitor PAD. It
compares the blood pressure in the feet to the blood pressure in the arms to determine how well blood is
flowing through the body. 8 According to the ESC/ESVS, the ABI is a valid test in various ethnicities,
regardless of risk factors. It is an inexpensive and relatively quick test to administer. An ABI > 1.40
indicates medial arterial calcification (arterial stiffening) and is associated with increased mortality.
This finding occurs more often in elderly patients who have diabetes or chronic kidney disease. An ABI
≤ 0.90 is associated with a 2- to 3-fold increase in the risk for CV death. Beyond indicating overall CV
risk, the ABI can highlight the risk for lower-extremity events, allowing the clinician to educate the
patient about and monitor for foot wounds. 10 Patients with abnormal ABI results may require
additional testing. Duplex ultrasound can be used to visualize an artery and measure blood flow to
determine the severity of lesions. 8; 10 It can also be used to check for carotid plaque as part of a
comprehensive CV risk assessment. 10 Computed tomography angiography (CTA) is a quick,
noninvasive test that provides a map of the vasculature to help clinicians determine which interventions
may be required for an individual patient. 10 CTA shows the arteries in the abdomen, pelvis, and legs,
and is useful in patients with pacemakers or stents. 8 However, CTA does not provide functional or
hemodynamic data, and since it exposes patients to radiation and iodinated contrast agents, it cannot be
used as readily in patients with renal disease. 10 Magnetic resonance angiography (MRA) can be used to
view the peripheral arteries with and without contrast. Though an MRA without contrast is helpful in
studies of patients with renal disease, the resulting images have inferior resolution. 10

2
Digital subtraction angiography was formerly the standard test for vascular imaging, but due to the risk
for complications, this invasive test is no longer used as often. It may be helpful when there are
discrepancies between noninvasive imaging modalities. 10

GUIDELINE RECOMMENDATIONS

In 2016, the American Heart Association/American College of Cardiology (AHA/ACC) published

revised guidelines on the management of patients with lower-extremity PAD. These guidelines
recommend comprehensive medical therapy for all patients with PAD, including supervised exercise
and lifestyle modification, smoking cessation, and pharmacologic therapy. A brief summary of medical
therapy recommendations follows 11:

● Antiplatelet therapy with aspirin 75 to 325 mg/day or clopidogrel 75 mg/day is recommended to

reduce MI, stroke, and vascular death in symptomatic patients (Class I) and antiplatelet therapy is a
reasonable consideration in asymptomatic patients with an ABI ≤ 0.90 (Class IIa)
● The guidelines note that the effectiveness of dual antiplatelet therapy (DAPT) in symptomatic
patients to reduce the risk of CV ischemic events is not well established (Class IIb); however,
DAPT may be considered to reduce the risk of limb-related events in symptomatic patients after
lower-extremity revascularization (Class IIb)
● Statins are recommended for all patients with PAD (Class I)
● Antihypertensive therapy is recommended for all patients with PAD to reduce the risk of MI,
stroke, heart failure, and CV death (Class I)
● Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are
effective to reduce the risk of CV ischemic events in patients with PAD (Class IIa)
● Smoking cessation is recommended for all patients with PAD and clinicians should assist patients
with pharmacotherapy and/or referral to a smoking cessation program (Class I)
● Patients with PAD and diabetes require a comprehensive care plan that may include diet and
weight management, pharmacologic therapy for glycemic control, management of other CV risk
factors, foot care, and ulcer prevention (Class I). Glycemic control can benefit patients with
critical limb ischemia to reduce limb-related outcomes (Class IIa)

In 2017, the ESC, in collaboration with the ESVS, also issued formal guidelines for the treatment of
PAD. These guidelines emphasize the importance of a multidisciplinary team when managing patients
with PAD. 10; 12

Guideline-recommended optimal medical therapy includes the following 10:

● Smoking cessation is recommended for all patients with PAD (Class I) along with a healthy diet
and physical activity (Class I)
● Statins are recommended for all patients (Class I); clinicians should attempt to reduce patients'
serum low-density lipoprotein cholesterol (LDL-C) to < 1.8 mmol/L (< 70 mg/dL) or to reduce it
by ≥ 50% if the initial LDL-C level is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL) (Class I).
10 The American College of Cardiology/American Heart Association cholesterol guidelines also
recommend that patients with PAD be treated with a moderate- to high-intensity statin 13
● In patients with comorbid PAD and diabetes, it is important to maintain optimal glycemic control
(Class I)
● As secondary prevention for CV events, antiplatelet agents are recommended for patients with
symptomatic PAD (Class I)

3
 ● Antihypertensive agents are recommended to reduce systolic blood pressure in an effort to reduce
CV events. A target blood pressure < 140/90 mm Hg is recommended (Class I); however, in
patients with diabetes, a target diastolic blood pressure ≤ 85 mm Hg can be used
● ACE inhibitors or ARBs are the recommended first-line treatment in patients with PAD and
hypertension (Class IIa)

Carotid Artery Stenosis

The ESC/ESVS recommend that patients with asymptomatic carotid artery stenosis be treated with
single antiplatelet therapy (SAPT) (aspirin 75 to 100 mg/day or clopidogrel 75 mg/day) – unless the
patient is at very high bleeding risk – for at least 1 year (Class IIa). Long-term SAPT is recommended
for all patients with symptomatic carotid stenosis (Class I). Patients who have undergone carotid artery
stenting should receive DAPT (aspirin plus clopidogrel) for 1 month (Class I), followed by SAPT to
complete 1 year of treatment (Class I). Patients who have carotid surgery should be treated with SAPT
for 1 year (Class I). 10

Lower-Extremity Artery Disease (LEAD)

For patients with LEAD who do not need anticoagulant therapy, treatment depends on the patient's
symptoms and is intended to prevent limb-related and CV events. Asymptomatic patients do not need
SAPT (Class III), but SAPT (aspirin or clopidogrel) is recommended for symptomatic patients for a
minimum of 1 year (Class I). For patients who need revascularization, treatment depends on the nature
of the interventions. For patients treated with percutaneous coronary intervention (PCI), DAPT is
recommended for 1 month (Class IIa), followed by SAPT to complete 1 year of treatment (Class IIa).
Patients treated with surgery should receive SAPT (Class IIb) or a vitamin K antagonist (VKA) (Class
IIb) for 1 year. Additionally, all patients with LEAD should receive statin therapy to improve walking
distance (Class I) as well as supervised exercise therapy. 10

Before determining treatment options for patients with LEAD who need long-term anticoagulant
therapy, patients should be stratified by symptoms and revascularization status. Both symptomatic and
asymptomatic patients and patients who have had surgery should receive an oral anticoagulant as
monotherapy (a VKA or a non-VKA oral anticoagulant [NOAC]) for 1 year (Class I). Patients who
have been treated with PCI and who have a low risk of bleeding should be treated with dual
antithrombotic therapy (an oral anticoagulant plus aspirin or clopidogrel) (Class IIa) for 1 month
followed by dual antithrombotic therapy (Class IIb) or oral anticoagulant monotherapy (Class IIb) to
complete 1 year of treatment. Patients treated with PCI who have a high risk of bleeding should be
treated with oral anticoagulant monotherapy for 1 year (Class IIa). 10

Antithrombotic Therapy for Patients With PAD Requiring Oral Anticoagulation

Patients with PAD and atrial fibrillation should receive oral anticoagulation if their CHA2DS2-VASc
score is ≥ 2 (Class I), and clinicians should consider this option in all other patients as well (Class IIa).
Patients with PAD who have an indication for oral anticoagulation (eg, atrial fibrillation or a
mechanical prosthetic valve) should receive oral anticoagulation only (Class IIa). In patients who
undergo endovascular revascularization, clinicians should consider aspirin or clopidogrel in addition to
oral anticoagulation for at least 1 month if the patient has a low risk of bleeding (Class IIa). If the

4
patient's bleeding risk is high, then oral anticoagulation alone is appropriate (Class IIa). Patient at high
ischemic risk and those with an indication for long-term SAPT can receive oral anticoagulation and
SAPT for > 1 month. 10

PATIENT MANAGEMENT

Comprehensive management for patients with PAD comprises treating specific arterial symptoms,
addressing the risk associated with specific lesions, and taking steps to reduce overall CV risk. 10

Antiplatelet Therapy

These treatments are intended to prevent the formation of thrombi, but these therapies do increase
patients' bleeding risk.

Aspirin (75 to 150 mg/day) is the antiplatelet therapy of choice, but clopidogrel may be used in patients
who are intolerant of or allergic to aspirin. 14

P2Y12 inhibitors (eg, clopidogrel, prasugrel, ticagrelor) inhibit platelet aggregation by antagonizing the
platelet adenosine diphosphate (ADP) receptor P2Y12. The CAPRIE trial demonstrated an overall
benefit of clopidogrel vs aspirin in preventing CV events in > 19,000 patients with previous MI,
previous stroke, or peripheral vascular disease (PVD). 14 Specifically, an intention-to-treat analysis
showed that patients treated with clopidogrel had an annual 5.32% risk of ischemic stroke, MI, or
vascular death, compared with 5.83% with aspirin, reflecting a reduction in relative risk of 8.7% in
favor of clopidogrel (95% confidence interval [CI]: 0.3%, 16.5%; P =.043). A corresponding
on-treatment analysis yielded a relative risk reduction of 9.4%. There were no major differences in
terms of safety. 15 A weakness of the CAPRIE results is that the CI was just clear of the neutral value
and the results varied according to the 3 diagnostic strata that were considered: while clopidogrel
yielded a risk reduction of 23.8% in patients with symptomatic PAD, and 7.3% in those with recent
ischemic stroke, aspirin produced a 3.7% risk reduction compared with clopidogrel in those with a
recent MI. 16 Furthermore, the aspirin dose (325 mg) used in the trial may not be a safe dose. 14

A small trial of 18 patients compared clopidogrel to ticagrelor plus aspirin therapy in patients with
femoral artery disease who had stents placed and had a clot detected by optical coherence tomography.
Patients in the clopidogrel arm received 75 mg of clopidogrel once daily for 1 month and 81 mg of
aspirin for 6 months. Patients in the ticagrelor arm received 90 mg of ticagrelor twice daily for 6
months plus 81 mg of aspirin for 6 months. At the 6-month follow-up visit, there was a greater decrease
in white thrombus in patients who received ticagrelor (median volume/stent length 0.067 vs 0.014 mm3
/mm, P =.05). At 6 months, there was no difference in ABI between the groups. 17 The study is limited
by the small number of patients and limited follow-up duration.

Clopidogrel plus aspirin was compared to aspirin monotherapy in the CHARISMA trial, and
investigators observed that the rate of CV death, MI, or stroke (the study's primary endpoint) was
higher in patients with PAD than in those without PAD. In a post hoc analysis of the 3096 patients with
PAD who were a part of the trial, the primary endpoint occurred in 7.6% of patients in the clopidogrel
plus aspirin group and in 8.9% in the placebo plus aspirin group (hazard ratio [HR] 0.85; 95% CI: 0.66,
1.08; P =.18). The rate of MI was lower in the DAPT arm than in the aspirin monotherapy arm: 2.3% vs

5
3.7% (HR 0.63; 95% CI: 0.42, 0.96; P =.029), as was the rate of hospitalization for ischemic events:
16.5% vs 20.1% (HR 0.81; 95% CI: 0.68, 0.95; P =.011). Although the rates of severe, fatal, or
moderate bleeding were similar in both groups, minor bleeding was increased with clopidogrel (34.4%
vs 20.8%; odds ratio 1.99; 95% CI: 1.69, 2.34; P < .001). 18 Since this was a post hoc analysis, these
results would need to be confirmed by prospective studies.

EUCLID was a head-to head trial of clopidogrel vs ticagrelor in patients with symptomatic PAD with
and without CAD (defined as prior MI or PCI or coronary artery bypass graft [CABG] surgery). The
trial enrolled 13,885 patients, 4032 (29%) of whom had PAD and CAD. After adjusting for baseline
characteristics, patients with PAD and CAD had higher rates of the primary endpoint of CV
death/MI/stroke compared to patients without CAD (15.3% vs 8.9%; HR 1.50; 95% CI: 1.13, 1.99; P
=.005). However, there was no statistically significant increase in acute limb ischemia (HR 1.28; 95%
CI: 0.57, 2.85; P =.55) or major bleeding (HR 1.10; 95% CI: 0.49, 2.48; P =.81). For the patients with
both PAD and CAD, there was no difference between ticagrelor and clopidogrel treatment for the
primary endpoint (HR 1.02; 95% CI: 0.87, 1.19; P =.84), acute limb ischemia (HR 1.03; 95% CI: 0.63,
1.69; P =.89), or major bleeding (HR 1.06; 95% CI: 0.66, 1.69; P =.81). There was a statistically
significant interaction between prior coronary stent placement and study medications: patients with a
coronary stent had a numerical reduction in the primary efficacy endpoint with ticagrelor vs clopidogrel
(13.8% vs 16.8%; HR 0.82; 95% CI: 0.65, 1.03; P =.09). 19 One limitation of this study is that
standard-of-care background therapies were permitted.

In the TRA2°P-TIMI 50 study, vorapaxar, a protease-activated receptor-1 inhibitor, was compared to

placebo on top of concomitant medical therapy, including use of other antiplatelet agents or
anticoagulants, in patients with stable atherosclerotic vascular disease, including 3787 with PAD. In the
PAD cohort, vorapaxar did not reduce the incidence of CV death, MI, or stroke (HR 0.94; 95% CI:
0.78, 1.14; P =.53), which was the primary efficacy endpoint, but it did significantly reduce the rates of
hospitalization for acute limb ischemia (2.3% vs 3.9%; HR 0.58; 95% CI: 0.39, 0.86; P =.006) and
peripheral revascularization (18.4% vs 22.2%; HR 0.84; 95% CI: 0.73, 0.97; P =.017). These beneficial
effects were counterbalanced by an increased risk of bleeding with the active drug vs placebo (7.4% vs
4.5%; HR 1.62; 95% CI: 1.21, 2.18; P =.001). There were several limitations to the study. The PAD
cohort was not sufficiently sized to show a significant reduction in the primary endpoint. The
heterogeneity of the background antiplatelet therapy limits the ability to discriminate differential
effects of vorapaxar added to specific antiplatelet agents, and also to assess the potential efficacy and
safety of vorapaxar as monotherapy. 20

Anticoagulation Therapy

Anticoagulant therapies include VKAs (eg, warfarin) and NOACs (eg, rivaroxaban, apixaban,
dabigatran). Though VKA therapy has been shown to reduce recurrent thrombotic events in patients
with CAD, it also caused major bleeding. 3

Rivaroxaban is a factor Xa inhibitor and is the only NOAC approved to treat patients with PAD. It is
also the only NOAC recommended in the ESC/ESVS guidelines. In Europe, rivaroxaban is indicated in
combination with aspirin to prevent atherothrombotic events in adults with CAD or symptomatic PAD
at high risk of ischemic events. It is also indicated in combination with aspirin or with aspirin plus
clopidogrel or ticlopidine to prevent atherothrombotic events in adults following an ACS with elevated
cardiac biomarkers. According to European labelling, the normal dosage in patients with CAD/PAD is
2.5 mg orally twice daily in combination with aspirin (75-100 mg) once daily. Rivaroxaban should not

6
be used in patients with serious renal impairment (creatinine clearance < 15 mL/min) and is
contraindicated in patients with liver disease associated with coagulopathy, including patients with
Child-Pugh classes B and C. 21 In the United States, rivaroxaban is approved to reduce the risk of stroke
and systemic embolism in patients with nonvalvular atrial fibrillation, to treat deep venous thrombosis
(DVT) and pulmonary embolism (PE), to reduce the risk of recurrent DVT and/or PE, and for DVT
prophylaxis following hip or knee replacement surgery. In October 2018, rivaroxaban received a new
indication to reduce the risk of major CV events in patients with CAD or PAD. The drug carries black
box warnings for epidural and spinal hematomas as well as a warning that premature discontinuation
can increase the risk of thrombotic events. According to US labelling, to reduce the risk of major CV
events in patients with CAD or PAD, the normal dosage is 2.5 mg orally twice daily (with or without
food) in combination with aspirin (75-100 mg) once daily. The dose may need to be adjusted in patients
with moderate renal impairment and the drug should not be used in patients with Child-Pugh class B or
C hepatic impairment or with any hepatic impairment associated with coagulopathy. The most
commonly reported adverse reaction during therapy is bleeding. 22

In the COMPASS trial, investigators compared rivaroxaban monotherapy, rivaroxaban plus aspirin, and
aspirin monotherapy in patients with stable atherosclerotic vascular disease. The trial enrolled 27,395
patients who were randomized to treatment with rivaroxaban 2.5 mg twice daily plus aspirin 100 mg
daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg once daily. The primary outcome was the
composite of CV death, stroke, or MI, and this outcome occurred in 379 patients (4.1%) in the group
receiving rivaroxaban plus aspirin vs 496 patients (5.4%) in the group treated with aspirin monotherapy
(HR 0.76; 95% CI: 0.66, 0.86; P < .001). The study was halted after a mean follow-up of 23 months
due to the superior results in the rivaroxaban plus aspirin group. There were more major bleeding
events in the rivaroxaban/aspirin group than in the aspirin monotherapy group (3.1% vs 1.9%; HR 1.7;
95% CI: 1.40, 2.05; P < .001). The authors concluded that patients treated with dual therapy had better
CV outcomes but more major bleeding events than patients who received aspirin monotherapy. 23
Investigations are ongoing to determine if adding proton pump inhibitor therapy could reduce the
gastrointestinal bleeding observed in this trial. 24 Rivaroxaban 5 mg twice daily did not improve CV
outcomes compared to aspirin monotherapy and caused more bleeding. 23 Study strengths include the
number of patients enrolled; however, long-term data are lacking because the study was ended early.
Additionally, patients' use of statins and baseline LDL-C were not recorded at baseline.

A separate analysis from the COMPASS trial looked at results in 7470 patients with PAD of the lower
extremities, of the carotid arteries, or CAD with an ABI < 0.90. The primary outcome was the
composite of CV death, stroke, or MI, and the primary PAD outcome was major adverse limb events
(including major amputation). Rivaroxaban plus aspirin reduced the primary endpoint vs aspirin alone
(126 patients [5%] vs 174 patients [7%]; HR 0.72; 95% CI: 0.57, 0.90; P =.0047) as well as major
adverse limb events (32 patients [1%] vs 60 patients [2%]; HR 0.54; 95% CI: 0.35, 0.82, P =.0037).
Rivaroxaban 5 mg twice a day compared with aspirin monotherapy did not significantly reduce the
primary endpoint, but it did reduce major adverse limb events including major amputation (40 patients
[2%] vs 60 patients [2%]; HR 0.67, 95% CI: 0.45, 1.00, P =.05). Consistent with the findings from the
overall trial, there was more major bleeding in the rivaroxaban/aspirin group vs the aspirin
monotherapy group (77 [3%] vs 48 [2%]; HR 1.61; 95% CI: 1.12, 2.31; P =.0089). 25 This analysis is
limited by the lack of long-term data due to the early termination of COMPASS.

Exercise Therapy

In addition to lifestyle modifications and pharmacologic therapy to reduce CV risk, exercise therapy
may also be used to improve symptoms of PAD. The extent of therapy varies depending on the patient's

7
symptoms. As an example, the patient should walk until reaching pain tolerance, stop to rest briefly, and
then begin walking again once the pain resolves. These exercise therapy sessions should be performed
for 30 to 45 minutes, 3 to 4 times weekly, for at least 12 weeks. 7

8
REFERENCES

[1] Mayo Clinic. Coronary artery disease.https://www.mayoclinic.org/dis…. Accessed October 9, 2018.

[2] Viles-Gonzalez JF, Fuster V, Badimon JJ. Atherothrombosis: a widespread disease with
unpredictable and life-threatening consequences. Eur Heart J. 2004;25:1197-1207.

[3] Pharmacy Times. Anticoagulation in the management of CAD and PAD.

https://www.pharmacytimes.com/…. Updated June 6, 2018. Accessed October 20, 2018.

[4] Mahoney EM, Wang K, Cohen DJ, et al. One-year costs in patients with a history of or at risk for
atherothrombosis in the United States. Circ Cardiovasc Qual Outcomes. 2008;1:38-45.

[5] Smolderen KG, Bell A, Lei Y, et al. One-year costs associated with cardiovascular disease in
Canada: insights from the REduction of Atherothrombosis for Continued Health (REACH) registry.
Can J Cardiol. 2010;26:e297-e305.

[6] Merck Manual. Peripheral arterial disease (peripheral vascular disease).

https://www.merckmanuals.com/p…. Accessed October 20, 2018.

[7] Bah F, Bimji SS. Peripheral arterial disease.https://www.ncbi.nlm.nih.gov/b…. Updated September

12, 2018. Accessed October 20, 2018.

[8] American Heart Association. Symptoms and diagnosis of PAD.http://www.heart.org/en/health….

Updated October 31, 2016. Accessed October 20, 2018.

[9] Mayo Clinic. Peripheral artery disease (PAD).https://www.mayoclinic.org/dis…. Accessed October

18, 2018.

[10] Aboyans V, Ricco JB, Bartelink MEL, et al; ESC Scientific Document Group. 2017 ESC
guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the
European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of
extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Endorsed by:
the European Stroke Organization (ESO), The Task Force for the Diagnosis and Treatment of

9
Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society
for Vascular Surgery (ESVS). Eur Heart J. 2018;39:763-816.

[11] Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management
of patients with lower extremity peripheral artery disease: Executive Summary: a report of the
American College of Cardiology/American Heart Association Task Force on Clinical Practice
Guidelines. Circulation. 2017;135:e686-e725.

[12] Halliday A, Bax JJ. The 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial
diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc
Surg. 2018;55:301-302.

[13] Khariton Y, Patel KK, Chan PS, et al. Guideline-directed statin intensification in patients with new
or worsening symptoms of peripheral artery disease. Clin Cardiol. 2018;41:1414-1422.

[14] Task Force Members, Montalescot G, Schtem U, et al. 2013 ESC guidelines on the management of
stable coronary artery disease: the Task Force on the management of stable coronary artery disease of
the European Society of Cardiology. Eur Heart J. 2013;34:2949-3003.

[15] CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients
at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339.

[16] Algra A, van Gijn J. Is clopidogrel superior to aspirin in secondary prevention of vascular disease?
Curr Control Trials Cardiovasc Med. 2000;1:143-145.

[17] Yang X, Leesar MA, Ahmed H, et al. Impact of ticagrelor and aspirin versus clopidogrel and
aspirin in symptomatic patients with peripheral arterial disease: thrombus burden assessed by optical
coherence tomography. Cardiovasc Revasc Med. 2018;19:778-784.

[18] Cacoub PP, Bhatt DL, Steg PG, Topol EJ, Creager MA, CHARISMA Investigators. Patients with
peripheral arterial disease in the CHARISMA trial. Eur Heart J. 2009;30:192-201.

[19] Berger JS, Abramson BL, Lopes RD, et al. Ticagrelor versus clopidogrel in patients with
symptomatic peripheral artery disease and prior coronary artery disease: Insights from the EUCLID
trial. Vasc Med. 2018;23:523-530.

10
 [20] Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in patients with peripheral artery disease:
results from TRA2°P-TIMI 50. Circulation. 2013;127:1522-1529, 1529e1-6.

[21] Xarelto (rivaroxaban). [Summary of Product Characteristics]. Leverkusen, Germany: Bayer AG;
May 22, 2018.

[22] Xarelto (rivaroxaban). [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals; October
2018.

[23] Eikelboom JW, Connolly SJ, Bosch J, et al; COMPASS Investigators. Rivaroxaban with or without
aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319-1330.

[24] Al Said S, Bode C, Duerschmied D. Anticoagulation in atherosclerotic disease. Hamostaseologie.

2018;38:240-246.

[25] Anand SS, Bosch J, Eikelboom JW, et al; COMPASS Investigators. Rivaroxaban with or without
aspirin in patients with stable peripheral or carotid artery disease: an international, randomised,
double-blind, placebo-controlled trial. Lancet. 2018;391:219-229.

[26] Branch KR. Rivaroxaban plus aspirin in patients with or without heart failure and chronic coronary
or peripheral artery disease: the COMPASS trial. Presented at: Heart Failure 2018 & World Congress
on Acute Heart Failure; May 26-29, 2018; Vienna.

[27] Healio/Cardiology Today. COMPASS: Low-dose rivaroxaban plus aspirin may benefit patients
with chronic CAD, PAD, HF.https://www.healio.com/cardiol…. Updated June 4, 2018. Accessed
October 10, 2018.

[28] Zannad F, Anker SD, Byra WM, et al; COMMANDER HF Investigators. Rivaroxaban in patients
with heart failure, sinus rhythm, and coronary disease. N Engl J Med. 2018;379:1332-1342.

11

Powered by TCPDF (www.tcpdf.org)