The Use of Anticoagulants in Peripheral Arterial Disease - American College of Cardiology (2023)

The Centers for Disease Control and Prevention estimates that approximately 8 million Americans have peripheral arterial disease (PAD).1 Although a number of disease processes can cause PAD, the most common etiology is atherosclerosis. An increased atherosclerotic burden predisposes the PAD population to increased risk for major adverse cardiac events (MACE) – myocardial infarction (MI), stroke, and death.2 Secondary prevention strategies for patients with PAD have focused on reducing MACE through the use antiplatelet therapies. Studies have demonstrated that aspirin monotherapy is not adequate to mitigate MACE in patients with PAD.3 The addition of P2Y12 inhibitors (e.g., clopidogrel) adds incremental benefit to aspirin. Unfortunately, augmenting aspirin with a P2Y12 inhibitor increases a patient's risk of bleeding.2 For this reason, guideline-recommended use of P2Y12 inhibitors is limited to a small subgroup of high risk PAD patients.3 The recent emergence of novel anticoagulants has rekindled interest regarding the use of anticoagulants for secondary prevention in the PAD population.

Figure 1
Reproduced with permission from The Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral Anticoagulant and Antiplatelet Therapy and Peripheral Arterial Disease. N Engl J Med 2007;357:217-27.

The associated reduction of MACE in PAD patients treated with antiplatelet therapy led to the hypothesis that an intensified antithrombotic regimen of aspirin plus warfarin, a vitamin K antagonist, would be more beneficial. Subsequently the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial randomized 2,161 patients with PAD to either antiplatelet therapy (aspirin, ticlopidine, or clopidogrel) plus warfarin (INR 2.0-3.0) versus antiplatelet therapy alone. Dual antiplatelet therapy was not permitted unless patients suffered an MI or underwent coronary stent placement during follow-up. No significant differences in the primary outcome components of MI [5.0% vs. 6.1%, relative risk (RR) 0.82; 95% confidence interval (CI) 0.57 – 1.18, P = 0.28], stroke (3.5% vs. 3.5%, RR 1.01; 95% CI 0.65 – 1.59, P = 0.96), or severe lower extremity ischemia (3.9% vs. 4.1%, RR 0.96; 95% CI 0.63 – 1.47, P = 0.86) were observed among patients receiving warfarin plus antiplatelet therapy compared to antiplatelet therapy alone, respectively. In addition to the overall lack of benefit, a significant increased risk of life-threatening bleeding was observed in the warfarin plus antiplatelet combination therapy cohort compared to antiplatelet therapy alone, (4.0% vs. 1.2%, RR 3.41; 95% CI 1.84 – 6.35, P < 0.001) (Figure 1).4 The findings in the WAVE trial and the lack of further evidence to support any benefit of the addition of warfarin to antiplatelet therapy in the reduction of thrombotic events in patients with PAD is highlighted in current guidelines as a Class IIIb (no benefit) recommendation.3

The use of anticoagulants in the PAD population has also been evaluated following surgical revascularization to maintain graft patency. The use of warfarin (INR 2.0-3.0) plus aspirin (325 mg) compared to aspirin monotherapy was initially evaluated in a pilot study of 54 patients with high-risk vein grafts (defined as having poor run off, suboptimal vein conduit, or need for repeat interventions). The three-year primary graft patency rates were (non-significantly) higher in the anticoagulant therapy cohort compared with the aspirin monotherapy group (75% vs. 51%, P = 0.4). There were no observed anticoagulation therapy related bleeding complications (gastrointestinal, intracranial, and genitourinary hemorrhage).5 In a larger follow-up study, the Dutch Bypass Oral Anticoagulants or Aspirin (BOA) trial evaluated anticoagulation with warfarin (INR goal 3.0-4.5) vs. aspirin 80 mg daily in 2,690 patients undergoing infrainguinal bypass surgery. There was no observed difference in the patency rates with warfarin compared to aspirin, respectively [hazard ratio (HR) 0.95; 95% CI 0.82 – 1.11). Subgroup analysis revealed that patients with vein grafts benefited from lower rates of graft occlusion (HR 0.69; 95% CI 0.54 – 0.88) with warfarin monotherapy. Patients with prosthetic grafts experienced higher rates of graft occlusion on warfarin monotherapy (HR 1.26; 95% CI 0.82 – 1.11). As with previous studies, patients treated with warfarin experienced an increased number of major bleeding episodes compared to aspirin (HR 1.96; 95% CI 1.42 – 2.71).6 The BOA trial again reiterated that only selected patients with PAD stand to benefit from chronic warfarin therapy – particularly patients undergoing lower extremity bypass with vein grafts.

Figure 2

The recent introduction of novel anticoagulants (specifically dabigatran, rivaroxaban, and apixaban) for prevention of nonvalvular atrial fibrillation (AF) and venous thromboembolism (VTE) has rekindled the idea of anticoagulant use for secondary prevention in patients with atherosclerotic disease. An advantage of novel anticoagulants over warfarin is the lack of need for chronic laboratory monitoring due to more predictable pharmacodynamics.7 Currently there are two phase III prospective clinical trials investigating the use of novel anticoagulants, rivaroxaban and edoxaban, in the PAD population. The potential benefits observed with low-dose rivaroxaban in combination with antiplatelet therapy in patients with acute coronary syndrome (ACS) in ATLAS ACS-TIMI 51 is being now explored in patients with PAD. In the Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS), approximately 20,000 patients with documented atherosclerosis (coronary and/or peripheral) will be randomized to either 2.5 mg of rivaroxaban twice-daily plus antiplatelet therapy, 5 mg rivaroxaban twice-daily monotherapy, or antiplatelet therapy alone.9 In a similar trial, edoxaban, a once-daily factor Xa inhibitor is being evaluated in a randomized multicenter study in patients with PAD to assess the efficacy of its addition to aspirin compared to a clopidogrel plus aspirin regimen in preventing stenosis or occlusion in patients undergoing femoropoplitieal endovascular intervention.10

In summary, patients with PAD are at increased risk of MACE – MI, stroke, and death. Previous studies have demonstrated limited benefit of adding warfarin to antiplatelet regimens for secondary prevention of MACE in patients with PAD that was outweighed by a disproportionate increased risk of major or severe bleeding (Figure 2). For this reason, contemporary guidelines support the use of anticoagulants in only select PAD populations – patients undergoing vein graft bypass.2,3 Studies are currently underway to evaluate the potential role of novel oral anticoagulants for thrombotic prevention in patients with PAD.


  1. National Center for Chronic Disease Prevention and Health Promotion, Division for Heart Disease and Stroke Prevention. Peripheral Arterial Disease (PAD) Fact Sheet (Centers for Disease Control and Prevention website). Available at: Accessed: 08/07/14.
  2. Brogneaux C, Sprynger M, Magnée M,, et al. 2011 ESC guidelines on the diagnosis and treatment of peripheral artery diseases. Rev Med Liege 2012;67:560-5.
  3. Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;58:2020-45.
  4. WAVE Investigators. The effects of oral anticoagulants in patients with peripheral arterial disease: rationale, design, and baseline characteristics of the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, including a meta-analysis of trials. Am Heart J 2006;151:1-9.
  5. Sarac TP, Huber TS, Back MR, et al. Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk for failure. J Vasc Surg 1998;28:446-57.
  6. Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial. Lancet 2000;355:346-51.
  7. Eikelboom JW, Weitz JI. Update on antithrombotic therapy: new anticoagulants. Circulation 2010;121:1523-32.
  8. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19.
  9. U.S. National Institutes of Health. Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) ( website). Available at: Accessed: 08/07/14.
  10. U.S. National Institutes of Health. Edoxaban in Peripheral Arterial Disease (ePAD) ( website). Available from: Accessed: 08/07/14.

Keywords: Anticoagulants, Aspirin, Atherosclerosis, Centers for Disease Control and Prevention, U.S., Cost of Illness, Myocardial Infarction, Peripheral Arterial Disease, Secondary Prevention, Stroke, Ticlopidine

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Why are anticoagulants used for PAD? ›

Anticoagulants have been used to reduce the risk of venous thromboembolism, but have recently been applied to the arterial circulation. Heparins were introduced to reduce short-term major adverse limb events in patients undergoing arterial revascularisation.

Do you give anticoagulants for PAD? ›

Peripheral arterial disease (PAD) is a major medical/surgical problem associated with high risk for coronary heart disease (CHD). Anticoagulation plays a significant role in the management of the PAD patient.

Do blood thinners help with peripheral artery disease? ›

XARELTO® is a prescription blood thinner that, when taken with low-dose aspirin, helps reduce the risk of a sudden decrease in blood flow to the legs, major amputation, serious heart problems, or stroke in adults with peripheral artery disease (a condition where the blood flow to the legs is reduced) and includes ...

What is the treatment of PAD guidelines? ›

Antiplatelet therapy with aspirin alone (range, 75-325 mg/day) or clopidogrel alone (75 mg/day) is recommended to reduce myocardial infarction (MI), stroke, and vascular death in patients with symptomatic PAD. Treatment with a statin medication is indicated for all patients with PAD.

Do anticoagulants work in the arteries? ›

Anticoagulants and antiplatelets are medicines that reduce blood clotting in an artery, vein or the heart. Doctors prescribe these to help prevent heart attacks and strokes caused by blood clots.

When Should anticoagulants be used? ›

Anticoagulants are used if you're at risk of developing blood clots that could potentially block a blood vessel and disrupt the flow of blood around your body.

Which anticoagulant is the only anticoagulant recommended for treatment of PAH? ›

Given limited experience with the novel oral anticoagulants such as dabigatran, rivaroxaban, and apixaban in PAH, warfarin remains the anticoagulant of choice.

Which medication should not be given to a patient on anticoagulant therapy? ›

Over the counter pain relievers that can also increase the effect of anticoagulants, thus increasing the chance of bleeding include: Aspirin. Advil, Motrin, Nuprin (ibuprofen) Aleve (naproxen)

What medications should patients on anticoagulants avoid? ›

Some of the medicines that can affect anticoagulants include certain:
  • antibiotics.
  • antidepressants.
  • steroids (medicines used to reduce inflammation)
  • anticonvulsants (medicines used to treat epilepsy)
  • non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (take paracetamol instead if you need pain relief)

What is the best treatment for peripheral artery disease? ›

Medications called statins are commonly prescribed for people with peripheral artery disease. Statins help lower bad cholesterol and reduce plaque buildup in the arteries. The drugs also lower the risk of heart attacks and strokes.

What is the best vitamin for peripheral artery disease? ›

found that consumption of vitamins A, C, E, B6, and B12 were associated with a lower odds of having PAD. Further analysis indicated that intake of fiber, vitamins A, C, E, B6, folate, and n-3 PUFAs correlated with a reduced prevalence of PAD. Most recently, Naqvi et al.

What is the new medication for PAD? ›

RARITAN, N.J., August 24, 2021 – The Janssen Pharmaceutical Companies of Johnson & Johnson today announced that the U.S. Food and Drug Administration (FDA) has approved an expanded peripheral artery disease (PAD) indication for the XARELTO® (rivaroxaban) vascular dose (2.5 mg twice daily plus aspirin 100 mg once daily) ...

What leg exercises can you do with peripheral artery disease? ›

The best exercise for PAD is interval walking. Find a treadmill or a route around your neighborhood that you enjoy. Walk for a few minutes at a good pace even if you feel mild pain, and then rest for a few minutes.

Should you elevate your legs with PAD? ›

Since this condition affects blood flow in your legs, elevating them can be highly beneficial for patients with PAD. This is especially helpful for those who are bedridden. Elevate your legs above heart level to keep blood from pooling in them. This increases circulation to the heart and prevents leg cramps and pain.

What are the 3 main anticoagulant medications? ›

There are three main types of anticoagulant medications:
  • Vitamin K antagonists.
  • Direct Oral Anticoagulants (DOACs)
  • Low molecular weight heparins (LMWH)
Mar 21, 2022

What are the 4 most common anticoagulants? ›

Types of anticoagulants
  • rivaroxaban (Xarelto)
  • dabigatran (Pradaxa)
  • apixaban (Eliquis)
  • edoxaban (Lixiana)

How effective are anticoagulants? ›

Warfarin and newer anticoagulants work equally well to prevent blood clots in extended treatment after venous thromboembolism. One clot is prevented for every 15 people receiving either anticoagulant.

When should elderly stop anticoagulation? ›

Unless the risk of bleeding is exceedingly high, anticoagulation is required [5]. When bleeding risk exceeds the risk of stroke, treatment should be discontinued; however, this is associated with an increased risk of death and thromboembolic complications [5].

What are the three contraindications to the use of anticoagulants? ›

Anticoagulation should be avoided in patients with absolute contraindications, such as in the following conditions: Active bleeding. Coagulopathy. Recent major surgeries.

Which anticoagulant is safe in elderly? ›

Among older patients treated with anticoagulation for atrial fibrillation, apixaban had the lowest adverse event rate vs warfarin among frail patients, compared with dabigatran and rivaroxaban.

What anticoagulant is best for APS? ›

Warfarin tablets are usually recommended if you have APS and a history of blood clots, such as previously having DVT (deep vein thrombosis) or a stroke.

What is the first line treatment for PAH? ›

Epoprostenol (Flolan)

This is the first drug specifically approved for the treatment of pulmonary hypertension.

What is the best and safest anticoagulant? ›

The FDA also notes that dabigatran, rivaroxaban, and apixaban are less likely to cause hemorrhagic stroke than warfarin. They also have other benefits: fewer drug interactions. rapid onset, eliminating the need to bridge with another medication that is necessary with warfarin.

What fruits should you avoid if you are on blood thinners? ›

Grapefruit and other citrus fruits can interfere with how your body metabolizes these medications.

What is the safest blood thinner to use? ›

A new study published in November 2022 in Annals of Internal Medicine found apibaxan to be the safest blood thinner among DOACs, including dabigatran, edoxaban and rivaroxaban. Apibaxan was associated with the lowest risk of gastrointestinal bleeding.

What is the most common major complication of anticoagulation therapy? ›

The major complication of anticoagulant therapy is bleeding. LMWH is associated with less major bleeding than UFH. The ease of use, absence of mandatory laboratory monitoring, and clinical efficacy of LMWH have led to its widespread use for anticoagulation therapy in a number of disorders.

What vitamins should you not take with blood thinners? ›

Berberine/goldenseal. CBD (cannabidiol) Chamomile. Cinnamon (high-dose)
Supplements that may reduce warfarin's ability to thin the blood include:
  • CoQ10.
  • Echinacea.
  • Ginseng.
  • Green tea.
  • St. John's wort.
  • Vitamin K.
Jun 2, 2014

What is a natural anticoagulant? ›

The most important natural anticoagulants are protein C, protein S, and antithrombin (which used to be called antithrombin III until its name was changed to antithrombin). Figure. The normal balance between clotting and bleeding is disrupted when there is a deficiency of one of the natural anticoagulants.

How do you remove plaque from arteries without surgery? ›

You can take steps to reduce plaques by losing weight, exercising more, or eating fewer foods high in saturated fat. In some cases, doctors may also prescribe medications to lower cholesterol.
These include:
  1. reducing high cholesterol.
  2. reducing high blood pressure.
  3. quitting smoking, if you smoke.

How can you prevent peripheral vascular disease from getting worse? ›

Get plenty of physical activity to help prevent PAD or improve symptoms of PAD. Do not use tobacco. Smoking increases the risk of PAD and makes PAD symptoms worse. Control high blood pressure and manage high blood cholesterol and diabetes.

Is heat good for peripheral artery disease? ›

Heat therapy has been shown to safely and effectively generate cardiovascular adaptations in PAD as well as reduce pain and improve overall physical function [13,14,15].

Is anticoagulation beneficial in pulmonary arterial hypertension? ›

The present meta-analysis shows that (1) anticoagulation is associated with reduced mortality in all comers with PAH and (2) anticoagulation may be associated with improved survival in idiopathic PAH but may be associated with reduced survival in systemic sclerosis-associated PAH.

How do anticoagulants prevent clot formation? ›

Anticoagulants derive their effect by acting at different sites of the coagulation cascade. Some act directly by enzyme inhibition, while others indirectly, by binding to antithrombin or by preventing their synthesis from the liver (vitamin K dependent factors).

Do anticoagulants prevent platelet aggregation? ›

Anticoagulants, such as heparin or warfarin (also called Coumadin), slow down your body's process of making clots. Antiplatelets, such as aspirin and clopidogrel, prevent blood cells called platelets from clumping together to form a clot.

Why would you use antiplatelet vs anticoagulant? ›

Anticoagulants slow down clotting, thereby reducing fibrin formation and preventing clots from forming and growing. Antiplatelet agents prevent platelets from clumping and also prevent clots from forming and growing.


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