Antithrombotic Management Pre & Post PAD Revascularization

ABI interpretation:

• Abnormal <0.9
• Abnormal >1.4 (potential non-compressible arteries)

Symptoms include:

• Loss of feeling or  tingling in the legs or feet?
• Toes that are pale, discolored or bluish?
• Feet that are cold to the touch or one foot that is colder than the other?
• Sores, wounds or ulcers on the legs or feet?
• Leg pain that disturbs your sleep or pain at rest?
• Aching, cramping or pain in your legs, calves, buttocks or thighs when you walk or exercise?
• Does the aching, cramping or pain in your legs, calves, buttocks or thighs when you walk or exercise persist even at rest?

*atrial fibrillation (Afib)

*antiphospholipid syndrome (APS)

*venous thromboembolism (VTE treatment)

Bleeding Risk Factors to Consider:

• Concurrent NSAID or other antiplatelet agents
• History of hemorrhagic stroke, intracranial hemorrhage, or significant bleeding
• Recent GI ulceration
• Active malignant neoplasms at risk of bleeding
• History of vascular aneurysms
• History of coagulopathies/bleeding disorders
• Uncontrolled hypertension (SBP > 160 mmHg)
• Heavy alcohol use or esophageal varices
• Acute liver or renal failure
• Recent trauma or surgery

These factors represent a sampling of bleeding risk factors from validated tools (HAS-BLED, HEMORR2HAGES, IMPROVE-VTE) and the primary literature (VOYAGER-PAD, COMPASS.)

• HAS-BLED
• HEMORR2HAGES
• IMPROVE-VTE
• VOYAGER-PAD

*e.g., acute coronary syndrome, recent DES placement inn coronary or below knee arteries

Bleeding Risk Factors to Consider:

• Concurrent NSAID or other antiplatelet agents
• History of hemorrhagic stroke, intracranial hemorrhage, or significant bleeding
• Recent GI ulceration
• Active malignant neoplasms at risk of bleeding
• History of vascular aneurysms
• History of coagulopathies/bleeding disorders
• Uncontrolled hypertension (SBP > 160 mmHg)
• Heavy alcohol use or esophageal varices
• Acute liver or renal failure
• Recent trauma or surgery

These factors represent a sampling of bleeding risk factors from validated tools (HAS-BLED, HEMORR2HAGES, IMPROVE-VTE) and the primary literature (VOYAGER-PAD, COMPASS.)

• HAS-BLED
• HEMORR2HAGES
• IMPROVE-VTE
• VOYAGER-PAD

Contraindication Examples

• Combined CYP3a and P-gp inducers and inhibitors (ketoconazole, ritonavir, erythromycin, carbamazepine, phenytoin, rifampin, St. John’s wort, etc.) - Xarelto Package Insert. Janssen Pharmaceuticals, 2023.

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Treatment Options

If Symptomatic - Dual Pathway Inhibition (DPI): 

• Rivaroxaban 2.5mg BID -PLUS-
• Aspirin 81 mg daily

If Symptomatic & high bleed risk - Monotherapy

• Aspirin 81mg daily

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

Possible reasons selected that may disqualify DPI as a safe treatment option:

• CrCl < 15ml/min
• Medication cost or lack of insurance coverage: Consider consult with Pharmacy or Social Work for assistance.
• Taking other medication that is contraindicated for use with rivaroxaban

Treatment Options

If Symptomatic - Dual Pathway Inhibition (DPI): 

• Rivaroxaban 2.5mg BID -PLUS-
• Aspirin 81 mg daily

If Symptomatic & high bleed risk - Monotherapy

• Aspirin 81mg daily

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

Aspirin allergy! Consider consultation with interventionalist for treatment options.

Dual Antiplatelet Therapy (DAPT): 

• P2Y12 inhibitor: (e.g., clopidogrel, ticagrelor, etc.) - PLUS 
• Aspirin: ACOX-1 inhibitor which blocks platelet activation via TXA-2

PAD & on antithrombotic therapy for alternate indication:

• Continue current antithrombotic strategy -PLUS- 
• ADD Aspirin 81 mg daily if bleeding risk allows.

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

Dual Antiplatelet Therapy (DAPT): 

• P2Y12 inhibitor: (e.g., clopidogrel, ticagrelor, etc.) - PLUS 
• Aspirin: ACOX-1 inhibitor which blocks platelet activation via TXA-2

Dual Pathway Inhibition (DPI): 

• Rivaroxaban: A factor Xa inhibitor which blocks platelet activation by inhibition of thrombin formation. 
• Aspirin: ACOX-1 inhibitor which blocks platelet activation via TXA-2 - PLUS
• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk

Possible reasons that may disqualify DPI as a safe treatment option:

• CrCl < 15ml/min
• Aspirin allergy
• High risk of bleeding
• Medication cost or lack of insurance coverage: Consider consult with Pharmacy or Social Work for assistance.
• Taking other medication that is contraindicated for use with rivaroxaban

View the full ACE Rapid Resource decision tree.

Dual Pathway Inhibition (DPI): 

• Rivaroxaban: A factor Xa inhibitor which blocks platelet activation by inhibition of thrombin formation. 
• Aspirin: ACOX-1 inhibitor which blocks platelet activation via TXA-2 - PLUS
• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk

Treatment Options (Review bleeding risk from previous assessment) -Bleed Risk!

PAD: Dual Pathway Inhibition (DPI) 

• Rivaroxaban 2.5mg BID -PLUS-
• Aspirin 81 mg daily

PAD & Increased Bleed Risk: Consider Monotherapy

• Aspirin 81mg daily

PAD & on antithrombotic therapy for alternate indication:

• Continue current antithrombotic strategy -PLUS- 
• ADD Aspirin 81 mg daily if bleeding risk allows.

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

PAD & on antithrombotic therapy for alternate indication:

• Continue current antithrombotic strategy -PLUS- 
• ADD Aspirin 81 mg daily if bleeding risk allows.

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

**Consider prompt care coordination with vascular interventionalist**

Treatment Options (With close monitoring - Increased Bleed Risk!)

Dual Pathway Inhibition (DPI) 

• Rivaroxaban 2.5mg BID -PLUS-
• Aspirin 81 mg daily
• Verify all P2Y12 prescriptions have been discontinued at pharmacy

-OR-

Alternative - Dual Antiplatelet Therapy (DAPT) 

• Clopidogrel 75mg daily -PLUS-
• Aspirin 81mg daily

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• No literature is available to compare the efficacy and safety of DPI and DAPT in this population. DPI has been shown to reduce the risk of MACE and MALE following endovascular or surgical intervention (HR 0.85, p = 0.009, VOYAGER-PAD trial). No increase in fatal bleeding or intracranial bleeding was seen. ISTH major bleeding occurred in 5.94% in DPI (vs. 4.06% aspirin alone; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P=0.007). 
• Rates of DAPT therapy have been extrapolated from percutaneous coronary interventions, with published major bleeding rates of 3.1-6.2% (ACC 2020, CHARISMA Trial.) 
• View the full Anticoagulation Forum ACE Rapid Resource decision tree on the use of DPI.

Treatment Options

If Symptomatic - Dual Pathway Inhibition (DPI): 

• Rivaroxaban 2.5mg BID -PLUS-
• Aspirin 81 mg daily

If Symptomatic & high bleed risk - Monotherapy

• Aspirin 81mg daily

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

Treatment Options

If Asymptomatic  - Monotherapy

• Aspirin 81mg daily -OR- Clopidogrel 75mg daily

If Asymptomatic & high bleed risk - Monotherapy

• Aspirin 81mg daily

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

Possible reasons selected that may disqualify DPI as a safe treatment option:

• CrCl < 15ml/min
• Medication cost or lack of insurance coverage: Consider consult with Pharmacy or Social Work for assistance.
• Taking other medication that is contraindicated for use with rivaroxaban

Treatment Options

If Symptomatic - Dual Pathway Inhibition (DPI): 

• Rivaroxaban 2.5mg BID -PLUS-
• Aspirin 81 mg daily

If Symptomatic & high bleed risk - Monotherapy

• Aspirin 81mg daily

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

Possible reasons that may disqualify DPI as a safe treatment option:

• CrCl < 15ml/min
• Aspirin allergy
• Medication cost or lack of insurance coverage: Consider consult with Pharmacy or Social Work for assistance.
• High risk of bleeding
• On long-term anticoagulation for Afib, mechanical valve, APS, or extended VTE treatment
• On short-term anticoagulation (e.g., VTE initial treatment)
• Taking other medication that is contraindicated for use with rivaroxaban

PAD & on antithrombotic therapy for alternate indication:

• Continue current antithrombotic strategy -PLUS- 
• ADD Aspirin 81 mg daily if bleeding risk allows.

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

Dual Pathway Inhibition (DPI): 

• Rivaroxaban: A factor Xa inhibitor which blocks platelet activation by inhibition of thrombin formation. 
• Aspirin: ACOX-1 inhibitor which blocks platelet activation via TXA-2 - PLUS
• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk

Treatment Options

If Asymptomatic  - Monotherapy

• Aspirin 81mg daily -OR- Clopidogrel 75mg daily

If Asymptomatic & high bleed risk - Monotherapy

• Aspirin 81mg daily

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2.

**Consider prompt care coordination with vascular interventionalist**

**Follow-up in 30 days**

Treatment Options < 30 days post revascularization: (With close monitoring if Increased Bleed Risk!)

Dual Pathway Inhibition (DPI): 

• Rivaroxaban 2.5mg twice daily -PLUS-
• Aspirin 81mg daily  -PLUS-
• Clopidogrel 75mg PO Daily for 30 days only (no refills)
• Verify all P2Y12 prescriptions have been discontinued at pharmacy.

-OR-

Dual Pathway Inhibition (DPI): 

• Rivaroxaban 2.5mg twice daily -PLUS-
• Aspirin 81mg daily  
• Verify all P2Y12 prescriptions have been discontinued at pharmacy.

-OR-

Dual Antiplatelet Therapy (DAPT): 

• Clopidogrel 75mg daily -PLUS-
• Aspirin 81mg daily
• Verify all P2Y12 prescriptions have been discontinued at pharmacy.

For Claudication symptoms:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• No literature is available to compare the efficacy and safety of DPI and DAPT in this population. DPI has been shown to reduce the risk of MACE and MALE following endovascular or surgical intervention (HR 0.85, p = 0.009, VOYAGER-PAD trial). No increase in fatal bleeding or intracranial bleeding was seen. ISTH major bleeding occurred in 5.94% in DPI (vs. 4.06% aspirin alone; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P=0.007). 
• Rates of DAPT therapy have been extrapolated from percutaneous coronary interventions, with published major bleeding rates of 3.1-6.2% (ACC 2020, CHARISMA Trial.) 
• View the full Anticoagulation Forum ACE Rapid Resource decision tree on the use of DPI.

**Consider prompt care coordination with vascular interventionalist**

Treatment Options (With close monitoring if Increased Bleed Risk!)

Dual Pathway Inhibition (DPI) 

• Rivaroxaban 2.5mg BID -PLUS-
• Aspirin 81 mg daily
• Verify all P2Y12 prescriptions have been discontinued at pharmacy

-OR-

Alternative - Dual Antiplatelet Therapy (DAPT) 

• Clopidogrel 75mg daily -PLUS-
• Aspirin 81mg daily

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• No literature is available to compare the efficacy and safety of DPI and DAPT in this population. DPI has been shown to reduce the risk of MACE and MALE following endovascular or surgical intervention (HR 0.85, p = 0.009, VOYAGER-PAD trial). No increase in fatal bleeding or intracranial bleeding was seen. ISTH major bleeding occurred in 5.94% in DPI (vs. 4.06% aspirin alone; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P=0.007). 
• Rates of DAPT therapy have been extrapolated from percutaneous coronary interventions, with published major bleeding rates of 3.1-6.2% (ACC 2020, CHARISMA Trial.) 
• View the full Anticoagulation Forum ACE Rapid Resource decision tree on the use of DPI.

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Treatment Options (Review bleeding risk from previous assessment)

PAD: Dual Pathway Inhibition (DPI) 

• Rivaroxaban 2.5mg BID -PLUS-
• Aspirin 81 mg daily

PAD & Increased Bleed Risk: Consider Monotherapy

• Aspirin 81mg daily

PAD & on antithrombotic therapy for alternate indication:

• Continue current antithrombotic strategy -PLUS-
• ADD Aspirin 81 mg daily if bleeding risk allows.

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.

Footnote

• The rationale behind dual pathway inhibition is to block two different mechanisms for platelet activation to further reduce thrombotic risk. In the COMPASS Trial, the combination of rivaroxaban (a factor Xa inhibitor) and aspirin has been shown to reduce the rates of MACE and MALE (6% vs. 9%, HR 0.69, P < 0.001) versus aspirin monotherapy without increases in fatal or nonfatal bleeding or intracranial hemorrhage. 
• Major bleeding was increased in DPI vs. ASA (3% vs. 2%, HR 1.61, p=0.008) and was driven by increased gastrointestinal bleeding, and front-loaded in the first year (COMPASS Trial).
• For more information, view the Anticoagulation Forum Rapid Resource on PAD and DPI.
• Factor Xa inhibitors (rivaroxaban) blocks platelet activation by inhibition of thrombin formation, while aspirin, a COX-1 inhibitor, blocks platelet activation via inhibition of thromboxane A2 .

For claudication symptoms consider:

• Cilostazol 75mg BID: Do NOT use in the presence of heart failure or cardiomyopathy.