In a patient with severe peripheral artery disease who is hospitalized and receiving aspirin (acetylsalicylic acid), clopidogrel (Plavix), and therapeutic enoxaparin (Lovenox) and now has an occult gastrointestinal bleed with falling hemoglobin, which medication(s) should be stopped and which can be continued if at least one antithrombotic must be maintained?

Management of Antithrombotic Therapy in Severe PAD with Gastrointestinal Bleeding

Stop enoxaparin immediately and discontinue clopidogrel temporarily, but continue aspirin monotherapy with proton pump inhibitor (PPI) co-therapy. 1

Immediate Medication Management

Stop Enoxaparin (Lovenox)

• Therapeutic anticoagulation with enoxaparin must be discontinued immediately in the setting of active GI bleeding with falling hemoglobin. 1
• The anticoagulant effect of low molecular weight heparin persists for 24 hours, and protamine sulfate provides only partial reversal. 1
• Enoxaparin combined with dual antiplatelet therapy creates a 2.7% incidence of GI bleeding in acute settings, with mortality risk primarily from cardiac events rather than bleeding complications. 2

Discontinue Clopidogrel Temporarily

• In the event of severe GI bleeding, antiplatelet therapy discontinuation should be limited to clopidogrel (the P2Y12 inhibitor), while aspirin is continued. 1
• Clopidogrel must be restarted within 5 days maximum owing to high risk of thrombosis after this timeframe, based on studies of drug-eluting stent discontinuation representing optimal balance between hemorrhage and thrombosis. 1
• Complete cessation of all antiplatelet therapy is an independent predictor of stent thrombosis and mortality. 3, 4

Continue Aspirin

• Aspirin for secondary prevention should not be routinely stopped, and if stopped, must be restarted as soon as hemostasis is achieved. 1
• Patients who discontinued aspirin after admission with lower GI bleeding had fewer rebleeding events but significantly more cardiovascular events and deaths compared to those who continued it. 1
• Aspirin 75-100 mg daily should be maintained even during active bleeding management in patients with severe PAD, as the cardiovascular mortality risk exceeds bleeding mortality risk. 5, 3

Critical Gastrointestinal Protection

Mandatory PPI Co-Prescription

• PPI co-prescription is mandatory and significantly reduces upper GI bleeding risk with antiplatelet therapy. 5, 2
• PPIs should be continued indefinitely while on any antiplatelet therapy to reduce recurrent bleeding risk. 5
• The age-adjusted odds ratio for GI bleeding was 0.068 (95% CI: 0.010-0.272) with PPI coprescription in patients on triple antithrombotic therapy. 2

Timing of Medication Resumption

Clopidogrel Restart Window

• Resume clopidogrel within 3-5 days once hemoglobin stabilizes and occult blood testing becomes negative. 1, 3
• The P2Y12 inhibitor should be restarted within 5 days at maximum due to high risk of thrombosis, representing optimal balance between hemorrhage and thrombosis. 1
• For patients with recent coronary stents (less than 1 month post-PCI), aim for resumption within 48-72 hours given extremely high stent thrombosis risk. 3

Enoxaparin Considerations

• Enoxaparin should only be restarted if there is a specific ongoing indication (such as acute venous thromboembolism or atrial fibrillation with high stroke risk) after bleeding has completely resolved. 1
• If anticoagulation is absolutely necessary, direct oral anticoagulants (DOACs) should be restarted at a maximum of 7 days after hemorrhage. 1

Supportive Management During Bleeding Episode

Hemostasis Optimization

• Avoid excessive red blood cell transfusion—transfuse only if hemodynamically unstable, as transfusion releases ADP and paradoxically increases platelet reactivity and thrombotic risk. 3
• Urgent interventional endoscopy should be performed to identify and treat the bleeding source, allowing earlier resumption of full antiplatelet therapy. 5, 6

Risk Factor Assessment

• Previous peptic ulcer disease has an age-adjusted odds ratio of 5.07 (95% CI: 1.31-16.58) for GI bleeding on triple antithrombotic therapy. 2
• Check hemoglobin, iron studies, and repeat stool occult blood testing to ensure hemoglobin is >12 g/dL before resuming dual therapy. 4

Common Pitfalls to Avoid

Never Stop All Antithrombotic Therapy Simultaneously

• Complete cessation of both antiplatelet agents is an independent predictor of stent thrombosis and mortality, particularly in patients with severe PAD. 5, 3, 4
• The mortality risk from thrombotic events (myocardial infarction, stroke, acute limb ischemia) far exceeds mortality risk from GI bleeding in most cases. 3
• Only one patient (0.15%) died of massive GI bleeding in a cohort of 666 patients on triple therapy, while 3.6% died of cardiac events. 2

Avoid Inappropriate Drug Selection

• Do not use ticagrelor or prasugrel in stable PAD patients with GI bleeding history, as these agents inappropriately increase bleeding risk compared to clopidogrel without evidence of benefit in this population. 5, 4
• Clopidogrel is preferred over aspirin as monotherapy in established peripheral arterial disease based on efficacy and safety profiles. 7, 8

Do Not Delay Endoscopy

• Early endoscopy is recommended for most patients with acute upper GI bleeding to achieve hemostasis and allow earlier resumption of antiplatelet therapy. 6
• Urgent interventional endoscopy (ideally within 12 hours) should be performed to identify and treat the bleeding source. 5