Can ketorolac (Toradol) be given to a patient taking apixaban (Eliquis) 5 mg?

Avoid Ketorolac (Toradol) in Patients Taking Apixaban (Eliquis) 5 mg

Ketorolac should not be administered to patients taking apixaban 5 mg twice daily due to a significantly increased risk of major bleeding. The combination of a direct oral anticoagulant with an NSAID creates additive antiplatelet and anticoagulant effects that substantially elevate hemorrhagic complications.

Mechanism of Increased Bleeding Risk

• The FDA explicitly warns that concomitant use of NSAIDs—including ketorolac—with apixaban increases the risk of bleeding and can cause serious, potentially fatal hemorrhage. 1

• Ketorolac reversibly inhibits cyclooxygenase and thromboxane synthesis, producing antiplatelet effects that prolong bleeding time, which compounds the anticoagulant effect of apixaban. 2

• The 2023 ACC/AHA/ACCP/HRS guidelines state that drugs affecting hemostasis—including NSAIDs—increase bleeding risk when combined with apixaban. 3

Evidence of Bleeding Complications

• Ketorolac is associated with gastrointestinal bleeding, perforation, and operative-site bleeding, with risk increasing at higher doses and in vulnerable patients such as the elderly. 4

• The incidence of serious adverse events with ketorolac has declined since dosage guidelines were revised, but the overall risk of gastrointestinal or operative-site bleeding remains slightly higher than with opioids and is substantially elevated when combined with anticoagulants. 4

• Apixaban already carries an inherent bleeding risk; in the ARISTOTLE trial, major bleeding occurred in patients receiving apixaban, and adding an NSAID would further amplify this risk. 5

Safer Analgesic Alternatives

• Acetaminophen (paracetamol) is the preferred first-line analgesic for patients on apixaban, as it does not inhibit platelet function or increase bleeding risk. 3

• If opioid analgesia is required, morphine or hydrocodone can be used cautiously, as these agents do not affect hemostasis and have been compared favorably to ketorolac in postoperative pain management. 3, 2

• Tramadol represents another option for moderate pain, offering analgesic efficacy without the antiplatelet effects of NSAIDs. 3

Additional Contraindications to Ketorolac

• Ketorolac is contraindicated in patients with a history of gastrointestinal bleeding, compromised hemostasis, or hypersensitivity to aspirin or other NSAIDs. 4

• Ketorolac can precipitate bronchospasm in patients with asthma, rhinitis, or nasal polyps, and should be avoided in these populations. 6

• Acute renal failure has been reported after ketorolac treatment, which is particularly concerning in patients taking apixaban who may already have renal impairment requiring dose adjustment. 4

Clinical Decision Algorithm

1. Confirm the patient is taking apixaban 5 mg twice daily and assess the indication for analgesia.

2. Avoid all NSAIDs, including ketorolac, ibuprofen, and naproxen, due to additive bleeding risk. 1, 3

3. Initiate acetaminophen up to 4 grams daily (divided doses) as first-line therapy for mild-to-moderate pain. 3

4. If acetaminophen is insufficient, add a short-acting opioid (e.g., oxycodone 5–10 mg every 4–6 hours) for moderate-to-severe pain. 3

5. Monitor for signs of bleeding (e.g., hematemesis, melena, hematuria, unexplained bruising, hemoglobin drop ≥2 g/dL) and advise the patient to report symptoms immediately. 1

6. Reassess renal function if opioids or acetaminophen are used long-term, as apixaban dosing depends on creatinine clearance calculated by the Cockcroft-Gault equation. 7

Common Pitfalls

• Do not assume that a single dose of ketorolac is safe; even short-term NSAID use in anticoagulated patients increases bleeding risk. 4

• Avoid topical NSAIDs (e.g., diclofenac gel) as well, since systemic absorption can still occur and contribute to bleeding risk. 4

• Do not use aspirin for analgesia in patients on apixaban unless there is a compelling cardiovascular indication (e.g., recent acute coronary syndrome), as dual antiplatelet-anticoagulant therapy markedly increases hemorrhagic complications. 8

• If the patient has already received ketorolac, monitor closely for 24–48 hours (approximately two half-lives of ketorolac) for signs of bleeding, and consider holding the next dose of apixaban if active bleeding occurs. 1, 9