Is diclofenac safe to use in a patient on warfarin with a deranged (out‑of‑range) INR?

Diclofenac is Contraindicated in Patients on Warfarin with Deranged INR

Diclofenac should be absolutely avoided in any patient on warfarin with a deranged INR due to the dual risk of pharmacokinetic drug interaction that further elevates INR and the independent platelet inhibition that amplifies bleeding risk. 1, 2

The Dual Mechanism of Harm

Pharmacokinetic Interaction

• Diclofenac directly increases INR in approximately 46% of patients on acenocoumarol (a coumarin anticoagulant similar to warfarin), with INR elevations ranging from 1 to 4 points above baseline. 1
• In the Dutch cohort study, 12 patients experienced INR values exceeding 6.0 when diclofenac was added to stable anticoagulation therapy, demonstrating that this interaction can push already-elevated INRs into dangerous territory. 1
• This pharmacokinetic effect is independent of CYP2C9 polymorphism, meaning all patients are at risk regardless of genetic factors. 1

Platelet Inhibition

• NSAIDs like diclofenac inhibit platelet aggregation through COX-1 inhibition, creating an additional bleeding mechanism that is entirely separate from the anticoagulant effect. 1, 3
• A case report documented spontaneous epidural spinal hematoma in a patient on warfarin with therapeutic INR (2.2-2.4) who was concurrently taking diclofenac, demonstrating that even "controlled" anticoagulation becomes dangerous when combined with NSAIDs. 2

Clinical Significance in Deranged INR

Bleeding Risk Thresholds

• The risk of major bleeding becomes clinically significant when INR exceeds 5.0, with one prospective study showing a 4.4% rate of major hemorrhage within 14 days in patients with INR >6.0. 4, 5
• Patients with INR >6.0 face an 8.8% risk of seeking medical attention for abnormal bleeding within 14 days, compared to 0% in patients with therapeutic INR. 4
• Adding diclofenac to an already deranged INR creates a compounding effect: the drug can elevate INR by an additional 1-4 points while simultaneously impairing hemostasis through platelet dysfunction. 1

Real-World Consequences

• The epidural spinal hematoma case illustrates that intraspinal hemorrhage can occur even with therapeutic INR when NSAIDs are co-administered, and this risk is exponentially higher with supratherapeutic INR. 2
• Most reported cases of serious bleeding complications from warfarin-NSAID interactions occurred in patients who were anticoagulated within or near the therapeutic range, meaning a deranged INR dramatically amplifies this baseline risk. 2

Management Algorithm for the Patient on Warfarin with Deranged INR

Step 1: Immediate Assessment

• Determine the INR level and assess for any signs of bleeding (overt hemorrhage, hemoglobin drop ≥2 g/dL, hemodynamic instability, or critical-site bleeding). 5
• Identify all concurrent medications, particularly NSAIDs, antiplatelet agents, antibiotics, and other drugs that interact with warfarin. 5, 1

Step 2: INR-Based Management (Without Bleeding)

For INR 5.0-9.0:

• Withhold warfarin for 1-2 doses and monitor serial INR measurements. 5
• Add oral vitamin K 1-2.5 mg only if high-risk bleeding factors are present (age >65-75 years, prior bleeding history, concurrent antiplatelet therapy, renal failure, or alcohol use). 5
• Absolutely discontinue diclofenac or any other NSAID immediately. 1, 2

For INR >10:

• Immediately stop warfarin and administer oral vitamin K 2.5-5 mg. 5
• Recheck INR within 24 hours. 5
• Discontinue diclofenac permanently and counsel patient on NSAID avoidance. 1, 2

Step 3: Management with Active Bleeding

For major bleeding (any INR level):

• Administer 4-factor prothrombin complex concentrate (PCC) 25-50 U/kg IV based on INR level (25 U/kg for INR 2-4,35 U/kg for INR 4-6,50 U/kg for INR >6). 5
• Co-administer vitamin K 5-10 mg by slow IV infusion over 30 minutes. 5
• Target INR <1.5 for hemostasis. 5
• PCC achieves INR correction within 5-15 minutes versus hours with fresh frozen plasma. 5

For life-threatening bleeding:

• Immediate PCC 50 U/kg IV plus vitamin K 10 mg IV. 5
• Recheck INR 30 minutes after PCC administration. 5
• Monitor for thrombotic complications, as PCC increases thrombosis risk during the recovery period. 5

Critical Pitfalls to Avoid

Never Use Diclofenac as "Bridge" Analgesia

• Some clinicians mistakenly prescribe NSAIDs for pain management while adjusting warfarin doses—this is extremely dangerous. 1, 2
• Even short-term NSAID use (days to weeks) can precipitate the pharmacokinetic interaction and elevate INR unpredictably. 1

Recognize the Delayed Effect

• The INR elevation from diclofenac may not be immediate; it can develop over several days as the drug accumulates and inhibits warfarin metabolism. 1
• Patients may present with deranged INR days after starting diclofenac, making the temporal relationship less obvious. 1

Alternative Analgesics

• Acetaminophen (paracetamol) is the preferred analgesic in anticoagulated patients, though doses >2 g/day for >1 week can also increase INR and require monitoring. 5
• Opioid analgesics do not interact with warfarin and are safer alternatives for moderate-to-severe pain. 3
• Topical NSAIDs have minimal systemic absorption and may be considered for localized musculoskeletal pain, though caution is still warranted. 3

Patient Education Essentials

• Explicitly counsel patients on warfarin to avoid all over-the-counter NSAIDs (ibuprofen, naproxen, diclofenac) and to check with their anticoagulation provider before starting any new medication. 1, 2
• Provide written lists of medications to avoid, as many patients do not recognize diclofenac as an NSAID or understand the interaction risk. 2
• Instruct patients to report any signs of bleeding immediately: unusual bruising, blood in urine or stool, prolonged bleeding from cuts, or severe headache. 4, 2

Monitoring After NSAID Discontinuation

• Recheck INR within 3-5 days after discontinuing diclofenac, as the drug's effect on warfarin metabolism may persist for several days. 1
• Once INR stabilizes in therapeutic range, continue monitoring weekly for 4 weeks, then return to routine monthly monitoring if stable. 5
• Investigate and correct other factors that may have contributed to INR elevation (dietary changes, antibiotics, intercurrent illness, medication non-adherence). 5