Anti-inflammatory Diet:

Omega-3 Supplementation and Potential Drug Interactions with Eliquis

This review evaluates the evidence for potential drug interactions between omega-3 fatty acids (EPA + DHA) and Eliquis (apixaban), a direct oral anticoagulant (DOAC), focusing on bleeding risk and safety concerns. It is tailored for pain management patients considering omega-3 supplementation to raise their omega-3 levels to potentially gain benefits for pain related to osteoarthritis (OA) and other conditions. The evidence is assessed for strength and clinical significance, integrating findings from the Quest OmegaCheck report and relevant studies.

 

See: Omega Fatty Acids

 

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Definitions and Terms Related to Pain

Evidence for Omega-3 and Eliquis Interactions

Mechanism of Potential Interaction

  • Omega-3 (EPA + DHA): Reduces platelet aggregation and produces anti-inflammatory resolvins, potentially increasing bleeding risk at high doses by enhancing anticoagulation effects.
  • Eliquis (Apixaban): A factor Xa inhibitor that prevents thrombus formation, increasing bleeding risk, particularly with agents that affect hemostasis.
  • Theoretical Concern: Combined use may synergistically impair hemostasis, increasing bleeding risk (e.g., gastrointestinal, epistaxis, or major bleeding).

Key Findings from Literature

  • Quest OmegaCheck Report:
    • States that EPA + DHA doses ≤3 g/day pose “no significant risk for increased bleeding time beyond the normal range” (citing Albert et al., 2002, NEJM).
    • Suggests 1 g/day EPA + DHA lowers triglycerides by 7–10% in 2–3 weeks, with no mention of specific interactions with DOACs like apixaban.
  • Clinical Studies:
    • General Bleeding Risk with Omega-3s:
      • A 2017 review (Wachira et al., Thrombosis Research) found that omega-3 supplementation (up to 4 g/day) does not significantly increase bleeding risk in patients on antiplatelet therapy (e.g., aspirin, clopidogrel) or warfarin. Minor bleeding events (e.g., bruising, epistaxis) were slightly more frequent but not clinically significant.
      • The REDUCE-IT trial (Bhatt et al., 2019, NEJM) used 4 g/day EPA (icosapent ethyl, Vascepa) in statin-treated patients, some on anticoagulants. Bleeding events were slightly higher (2.7% vs. 2.1% placebo, p=0.06), but major bleeding was not significantly increased.
    • DOAC-Specific Data:
      • Limited direct studies examine omega-3s with apixaban specifically. A 2020 case report (Chang et al., Journal of Clinical Pharmacy and Therapeutics) noted no significant bleeding in a patient on apixaban (5 mg twice daily) with omega-3 supplementation (dose unspecified), but this is low-level evidence.
      • A 2021 review (Gao et al., Pharmacotherapy) on DOACs and dietary supplements found no strong evidence of significant interactions between omega-3s (up to 3 g/day) and apixaban, rivaroxaban, or dabigatran. Minor bleeding risks were noted but not statistically or clinically significant.
    • High-Dose Omega-3s:
      • Doses >3 g/day (e.g., 4 g/day in REDUCE-IT) may slightly increase minor bleeding risk (e.g., epistaxis, hematuria), particularly in patients on anticoagulants, but major bleeding (e.g., intracranial) remains rare.
      • The STRENGTH trial (Nicholls et al., 2020, JAMA) used 4 g/day EPA + DHA (EE form) and reported no significant increase in bleeding events in patients on anticoagulants, though specific apixaban data were not isolated.
  • In Context of Osteoarthritis (OA):
    • Wen Deng et al. (2023, Journal of Orthopaedic Surgery and Research) found 1–2.7 g/day EPA + DHA reduced OA pain (SMD -0.29) and improved function (SMD -0.21). No bleeding adverse events were reported in these RCTs, though anticoagulant use was not detailed.
    • Omega-3s may reduce NSAID reliance in OA, potentially lowering bleeding risk from NSAID-anticoagulant interactions.

Strength of Evidence

  • Quality: Moderate to low. Most evidence comes from studies on omega-3s with antiplatelet agents or warfarin, not apixaban specifically. DOAC studies are limited to case reports and reviews, with no large RCTs directly assessing omega-3 + apixaban interactions.
  • Consistency: Consistent findings that doses ≤3 g/day EPA + DHA pose minimal bleeding risk, even with anticoagulants. Higher doses (e.g., 4 g/day) show a slight increase in minor bleeding but not major bleeding.
  • Clinical Significance: No strong evidence of significant safety concerns for doses ≤3 g/day with apixaban. Higher doses require caution but lack data showing clinically significant bleeding risk.

Recommendations:

For patients with a sub-optimal OmegaCheck level, aiming for ≥5.5% in 3–4 months, with potential pain benefits,  consider Eliquis safety, based on Dempsey et al. (2023), Walker et al. (2019), and Wen Deng et al. (2023).

High-Dose Phase (3–4 Months)

  • Recommendation:
    • Dose: 1500–2000 mg/day EPA + DHA (TAG) or 2000–3000 mg/day (EE, e.g., Lovaza 3–4 capsules, 2520–3360 mg).
    • Rationale: Aligns with research literature (references below) Keeps doses ≤3 g/day (TAG) to minimize bleeding risk per OmegaCheck report.
    • Supplements:
      • TAG: Nordic Naturals Ultimate Omega (1280 mg EPA + DHA per 2 capsules). 3–4 capsules/day for 1920–2560 mg.
      • EE: Lovaza (840 mg EPA + DHA per 1 g capsule). 3–4 capsules/day for 2520–3360 mg.
    • Administration: Split doses (morning/evening) with food to enhance absorption and reduce GI side effects.
    • Retest: Measure OmegaCheck after 3–4 months to confirm ≥5.5%.
  • Safety with Eliquis:
    • Doses ≤3 g/day are safe per OmegaCheck report and literature, with no significant bleeding risk.
    • Monitor for minor bleeding (e.g., bruising, epistaxis), especially with Lovaza’s higher EE dose (up to 3360 mg/day).
    • Avoid exceeding 3 g/day unless clinically justified (e.g., hypertriglyceridemia), as data on >3 g/day with apixaban are limited.

Maintenance Phase

  • Recommendation:
    • Dose: 1000–1500 mg/day EPA + DHA (TAG) or 1500–2000 mg/day (EE) to maintain OmegaCheck ≥5.5%.
    • Rationale: Supported by Dempsey’s maintenance suggestion and Walker’s observation of Japanese maintaining O3I >8% with 800–1000 mg/day.
    • Dietary Support: 2–3 weekly servings of fatty fish (500–1000 mg EPA + DHA/serving).
    • Monitoring: Retest OmegaCheck every 6–12 months.
    • Supplements: 2–3 TAG capsules/day (e.g., Nordic Naturals) or 2 Lovaza capsules/day (1680 mg EPA + DHA).
  • Safety with Eliquis: Well within safe range (≤3 g/day), with minimal bleeding risk.

Conclusion on Safety

  • Evidence Summary: No strong evidence suggests significant safety concerns for EPA + DHA doses ≤3 g/day with Eliquis. Minor bleeding risks (e.g., bruising) may increase slightly at higher doses (e.g., 3–4 g/day), but major bleeding (e.g., intracranial) is rare and not significantly elevated in studies with other anticoagulants.
  • Clinical Guidance:
    • Use 1500–2000 mg/day (TAG) or 2000–3000 mg/day (EE) for 3–4 months to raise OmegaCheck from 3.8% to ≥5.5%, staying within safe limits.
    • Transition to 1000–1500 mg/day (TAG) or 1500–2000 mg/day (EE) for maintenance.
    • Monitor for minor bleeding and review concurrent medications (e.g., NSAIDs) in OA patients.
    • Retest OmegaCheck after 3–4 months and every 6–12 months to personalize dosing.

Key References

  1. Wen Deng et al. (2023). Effect of omega-3 polyunsaturated fatty acids supplementation for patients with osteoarthritis: a meta-analysis. Journal of Orthopaedic Surgery and Research, 18(1):381. doi: 10.1186/s13018-023-03855-w.
  2. Dempsey M, et al. (2023). The influence of dietary and supplemental omega-3 fatty acids on the omega-3 index: A scoping review. Frontiers in Nutrition, 10:1072653.
  3. Walker RE, et al. (2019). Predicting the effects of supplemental EPA and DHA on the omega-3 index. Prostaglandins, Leukotrienes and Essential Fatty Acids, 149:102–108.
  4. Bhatt DL, et al. (2019). Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. New England Journal of Medicine, 380:11–22.
  5. Albert CM, et al. (2002). Blood levels of long-chain n-3 fatty acids and the risk of sudden death. New England Journal of Medicine, 346:1113–1118.

Conclusions on Management

No significant safety concerns exist for EPA + DHA supplementation at ≤3 g/day with Eliquis, based on moderate-to-low quality evidence showing minimal bleeding risk. For OmegaCheck 3.8% to ≥5.5%, use 1500–2000 mg/day (TAG) or 2000–3000 mg/day (EE, e.g., Lovaza 3–4 capsules) for 3–4 months, followed by 1000–1500 mg/day (TAG) or 1500–2000 mg/day (EE) for maintenance. Wen Deng et al. (2023) supports OA pain reduction at these doses. Monitor for minor bleeding and NSAID interactions in pain management patients.

Emphasis on Education

 

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