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OtherPractice

Cardiovascular safety of NSAIDs

Megan Harbin, Ricky D. Turgeon and Michael R. Kolber
Canadian Family Physician March 2014, 60 (3) e166;
Megan Harbin
Clinical pharmacist working in internal medicine at Vancouver General Hospital in British Columbia.
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Ricky D. Turgeon
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Michael R. Kolber
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Clinical question

Do different nonsteroidal anti-inflammatory drugs (NSAIDs) have different cardiovascular (CV) risks?

Bottom line

Cyclooxygenase-2 (COX-2) inhibitors and traditional NSAIDs except naproxen increase the risk of serious CV events and death. When prescribing NSAIDs, patients’ gastrointestinal (GI) and CV risks should be assessed, with naproxen or low-dose ibuprofen preferentially chosen for patients at risk of CV disease.

Evidence

  • Meta-analysis of 754 RCTs (about 350 000 patients)1:

    • -Mixed population, primarily patients with arthritis at low to moderate CV risk (ie, CV event rate about 1% per year).

    • -Use of COX-2 inhibitors compared with placebo increased

      • —all-cause mortality, rate ratio (RR) = 1.22 (95% CI 1.04 to 1.44); and

      • —serious CV events, RR = 1.37 (95% CI 1.14 to 1.66).

    • -Diclofenac (150 mg daily): similar risks to COX-2 inhibitors for mortality (RR = 1.02 [95% CI 0.84 to 1.24]) and CV events (RR = 0.97 [95% CI 0.84 to 1.12]).

      • —Indirectly, diclofenac significantly increases CV events (RR = 1.41 [95% CI 1.12 to 1.78; P = .0036]) but not mortality (RR = 1.20 [95% CI 0.94 to 1.54]) compared with placebo.

    • -Naproxen (1000 mg daily) is associated with fewer CV events and lower mortality than COX-2 inhibitors and might be similar to placebo.

    • -Relative risk similar between patients with and without existing CV disease.

  • Meta-analysis of observational trials2:

    • -All COX-2 inhibitors and NSAIDs except naproxen and low-dose ibuprofen (≤ 1200 mg daily) increase CV risk.

    • -Risk increases with increasing NSAID dose.

  • Results are consistent with previous meta-analysis.3

Context

  • In Canada, naproxen (28%), celecoxib (21%), and diclofenac (17%) account for most of the NSAIDs prescribed.4

  • The magnitude of CV risk with high-risk NSAIDs is similar to the magnitude of the CV benefit with statin therapy. Taking high-risk NSAIDs daily can cause 1 additional CV event in 5 years in1

    • -about 100 low-risk patients (baseline 5% 10-year CV risk); and

    • -about 25 high-risk patients (baseline 20% 10-year CV risk).

  • Generally, NSAIDs with low CV risks (naproxen) have high GI risks (ulcers and bleeding) and vice versa.5

    • -Adding a proton pump inhibitor to a non-selective NSAID has similar GI complication risks to a COX-2 inhibitor.6

  • All NSAIDs increase the risk of heart failure.1

Implementation

Long-term CV and GI risks of NSAIDs drive the need for safer options. In patients with hand or knee osteoarthritis in whom acetaminophen results in suboptimal pain relief,7 topical NSAIDs are an option. Compared with placebo, more patients using topical diclofenac achieved a 50% reduction in pain (number needed to treat 5 to 10).8 Topical diclofenac also had similar pain reduction as oral NSAIDs but fewer GI side effects (RR = 0.66 [95% CI 0.56 to 0.77]). With negligible systemic absorption,9 topical NSAIDs are expected to have minimal CV effects versus oral agents, although actual clinical evidence is limited.8,10 Topical NSAIDs should be considered before oral NSAIDs in patients with hand or knee osteoarthritis who have the manual dexterity to apply these products.

Notes

Tools for Practice articles in Canadian Family Physician (CFP) are adapted from articles published on the Alberta College of Family Physicians (ACFP) website, summarizing medical evidence with a focus on topical issues and practice-modifying information. The ACFP summaries and the series in CFP are coordinated by Dr G. Michael Allan, and the summaries are co-authored by at least 1 practising family physician and are peer reviewed. Feedback is welcome and can be sent to toolsforpractice{at}cfpc.ca. Archived articles are available on the ACFP website: www.acfp.ca.

Footnotes

  • The opinions expressed in Tools for Practice articles are those of the authors and do not necessarily mirror the perspective and policy of the Alberta College of Family Physicians.

  • Copyright© the College of Family Physicians of Canada

References

  1. 1.↵
    1. Coxib and Traditional NSAID Trialists’ Collaboration
    . Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials. Lancet 2013;382(9894):769-79.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. McGettigan P,
    2. Henry D
    . Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med 2011;8(9):1-18.
    OpenUrl
  3. 3.↵
    1. Trelle S,
    2. Reichenbach S,
    3. Wandel S,
    4. Hildebrand P,
    5. Tschannen B,
    6. Villiger PM,
    7. et al
    . Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. McGettigan P,
    2. Henry D
    . Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med 2013;10(2):1-6.
    OpenUrl
  5. 5.↵
    1. Castellsague J,
    2. Riera-Guardia N,
    3. Calingaert,
    4. Varas-Lorenzo C,
    5. Fourrier-Reglat A,
    6. Nicotra F,
    7. et al
    . Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf 2012;35(12):1127-46.
    OpenUrlPubMed
  6. 6.↵
    1. Wang X,
    2. Tian HJ,
    3. Yang HK,
    4. Wanyan P,
    5. Peng YJ
    . Meta-analysis: cyclooxygenase-2 inhibitors are no better than nonselective nonsteroidal anti-inflammatory drugs with proton pump inhibitors in regard to gastrointestinal adverse events in osteoarthritis and rheumatoid arthritis. Eur J Gastroenterol Hepatol 2011;23(10):876-80.
    OpenUrlPubMed
  7. 7.↵
    1. Hochberg MC,
    2. Altman RD,
    3. April KT,
    4. Benkhalti M,
    5. Guyatt G,
    6. McGowan J,
    7. et al
    . American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip and knee. Arthritis Care Res (Hoboken) 2012;64(4):465-74.
    OpenUrlPubMed
  8. 8.↵
    1. Derry S,
    2. Moore RA,
    3. Rabbie R
    . Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 2012;(9):CD007400.
  9. 9.↵
    1. Kienzler JL,
    2. Gold M,
    3. Nollevaux F
    . Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac in healthy volunteers. J Clin Pharmacol 2010;50(1):50-61.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Roth SH,
    2. Fuller P
    . Diclofenac topical solution compared with oral diclofenac: a pooled safety analysis. J Pain Res 2011;4:159-67.
    OpenUrlPubMed
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Canadian Family Physician: 60 (3)
Canadian Family Physician
Vol. 60, Issue 3
1 Mar 2014
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Cardiovascular safety of NSAIDs
Megan Harbin, Ricky D. Turgeon, Michael R. Kolber
Canadian Family Physician Mar 2014, 60 (3) e166;

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Megan Harbin, Ricky D. Turgeon, Michael R. Kolber
Canadian Family Physician Mar 2014, 60 (3) e166;
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