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Cardiovascular effects and safety of (non-aspirin) NSAIDs

Nature Reviews Cardiology volume 17, pages 574–584 (2020)Cite this article

Subjects

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective, widely used analgesics. For the past 2 decades, considerable attention has been focused on their cardiovascular safety. After early studies indicating an association between NSAID use and increased risks of heart failure and elevated blood pressure, subsequent studies found a link between NSAID use and an increased risk of thrombotic events. Selective cyclooxygenase 2 (COX2) inhibitors (also known as coxibs) have been associated with the greatest risk of adverse vascular effects but concern also relates to non-selective NSAIDs, especially those with strong COX2 inhibition such as diclofenac. Although NSAID use is discouraged in patients with cardiovascular disease, pain-relief medication is often required and, in the absence of analgesics that are at least as effective but safer, NSAIDs are frequently prescribed. Furthermore, non-prescription use of NSAIDs, even among people with underlying cardiovascular risks, is largely unsupervised and varies widely between countries. As concern mounts about the disadvantages of alternatives to NSAIDs (such as opioids) for pain management, the use of NSAIDs is likely to rise. Given that the pharmaceutical development pipeline lacks new analgesics, health-care professionals, patients and medicine regulatory authorities are focused on optimizing the safe use of NSAIDs. In this Review, we summarize the current evidence on the cardiovascular safety of NSAIDs and present an approach for their use in the context of holistic pain management.

Key points

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased cardiovascular risk but are often still used for pain management.

  • Even with short-term use (<7 days), NSAIDs have been associated with an increased risk of thrombotic cardiovascular events.

  • Ageing populations, concern about the disadvantages of alternative analgesics (such as opioids) and a sparse analgesic drug development pipeline all suggest that NSAID use will rise in the future.

  • Non-pharmacological measures (physiotherapy, exercise and weight management) are feasible options for many patients to achieve pain control while minimizing pharmacological analgesic needs, with additional benefits in terms of cardiovascular risk management and wellbeing.

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Fig. 1: Mechanism of action of NSAIDs.
Fig. 2: Mechanisms underlying adverse cardiovascular events associated with NSAIDs.
Fig. 3: OECD data on analgesic consumption by country for 2005 and 2017.

References

  1. McGettigan, P. & Henry, D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 8, e1001098 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bhala, N. et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 382, 769–779 (2013).

    CAS  PubMed  Google Scholar 

  3. Antman, E. M. et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 115, 1634–1642 (2007).

    PubMed  Google Scholar 

  4. Danish Cardiology Society. NSAID treatment in patients with cardiovascular disease. Danish Cardiology Society https://www.cardio.dk/nsaid-behandling-hos-patienter-med-hjertekarsygdom (2016).

  5. US Food and Drug Administration. FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory (NSAIDs) can cause heart attacks or strokes. FDA https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warning-non-aspirin-nonsteroidal-anti-inflammatory (2015).

  6. European Medicines Agency. Assessment report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and cardiovascular risk. EMA https://www.ema.europa.eu/en/documents/referral/assessment-report-article-53-procedure-non-steroidal-anti-inflammatory-drugs-nsaids-cardiovascular_en.pdf (2012).

  7. Gislason, G. H. et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch. Intern. Med. 169, 141–149 (2009).

    CAS  PubMed  Google Scholar 

  8. Gislason, G. H. et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation 113, 2906–2913 (2006).

  9. Schjerning Olsen, A. M. et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation 123, 2226–2235 (2011).

    CAS  PubMed  Google Scholar 

  10. Schjerning Olsen, A. M. et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA 313, 805–814 (2015).

    CAS  PubMed  Google Scholar 

  11. Lamberts, M. et al. Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in patients with atrial fibrillation receiving antithrombotic therapy: a nationwide cohort study. Ann. Intern. Med. 161, 690–698 (2014).

    PubMed  Google Scholar 

  12. Dubois, R. N. et al. Cyclooxygenase in biology and disease. FASEB J. 12, 1063–1073 (1998).

    CAS  PubMed  Google Scholar 

  13. Antman, E. M., DeMets, D. & Loscalzo, J. Cyclooxygenase inhibition and cardiovascular risk. Circulation 112, 759–770 (2005).

    CAS  PubMed  Google Scholar 

  14. Mukherjee, D., Nissen, S. E. & Topol, E. J. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286, 954–959 (2001).

    CAS  PubMed  Google Scholar 

  15. Grosser, T., Fries, S. & FitzGerald, G. A. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J. Clin. Invest. 116, 4–15 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Warner, T. D. et al. Cyclooxygenases 1, 2, and 3 and the production of prostaglandin I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues. J. Pharmacol. Exp. Ther. 310, 642–647 (2004).

    CAS  PubMed  Google Scholar 

  17. Timmers, L. et al. Cyclooxygenase-2 inhibition increases mortality, enhances left ventricular remodeling, and impairs systolic function after myocardial infarction in the pig. Circulation 115, 326–332 (2007).

    CAS  PubMed  Google Scholar 

  18. Francois, H. et al. Prostacyclin protects against elevated blood pressure and cardiac fibrosis. Cell Metab. 2, 201–207 (2005).

    CAS  PubMed  Google Scholar 

  19. FitzGerald, G. A. & Patrono, C. The coxibs, selective inhibitors of cyclooxygenase-2. N. Engl. J. Med. 345, 433–442 (2001).

    CAS  PubMed  Google Scholar 

  20. Warner, T. D. & Mitchell, J. A. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 18, 790–804 (2004).

    CAS  PubMed  Google Scholar 

  21. Grosser, T., Yu, Y. & Fitzgerald, G. A. Emotion recollected in tranquility: lessons learned from the COX-2 saga. Ann. Rev. Med. 61, 17–33 (2010).

    CAS  PubMed  Google Scholar 

  22. Minuz, P. Nonsteroidal anti-inflammatory drugs and cardiovascular risk: is prostacyclin inhibition the key event? J. Am. Coll. Cardiol. 52, 1637–1639 (2008).

    PubMed  Google Scholar 

  23. Aw, T. J., Haas, S. J., Liew, D. & Krum, H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch. Intern. Med. 165, 490–496 (2005).

    CAS  PubMed  Google Scholar 

  24. White, W. B. et al. Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension 39, 929–934 (2002).

    CAS  PubMed  Google Scholar 

  25. Kumar, B. & Swee, M. L. Nonsteroidal anti-inflammatory drug use in a patient with hypertension: a teachable moment. JAMA Intern. Med. 175, 892–893 (2015).

    PubMed  Google Scholar 

  26. Johnson, A. G., Simons, L. A., Simons, J., Friedlander, Y. & McCallum, J. Non-steroidal anti-inflammatory drugs and hypertension in the elderly: a community-based cross-sectional study. Br. J. Clin. Pharmacol. 35, 455–459 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bally, M. et al. Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. BMJ 357, j1909 (2017).

    PubMed  PubMed Central  Google Scholar 

  28. Masclee, G. M. C. et al. Risk of acute myocardial infarction during use of individual NSAIDs: a nested case-control study from the SOS project. PLoS One 13, e0204746 (2018).

    PubMed  PubMed Central  Google Scholar 

  29. Fosbol, E. L. et al. The pattern of use of non-steroidal anti-inflammatory drugs (NSAIDs) from 1997 to 2005: a nationwide study on 4.6 million people. Pharmacoepidemiol. Drug Saf. 17, 822–833 (2008).

    PubMed  Google Scholar 

  30. Olsen, A. M. et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients—a nationwide study. PLoS One 8, e54309 (2013).

    CAS  PubMed  Google Scholar 

  31. Trelle, S. et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 342, c7086 (2011).

    PubMed  PubMed Central  Google Scholar 

  32. Coxib and Traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 382, 769–779 (2013).

    Google Scholar 

  33. Sorensen, R. et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 374, 1967–1974 (2009).

    CAS  PubMed  Google Scholar 

  34. Scally, B. et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. Lancet Gastroenterol. Hepatol. 3, 231–241 (2018).

    PubMed  PubMed Central  Google Scholar 

  35. Olsen, A. M. et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation 126, 1955–1963 (2012).

    CAS  PubMed  Google Scholar 

  36. Kearney, P. M. et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 332, 1302–1308 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Reilly, I. A. & FitzGerald, G. A. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 69, 180–186 (1987).

    CAS  PubMed  Google Scholar 

  38. Antman, E. M. The aspirin-NSAID interaction: more data, but a lack of clarity remains. J. Am. Coll. Cardiol. 71, 1752–1754 (2018).

    PubMed  Google Scholar 

  39. Whelton, A. Renal aspects of treatment with conventional nonsteroidal anti-inflammatory drugs versus cyclooxygenase-2-specific inhibitors. Am. J. Med. 110 (Suppl. 3A), 33S–42S (2001).

    CAS  PubMed  Google Scholar 

  40. Komhoff, M., Grone, H. J., Klein, T., Seyberth, H. W. & Nusing, R. M. Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function. Am. J. Physiol. 272, F460–F468 (1997).

    CAS  PubMed  Google Scholar 

  41. Appel, G. B. COX-2 inhibitors and the kidney. Clin. Exp. Rheumatol. 19 (Suppl. 25), S37–S40 (2001).

    CAS  PubMed  Google Scholar 

  42. Breyer, M. D., Hao, C. & Qi, Z. Cyclooxygenase-2 selective inhibitors and the kidney. Curr. Opin. Crit. Care 7, 393–400 (2001).

    CAS  PubMed  Google Scholar 

  43. Zhang, J., Ding, E. L. & Song, Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA 296, 1619–1632 (2006).

    CAS  PubMed  Google Scholar 

  44. Back, M., Yin, L. & Ingelsson, E. Cyclooxygenase-2 inhibitors and cardiovascular risk in a nation-wide cohort study after the withdrawal of rofecoxib. Eur. Heart J. 33, 1928–1933 (2012).

    PubMed  Google Scholar 

  45. Krijthe, B. P., Heeringa, J., Hofman, A., Franco, O. H. & Stricker, B. H. Non-steroidal anti-inflammatory drugs and the risk of atrial fibrillation: a population-based follow-up study. BMJ Open 4, e004059 (2014).

    PubMed  PubMed Central  Google Scholar 

  46. Schmidt, M., Christiansen, C. F., Mehnert, F., Rothman, K. J. & Sorensen, H. T. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study. BMJ 343, d3450 (2011).

    PubMed  Google Scholar 

  47. Chao, T. F. et al. The association between the use of non-steroidal anti-inflammatory drugs and atrial fibrillation: a nationwide case-control study. Int. J. Cardiol. 168, 312–316 (2013).

    PubMed  Google Scholar 

  48. Liu, G. et al. Meta-analysis of nonsteroidal anti-inflammatory drug use and risk of atrial fibrillation. Am. J. Cardiol. 114, 1523–1529 (2014).

    CAS  PubMed  Google Scholar 

  49. Mamdani, M. et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 363, 1751–1756 (2004).

    CAS  PubMed  Google Scholar 

  50. Arfe, A. et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ 354, i4857 (2016).

    PubMed  Google Scholar 

  51. Hudson, M., Richard, H. & Pilote, L. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study. BMJ 330, 1370 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Hudson, M., Rahme, E., Richard, H. & Pilote, L. Risk of congestive heart failure with nonsteroidal antiinflammatory drugs and selective cyclooxygenase 2 inhibitors: a class effect? Arthritis Rheum. 57, 516–523 (2007).

    CAS  PubMed  Google Scholar 

  53. Silverstein, F. E. et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284, 1247–1255 (2000).

    CAS  PubMed  Google Scholar 

  54. Bombardier, C. et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N. Engl. J. Med. 343, 1520–1528 (2000).

    CAS  PubMed  Google Scholar 

  55. Baron, J. A. et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet 372, 1756–1764 (2008).

    CAS  PubMed  Google Scholar 

  56. Solomon, S. D. et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352, 1071–1080 (2005).

    CAS  PubMed  Google Scholar 

  57. Solomon, S. D. et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation 114, 1028–1035 (2006).

    CAS  PubMed  Google Scholar 

  58. Arber, N. et al. Celecoxib for the prevention of colorectal adenomatous polyps. N. Engl. J. Med. 355, 885–895 (2006).

    CAS  PubMed  Google Scholar 

  59. Bresalier, R. S. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 352, 1092–1102 (2005).

    CAS  PubMed  Google Scholar 

  60. Bertagnolli, M. M. et al. Celecoxib for the prevention of sporadic colorectal adenomas. N. Engl. J. Med. 355, 873–884 (2006).

    CAS  PubMed  Google Scholar 

  61. Nissen, S. E. et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N. Engl. J. Med. 375, 2519–2529 (2016).

    CAS  PubMed  Google Scholar 

  62. Solomon, S. D. et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation 117, 2104–2113 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Reed, G. W. et al. Effect of aspirin coadministration on the safety of celecoxib, naproxen, or ibuprofen. J. Am. Coll. Cardiol. 71, 1741–1751 (2018).

    CAS  PubMed  Google Scholar 

  64. MacDonald, T. M. et al. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT). Eur. Heart J. 38, 1843–1850 (2017).

    PubMed  Google Scholar 

  65. Grosser, T., Ricciotti, E. & FitzGerald, G. A. The cardiovascular pharmacology of nonsteroidal anti-inflammatory drugs. Trends Pharmacol. Sci. 38, 733–748 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) CAPRIE Steering Committee. Lancet 348, 1329–1339 (1996).

    Google Scholar 

  67. Connolly, S. J. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151 (2009).

    CAS  PubMed  Google Scholar 

  68. Dentali, F. et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 126, 2381–2391 (2012).

    CAS  PubMed  Google Scholar 

  69. Eikelboom, J. W. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 123, 2363–2372 (2011).

    CAS  PubMed  Google Scholar 

  70. Kent, A. P. et al. Concomitant oral anticoagulant and nonsteroidal anti-inflammatory drug therapy in patients with atrial fibrillation. J. Am. Coll. Cardiol. 72, 255–267 (2018).

    CAS  PubMed  Google Scholar 

  71. Davidson, B. L. et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern. Med. 174, 947–953 (2014).

    CAS  PubMed  Google Scholar 

  72. Schjerning Olsen, A. M. et al. Risk of gastrointestinal bleeding associated with oral anticoagulation and non-steroidal anti-inflammatory drugs in patients with atrial fibrillation: a nationwide study. Eur. Heart J. Cardiovasc. Pharmacother. https://doi.org/10.1093/ehjcvp/pvz069 (2019).

    Article  Google Scholar 

  73. Gadsboll, K. et al. Increased use of oral anticoagulants in patients with atrial fibrillation: temporal trends from 2005 to 2015 in Denmark. Eur. Heart J. 38, 899–906 (2017).

    PubMed  Google Scholar 

  74. Grosser, T., Theken, K. N. & FitzGerald, G. A. Cyclooxygenase inhibition: pain, inflammation, and the cardiovascular system. Clin. Pharmacol. Ther. 102, 611–622 (2017).

    PubMed  Google Scholar 

  75. Jacob, L. & Kostev, K. Prevalence of pain medication prescriptions in France, Germany, and the UK — a cross-sectional study including 4,270,142 patients. Postgrad. Med. 130, 32–36 (2018).

    PubMed  Google Scholar 

  76. Schmidt, M., Hallas, J. & Friis, S. Potential of prescription registries to capture individual-level use of aspirin and other nonsteroidal anti-inflammatory drugs in Denmark: trends in utilization 1999-2012. Clin. Epidemiol. 6, 155–168 (2014).

    PubMed  PubMed Central  Google Scholar 

  77. Shmagel, A., Ngo, L., Ensrud, K. & Foley, R. Prescription medication use among community-based U.S. adults with chronic low back pain: a cross-sectional population based study. J. Pain 19, 1104–1112 (2018).

    PubMed  PubMed Central  Google Scholar 

  78. Ruscitto, A., Smith, B. H. & Guthrie, B. Changes in opioid and other analgesic use 1995–2010: repeated cross-sectional analysis of dispensed prescribing for a large geographical population in Scotland. Eur. J. Pain 19, 59–66 (2015).

    CAS  PubMed  Google Scholar 

  79. Bouck, Z. et al. Frequency and associations of prescription nonsteroidal anti-inflammatory drug use among patients with a musculoskeletal disorder and hypertension, heart failure, or chronic kidney disease. JAMA Intern. Med. 178, 1516–1525 (2018).

    PubMed  PubMed Central  Google Scholar 

  80. McGettigan, P. & 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. 10, e1001388 (2013).

    PubMed  PubMed Central  Google Scholar 

  81. Hunter, D. J. & Bierma-Zeinstra, S. Osteoarthritis. Lancet 393, 1745–1759 (2019).

    CAS  PubMed  Google Scholar 

  82. Agca, R. et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann. Rheum. Dis. 76, 17–28 (2017).

    CAS  PubMed  Google Scholar 

  83. Hochberg, M. C. 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. 64, 465–474 (2012).

    CAS  Google Scholar 

  84. The Royal Australian College of General Practitioners. Guideline for the management of knee and hip osteoarthritis: second edition. RACGP https://www.racgp.org.au/download/Documents/Guidelines/Musculoskeletal/guideline-for-the-management-of-knee-and-hip-oa-2nd-edition.pdf (2018).

  85. Roberts, E. et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann. Rheum. Dis. 75, 552–559 (2016).

    CAS  PubMed  Google Scholar 

  86. Meara, A. S. & Simon, L. S. Advice from professional societies: appropriate use of NSAIDs. Pain Med. 14 (Suppl. 1), S3–S10 (2013).

    PubMed  Google Scholar 

  87. Schmidt, M. et al. Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for cardiovascular pharmacotherapy of the European Society of cardiology. Eur. Heart J. 37, 1015–1023 (2016).

    CAS  PubMed  Google Scholar 

  88. Bhatt, D. L. et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 118, 1894–1909 (2008).

    PubMed  Google Scholar 

  89. Bennett, J. S. et al. The use of nonsteroidal anti-inflammatory drugs (NSAIDs): a science advisory from the American Heart Association. Circulation 111, 1713–1716 (2005).

    PubMed  Google Scholar 

  90. National Heart Foundation of Australia. Medications to avoid in ACS and heart failure. Heart online https://www.heartonline.org.au/articles/medications/cautions-and-monitoring#medications-to-avoid-in-acs-and-heart-failure (2020).

  91. European Medicines Agency. Ibuprofen- and dexibuprofen-containing medicines. EMA https://www.ema.europa.eu/en/medicines/human/referrals/ibuprofen-dexibuprofen-containing-medicines (2015).

  92. European Medicines Agency. European Medicines Agency finalises review of recent published data on cardiovascular safety of NSAIDs. EMA https://www.ema.europa.eu/en/news/european-medicines-agency-finalises-review-recent-published-data-cardiovascular-safety-nsaids (2012).

  93. European Medicines Agency. European Medicines Agency review concludes positive benefit-risk balance for non-selective NSAIDs. EMA https://www.ema.europa.eu/en/news/european-medicines-agency-review-concludes-positive-benefit-risk-balance-non-selective-nsaids (2006).

  94. European Medicines Agency. European Medicines Agency concludes action on COX-2 inhibitors. EMA https://www.ema.europa.eu/en/news/european-medicines-agency-concludes-action-cox-2-inhibitors (2005).

  95. Therapeutic Goods Administration. Review of cardiovascular safety of non-steroidal anti-inflammatory drugs. TGA https://www.tga.gov.au/sites/default/files/medicines-review-nsaid.pdf (2014).

  96. Therapeutic Goods Administration. Submissions and TGA response: paracetamol and ibuprofen: proposed additional advisory statement. TGA https://www.tga.gov.au/submissions-and-tga-response-paracetamol-and-ibuprofen-proposed-additional-advisory-statement (2017).

  97. National Institute for Health and Care Excellence. Non-steroidal anti-inflammatory drugs. NICE https://www.nice.org.uk/advice/ktt13/chapter/Evidence-context (2018).

  98. Case, A. & Deaton, A. Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century. Proc. Natl Acad. Sci. USA 112, 15078–15083 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Saragiotto, B. T., Abdel Shaheed, C. & Maher, C. G. Paracetamol for pain in adults. BMJ 367, l6693 (2019).

    PubMed  Google Scholar 

  100. [No authors listed] Abuse-deterrent opioids. JAMA 319, 2036–2037 (2018).

  101. US Food and Drug Administration. Abuse-deterrent opoid analgesics. FDA https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/abuse-deterrent-opioid-analgesics (2019).

  102. Cato Institute. Abuse-deterrent opioids and the law of unintended consequences. Cato https://www.cato.org/publications/policy-analysis/abuse-deterrent-opioids-law-unintended-consequences (2018).

  103. Cicero, T. J., Ellis, M. S. & Surratt, H. L. Effect of abuse-deterrent formulation of OxyContin. N. Engl. J. Med. 367, 187–189 (2012).

    CAS  PubMed  Google Scholar 

  104. Withington, L., Chen, H. & Yip, S. Pipeline drill-down: expert perspectives on Alzheimer’s, opioids, and cannabis. Pharmaceutical Executive http://www.pharmexec.com/pipeline-drill-down-expert-perspectives-alzheimers-opioids-and-cannabis-0?pageID=2 (2018).

  105. BioSpace. Galt Pharmaceuticals receives FDA priority review for non-controlled pain management drug, orphengesic forte, an opioid-free alternative for patients. BioSpace https://www.biospace.com/article/releases/galt-pharmaceuticals-receives-fda-priority-review-for-non-controlled-pain-management-drug-orphengesic-forte-an-opioid-free-alternative-for-patients/ (2019).

  106. Drugs.com. NKTR-181 approval status. Drugs.com https://www.drugs.com/history/nktr-181.html (2020).

  107. U.S. National Library of Medicine. ClinicalTrials.gov https://clinicaltrials. gov/ct2/show/NCT03304379 (2020).

  108. Tive, L. et al. Pooled analysis of tanezumab efficacy and safety with subgroup analyses of phase III clinical trials in patients with osteoarthritis pain of the knee or hip. J. Pain Res. 12, 975–995 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Centrexion Therapeutics. Centrexion Therapeutics announces completion of patient enrollment in pivotal clinical trial of repeat doses of CNTX-4975 in patients with moderate to severe osteoarthritis knee pain. Centrexion https://centrexion.com/wp-content/uploads/2019/06/FINAL_Centrexion_Victory-2-Patient-Enrollment_060519.pdf (2019).

  110. BioSpace. Nektar stumbles as the FDA delays advisory committee hearing for NKTR-181. BioSpace https://www.biospace.com/article/nektar-stumbles-as-the-fda-delays-advisory-committee-hearing-for-nktr-181/ (2019).

  111. Pharmaphorom. Pfizer/Lilly non-opioid pain drug shows more positive results. Pharmaphorom https://pharmaphorum.com/news/pfizer-lilly-non-opioid-pain-drug-shows-more-positive-results/ (2019).

  112. Scholl, L., Seth, P., Kariisa, M., Wilson, N. & Baldwin, G. Drug and opioid-involved overdose deaths-United States, 2013–2017. Morb. Mortal. Wkly. Rep. 67, 1419–1427 (2018).

    Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology, Zealand University Hospital, Roskilde, Denmark

    Anne-Marie Schjerning

  2. The Danish Heart Foundation, Copenhagen, Denmark

    Anne-Marie Schjerning & Gunnar Gislason

  3. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Patricia McGettigan

  4. Department of Cardiology, Copenhagen University, Herlev and Gentofte Hospital, Herlev, Denmark

    Gunnar Gislason

Authors
  1. Anne-Marie Schjerning
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  2. Patricia McGettigan
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  3. Gunnar Gislason
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All the authors researched data for the article and contributed to discussions of its content. All the authors wrote the manuscript and reviewed and edited it before submission.

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Correspondence to Gunnar Gislason.

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Nature Reviews Cardiology thanks C. Hennekens, C. Patrono and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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OECD Health Statistics 2019: http://www.oecd.org/els/health-systems/health-data.htm

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Schjerning, AM., McGettigan, P. & Gislason, G. Cardiovascular effects and safety of (non-aspirin) NSAIDs. Nat Rev Cardiol 17, 574–584 (2020). https://doi.org/10.1038/s41569-020-0366-z

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