Clinical Pharmacology and Cardiovascular Safety of Naproxen

Am J Cardiovasc Drugs (2017) 17:97–107 DOI 10.1007/s40256-016-0200-5 REVIEW ARTICLE Clinical Pharmacology and Cardiovascular Safety of Naproxen Dominick J. Angiolillo1 • Steven M. Weisman2 Published online: 8 November 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract The voluntary withdrawal of Vioxx (rofecoxib) from the market in 2004, as well as the 2005 and 2014 US FDA Advisory Committee meetings about non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk, have raised questions surrounding the use of NSAIDs in atrisk populations. This paper discusses the cardiovascular safety profile of naproxen in the context of the NSAID class. The balance of evidence suggests that cardiovascular risk correlates with cyclooxygenase (COX)-2 selectivity, and the low COX-2 selectivity of naproxen results in a lower cardiovascular risk than that of other NSAIDs. The over-the-counter (OTC) use of naproxen is expected to pose minimal cardiovascular risk; however, the benefit– risk ratio and appropriate use should be considered at an individual patient level, particularly to assess underlying conditions that may increase the risk of events. Likewise, regulatory authorities should revisit label information periodically to ensure labeling reflects the current understanding of benefits and risks. Key Points The totality of evidence suggests that while nonsteroidal anti-inflammatory drugs (NSAIDs) likely increase the risk of cardiovascular events, they do so based on cyclooxygenase (COX)-2 selectivity, with greater affinity for COX-2 imparting greater risk. Naproxen has low COX-2 selectivity, instead demonstrating greater selectivity for COX-1 inhibition, imparting a consistent and demonstrably favorable thromboembolic and overall cardiovascular safety profile among the most commonly used non-aspirin NSAIDs. 1 Introduction 1.1 Non-Steroidal Anti-Inflammatory Drug (NSAID) Background 1.1.1 Therapeutic Importance & Dominick J. Angiolillo 1 Division of Cardiology, University of Florida College of Medicine-Jacksonville, ACC Building 5th floor, 655 West 8th Street, Jacksonville, FL 32209, USA 2 Innovative Science Solutions, LLC, Morristown, NJ, USA Musculoskeletal aches and pains are one of the most common medical complaints around the world, and increasing life expectancies are driving an increased incidence of degenerative joint disease, burdening patients and healthcare systems [1]. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used class of analgesic drugs, with approximately 30 million users worldwide daily [2] and over 100 million prescriptions 98 D. J. Angiolillo, S. M. Weisman Fig. 2 Odds ratios and 95 % confidence intervals for cardiovascular death based on non-steroidal anti-inflammatory drug (NSAID) dose. Odds ratios for cardiovascular death (composite endpoint of death or myocardial infarction) in association with NSAID exposure Data from Fosbøl et al. [98] Fig. 1 Non-steroidal anti-inflammatory drug cyclooxygenase selectivity and half-life. Adapted from Goodman and Gilman [19]. COX cyclooxygenase, NSAID non-steroidal anti-inflammatory drug every year in the USA [3]. NSAIDs continue to be one of the most effective and widely used forms of non-surgical pain relief for osteoarthritis [1]. A significant portion of the population appropriately manages pain with over-thecounter (OTC) NSAIDs [4]. In contrast, other prescription pain relievers (e.g., opioids) lend themselves to abuse, which has become a growing epidemic [5]. 1.1.2 Regulatory Interest The widespread use of NSAIDs means there is significant regulatory interest in this therapeutic category. Furthermore, after the voluntary withdrawal of Vioxx (rofecoxib) in 2004, regulatory authorities have focused on potential adverse cardiovascular outcomes. The US FDA Advisory Committee meetings in both 2005 and 2014 concluded that NSAIDs increased the risk of myocardial infarction (MI) in high-risk individuals, and they supported the need for additional label warnings and studies to further clarify whether the increased risk was truly a class effect or the result of cyclooxygenase (COX)-2 selectivity. The 2005 meeting resulted in changes to the label for all NSAIDs, including OTC NSAIDs, to highlight this risk [6–8]. The 2014 FDA Advisory Committee meeting on the cardiovascular risk of NSAIDs included an FDA review of data available after 2005, highlighting a potential lower cardiovascular risk with naproxen than with other NSAIDs, as well as a discussion of the progress of PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen), an ongoing cardiovascular safety study [9]. The committee reaffirmed the position that class labeling was appropriate and should not differentiate between products, forms, and dose (including for OTC medications). Nonetheless, many of the committee members expressed the view that the data suggest a more favorable cardiovascular risk profile for naproxen than for other NSAIDs, even if it did not meet the evidentiary standard for supporting a regulatory label change. Furthermore, risk may be mitigated through low doses or a shorter duration of use, such as that with OTC naproxen. In addition, numerous other regulatory bodies have contributed to NSAID safety, with ingredient-specific differences in recommendations by country. For instance, in the UK, diclofenac was switched back from OTC to prescription status based on safety concerns, and the European Medicines Agency (EMA) determined that naproxen ‘‘may be associated with a lower risk for arterial thrombotic events than COX-2 inhibitors and other NSAIDs, but a small risk cannot be excluded’’ [10]. We review the totality of evidence regarding naproxen and cardiovascular safety in the context of NSAIDs as a class. 1.2 Naproxen Background 1.2.1 History Naproxen has been available as a prescription product in the USA since 1976, and naproxen sodium has been approved for OTC use in many countries. Non-prescription dosing is appropriate every 8–12 h, with a maximum total daily OTC dose of 440–660 mg, as approved by local regulatory authorities. This differs from the prescription Clinical Pharmacology and Cardiovascular Safety of Naproxen dosing regimen, which is usually 500 mg two to three times daily with a maximum total daily dose of 1500 mg. Little difference in acute or chronic pain relief has been demonstrated between traditional NSAIDs, such as naproxen, and COX-2 selective NSAIDs (coxibs) [11, 12]. However, many of the studies comparing the efficacy of traditional NSAIDs and coxibs were inadequately powered to detect small differences between the compounds, should they exist [13]. In contrast, a recent network analysis found a significant difference between NSAIDs and acetaminophen in the treatment of pain in knee and hip osteoarthritis. The authors concluded that NSAIDs delivered clinically meaningful pain (...truncated)