Reviewing the Major Risks of NSAIDS, the Most Commonly Used Class of Drugs in the U.S. Part 1: Introduction and Cardiovascular Complications By John Kiel, DO, MPH, CAQ-SM,1 Alexandra L. Mannix, MD,2 and Gregory Rubin, DO, CAQ-SM3 1Dept. of Emergency Medicine and Sports Medicine, University of Florida College of Medicine – Jacksonville, Jacksonville, FL 2Dept. of Emergency Medicine, University of Florida College of Medicine – Jacksonville, Jacksonville, FL 3Dept. of Internal Medicine, University of Central Florida and NCH Healthcare System Internal Medicine Residency, Naples, FL Address correspondence to: John Kiel DO, MPH, CAQ-SM University of Florida College of Medicine - Jacksonville 655 West 8th Street, Jacksonville, FL, 32209 904-244-6340 [email protected] Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drug class in the United States according to the Centers for Disease Control and Prevention (CDC). NSAIDs address a wide range of maladies related to pain, as well as fever and inflammation. For this reason, they are commonly used to treat a broad spectrum of ailments. NSAID use is increasing over time; as recently as 2013, NSAIDs had accounted for more than 70 million prescriptions and 30 billion over-the-counter purchases.1 Ibuprofen is the 34th most prescribed drug in the United States followed by meloxicam (35th), aspirin (39th), naproxen (69th), diclofenac (84th), and celecoxib (109th) as of 2018.2 One study estimated that 36 million Americans use over the counter analgesia daily, with 23 million using NSAIDS and one-fourth of users exceeding the recommended dose.3 Users are generally unaware of the potential for adverse side effects. At least 75% of patients present to the emergency department (ED) with a chief complaint related to pain, with pain being the third most common healthcare problem overall.4 Pain management is challenging for emergency medicine physicians. Research has repeatedly found that pain is undertreated or inadequately treated in the ED.5 Among emergency department patients, 67% report having used an NSAID prior to presentation to the ED.6 The opioid epidemic has increased scrutiny of pain management and increased pressure to utilize non-opioid analgesia. NSAIDs are one of the most frequently used classes of medications to treat acute pain in the ED and in many cases provide adequate pain relief. In patients presenting to the ED after a motor vehicle collision, NSAIDs have been shown to be non-inferior to opioids for the risk of persistent musculoskeletal pain at six weeks.7 In another study of patients presenting to the emergency department for acute extremity pain, there was no difference in pain reduction at two hours in patients treated with 400 mg ibuprofen and 1000 mg acetaminophen compared to patients receiving 5 mg of oxycodone and 325 mg of acetaminophen; 5 mg of hydrocodone and 300 mg of acetaminophen; or 30 mg of codeine and 300 mg of acetaminophen.8 NSAIDs are also one of the most frequently inappropriately prescribed medications, especially in the elderly population.9 Patients over 60 years of age, women, and individuals with high body mass index, increased waist circumference or heart disease are significantly more likely to be regular NSAID users.10 NSAIDs may be non-selective cyclooxygenase (COX) inhibitors, or selective COX-2 inhibitors, both of which have different safety profiles. The cyclooxygenase enzyme converts arachidonic acid to prostaglandins.11 Prostaglandins are involved in pain transmission and NSAIDs will inhibit their release.11 In both acute and chronic use, NSAID consumption has several significant risk factors with life threatening potential including gastrointestinal toxicity, cardiovascular toxicity, and nephrotoxicity.12 Given the broad NSAID use among the general population, the growing pressure to use non-opioid analgesia in patients with both acute and chronic pain, the non-inferiority of NSAID use compared to opioids and the potential for adverse events, it is critical that the emergency physician be aware of and develop best practice patterns for their patients. The primary risks of NSAID use can generally be categorized into three major organ systems: gastrointestinal, cardiovascular, and renal. There are several challenges in evaluating the risk of NSAID use, including the wide variety of medications on the market. In addition to the most prescribed medications (ibuprofen, meloxicam, aspirin, naproxen, diclofenac, and celecoxib) there are many more available for commercial use. This list includes but is not limited to non- selective COX inhibitors (ketorolac, ketoprofen, nabumetone, acemetacin, aceclofenac, sulindac, nimesulide, piroxicam, azapropazone) and selective COX-2 inhibitors (lumiracoxib, etoricoxib). Additionally, there is a wide heterogeneity among studies evaluating NSAID risk. This is true both of studies evaluating individual organ system risk as well as among studies evaluating specific NSAID risk. For these two reasons, interpreting and synthesizing the data and making pointed, specific recommendations is challenging. The purpose of this review is to evaluate the available evidence and discuss the cardiovascular risks associated with the use of these medications. Cardiovascular Risk Risks of long term NSAID use on the cardiovascular system include edema, hypertension, congestive heart failure, myocardial infarction, stroke, and other thromboembolic events.13 Aspirin, an NSAID, is well accepted as an agent for the treatment and prevention of secondary cardiovascular effects events. Current guidelines also support the role of aspirin for prevention of primary cardiovascular disease, although this is more contentious. Other NSAIDs do not convey the same cardioprotective benefits. Non-aspirin NSAIDS have been linked to cardiovascular risk and higher doses of NSAIDs increases your risk of myocardial infarction.14 The development of selective COX-2 inhibitors was considered a breakthrough due to their favorable gastrointestinal (GI) profile. However, in 2004, rofecoxib (Vioxx) was found to increase cardiovascular events and was withdrawn from the market. Subsequently, there has been increased research evaluating cardiovascular safety of both selective COX-2 inhibitors and non-selective NSAIDs. Multiple mechanisms contribute to the cardiovascular risks associated with NSAID use. Differences in endothelial function, oxidative stress, renal hemostasis, and hypertension have all been implicated. The COX-2 selective inhibitors may increase the risk of thrombotic events primarily due to the imbalance caused by inhibition of COX-2–mediated prostacyclin production which is involved in platelet aggregation without inhibition of COX-1-mediated thromboxane production which is pro-thrombotic.14,15 NSAID use increases the risk of myocardial infarction and major cardiovascular disease. A 2011 study found the risk of myocardial infarction to be greatest with ibuprofen, celecoxib, and lumiracoxib and no risk was found with naproxen, diclofenac, and etoricoxib.13 A follow-up study in 2017 found that naproxen increases risk of myocardial infarction.16 The PRECISION trial showed there was no difference in risk of non-fatal myocardial infarction between celecoxib, naproxen, and ibuprofen.17 A separate study found that meloxicam and diclofenac were associated with a 38% and 37% increased risk of having a myocardial infarction when compared to patients with remote use of NSAIDs.18 When clustering all myocardial infarction risk together, all NSAIDS are associated with an increased risk. NSAID use is also associated with increased risk of hypertension. This effect is more significant with COX-2 inhibitors than with non-selective NSAIDs.19 NSAID use also increases the risk of developing congestive heart failure and exacerbating underlying disease. The risk was greatest in rofecoxib which is no longer commercially available, followed by non-selective NSAIDs.20 Celecoxib was not associated with increased risk. Most of the literature on NSAID use is focused on cardiovascular events, and the literature is sparse regarding NSAID use and cerebrovascular events. Among both selective and non- selective NSAIDs, there is a lack of clarity regarding individual medications association with increased risk of cerebrovascular events.21 In the 2011 meta-analysis, all NSAIDs studied, including ibuprofen, diclofenac, celecoxib, etoricoxib, and lumiracoxib were associated with an increased risk of cerebrovascular events. In patients with underlying hypertension, non-selective NSAIDs, notably diclofenac and ketorolac, but not selective COX-1 inhibitors were associated with increased risk of cerebrovascular events.22 Among patients with osteoarthritis, the overall rate of cerebrovascular events was not elevated with current NSAIDs overall when compared with past use. Among individual NSAIDs, diclofenac and ketoprofen were the NSAIDs most significantly associated with an increased rate of cerebrovascular events.22 Varas-Lorenzo et al. found that ischemic stroke risk was increased with diclofenac, but not naproxen, ibuprofen, and celecoxib.23 The risk of cardiovascular and cerebrovascular disease appears to be a class-wide effect with NSAID use. A systematic review published in 2011 found ibuprofen and naproxen to be the safest while finding diclofenac to have the highest risk.24 A study in 2011 found all drugs except naproxen showed some evidence for increased risk of cardiovascular death.13 In 2016, Pelletier et al. showed that celecoxib