n REPORTS n Quantifying the Impact of NSAID-Associated Adverse Events Michael Fine, MD onsteroidal anti-inflammatory drugs (NSAIDs) are the cornerstone of pain management in patients Abstract who have inflammatory, acute pain (eg, headache, Nonsteroidal anti-inflammatory drugs postoperative pain, and orthopedic fractures), and (NSAIDs) are widely used among patients Nchronic pain (eg, rheumatoid arthritis, osteoarthritis, and gout).1,2 experiencing many different types of pain, Approximately 70% of people 65 years or older use NSAIDs at including inflammatory, acute pain (eg, injury, low back pain, headache, postopera- least once per week, with half of them taking at least 7 doses per tive pain), and chronic pain (eg, rheumatoid week. In 2000, more than 111 million prescriptions were written arthritis, osteoarthritis). However, both for NSAIDs in the United States, at an approximate cost of $4.8 traditional NSAIDs and second-generation billion.3 The use of NSAIDs is likely to increase even more as the NSAIDs (cyclooxygenase-2 inhibitors) can US population continues to age and experience painful condi- lead to very expensive and serious adverse events. Gastrointestinal, cardiovascular, and tions that are more common among older adults.4 renal complications associated with NSAIDs Both traditional© NSAIDs Managed and Carethe second & generation cyclo- have been shown to be dose-dependent. oxygenase-2Healthcare (COX-2) inhibitors Communications, offer superior efficacyLLC compared In 2005, to help minimize these risks, the with acetaminophen, but also carry significant risk for serious US Food and Drug Administration issued a gastrointestinal (GI), cardiovascular (CV), and renal adverse public health advisory stating that “NSAIDs events.1,5-7 A systematic review of 17 prospective observational should be administered at the lowest effec- tive dose for the shortest duration consistent studies found that 11% of preventable drug-related hospital with individual patient treatment goals.” This 8 admissions could be attributed to NSAIDs. Studies have docu- article reviews the undue clinical and eco- mented that the risk of adverse events associated with NSAIDs nomic burden associated with NSAID-related are both dose-dependent and duration dependent.1,7,9 serious adverse events. In 2005, the US Food and Drug Administration (FDA) issued Am J Manag Care. 2013;19(14 suppl):S267-S272 a public health advisory warning of an increased risk for serious CV events with NSAID use.10 In 2007, the FDA published a medication guide for NSAIDs that recommended using the lowest dose possible for treatment. The guide listed myocardial infarc- tion (MI), stroke, kidney problems, and GI bleeding as some of the serious potential side effects. Despite the emerging evidence, few studies have been conducted to help quantify the true burden of these side effects, especially when NSAIDs are used for acute pain. The Impact of Pain Management Acute pain is typically associated with an event, such as an injury or surgery, and usually resolves when the underlying event is treated or healed. Examples include headache, postoperative pain, fractures, low back pain, and neck pain.11,12 Approximately 40% of patient visits to primary care providers are due to mild to For author information and disclosures, see end of text. moderate acute pain.2 More than 70% of emergency department (ED) visits are for acute pain, making it the most common reason VOL. 19, NO. 14 n THE AMERICAN JOURNAL OF MANAGED CARE n S267 Reports why patients seek treatment. Among the over 115 million utilization that results from the morbidity and mortality asso- ED visits annually in the United States, headache alone ciated with these adverse events. accounts for 2.1 million.11,13 Considering that the average cost of a visit to the ED is $1349, the costs associated with Gastrointestinal Adverse Events acute pain are substantial.14 A meta-analysis published in 2012 examined the rela- Acute pain can also occur in the presence of chronic pain tive risk (RR) of upper GI complications (upper GI bleed- conditions such as osteoarthritis and low back pain; this type ing and/or perforation, or peptic ulcer) for both traditional of pain is referred to as breakthrough pain. Both osteoarthritis NSAIDs and COX-2 inhibitors using pooled data from 28 and low back pain have placed significant economic burden observational studies published between 1980 and May 2011. on the US healthcare system.12,15 Data from the National Researchers found an increased risk for upper GI complica- Health Interview Survey show that in 2011, 28.4% of tions across all 16 of the NSAIDs studied. Data showed that American adults reported experiencing low back pain within the risk was lowest for aceclofenac and celecoxib (RR, 1.4 the previous 3 months.16 Buurma et al (2012) estimated that and 1.5, respectively) and highest for ketorolac and azapropa- in 2011, there were 116.5 million cases of acute low back zone (RR, 11.5 and 18.5, respectively). Most of the NSAIDs and neck pain in the United States. By 2021, the number is were associated with an RR for upper GI complications expected to reach 128.5 million cases (or, a 10% growth over between approximately 2 and 4. Researchers also found that the next decade).17 the risk was dose-dependent. The use of high daily doses was Similarly, the number of Americans with osteoarthritis is associated with an approximately 2- to 3-fold increase in RR rising. Researchers estimate that the prevalence of arthritis in compared with low to medium doses for all NSAIDs except the United States among patients over 40 years of age grew celecoxib, for which the effect was not dose-dependent.1 from 10.1% in 1999 to 12.8% in 2008 (P = .011).18 Data from One of the more recent studies conducted regarding the the Medical Expenditure Panel Survey (MEPS) showed that GI side effects associated with NSAIDs was a 2013 meta- osteoarthritis was among the 5 most commonly treated con- analysis by the Coxib and traditional NSAID Trialists’ ditions in 2009, totaling $29.5 billion. MEPS data showed (CNT) Collaboration of 280 studies (124,514 participants). that 17.4 million adults between the ages of 40 and 64 years The study examined the relationship between the use of were treated for osteoarthritis in 2009.19 NSAIDs and upper GI complications, such as peptic ulcer perforations, obstructions, and bleeding. Data for naproxen, NSAIDs: The Hidden Costs ibuprofen, and diclofenac, as well as for the COX-2 inhibi- The cost of treating acute and chronic pain conditions is tors rofecoxib, etoricoxib, lumiracoxib, valdecoxib, and well documented. What is less well understood is the price tag GW403681, were analyzed. CNT researchers found an attached to the side effects associated with their treatment. elevated risk for upper GI complications across all of the Some estimates suggest that each year more than 100,000 medications studied. The RR was nearly twice as high for ibu- patients are hospitalized for NSAID-related GI complications profen and naproxen compared with diclofenac and COX-2 alone, with direct costs ranging from $1800 to $8500 per inhibitors (Figure 1).6 patient per hospitalization. Moreover, it has been reported A similar increased risk was found in a study among that 16,500 persons die annually from these complications. In Quebec residents. Patients using NSAIDs had a risk of devel- the elderly, the medical costs of adverse GI events associated oping GI adverse events that was 2.5 times (95% confidence with NSAID use likely exceed $4 billion per year.20 interval [CI], 2.04-3.00) that of patients not taking NSAIDs. NSAID use is also associated with costly adverse events In addition, researchers estimated that the average cost for GI impacting the CV and renal systems. For example, NSAID adverse events added an average of 66% to the cost of care. In use has been associated with increased risk for hospitaliza- patients over the age of 85 years with more than 5 physician tion due to MI as well as for heart failure (HF). According claims, the costs of management of adverse events associated to recent data from the Agency for Healthcare Research and with NSAIDs increased the cost of each prescription by a Quality, the average hospitalizations for acute MI and con- factor of 7.5.21 gestive HF cost $18,500 and $10,500, respectively. Likewise, acute renal failure, which is also associated with NSAID use, Cardiovascular Risks can ultimately lead to expensive dialysis treatment. The CNT study described above also examined the vas- Although direct cost data specific to NSAID adverse cular risk associated with NSAIDs. The primary outcome events are limited, several studies have examined healthcare was major vascular events, defined as nonfatal MI, nonfatal S268 n www.ajmc.com n NOVEMBER 2013 Quantifying the Impact of NSAID-Associated Adverse Events 6 n Figure 1. Relative Risk of Vascular and Upper GI Events by Drug Type: Results From the CNT Collaboration 4.5 a 4.22 3.97a 4 3.5 3 2.49a 2.5 2.28a a a 1.87a a 1.89 2 1.85 1.81 1.61 a 1.41a 1.44 Relative Risk Relative 1.37 1.5 a 1.22 1.20 1.03 0.93 1 0.5 0 Major Vascular Heart Failure Cause-Specific Upper GI Events Mortality COX-2 Inhibitors Diclofenac Ibuprofen Naproxen CNT indicates Coxib and traditional NSAID Trialists; COX-2, cyclooxygenase-2; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug. aP <.05. stroke, or death from a vascular cause. The study also mea- the NSAIDs studied, there was a clear, dose-dependent risk sured the risk for major coronary events, stroke, hospitaliza- across all 3 end points. For example, high-dose diclofenac was tion for HF, and death.