Writing in Alimentary Pharmacology and Therapeutics, researchers in the Netherlands examined a primary care population comprised of 50,126 NSAID users ≥50 years of age during an 11-year period (1996-2006) [Valkhoff et al. 2010]. Their objective was to determine trends in the use of preventive strategies to reduce GI complications of NSAIDs.
Adverse upper-GI events with NSAIDs can range from simple indigestion to more serious bleeding, ulceration, perforation, or obstruction, which can lead to hospitalization or, in some cases, death. Recommended preventive strategies typically include either prescribing a COX-2-selective inhibitor (coxib) or combining traditional nonselective NSAIDs (including aspirin) with a gastroprotective agent (eg, proton pump inhibitor [PPI], histamine blocker, or misoprostol).
In the study, patients receiving NSAIDs were categorized as high risk because of either (1) a history of GI bleeding/ulceration, (2) being age 65 or older, or (3) using anticoagulants, aspirin, or corticosteroids. [Note: some investigators also include other risk factors, such as using high-dose or multiple NSAIDs, presence of cardiovascular disease or infection with H. pylori, or concurrent use of SSRIs.] Key findings of the study include:
- Twenty-six different types of NSAIDs were prescribed during the study, with only 7% of patients receiving a coxib prescription. The remaining 93% received a traditional NSAID, with diclofenac accounting for the greatest proportion (39%), followed by ibuprofen (17%) and naproxen (16%). [The study did not take into account over-the-counter purchases of either nonprescription NSAIDs or gastroprotective agents.]
- Just over 43% of all prescription-NSAID users were defined as high-risk because of having at least one risk factor. Being 65 years of age or older was the most frequent risk factor followed by use of anticoagulants. The remaining 57% of the study population had no NSAID-related GI risk factors and were therefore deemed as low risk.
- The correct prescribing of GI-protective strategies in high-risk NSIAD users rose from roughly 7% in 1996 to 40% in 2006. However, in low-risk NSAID users, the “over-prescription” of unnecessary preventative strategies also rose, from 3% to 12%. All change data were statistically significant.
- The most commonly prescribed gastroprotective agents were PPIs (77%), followed by histamine antagonists (22%), and misoprostol (1%). Only 4% of patients prescribed a histamine blocker were given the high dosages that have been recommended for reducing endoscopic ulcer rates.
There were two interesting ancillary observations in the Dutch study: (A) after the withdrawal of rofecoxib (Vioxx®) from the market in 2004 and valdecoxib (Bextra®) in 2005 there were coinciding upsurges in the prescribing of traditional nonselective NSAIDs but without appropriate gastroprotection, which exemplifies the sort of unintended consequence for regulators to consider when risk-minimization measures call for removal of any drug from the market; (B) the researchers found that prescribers were generally unaware of or overlooked the need for gastroprotective strategies with chronic aspirin use in high-risk patients.
COMMENTARY: We have previously discussed risks and necessary precautions with NSAIDs [here] and [here], noting that an estimated 60 million Americans regularly use NSAIDs, resulting in clinically significant upper-GI complications in up to 1.2 million of them. So, this should be a concern of great importance.
While the Dutch study has the limitation of examining only a single-country population, all indications are that the results have significant external validity. In 2006, researchers from the UK conducted an extensive systematic review of clinical evidence assessing the effectiveness of either coxibs alone or NSAIDs combined with gastroprotective strategies [Moore et al. 2006]. Aggregating numerous studies via meta-analysis resulted in a very large population for examination (ie, 1.6 million patients, over 900,000 of whom were prescribed NSAIDs). Overall, the prescribing of coxibs was found to consistently reduce upper-GI adverse events by at least 50%, whereas NSAIDs plus gastroprotection with acid suppressants were somewhat less effective. At that, however, 75% of patients on average (range 65% to 90% in various studies) received no prescription at all for a gastroprotective agent with a nonselective NSAID. Furthermore, there was some evidence that those patients who were prescribed gastroprotection in the form of a PPI or histamine antagonist were not compliant with the regimen.
Together, the research results pose a multifaceted dilemma. One of the problems overlooked in most of the research may be the considerable added costs of gastroprotective strategies, whether considering a coxib, NSAID plus a gastroprotective agent (GPA), or newer combination NSAID-GPA products. Evidently, better education is needed on all fronts — for prescribers and patients — taking into account the many risks of NSAIDs and the benefits of implementing safety strategies that might justify costs. Along with this, it could be appropriate to also consider the relative risks/benefits/costs of alternate pain management medications.
SAFETY ADDENDUM: In late May 2010, the U.S. FDA issued a safety announcement about revised prescription and over-the-counter (OTC) labelling for all proton pump inhibitors (PPIs or “prazoles”) to warn of possible increased risk of fractures of the hip, wrist, and spine with the use of these medications. This risk had primarily been observed in persons receiving high doses of PPIs, or using them for one year or longer, and/or in those 50 years of age or older. See further information from the FDA [here].
> Moore RA, Derry S, Phillips CJ, McQuay HJ. Nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 selective inhibitors (coxibs) and gastrointestinal harm: review of clinical trials and clinical practice. BMC Musculoskeletal Disorders. 2006,7:79 [article available here].
> Valkhoff VE, Van Soest EM, Sturkenboom MCJM, Kuipers EJ. Time-trends in gastroprotection with nonsteroidal anti-inflammatory drugs (NSAIDs). Alimen Pharmacol Ther. 2010(Jun);31:1218-1228 [article PDF available here].