Abstract
Objective. Nonsteroidal antiinflammatory drugs (NSAID) not only cause damage to the upper gastrointestinal (GI) tract but also affect the lower GI tract. To date, there is no endpoint that evaluates serious GI events in the entire GI tract. The objective of this report is to introduce a novel composite endpoint that measures damage to the entire GI tract — clinically significant upper and lower GI events (CSULGIE) — in patients with NSAID-induced GI damage.
Methods. We reviewed the data from largescale, multicenter, randomized, clinical trials on lower GI toxicity associated with NSAID use. The rationale for using CSULGIE as a primary endpoint in 2 ongoing trials — the Celecoxib vs Omeprazole and Diclofenac for At-risk Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Patients (CONDOR) trial and the Gastrointestinal Randomized Events and Safety Open-Label NSAID Study (GI-REASONS) — is also discussed.
Results. Previous randomized trials focused primarily on damage to the upper GI tract and often neglected the lower GI tract. The CSULGIE endpoint extends the traditional “perforation, obstruction, and bleeding” assessment of upper GI complications by including events in the lower GI tract (small/large bowel) such as perforation, bleeding, and clinically significant anemia.
Conclusion. By providing clinicians with a new, descriptive language for adverse events through the entire GI tract, the CSULGIE endpoint has the potential to become a standard tool for evaluating the GI effects of a range of therapies.
- UPPER/LOWER GASTROINTESTINAL TRACT
- CYCLOOXYGENASE INHIBITORS
- NONSTEROIDAL ANTIINFLAMMATORY AGENTS
- OSTEOARTHRITIS
- RHEUMATOID ARTHRITIS
Drug-induced gastrointestinal (GI) toxicity remains a major clinical problem; in the United States, 20%–40% of all drug-induced side effects are associated with the GI tract1. Nonsteroidal antiinflammatory drugs (NSAID) are well known to cause potentially serious adverse GI events such as ulcers, perforation, hemorrhage, and death2. Due to their antiinflammatory, antipyretic, and analgesic properties, NSAID are among the most widely prescribed medications worldwide. However, the GI side effects associated with their use are a significant cause of hospital admissions, mortality, and healthcare expenditure3–5.
Although NSAID-induced upper GI toxicity has been well characterized6–8, the risk of lower GI tract events is less well recognized. Traditional “perforation, obstruction, and bleeding” (POB) assessments are often used to characterize upper GI tract events; however, it should be noted that these assessments are often dominated by bleeding events. Bjarnason, et al were among the first group to report that nonselective NSAID could damage the lower GI tract. They showed an abnormal effect of NSAID on the permeability of both the proximal and the distal intestine9. In a postmortem examination, Allison, et al10 found there was a significant increase in small bowel ulcerations among patients taking NSAID compared with nonusers; further, in this study, 3 patients were reported to have died from perforation of the small bowel. In the same year, Lanas, et al also reported an association between NSAID use and an increased risk for lower GI bleeding11.
There has been an increasing body of evidence to suggest that NSAID-induced GI toxicity does extend to the lower GI tract12–19. A number of case-control studies have consistently shown that NSAID use increases the risk of lower GI bleeding and perforation20–22, while data derived from secondary analyses of randomized NSAID trials13,23 suggest that 33%–50% of serious GI events reported occur in the lower GI tract. In a systematic review of published studies to identify possible adverse effects of NSAID on the small intestine24, it was found that NSAID caused a variety of small intestinal damage such as ulcers, perforation, strictures, anemia, and hypoalbuminemia. However, assessment of NSAID damage to the small intestine has proven to be extremely difficult and many physicians were skeptical regarding the concept that NSAID could cause such damage.
Among various small intestinal events associated with NSAID use, the diagnosis of significant occult bleeding (with or without anemia) is most difficult and has often been overlooked by physicians. Although more advanced diagnostic technologies such as capsule endoscopy or double-balloon enteroscopy have provided physicians with a means of visualizing the lower GI tract, they are currently not widely adopted by the medical community due to their limitations. For example, both procedures are time-consuming, costly, and are only available in specialized centers. There are also reports that significant lesions have been missed with capsule endoscopy25,26 and, due to the invasive nature of the procedure, serious complications such as pancreatitis and perforation have been reported with double-balloon enteroscopy27. On the other hand, the clinical significance of finding asymptomatic mucosal breaks among patients taking NSAID remains uncertain. Thus, while these new technologies may serve as adjuvant diagnostic tools, NSAID-induced occult bleeding from the small bowel remains largely a clinical diagnosis that is often established by excluding other causes of a drop in hemoglobin.
Recent data suggest that hospitalizations for lower GI complications are increasing. In a study in Spain, Lanas, et al demonstrated that, while hospitalizations due to upper GI complications fell in the decade 1996–2005 (from 87 to 47/100,000), lower GI complications increased from 20 to 33/100,00028; in the same study, lower GI events were also associated with higher mortality rates, longer hospitalization, and higher resource utilization than upper GI events. These data are further supported by the findings from a recent study in the US looking at the number of hospitalizations between 1998 and 200629. During this period, hospitalizations for lower GI bleeding increased by 8% (per 100,000 people), while the number of upper GI bleeding events fell (14% decrease per 100,000).
We aimed to evaluate the outcomes of several pivotal trials and introduce a novel composite endpoint that measures damage to the entire GI tract — clinically significant upper and lower GI events (CSULGIE) — in patients with NSAID-induced GI damage.
MATERIALS AND METHODS
We reviewed the study design, duration of followup, endpoint definitions, and GI adverse event (AE) rates of several pivotal trials, including MUCOSA (Misoprostol Ulcer Complications Outcomes Safety Assessment)30, CLASS (Celecoxib Long-term Arthritis Safety Study)6, VIGOR (Vioxx Gastrointestinal Outcomes Research)31, TARGET (Therapeutic Arthritis Research and Gastrointestinal Event Trial)32, SUCCESS-I (Successive Celecoxib Efficacy and Safety Study I)33, and MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-term)34 (Table 1).
In addition, 2 ongoing double-blind, randomized, multicenter trials, the Celecoxib vs Omeprazole and Diclofenac for At-risk Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Patients (CONDOR) trial (NCT00141102), and the Gastrointestinal Randomized Events and Safety Open-label NSAID Study (GI-REASONS) (NCT00373685), were also included for comparison (Table 2). Both trials will include > 12,000 OA and RA subjects with moderate to high GI risk (including patients with recognized GI risk factors such as a history of upper/lower GI event, old age, and/or comorbid disease) and will use a new composite measure of GI safety — CSULGIE (Table 3).
The CONDOR trial is a double-blind, triple-dummy, randomized, parallel-group, multicenter, international study comparing treatment with celecoxib versus slow release (SR) diclofenac plus omeprazole in 4402 subjects with OA and/or RA at high risk of GI AE (Table 2; Figure 1). The primary objective of the CONDOR study is to determine whether celecoxib is superior to the combination of diclofenac plus omeprazole in the incidence of CSULGIE, as adjudicated by an independent, blinded GI events committee. The GI-REASONS trial is a prospective, randomized, open-label, blinded endpoint (PROBE) design study conducted in the US. Approximately 8000 subjects with moderate GI risk (aged ≥ 55 yrs) will be randomly assigned in a 1:1 fashion to either celecoxib or any nonselective NSAID (not aspirin) for 6 months (Table 2; Figure 1). Similar to CONDOR, aspirin users (including low-dose aspirin for cardiovascular prophylaxis) are excluded from the GI-REASONS study. The primary objective of GI-REASONS is to determine whether celecoxib use in OA subjects at moderate GI risk is associated with a lower incidence of adjudicated CSULGIE than treatment with nonselective NSAID, with or without concomitant proton-pump inhibitors.
RESULTS
To date, published clinical trials have focused primarily on damage to the upper GI tract and generally included low-risk populations; however, differences in trial designs, patient populations, and treatment comparators, as well as the use of different terminology for defining an event, have made cross-study comparisons difficult (Table 1). In addition, the use of aspirin and gastroprotective agents, and the lack of a standardized time period between first identification of an event and endoscopy, has further hindered accurate treatment comparisons. Conventional methods of GI evaluation also omit potentially important information regarding damage to the small and large bowel and thus, significant gaps remain in our understanding of the drug-induced toxicity through the entire GI tract. Given the high prevalence of NSAID use, this gap in knowledge has significant potential for suboptimal treatment.
A more comprehensive and patient-focused evaluation of therapeutic toxicity through the entire GI tract is needed. We propose a new composite measure of GI safety — CSULGIE. The CSULGIE endpoint has been developed based on lessons from previous GI outcomes studies. Extending the POB assessment of upper GI complications by including events in the lower GI tract, and thus identifying damage to the entire GI tract, we hope that the CSULGIE endpoint (Table 3), which is currently being used as a primary endpoint in the CONDOR and GI-REASONS clinical trials, will provide a more clinically relevant evaluation of drug-induced damage in the upper and lower GI tracts for these trials.
Separate adjudication committees for GI events are established for CONDOR and GI-REASONS. The GI events adjudication committees comprise a team of gastroenterologists recognized for their expertise in this area. All members of the adjudication committees are blinded to treatment (Figure 2). As discussed, the primary endpoint in these trials is the incidence of CSULGIE, a composite of clinical or laboratory changes that could lead to further investigations for GI blood loss and/or modification of current therapies (Table 3). All suspected GI events are referred to the adjudication committees for consideration; an event was confirmed when consensus could be reached by all members of the committee. Adjudication was reached if all committee members agreed on the event in the first round of review or, if a second round of review was needed, then consensus was reached following a discussion of the case among committee members. Suspected GI events include hematemesis, melena, perforation, obstruction, a reduction of hemoglobin ≥ 2 g/dl and/or hematocrit ≥ 10 percentage points from baseline, or other significant signs or symptoms that the investigator considers may represent a possible GI event. Only events confirmed by the GI events adjudication committee are included in the primary analysis.
DISCUSSION
Previous GI outcomes studies have provided valuable data on drug-induced toxicity in the upper GI tract; however, appropriate risk reduction strategies and future patient management require a better understanding of GI risk throughout the entire GI tract. Although the effect of NSAID-induced enteropathy is becoming increasingly recognized following the emergence of technologies such as wireless capsule endoscopy, there are limitations associated with the latter; these include missing significant lesions as well as detecting trivial mucosal breaks of uncertain clinical significance.
Addressing the need for a more comprehensive and patient-focused evaluation of toxicity through the entire GI tract, the CSULGIE endpoint represents an important step in the evaluation of GI safety. The CSULGIE endpoint will not only reveal damage to the upper GI tract but, it is hoped, will also help raise awareness of damage to the lower GI tract. In addition, the CSULGIE endpoint has the potential to improve our understanding of GI risk. By enabling healthcare providers to assess patient risk and the GI effects of various therapies, both in and outside of clinical trials, CSULGIE may facilitate more effective and informed decision-making.
Further, consistent adjudication of events by expert GI committees will help investigators collect more complete and clinically relevant GI safety data from a range of therapies, across clinical trials, thus helping to create a more statistically robust measure of GI safety. CONDOR and GI-REASONS will be the first trials to evaluate the GI burden of NSAID therapies using the CSULGIE endpoint.
When interpreting the results of clinical studies it is important to consider the study limitations. Although the CSULGIE endpoint aims to identify AE of the entire GI tract, the adjudication of “clinically significant anemia of presumed occult GI origin, including possible small bowel blood loss” remains a continuing challenge to members of the GI events adjudication committees. In the CONDOR and GI-REASONS studies, “clinically significant anemia of presumed occult GI origin, including possible small bowel blood loss” is defined as a fall in hemoglobin of ≥ 2 g/dl and/or fall in hematocrit ≥ 10 percentage points from baseline (Table 2). We found that most patients with a significant fall in hemoglobin did not undergo extensive small bowel investigation such as capsule endoscopy or double-blind balloon enteroscopy; this may be due to the availability of diagnostic procedures in different centers or compliance with local practice guidelines. However, as previously discussed, these new technologies only serve as adjuvant, rather than mandatory diagnostic tools. The diagnosis for a fall in hemoglobin is largely based on clinical judgment and exclusion of other non-GI causes such as dilutional anemia, anemia of chronic illness, or flare of RA. Nevertheless, there remains a possibility that some patients who were adjudicated to have “clinically significant anemia of presumed occult GI origin” actually had a fall in hemoglobin due to a multitude of factors. This limitation is particularly relevant to patients who had a drop in hemoglobin of ≥ 2 g/dl but did not become truly anemic (e.g., hemoglobin level fell from 14 g/dl to 12 g/dl). To overcome this limitation, members of the CONDOR and GI-REASONS adjudication committees met to ensure that there was consistency in adjudicating lower GI events, such that any uncertainty in the diagnosis would be equally reflected in the 2 treatment arms.
It is hoped that CSULGIE will become the gold standard for evaluating the gastrointestinal effects of a range of therapies, providing clinicians with a new descriptive language for adverse events through the entire GI tract. By providing a more complete measure of GI risk, the use of CSULGIE may help physicians to identify risk reduction strategies and encourage them to make more effective treatment decisions and ultimately help improve patient care.
Footnotes
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Sponsored by Pfizer Inc. Editorial support was provided by L. Prevost of PAREXEL and was funded by Pfizer Inc.
- Accepted for publication July 17, 2009.