Prescribing COX-2s for Patients New to Cyclo-oxygenase Inhibition Therapy

November 1, 2003
Emily R. Cox, PhD

Brenda Motheral, PhD

Mark Frisse, MD*

Andrew Behm, PharmD

Doug Mager, BS

Volume 9, Issue 11

Objectives: To profile the pattern of cyclo-oxygenase 2 inhibitor (COX-2) use, including length of therapy, medical conditions treated, and gastrointestinal (GI) risk profile of users.

Study Design: Descriptive retrospective analysis of medical and prescription claims data from a large preferred provider organization in the Midwest.

Methods: During an index period of January through May 31, 2000, patients new to COX-2 therapy were evaluated 365 days before and after their first prescription. Among the inclusion criteria, patients had to have no previous use of COX-2 therapy, be at least 18 years of age, and be continuously eligible during the entire study period.

Results: Of the more than 300 000 members with at least 1 day of coverage in the index window, 1312 members met the inclusion criteria. The average age of COX-2 users was 49.5 years (SD = 11.4) and 60% were female. The number of days’ supply of COX-2 agent obtained by members was highly skewed, with a mean of 116 days (SD = 119.5) and a median of 60 days. The medical conditions associated with COX-2 use included a variety of musculoskeletal conditions, the most common being low back pain (22%) and osteoarthritis (18%). Approximately 19% of members did not have a diagnosis associated with COX-2 use. Sixty-five percent of those new to COX-2 therapy did not have an indication of being at risk for GI events, and 68% had no indication for trying a lower-cost nonselective nonsteroidal anti-inflammatory drug (NSAID) prescription prior to beginning COX-2 therapy. Taken together, 45% did not have a GI risk factor or prior use of nonselective NSAID prescription therapy.

(Am J Manag Care 2003;9:735-742)

Conclusions: These findings suggest that opportunities exist to encourage the cost-effective prescribing of COX-2 therapy. Possible methods include implementation of step therapy, academic detailing, and physician education programs, among others.

Drug Trend Report.

From 1999 to 2000, the per member per year costs for the drug class analgesic anti-inflammatories grew by 37.9%, the highest rate of growth among the top 25 therapy categories, as measured by Express Scripts' 1 Contributing to this growth was the introduction of the newer, more expensive cyclo-oxygenase-2 (COX-2) specific inhibitors, whose combined market share grew by approximately 40% from 1999 to 2000.1 The first COX-2 inhibitor approved in the United States was celecoxib (Celebrex) in December 1998 and the second, rofecoxib (Vioxx), entered the market in May 1999. Valdecoxib (Bextra) was approved by the US Food and Drug Administration (FDA) in November 2001.

All three COX-2 therapies are approved for relief of the signs and symptoms of osteoarthritis (OA), rheumatoid arthritis (RA), and for the treatment of primary dysmenorrhea. Celebrex and Vioxx are also approved for the management of acute pain in adults. Additionally, Celebrex is approved as adjuvant treatment of familial adenomatous polyposis. The COX-2 specific inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen, naproxen) have shown similar clinical efficacy at equipotent doses for the management of acute pain and other conditions associated with pain.2-15

Pharmacologically, COX-2 inhibitors are distinct from nonselective NSAIDs because of their ability to selectively inhibit the COX-2 pathway.16 Nonselective NSAIDs inhibit both COX-1 and COX-2. Inhibition of COX-1 is associated with gastrointestinal (GI) toxicity,5 whereas COX-2 inhibition leads to relief of pain and inflammation. The GI toxicity associated with COX-1 inhibiting agents ranges from symptoms such as nausea, dyspepsia, anorexia, abdominal pain, flatulence, and diarrhea, to potentially life-threatening complications such as upper GI bleeding, perforation, and gastric outlet obstruction.16



It was thought that newly developed drugs designed to block COX-2 but not COX-1 would have anti-inflammatory properties but would avoid the ulcers and other GI events associated with COX-1 inhibition. Two large trials designed to test this theory have been conducted: the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial17 and the Celecoxib Long-Term Arthritis Safety Study (CLASS) trial.18 In the VIGOR trial, the rate of complicated confirmed upper GI events (i.e., perforation, gastric or duodenal ulcer, obstruction, and bleeding) was significantly lower in the rofecoxib group compared with the naproxen group (0.52% vs. 1.22%; < .005).17 However, the CLASS trial, in which celecoxib was compared with traditional NSAIDs (i.e., ibuprofen and diclofenac), did not show a statistically significant difference in the rate of ulcer perforation, gastric outlet obstruction, or upper GI bleeding between celecoxib and nonselective NSAIDs (0.76% vs. 1.45%; = .09).18 Although the rate of serious GI complications observed in these studies was low (< 2%), the absolute number of patients affected is large considering the number of individuals currently taking NSAIDs. With an estimated 13 million Americans taking NSAIDs on a regular basis, annual estimates of hospitalization costs due to serious GI complications exceed $1 billion.19



Both rofecoxib and celecoxib have been found to be associated with significantly reduced mild-to-moderate GI adverse events (event rates for rofecoxib compared with naproxen20 = 23.5% vs. 25.5%, = .02; celecoxib compared with nonselective NSAID18 = 31.4% vs. 36.8%, ¡Ü .05).

One clearly distinguishing feature between COX-2s inhibitors and nonselective NSAIDs is their cost. In 2001, the average wholesale price per prescription was approximately $98 for Celebrex and $86 for Vioxx, compared with $29 for generic nonselective NSAIDs.21 Due in part to the cost difference, many researchers question the widespread use of COX-2s based on symptom benefit alone,22,23 particularly given that mild symptoms do not correlate well with serious adverse events (perforation, obstruction, ulceration, bleeding) and are often managed clinically with histamine-2 receptor antagonists (H2s) and proton pump inhibitors (PPIs). As a result, some researchers recommend that COX-2s be reserved for those patients at high risk for GI adverse events,24 and formal guidelines have been developed to reflect this advice.25,26

The rapid increase in the use of the more expensive COX-2 therapies, coupled with their comparable clinical efficacy to traditional NSAIDs, led to a series of research questions surrounding the use of COX-2s. The goal of our study was to answer these questions:

- What is the pattern of COX-2 use with respect to patient demographics and length of therapy?

- What conditions are COX-2s being used to treat?

- Are these agents being reserved for patients at risk for GI-related events?


Medical and prescription claims data from a large preferred provider organization in the Midwest were used to evaluate diagnostic conditions and patterns of use among new COX-2 users. The prescription copay structure varied across members, however. More than 90% of sample members had a 3-tier benefit structure with first-tier co-pays varying from $8 to $10, second tier from $15 to $20, and third tier from $25 to $30. COX-2s were on the third tier, and no other restrictions regarding their use were in place during the time of evaluation (i.e., step therapy or prior approval).

New COX-2 users were defined as patients with a prescription claim for a COX-2 during the index window January 1, 2000, to May 31, 2000, and with no COX-2 claim during the 12 months prior to the first claim in the index window. Patient's prescription and medical claims were evaluated 365 days before and 365 days after the index prescription (e.g., the first prescription in the index window). Other study inclusion criteria were that patients had to be at least 18 years of age and continuously eligible during the study period.

The COX-2 prescription claims were identified using the generic product identifier (GPI; First Databank [Medispan], Indianapolis, Ind.) code beginning "661005." The GPI is a 14-character code consisting of a hierarchy of 7 subsets, each providing more specific information about a drug product. The total days' supply of COX-2 therapy was calculated as the sum of the days' supply field for all COX-2 claims in the 365 days after and including the index prescription.

Medical Conditions

Medical conditions were evaluated using the primary, secondary, and tertiary International Classification of Diseases (ICD-9) fields. Table 1 outlines the diagnoses considered to be associated with COX-2 use, including how they were defined and measured. Medical conditions were rank ordered with FDA-approved indications ranked highest, followed by non-FDA approved, but possible indications for use. Patients were assigned to a diagnosis hierarchically. For example, patients with more than one of the diagnoses listed were grouped in the diagnosis category higher on the list.

Helicobacter pylori

Risk Factors Prescription and medical claims data were used to identify members with risk factors for NSAID-related GI events. These criteria were adapted from the literature of established and possible risk factors of NSAID associated GI ulcer.27-29 The risk factors used in this study and how they were defined and measured are presented in Table 2. Risk for GI-related events was defined as any one of the following factors: history of a GI event; age 60 years or older; recent use of anticoagulant or corticosteroid agents; and higher doses of COX-2 therapy. History of a GI event included diagnosis of gastric, duodenal, or peptic ulcers; infection; GI hemorrhage; and evidence of an endoscopy. Prior use of gastroprotective agents (i.e., PPIs and H2 blockers) was also included as a GI risk factor given recent evidence in the literature suggesting that use of these agents may serve as a proxy for GI risk.30,31 Although not established risk factors, we also included acid-related diagnoses such as gastroesophageal reflux disease, heartburn, and esophagitis, including ulceration or perforation of the esophagus. These factors were included to be as generous as possible in identifying individuals as possible at risk for GI events, recognizing the limitations of claims data and the time over which we evaluated GI risk. As a sensitivity analysis, and because of the lack of specificity around the age criteria, we also included estimates of GI risk using age ¡à 65 years.


Of the 319,263 members with at least 1 day of enrollment during the index window, 5,561 had a COX-2 prescription claim. After screening for eligibility and age, 2,450 members remained. An additional 1138 were excluded due to prior use of a COX-2, resulting in a final sample size of 1,312.

Sample Demographics and Patterns of Use

Approximately 60% of those new to COX-2 therapy were female; the mean age was 49.5 years (SD = 11.4). The days' supply among new COX-2 users during the 365-day follow-up was highly skewed (Figure). The mean days' supply was 116 days (SD = 119.5) and the median was 60 days.

Medical Conditions

Approximately 19% (n = 245) of members had no medical condition that would indicate the need for a COX-2 inhibitor (Table 1). The diagnosis representing the largest proportion of new COX-2 users was low back pain (22%). Next were diagnoses related to joint pain and inflammation including OA (18%) and joint derangements and other unspecified disorders of the joint (20%). Other conditions related to COX-2 use included various disorders of the muscle tissue and soft tissue, including sprains and strains (3%), disorders of the muscles and tendons and their attachments (6%), and RA (3%).

Risk Factors

Table 2 profiles the percent of members meeting each of the GI risk factor criteria and the percent with 1 or more risk factor. Among individuals new to COX- 2 therapy, 18.8% met the age criterion of being at least 60 years. Increasing the age criterion to a minimum of 65 years decreased the absolute percentage meeting the criteria by 12 percentage points to 6.8%. Approximately 17% had a history of GI problems, the vast majority of which represented prior use of gastroprotective agents. Approximately 6% and 3%, respectively, had recent use of corticosteroid agents or anticoagulant agents.

Overall, using the age criterion of a minimum of 60 years, 65% of persons new to COX-2 therapy had no evidence of being at risk for NSAID-related GI problems. Using the age criterion of a minimum of 65 years, 73% of those new to COX-2 therapy had no evidence of being at risk for NSAID-related GI problems.

Prior Use of Nonselective Nonsteroidal Anti-inflammatory Drug Therapy


Approximately 68% of new COX-2 users did not have a claim for a nonselective NSAID during the 1 year prior to beginning their COX-2 therapy. The likelihood of using a nonselective NSAID prior to COX-2 use was not significantly different among those with and without a GI risk factor (¦Ö2 = 1.07, = .302). Taken together, approximately 45% of new COX-2 users did not have a GI risk factor or prior use of a nonselective NSAID agent.


The profile of COX-2 use within our sample was for predominantly short-term treatment of a variety of musculoskeletal conditions. Such individuals are often not at risk for GI events, or have not tried a lower-cost nonselective NSAID agent prior to beginning COX-2 therapy. These findings suggest the need for more cost-effective prescribing of COX-2 medications among those new to therapy. This conclusion is based on findings of the sensitivity of COX-2 cost-effectiveness models to assumptions regarding the underlying GI risk of the modeled population,32-34 and no evidence to suggest that COX-2s are cost effective in the short-term treatment of pain. When cost-effectiveness models evaluate the sensitivity of results to assumptions regarding GI risk, incremental costs per event avoided go beyond that considered economically acceptable32,34 or differences in total expected costs between COX-2s and nonselective NSAIDs are practically indistinguishable.33

Several study limitations may limit generalizability of the study findings. The data represent only one plan's experience, and COX-2 prescribing patterns could vary depending on numerous factors including physician incentives and plan design. Limitations of medical claims data, particularly to identify specific diagnoses, are also recognized.35 Diagnoses associated with COX-2 use or GI risk may have been missed because of undercoding. We attempted to overcome these limitations through inclusion of gastroprotective agent therapy identified using prescription claims data, which has been shown to be a reliable and valid source of data compared with medical claims data.36,37 The time during which we evaluated individual history of GI events was limited to 365 days. We recognize that a GI event could have occurred prior to this look-back period. However, we were generous in our definition of GI risk (i.e., meeting any one criteria), possibly overstating the percent with GI risk. Further research, using a longer look-back period or medical record review, would need to be conducted to determine the extent of false-negative or false-positive identification of risk.

The conditions for which COX-2s appeared to be used included a variety of musculoskeletal conditions. Although COX-2s are indicated for acute pain, the fact that close to 1 in 4 new COX-2 users appeared to be prescribed such therapy for the treatment of low back pain was a surprising finding. Etiology of low back pain is often difficult to determine, and the manifestations can include both inflammatory and non-inflammatory pain. Some proportion of COX-2 therapy is likely for low back pain associated with OA; however, further analysis would be needed to determine the extent of OA within this diagnosis category. Approximately 20% of members did not have a diagnosis that would be an indication for COX-2 use, which could be related to the limitations of medical claims data discussed earlier, or use of COX-2 inhibitors in dental practice, data not captured in our medical claims database.

Forty-five percent of new COX-2 users-individuals with no GI risk or prior traditional NSAID use-were given a COX-2 inhibitor as first line-therapy when lower-cost nonselective NSAIDs might have been the most cost-effective approach. The premise of this conclusion rests on the wealth of research evaluating predictors of NSAID-associated GI complications, no evidence of superior clinical efficacy of COX-2s, and no evidence of the cost effectiveness of COX-2s in patients not at risk for GI events. The research on predictors of NSAID-related GI events have resulted in a generally accepted list of factors thought to significantly increase a patient's risk of developing an NSAID-related GI ulcer.27-29,38-40 While the presence of any 1 risk factor is an important determinant in predicting overall GI risk, the presence of more than 1 factor has also been shown to increase a patient's risk for GI toxicity. Silverstein and colleagues noted that among the 4 risk factors found to be significantly related to the risk of serious upper GI complications, patients with no risk factor have a 0.4% risk for having a serious GI complication, those with any 1 risk factor have ~1% risk, and those with all 4 risk factors a 9% risk.41

The evidence of GI risk should also take into consideration the fact that more than half of the patients who were new to COX-2 therapy obtained at most a 60 days' supply of therapy during the 1-year follow-up. This pattern of use is not unlike that observed in studies of OA patients prescribed nonselective NSAIDs-half of the patients on aspirin, ibuprofen, naproxen, or piroxicam had discontinued therapy after 66, 53, 51, and 120 days, respectively.42

With regard to duration of therapy and the risk of nonselective NSAID-related GI adverse events, whereas the relative risk of adverse GI events is greatest within the first month of therapy,40 findings from the Arthritis, Rheumatism, and Aging Medical Information System database (ARAMIS) suggest that the risk of GI bleed remains constant during a 10-year follow-up.28 The ARAMIS findings indicated that patients taking NSAIDs for 5 years have a 5-times greater risk of bleeding than do patients taking NSAIDs for 1 year. The bleeding risk for individuals undergoing NSAID therapy for 3 months was one quarter that for individuals taking NSAIDs for 1 year. The degree of GI risk associated with short-term NSAID use is an important issue for further research, given the large amount of short-term COX-2 use.

The high proportion of COX-2 use by persons with no evidence of GI risk or trial of nonselective NSAID, together with the substantial amount of short-term use, suggest that steps could be taken to encourage more cost-effective prescribing of COX-2 agents. Ways in which plans can encourage the cost-effective prescribing of COX-2s include programs such as step therapy, prior approval, and academic detailing. Step therapy is a program designed to manage the use of select or first-line therapies (i.e., nonselective NSAIDs) before alternative or second-line therapies (i.e., COX-2s) are covered. These programs are typically automated at the point of service. The limitation of step therapy for NSAIDs is that this strategy does not take into consideration the GI risk profile of the patient.

Prior authorization requires that approval for the product be given prior to prescribing the product. The criteria for determining approval can vary, but in the case of COX-2s, could include the generally agreed upon list of established risk factors.27 Prior approval has the advantage of ensuring that these high-cost products are reserved for patients at risk for NSAID-related GI events; however, plans would have to balance program costs carefully against the potential savings given the high volume of calls that such a program could generate. To overcome the limitations of both step therapy and prior approval for this therapy class, some plans have used a combination of step therapy and prior approval using an automated process at the point of service.

An example of a combined step therapy¡Ìprior approval program was described by Tucker and colleagues. 43 Their step therapy component included prior use of nonselective NSAIDs and the prior approval component included checks for GI risk (i.e., prior use of a gastroprotective agent or other ulcer treatment, or anticoagulant or antiplatelet therapy).43 Other criteria could also be automated, including patient age and use of corticosteroids. When implementing prior approval programs for COX-2s, plan administrators should be aware that the age selected as the criterion for increased GI risk is important in determining the overall percent of members who would be affected by these programs. Our results varied by approximately 8 percentage points when the age criterion was 60 versus 65 years. There is no definitive age at which a person suddenly is at risk for an NSAID-related GI event; rather, findings suggest that the relationship between GI risk and age is linear, increasing steadily by ~4% per year increase in age.28

Evidence that plans are implementing academic detailing or physician education programs for COX-2s has also appeared in the literature.25 Treatment guidelines based on The Standardized Calculator of Risk for Events (SCORE) criteria were disseminated among physicians of a northern California HMO and reinforced through academic detailing by drug education pharmacists. SCORE is an instrument designed to estimate an individual's risk for serious NSAID-induced GI toxicity (e.g., stomach ulcer or bleeding ulcer).44,45 It is based on 6 criteria: age, self-reported health status, diagnosis of RA, use of oral corticosteroids, hospitalization for a stomach or intestinal problem or prior history of stomach ulcer, and history of GI side effects (heartburn, stomach pain, nausea, vomiting) when taking NSAIDs. SCORE was developed by researchers at Stanford University using data from ARAMIS.45

These examples are just some of the steps plan sponsors are taking to encourage the cost-effective use of COX-2 therapy. As more health plans move toward adoption of these programs, research should be conducted to ensure that the risk identification tools avoid false-negative results (i.e., those with risk are identified as not having risk) and false-positive results (i.e., those without risk are identified as having risk). Such research is critical to the provision of quality, cost-effective healthcare.

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