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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56:M167-M175 (2001)
© 2001 The Gerontological Society of America

Functional Status and Health-Related Quality of Life of Elderly Osteoarthritic Patients Treated With Celecoxib

Jeffrey Lissea, Luis Espinozab, Sean Z. Zhaoc, Seema D. Dedhiyad and Jane T. Osterhausd

a University of Texas, Galveston
b Louisiana State University, New Orleans
c Pharmacia Corporation, Peapack, New Jersey
d Pharmacia Corporation, Skokie, Illinois

Seema D. Dedhiya, Pharmacia Corporation, 5200 Old Orchard Road, Skokie, IL 60077 E-mail: dedhiya_seema{at}hotmail.com.

Decision Editor: John E. Morley, MB, BCh


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 Conclusions
 References
 
Background. This study evaluates the impact of celecoxib on functional status, health-related quality of life (HRQOL), and safety of elderly patients (>=70 years) with osteoarthritis (OA) of the knee and/or hip.

Methods. Data were pooled from three prospective, randomized, multicenter, double-blind, parallel group trials, each having a 12-week treatment period. Multicenter studies were conducted in the United States and Canada. Data for patients diagnosed with active OA of the knee and/or hip in a flare state who were 70 years of age and older were included in the comparison of therapeutic doses of celecoxib or naproxen versus placebo (N = 768). Elderly patients from each of the three trials who were randomly assigned to groups treated with a placebo, 200 mg/day of celecoxib, 400 mg/day of celecoxib, or 1000 mg/day of naproxen were included in this analysis. The Western Ontario and McMaster Universities Osteoarthritis Index was used to measure functional status. The Short Form-36 was used as a general measure of HRQOL. Safety was assessed according to the incidence and type of adverse reactions as reported by the patients and the rate of withdrawal due to adverse events.

Results. At the end of the treatment period, patients in the celecoxib groups had significant improvement in both functional status and HRQOL in comparison with the placebo group. The effects of total daily doses of 200 mg of celecoxib, 400 mg of celecoxib, and 1000 mg of naproxen on functioning and HRQOL were not found to be significantly different from each other. The incidence of serious adverse events and withdrawal from the studies due to adverse events were similar in the celecoxib groups as they were in the placebo group. Overall, the naproxen group reported a significantly higher incidence of gastrointestinal adverse events than did the placebo and the 200-mg-daily celecoxib groups.

Conclusions. This study showed that celecoxib and naproxen significantly improved functional status and HRQOL in elderly patients compared with those treated with a placebo. Celecoxib-treated patients were also found to experience safety and tolerability similar to that of the placebo-treated patients.

THE elderly population is of special interest because pharmacological outcomes are affected by the combination of multiple disease processes and the physiologic effects of aging (1)(2)(3). Problems in this population can manifest themselves as exaggerated or less-than-optimal responses to medication, symptoms of drug-induced illness, lack of therapeutic response to medication, and adverse events (4)(5). It is therefore especially important to monitor the effects of treatment on safety, efficacy, and health-related quality of life (HRQOL) in elderly persons.

One of the prevalent chronic conditions in this population is osteoarthritis (OA), a degenerative joint disorder characterized by pain, joint swelling, stiffness, and limitations in physical functioning. About 80% of the population over the age of 55 years are affected by OA (6). Impairments, as a direct result of OA and due to the associated pain and immobility, can impose substantial humanistic and economic burdens on patients and health care providers. Patients' pain, joint swelling and stiffness, and forced immobility gradually lead to difficulty with physical functioning, such as walking and ascending or descending stairs (7). Also, impaired functional status or inability to perform activities of daily living leads to interference with social lives and personal relationships, reduces levels of independence, and increases the need for assistance (6). Because treatments for OA are largely aimed at the reduction of symptoms, treatments that significantly reduce the signs and symptoms of arthritis should also lead to an improvement in patients' functional status as the severity of their symptoms decline. The assessment of functional status in OA patients, therefore, is an important means of evaluating the benefits of treatment.

Traditional treatment for OA, consisting mainly of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics, is often suboptimal, requiring a balance between efficacy and tolerance of associated side effects (8). Although efficacious at relieving pain, NSAIDs are frequently associated with a number of side effects, some of which are potentially life threatening. These include gastrointestinal (GI) events (e.g., upset stomach, ulceration, and hemorrhagic ulceration), alteration of platelet function, impairment of renal function, and interaction with other medications commonly used in the elderly population (4)(5)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Alternative treatments with long-standing analgesics such as acetaminophen may not provide adequate pain relief and, in high doses, can be associated with a host of undesirable side effects (e.g., dizziness, nausea, abdominal pain, and shortness of breath).

The mechanism of action for currently available NSAIDs is the prevention of the formation of prostaglandins by inhibition of the enzyme cyclooxygenase (COX) (19). COX exists in at least two forms: COX-1 (constitutive form) and COX-2 (inducible form). Preclinical data suggest that inhibition of COX-2 may be responsible for the anti-inflammatory and analgesic effects of COX enzyme inhibition, whereas inhibition of COX-1 may be responsible for the adverse events in the upper GI tract and platelets (20)(21)(22)(23). Most NSAIDs currently available are nonselective inhibitors of both COX-1 and COX-2. In contrast, celecoxib is a COX-2 specific inhibitor that maintains the beneficial effects of traditional NSAIDs with a superior safety profile. Studies in OA patients have demonstrated that at full therapeutic doses, celecoxib has an equivalent efficacy to first-generation NSAIDs, but with fewer adverse events (24), leading to the expectancy that celecoxib will improve functional status and HRQOL among elderly OA patients and cause fewer side effects. Although these studies included elderly patients, their number was limited in each of these studies, restricting the opportunity to assess treatment effects in this population.

This study, using pooled data from three OA studies, evaluated the impact of celecoxib on OA in elderly patients (>=70 years). The study determined whether celecoxib improved functional status and HRQOL and was safe and well tolerated by elderly patients.


   Methods
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 Abstract
 Methods
Results
 Discussion
 Conclusions
 References
 
Data Collection and Study Design
This study used data from three prospective, randomized, double-blind, parallel group trials conducted at various sites in the United States and Canada. The trials were conducted in accordance with the principles of good clinical practice and the Helsinki Declaration of 1975. The institutional review board at each clinical site approved the protocol, and all patients were required to provide written informed consent.

The design of the three trials was similar with the exception that two studies assessed patients with OA of the knee and/or hip and one study assessed patients with OA of the hip only. Male and female outpatients, 18 years of age or older, were eligible to participate in the trials if they met predetermined criteria; however, only patients 70 years of age or older were included in this analysis. Following a 2- to 7-day washout period of NSAIDs or any analgesic medication, symptomatic OA ("flare") was confirmed at a baseline visit according to predefined criteria for changes in the results of the arthritis assessments performed at screening. Elderly patients who demonstrated an OA flare within 14 days of discontinuing NSAID or analgesic treatment for OA and who were randomly assigned to placebo, 100-mg BID (twice daily) celecoxib, 200-mg BID celecoxib, or 500-mg BID naproxen groups were included in this analysis. Low-dose aspirin (<=325 mg/d) and acetaminophen (up to 2 g/d for periods no greater than 3 consecutive days) were allowed as concomitant medications, except within 48 hours prior to arthritis assessments during which no concomitant analgesics were allowed. The use of other NSAIDs, oral or injectable corticosteroids, or anticoagulants were prohibited. Data were collected on patients' demographic characteristics, functional status, HRQOL, and safety.

Description of the Western Ontario and McMaster Universities Osteoarthritis Index..-- The functional status of OA patients was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The WOMAC is a reliable, validated instrument that has been used extensively to determine the functional status in patients with OA of the knee and hip (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). It has three subscales with a total of 24 items (pain with 5 items, stiffness with 2 items, and physical functioning with 17 items) and can be self-administered in less than 5 minutes. The Likert version of the WOMAC reports responses on a 5-point scale where 0 represents "none," 1 is "mild," 2 is "moderate," 3 is "severe," and 4 is "extreme." Therefore, the 5-item pain subscale score ranges from 0 to 20, the 2-item stiffness subscale score ranges from 0 to 8, the 17-item physical functioning subscale score ranges from 0 to 68, and the composite WOMAC score has a range of 0 to 96. A lower score on any subscale represents better functional status and, when change in scores over time is calculated, a negative score represents an improvement in functional status (35).

Description of the Short Form-36..-- HRQOL was assessed using the acute version of the Short Form-36 Health Survey (SF-36). The SF-36 is a reliable, validated, generic instrument that has been used extensively to measure HRQOL in diverse patient groups, including arthritis patients (28)(36)(37)(38)(39)(40)(41). It measures HRQOL using eight separate domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Two summary scores, the physical component score (PCS) and the mental component score (MCS), can then be computed by weighting the corresponding domains. A higher score on the eight domains and two summary scores represents a higher level of HRQOL (42).

Both the WOMAC and the SF-36 were administered to patients at baseline (prior to receiving the study drug) and at Weeks 2 and 12.

Description of safety assessment..-- Safety was assessed according to the incidence and type of adverse reactions reported by the patients and the rate of withdrawal due to adverse events. Adverse events were recorded and coded according to the World Health Organization Adverse Reaction Terminology list. These events were graded by the investigator as mild (causing no limitation of usual activities), moderate (causing some limitation of usual activities), or severe (causing inability to carry out usual activities). Safety was assessed at baseline, Week 2, and Week 12.

Statistical Methods
All randomized elderly patients were included in the analyses of pretreatment variables. All statistical analyses on treatment period variables were based on the intent-to-treat population, defined as all patients who were randomized and took at least one dose of study medication. The Last Observation Carried Forward approach was used for imputing missing values (43). All statistical testing was two-sided at a 5% level of significance, and changes in WOMAC and SF-36 scores from baseline are reported as least square means. The statistical package SAS for Windows version 6.03 (SAS Institute, Cary, NC) was used to conduct all analyses. For statistical analyses with center as a factor, any center with no patients in at least one of the five treatment groups was pooled with another center geographically. Chi-square tests were used to analyze homogeneity of treatment groups for categorical variables. A two-way analysis of variance with treatment and center included in the model was used to examine the homogeneity among treatment groups for continuous variables and also to analyze baseline WOMAC and SF-36 scores. Treatment comparisons were assessed using change from baseline scores for each of the WOMAC subscales and for the eight domains and two summary scores of the SF-36. Statistical significance was tested using a two-way analysis of covariance with treatment and center as factors and baseline scores included in the model as a covariate. If the change in domain or composite score was significant, then pairwise comparisons were performed.

In addition, the proportion of patients in each treatment group who were able to improve from reporting "moderate" to "extreme" pain on the WOMAC at baseline to reporting "none" or "mild" pain at Week 12 were compared between the total-daily-dose 200-mg celecoxib, 1000-mg naproxen, and placebo groups. To test the differences in pain scores between treatment groups, patients who experienced "moderate," "severe," or "extreme" pain were combined. The percentages of patients who moved from these categories at baseline to "none" or "mild" pain at Week 12 were calculated. The denominator of the proportion was the total number of patients in the categories of "moderate," "severe," or "extreme" pain at baseline. The numerator was the difference in the total number of patients in the categories of "moderate," "severe," or "extreme" pain at Week 12 and baseline. This means that patients who moved into these three categories from the "none" and "mild" pain categories by the end of the treatment period were also considered. A two-sample test for binomial proportions was used to determine treatment differences for each item (44). A similar item analysis was conducted for the physical functioning subscale to calculate the percentage of patients who improved from the more limited physical functioning categories to the less limited physical functioning categories.


   Results
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 Abstract
 Methods
 Results
Discussion
 Conclusions
 References
 
Descriptive Statistics
The study had a total of 768 patients with OA of the knee and/or hip who were 70 years of age or older. The baseline demographic characteristics and disease activity of the patients are summarized in Table 1 . There were no statistically significant differences between the four treatment groups with respect to demographic characteristics or disease activity at baseline.


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  		Table 1. Baseline Demographic Characteristics and Disease Activity

 
Functional Status and HRQOL Evaluations
Baseline WOMAC and SF-36 scores showed no statistically significant differences between the treatment groups except for the social functioning domain of the SF-36 (p < .05; Table 2 ). The social functioning score in the 200-mg-daily celecoxib group was the lowest (60.5), while scores in the placebo, 400-mg-daily celecoxib, and 1000-mg-daily naproxen groups were 65.8, 68.1, and 68.2, respectively.


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  		Table 2. WOMAC and SF-36 Scores at Baseline

 
At Week 2, the 200-mg- and 400-mg-daily celecoxib groups and the 1000-mg-daily naproxen group showed statistically significant improvement in the WOMAC pain, stiffness, physical functioning, and composite scores compared with the placebo-treated group (p < .001; Table 3 ). No significant differences between the celecoxib groups and the naproxen group were observed. Similarly, the general HRQOL among patients in the 200-mg- and 400-mg-daily celecoxib groups and the naproxen group showed significant improvement in all eight domains and the two summary scores of the SF-36 compared with patients in the placebo group (Table 3 ). There was no difference in change scores among the 200-mg-daily celecoxib, 400-mg-daily celecoxib, and naproxen groups.


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  		Table 3. Change From Baseline in WOMAC and SF-36 Scores at Week 2

 
At Week 12, the two celecoxib groups and the naproxen group had statistically significant improvement on the WOMAC pain, stiffness, physical functioning, and total scores compared with the placebo-treated group (p < 0.001; Table 4 ). These improvements were not significantly different between the celecoxib groups and the naproxen group. Similarly, the HRQOL scores among patients in the 200-mg- and 400-mg-daily celecoxib groups, as well as the naproxen group, showed significant improvement in six (i.e., physical functioning, role physical, bodily pain, vitality, social functioning, and mental health) of the eight SF-36 domains and the PCS, compared with patients in the placebo group (Table 4 ). In addition, the two celecoxib groups showed significant change over the placebo group on the general health domain. The 200-mg-daily celecoxib group also showed significant improvement in the MCS compared with the placebo-treated group.


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  		Table 4. Change From Baseline in WOMAC and SF-36 Scores at Week 12

 
Another way of evaluating the impact on aspects measured by the WOMAC is to consider the proportion of patients who improved from a "moderate," "severe," or "extreme" pain or difficulty category to a "none" or "mild" pain or difficulty category after treatment (Table 5 ). At Week 12, 33% (range, 21%–39%) of patients in the 200-mg-daily celecoxib group and 29% (range, 18%–41%) of patients in the 1000-mg-daily naproxen group improved from the "moderate," "severe," or "extreme" pain categories to the "none" or "mild" pain categories for each of the five WOMAC pain items, compared with 15% (range, 10%–21%) in the placebo group. The least frequent activity to achieve a "none" or "mild" rating was for pain experienced while going up or down stairs. The 200-mg-daily celecoxib group was significantly different from the placebo-treated group on all items and had a larger percentage of change on four of the five items in comparison with the naproxen group, although these differences were not statistically significant. The naproxen group showed significant differences from the placebo group on four of the five items.


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  		Table 5. Patients' Shift From WOMAC Categories of "Moderate," "Severe," or "Extreme" to "None" or "Mild" at Week 12 Compared With Baseline

 
A similar item level analysis was conducted for the physical functioning items (Table 5 ). The reduction in the percentage of patients in the "moderate," "severe," or "extreme" difficulty categories for the 17 physical functioning items in the placebo, 200-mg-daily celecoxib, and naproxen treatment groups was 9% (range, 2%–18%), 28% (range, 18%–43%), and 27% (range, 14%–39%), respectively. The 200-mg-daily celecoxib group was significantly different from the placebo group on all physical functioning items. On 9 of the 17 physical functioning items, higher percentages of patients moved to the less severe category in the 200-mg-daily celecoxib treatment group than in the naproxen-treated group, but these differences were not statistically significant. In the naproxen group, with the exception of one item (i.e., standing), all other items were found to be statistically significantly different from the placebo-treated group.

Safety Evaluations
Both doses of celecoxib were well tolerated. In total, 92 (48.9%), 125 (65.4%), 128 (64.0%), and 125 (60.7%) patients in the placebo, 200-mg-daily celecoxib, 400-mg-daily celecoxib, and 1000-mg-daily naproxen groups, respectively, reported at least one adverse event (Table 6 ). Serious adverse events occurred in eight (4.3%) placebo, seven (3.7%) 200-mg-daily celecoxib, nine (4.9%) 400-mg-daily celecoxib, and four (1.9%) 1000-mg-daily naproxen group patients, but differences were not statistically significant. Nonserious adverse events were reported in 84 (44.7%) placebo, 118 (61.8%) 200-mg-daily celecoxib, 119 (59.5%) 400-mg-daily celecoxib, and 121 (58.7%) 1000-mg-daily naproxen group patients. Only the 200-mg-daily celecoxib group showed a statistically significant difference from the placebo group with regard to the incidence of nonserious adverse events. With respect to the overall incidence of GI-related adverse events, there were no significant differences between the two celecoxib groups and the placebo group. In contrast, statistically significant differences were found between the naproxen group and the placebo group, and the naproxen group and the 200-mg-daily celecoxib group. No differences were observed between the treatment groups among other more commonly reported non-GI-related adverse events. Differences in the rates of withdrawal due to adverse events in the two celecoxib groups and the naproxen group were not statistically significant from the placebo-treated group.


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  		Table 6. Comparison of Adverse Events and Withdrawal Rates

 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
Conclusions
 References
 
It has become increasingly important to study the effects of medications in the elderly population because demographic changes in the United States over the past century have led to an increased attention to special needs of this population within the health care system. Over the next decade, the number of people over the age of 65 is expected to increase substantially, with the elderly population estimated to constitute 13.2% of the U.S. population in 2010 (45). This population experiences different reactions to medications, has more comorbidities, and needs more medications. For these reasons, it was important to study the effect of treatment on the elderly patients suffering from a chronic condition such as OA. The results of this study using pooled data of elderly patients from three large multicenter trials show that celecoxib not only improves functional status and HRQOL, but is also a safe and well-tolerated treatment option for OA of the knee and/or hip.

The importance of pain relief and improvement in physical functioning is highlighted with the improvement in the ability of patients to care for themselves. Both celecoxib and naproxen helped patients reduce their pain while performing physical activities such as walking on a flat surface, going up and down stairs, and standing upright. The medications also helped them to perform daily activities, such as rising from a chair, bending, and getting in and out of cars with more ease. In addition to the improvement observed in overall pain, stiffness, and physical functioning subscale scores, it is important to note that improvement was observed across all individual items contributing to the subscale scores, signifying an improvement on all aspects of functional status. The ramifications of such improvements may include patients being able to participate in more physical activities, such as scheduled exercise programs designed to help retard the progress of the disease condition. A recent study has shown that exercise and physical therapy can dramatically decrease the pain associated with arthritis and even prevent the need for surgery (46).

Improvements in HRQOL are important because population studies have shown that elderly patients with OA report significantly lower functioning when compared with healthy controls and patients with other chronic conditions (47). Therapeutic interventions with celecoxib and naproxen resulted in significant improvements in HRQOL when compared with placebo, as measured by the SF-36. These improvements in HRQOL mean that elderly patients may be able to continue with their physical activities, maintain their desired level of independence, and therefore experience an overall more enriched life.

Improvements in functional status and HRQOL are not only important to patients' levels of independence and disability, but also have economic implications; decrements in functional status and HRQOL have been shown to be associated with increased use of medical resources (48). In addition to concern about patient outcomes, payers may be interested in functional status and HRQOL assessments because they can help predict patients' resource utilization patterns. If resource use can be diminished, as would be expected with higher levels of HRQOL experienced by patients in the active treatment groups, payers may experience important budget impacts. Improved HRQOL would also increase chances of independent living, which would have additional payer impact. Overall, treatments that provide improved functional status and relief from symptoms may reduce the economic burden placed on payers, while improving the level of patients' physical activity. Patients and physicians are also interested in functional status and HRQOL assessments because they help in choosing between treatment options; functional status and HRQOL are impacted by both efficacy and safety of treatment options. Improved treatments and evaluations for the management of OA are important, especially in this subpopulation.

Results of this study also show that only the 200-mg-daily celecoxib group was significantly different from the placebo group with respect to the incidence of nonserious adverse events. There was no significant difference between the active treatment and placebo groups with respect to serious adverse events. The incidence of upper GI-related adverse events is an important consideration for elderly persons with OA because they are at an increased risk of these adverse events (16). The incidence of GI-related adverse events, as well as withdrawal from the study due to GI-related adverse events, was significantly higher for patients in the naproxen group compared with the placebo group. However, the celecoxib groups did not experience significant differences from the placebo-treated group, with respect to the GI-related adverse event incidence or the individual reasons for GI-related withdrawal from the study.

Study findings were consistent with safety and efficacy results that showed all doses of celecoxib to be safe and generally well tolerated (24)(49)(50). The magnitude of improvement in the functional status and HRQOL of patients treated with a daily dose of 200 mg of celecoxib was comparable to that of a daily dose of 1000 mg of naproxen, but superior to that of the placebo treatment results. In addition, the incidence of GI-related adverse events was significantly less than that in the naproxen group, but comparable to the placebo group, making celecoxib a viable treatment option for OA.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
This study showed that celecoxib and naproxen significantly improve the functional status and overall HRQOL of elderly patients with OA compared with placebo treatment and that celecoxib is similar to naproxen in its improvements in functional status and HRQOL. Celecoxib, unlike naproxen, was also found to be safe to use among this population with no significant difference in adverse events between the two celecoxib and placebo groups.


   Acknowledgments
 
This study was supported by Pharmacia Corporation and Pfizer, Inc. We thank Somali Misra Burgess, PhD, and Steven P. Burch, PhD, of Strategic Outcomes Services, Inc., for their assistance in preparing this manuscript. Results from this study were presented as a poster session entitled "Celecoxib improves health-related quality of life (HRQOL) of elderly patients with osteoarthritis (OA)" by Sean Z. Zhao, Seema D. Dedhiya, Ken Verburg, and Jane T. Osterhaus at the 63rd Annual Scientific Meeting of the American College of Rheumatology, Boston, Massachusetts, November 13–17, 1999.

Received August 14, 2000

Accepted August 25, 2000


   References
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 Discussion
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 References
 

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