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Studies of COX-2 inhibitors have ramifications for other drugs and pharmaceutical policies

In recent months, the safety of a class of nonsteroidal antiinflammatory drugs (NSAIDs), the COX-2 inhibitors (including Vioxx®, Celebrex®, and Bextra®), has been called into question. Typically used for arthritis and other inflammatory diseases, the COX-2 inhibitors provide an alternative for patients who suffer gastrointestinal (GI) bleeding and other complications from older nonselective NSAIDs.

Results of three recent studies of COX-2 inhibitors supported by the Agency for Healthcare Research and Quality (HS10881) have ramifications for other drugs and pharmaceutical policies. They found that Medicaid prior-authorization plans may reduce unnecessary use of certain costly drugs, that newly marketed drugs may prompt physicians to enthusiastically prescribe them to a wider swath of patients, and that claims databases can be combined with survey data to decrease confounding in drug safety studies. The studies, led by Sebastian Schneeweiss, M.D., Michael Fischer, M.D., and Daniel Solomon, M.D., M.P.H., of Harvard Medical School and Brigham and Women's Hospital, are briefly summarized here.

Fischer, M.A., Schneeweiss, S., Avorn, J., and Solomon, D.H. (2004, November). "Medicaid prior-authorization programs and the use of cyclooxygenase-2 inhibitors." New England Journal of Medicine 352, pp. 2187-2194.

The popularity and cost of selective COX-2 inhibitors have imposed financial stress on many prescription drug insurance programs, including State Medicaid programs, whose mandate is to cover the medical expenses of the poor. In an attempt to control medication costs, many States have implemented prior authorization requirements for COX-2 inhibitors, according to this study. The programs allow use of COX-2 inhibitors by patients who meet high-risk criteria (for example, GI bleeding from nonselective NSAIDs) while reducing use by others, thus targeting the use of these expensive agents to appropriate patients. The researchers' earlier work indicated substantial overuse of these medications among patients at low risk for complications from traditional NSAIDs.

In this study, the researchers used data from State Medicaid programs for 1999 through 2003 to calculate the proportion of NSAID use accounted for by COX-2 inhibitors, and they evaluated the effect of 22 State prior authorization programs on the use of these drugs (before Vioxx was withdrawn from the market). By 2001, COX-2 inhibitors accounted for half of all NSAID doses covered by State Medicaid programs. However, this proportion varied widely by 2003, from a low of 11 percent in some States to a high of 70 percent in others.

The implementation of prior authorization requirements for COX-2 inhibitors reduced the proportion of NSAID doses made up by COX-2 inhibitors by 15 percent. This corresponded to a decrease of $10.28 in spending per NSAID prescription. With nearly 18 million NSAID prescriptions covered by Medicaid in 2003, this decrease can be projected to an annual reduction in spending of $185 million. Determining whether these reductions are clinically appropriate will have important implications for the development of rational drug-reimbursement policies.

Schneeweiss, S., Glynn, R.J., Avorn, J., and Solomon, D.H. (2005). "A Medicare database review found that physician preferences increasingly outweighed patient characteristics as determinants of first-time prescriptions for COX-2 inhibitors." Journal of Clinical Epidemiology 58, pp. 98-102.

The rapid diffusion of COX-2 inhibitors led to prescribing of these drugs even to patients who lacked a clear indication for their use (GI bleeding from traditional NSAIDs), according to this study. First-time COX-2 inhibitor prescribing was somewhat dependent on patient factors in the first quarter of marketing. However, the proportional influence of physician preferences increased substantially over the following 2 years. Rapid adoption of new drugs after market introduction may prompt doctors to enthusiastically prescribe them even for patients without a clear indication, suggest the researchers.

They examined data on 37,957 Medicare beneficiaries who were enrolled in the Pharmaceutical Assistance Contract for the Elderly in Pennsylvania. All patients had started using nonselective NSAIDs or selective COX-2 inhibitors between January 1, 1999, and December 31, 2000, had no prior NSAID use, and had full prescription drug coverage. The researchers quantified the amount of variation in first-time COX-2 prescribing that could be explained by predictors of GI toxicity, other patient characteristics, or physician preferences.

COX-2 inhibitors were adopted as the preferred NSAID by 55 percent of physicians within 6 months after they were marketed. In new NSAID users, COX-2 prescribing was twice as dependent on physician prescribing preferences (60 percent) as on the combined predictors of GI toxicity (3 percent) and other patient factors (30 percent). The ratio of COX-2 prescribing explained by physician preferences over patient factors increased from 2 to more than 10 over a 24-month period.

Schneeweiss, S., Glynn, R.J., Tsai, E.H., and others (2005, January). "Adjusting for unmeasured confounders in pharmacoepidemiologic claims data using external information: The example of COX-2 inhibitors and myocardial infarction." Epidemiology 16(1), pp. 17-24.

Rare adverse drug effects usually show up only after a medication has been used widely. Large databases, such as Medicare claims data, which reflect routine practice for large and representative populations, are often the best source of data to analyze the incidence of such adverse effects. However, these datasets often don't measure such confounding factors as use of over-the-counter medications (for example, aspirin), body mass index, or smoking status. Not accounting for these factors could lead to underestimates of problems caused by certain medications, caution the investigators.

They used Medicare Current Beneficiary Survey data on 8,785 elderly men and women to assess the association between use of COX-2 inhibitors and five potential confounders not measured in Medicare claims data: body mass index, aspirin use, smoking, income, and educational attainment. Users of COX-2 inhibitors were less likely to be smokers than users of other NSAIDs (8 vs. 10 percent), while the prevalence of obesity was comparable (24 percent). Aspirin use was also balanced among all drug categories. Failure to adjust for these potential confounders (that are independently associated with heart attack) led to a small underestimation of the association between COX-2 inhibitors and heart attack.

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