Evidence mounting for NSAID plus proton pump inhibitor over coxibs

New cost-effectiveness and cost-utility analyses reveal that coxibs are inferior to a nonsteroidal anti-inflammatory drug plus proton pump inhibitor approach. In a recent issue of Arthritis and Rheumatism, investigators report that their findings emerged despite explicitly biasing their model in favor of the coxibs. “Our research shows that under no circumstances is it cost-effective to administer a COX-2 inhibitor,” lead author Dr Brennan Spiegel (University of California, Los Angeles) told rheumawire. “The COX-2 inhibitors really lose ground because they are so expensive, using them in combination with aspirin reduces their effectiveness, and there are concerns over cardiovascular risks.” Spiegel and his team found that for high-risk patients, the combination of a NSAID taken with an acid-lowering drug is not only less expensive, but also safer and more effective.

Spiegel says the study took baseline CV risks of traditional NSAIDs into account. “But I can tell you that even if we had increased the risk of traditional NSAIDs, it wouldn’t have changed the results of our study.”In their paper, the researchers report that NSAIDs are the most commonly used medications for chronic arthritis accounting for 111 million prescriptions annually and 3% of the American prescription drug market. The economic impact of these adverse events is significant resulting in more than 100 000 hospitalizations annually at a cost of $1.6 billion. The group adds that each year there are 17 000 deaths in the United States as a result of NSAID-related GI complications. “In light of the substantial human and economic costs of NSAID-related adverse events, the decision to use NSAIDs requires a delicate balance between effective pain relief on the one hand and GI complications on the other,” the researchers write.Emerging data suggest that alternative therapies equal or preferable to coxibsSpiegel and his team write that despite enthusiasm for the coxibs, a number of recent findings cast doubt on the endorsement of coxibs in favor of alternative therapies: Despite the significant relative risk reduction in GI complications afforded by coxibs, their absolute risk reduction compared with NSAIDs is less than 1% for significant ulcer complications. Recent economic models show that the small degree of risk reduction is insufficient to offset the increased cost of coxibs versus generic NSAIDs for average-risk patients. Prospective studies in high-risk patients indicate that coxibs do not provide an additional risk reduction when compared with the NSAID plus proton pump inhibitor combination. Data reveal that the use of concurrent aspirin attenuates the relative GI protective effects of coxibs versus NSAIDs. One randomized controlled trialthe Vioxx Gastrointestinal Outcomes Research (VIGOR) trialrevealed a significantly increased risk for cardiovascular events with rofecoxib versus naproxen.In light of these new data and uncertainties, Spiegel and colleagues sought to reappraise the initial treatment of choice for arthritis patients with varying risk factors. Their work was funded by Tap Pharmaceutical Products Inc, the maker of the proton pump inhibitor lansoprazole. Spiegel told rheumawire that the company’s involvement was investigator initiated and involved no participation in the study’s design, management or writing. In their cost-effectiveness and cost-utility analyses, the researchers evaluated 3 competing strategies. They reviewed a generic nonsteroidal anti-inflammatory drug, a NSAID plus a proton pump inhibitor (PPI), and a COX-2 inhibitor. Cost estimates were from a third-party payer perspective. The outcomes were incremental cost per ulcer complication avoided and incremental cost per quality-adjusted life year gained. They performed a sensitivity analysis to evaluate the impact of varying patient GI risks and aspirin use.Coxib strategy found to be less effective and more expensiveSpiegel and his team found that in average-risk patients, the NSAID and PPI strategy cost an incremental $45 350 per additional ulcer complication avoided and $309 666 per quality-adjusted life year gained compared with the NSAID alone. They found that the coxib strategy was less effective and more expensive than the NSAID plus PPI strategy. Sensitivity analysis revealed that the NSAID with PPI became the dominant approach in patients at high risk for a NSAID adverse event such as in those on aspirin with risk factors for a GI complication. “Previous studies of COX-2 inhibitors looked at dramatic bleeds and perforations,” Spiegel said during an interview. “But we found that the coxibs led to more dyspepsia compared to other drugs.”Spiegel and colleagues calculate that substituting either a coxib or a NSAID with PPI combination instead of a generic naproxen may cost over $300 000 more per quality-adjusted life year gained in average-risk patientsa cost that is significantly higher than most accepted interventions in medicine.The researchers say their findings emerged despite biasing the model in favor of the coxibs. Four assumptions exemplify this bias. One, rather than assume that PPIs reduce clinically significant ulcer complications by up to 80%, as suggested by the literature, the group adopted a 50% risk reduction as their base-case estimate. Two, rather than assume that PPIs reduce non-ulcer dyspepsia by 50%, as suggested by a recent meta-analysis, they chose an 18% risk reduction (representing the lower 95% confidence interval from the meta-analysis). Also, rather than assume that up to 50% of the hypothetical 60-year-old cohort was eligible for cardioprophylaxis, as suggested by current guidelines, they assumed that only 20% received aspirin. And finally, rather than assume that the incidence of overall serious adverse events is lower with nonselective NSAIDs than coxibs, as indicated by a US Food and Drug Administration review measuring outcomes across all organ systems, this analysis only included GI adverse events.The investigators also point out several limitations to their study. They note that because their base case point estimates are largely derived from randomized controlled trials and expert opinion, the findings may not be generalizable to all relevant arthritis populations. “Moreover, several of our estimates are based on studies of varying design, patient population, follow-up, and quality,” they write. “However, we attempted to guard against inaccurate base case results by systematically reviewing the literature, relying on pre-existing meta-analyses when available, and conducting our own meta-analyses when necessary to develop precise point estimates. In addition, we relied upon an expert panel of physicians to provide estimates in areas in which data are lacking.”Spiegel and colleagues conclude, “This analysis reveals that the cost-effectiveness of competing NSAID strategies in chronic arthritis is highly dependent on individual risk factors. Our analysis suggests that generic nonselective NSAIDs are most cost-effective in patients at low risk for an adverse event. However, as both the GI and cardiovascular risk increase, the addition of a PPI to a nonselective NSAID may be preferable to coxib-based strategies.”(Source: Spiegel BM, Chiou CF, Ofman JJ. Minimizing complications from nonsteroidal anti-inflammatory drugs: cost-effectiveness of competing strategies in varying risk groups. Arthritis Rheum 2005; 53:185-197: Joint and Bone: May 2005.)