Richard A. Zabinski, PharmD

As pharmacy benefit costs continue to rise, health insurers and plan sponsors are increasingly implementing utilization management programs across a broad array of drugs and drug classes.

 The Academy of Managed Care Pharmacy defines utilization management as

“…managing the use of medical services to ensure that a patient receives necessary, appropriate, highquality care in a cost-effective manner. As it applies to a pharmacy benefit, utilization management is any of a number of measures used to ensure appropriate medication utilization. Such measures may include quantity limitations, step-therapy, prior authorization, and/or additional steps as deemed appropriate by the health plan’s Pharmacy and Therapeutics (P&T) Committee.”

Utilization management programs have been a mainstay of managed care pharmacy clinical programs for over 20 years, with prior authorization (PA) being the most common.

 A 2013 survey conducted by the Pharmacy Benefit Management Institute reported that 86% of 424 employers use PA as one of their utilization management tools, a 10% increase from the prior year.

 However, PA programs have been criticized for being time consuming and a potential barrier to medication access. Although little research has been done to evaluate these criticisms, there is concern that PA programs may lead to increased healthcare resource consumption and costs.

One reason for prescription abandonment is high out-of-pocket (OOP) member cost shares.

 A linezolid claim could be more than $2000, and often carries high member cost share; as such, studies on linezolid have primarily focused on the economic outcomes following a reversed claim. A reversed claim generally indicates that a prescription was received by a pharmacy but never dispensed to the member. A 2010 retrospective analysis of Medicare Advantage claims evaluated the incidence of linezolid claim reversals in patients recently discharged from the hospital. In the 60-day period following the linezolid reversal, investigators found that 34.9% of patients did not receive any antibiotics and that there were signifi cantly higher medical costs among those with a reversed claim for linezolid. When costs among members with paid (non-reversed) linezolid claims were compared with those with reversed claims, the group with paid linezolid claims had higher drug costs offsetting their lower medical costs, making total cost of care no different between groups.

 Another Medicare study found similar results: higher total medical costs were associated with linezolid claim reversals, and the reversals were more common among members with a high cost share. In addition, members with a reversed linezolid claim also experienced higher rates of rehospitalization.

 These study findings may discourage development of programs aimed at linezolid or antibiotics in general.

Linezolid, a synthetic oxazolidinone antibiotic, was approved by the US Food and Drug Administration (FDA) in 2000 for the treatment of bacterial pneumonia, skin and skin structure infections, and vancomycinresistant enterococcal (VRE) infections.

 While linezolid is considered a broad spectrum Gram-positive antibiotic with low resistance rates, widespread use is not without risk. Reportedly, up to 50% of all antibiotic use is unnecessary and can contribute to antibiotic resistance.

Also, antibiotic prescribing trends differ regionally across the United States, with southern states showing rates of 936 per 1000 persons compared with 639 per 1000 persons in the western states.

In 2007, the FDA issued a safety alert after results from a study evaluating linezolid use in catheter-related infections demonstrated higher mortality in patients treated with linezolid (21.5% vs 16.0%).

 Furthermore, linezolid has been associated with serious central nervous system reactions when administered with commonly prescribed serotonergic medications (eg, SSRI antidepressants).

Antibiotic resistance is a global problem. The gaps in our knowledge about resistance are due to limited capacities to detect and respond to emerging antibiotic resistance threats.

VRE infections are considered a serious threat by the Centers for Disease Control and Prevention.

 Appropriate use of linezolid is paramount, considering the potential for antibacterial resistance and safety concerns. The objective of this study was to evaluate the economic and clinical outcomes of a linezolid appropriate-use PA program in commercially insured members compared with a concurrent comparison group who were not exposed to the program.

The study compared an intervention group with a comparison group using a quasi-experimental concurrent design. The intervention group study population was identified using retrospective administrative pharmacy claims data from a commercial Blue Cross Blue Shield (BCBS) plan in the southern United States. This health plan had an average of 1.4 million members per month and implemented a linezolid PA policy on January 1, 2009. A concurrent comparison group was identified from a different commercially insured BCBS population in the Midwest United States with an average of 1 million members per month that did not implement the linezolid PA program. For both the intervention and comparison groups, members were required to be continuously enrolled for 6 months prior to their index linezolid claim.

The PA policy rejected all linezolid claims at the point of sale. A prescriber was required to contact the health plan and request coverage. The PA policy stated that the intent of the linezolid PA was to ensure appropriate selection of patients for treatment according to product labeling and/or clinical studies and/or guidelines. Appropriate use was defined as treatment of a serious, life-threatening infection or sepsis due to vancomycin-resistant Enterococcus faecium or Enterococcus faecalis, or a documented infection due to Staphylococci that are resistant to beta-lactams, macrolides, clindamycin, and co-trimoxazole (eg, methicillin-resistant Staphylococcus aureus [MRSA]). Oral tablet and oral suspension dosage forms were included in the program, and approval—when granted&mdash;was for 6 months.

During the period of January 1, 2011, through June 30, 2011, each member’s earliest linezolid pharmacy claim that was rejected (for the intervention group) and paid (for the comparison group) was identified and defined as the index claim. All pharmacy claims were identified using the assigned Generic Product Identifi er (GPI, Medi- Span, Indianapolis, Indiana), starting with 1623. Member characteristics from the index claim included age, gender, and zip code—derived median income and education. Charlson Comorbidity Index (CCI) score was calculated in the pre-6–month period.

 The baseline number of outpatient visits, hospitalizations, and emergency department (ED) visits were also collected in the 6 months prior to the index linezolid claim. Members’ infectious organism(s) were collected using

 International Classification of Diseases, Ninth Revision

) codes found in the 6 months prior to the index claim in any field of the member’s medical claims. Infectious organisms were hierarchically ordered and categorized as follows: (1) infections with drug-resistant organisms specific to vancomycin, MRSA pneumonia, MRSA septicemia, or MRSA carrier status; (2) infections due to undefi ned organisms; and (3) all other infectious organisms.

To assess the drug-use patterns following the index claim, all pharmacy and medical claims were queried during the 30 days after the index date for the presence of drug supply for linezolid or any other antibiotic agent. Linezolid medical claims were identified using the Healthcare Common Procedure Coding System (Level II) J2020 code. For evaluating drug supply presence on specific follow-up dates, an end date for each claim (ie, fill date plus days of supply on the claim) was created. On each day evaluated after the index date (ie, day 30 and 60), presence of linezolid and any other antibiotic was reported in the following hierarchical order: (1) linezolid with or without another antibiotic; (2) other antibiotics (without linezolid); and (3) no antibiotic therapy. Hospitalizations and ED visits were identifi ed in the medical claims using revenue codes or place-of-service codes when revenue codes were not available. Outpatient visits were also identifi ed using medical claims Current Procedural Terminology codes (99201 through 99205 and 99211 through 99215). Economic outcomes were evaluated in the follow-up periods using all pharmacy and medical claims and total paid amounts (member share plus health insurer payment). Costs specific to linezolid and all other antibiotics are reported separately. Linezolid and all other antibiotic costs from both the pharmacy and medical benefi t were identifi ed and reported. Total cost included all pharmacy plus all medical costs.

Unadjusted comparisons between groups were performed with the χ² test for categorical variables, Fisher’s exact test for those with counts less than 5, Wilcoxon rank-sum test for counts, and the likelihood ratio test for expenditures. A logistic regression model was used to test hospitalization and ED visit differences between the intervention and comparison groups, with adjustment for: age group, male gender, Charlson Comorbidity Index score categories (0 as the reference, 1-2, and greater than or equal to 3), zip code—derived education dichotomized to those with a bachelor’s degree or above and all others, zip code–derived income dichotomized to $0 to $49,999 and greater than or equal to $50,000, existence of baseline hospitalization or ED visit, and hierarchical presence of specific 

) with Group 2 as the reference. The logistic regression fit was assessed using the C-statistic and Hosmer-Lemeshow goodness-of-fit statistic. Cost analyses were performed using the generalized linear model with Gamma distribution and adjusted for the same covariates listed above. The overall fit of the generalized linear model was assessed using the scaled deviance and Pearson χ² goodness- of-fi t statistic. All statistical testing was performed using SAS version 9.2 (Cary, North Carolina). All 

 values were 2-sided with an a priori alpha of .05. A sensitivity analysis was performed repeating all analyses using a 60- day follow-up period, post index date.

 shows the analysis fl ow for the intervention and comparison health plan members. Of the 1,167,888 eligible members exposed to the PA in the intervention group, 217 (2 per 10,000) had a rejected linezolid index claim between January 1, 2011, and June 30, 2011. The prevalence of members who were continuously enrolled 6 months prior to their index claim was 185 (85.3%) of the 217 members with a linezolid rejected claim. The comparison group had 77 (1 per 10,000) members with a paid linezolid claim, and 69 (89.6%) met analysis criteria. A χ² test was performed to test the difference in rate of linezolid prescribing between the 2 groups, and the intervention group had a significantly higher linezolid prescribing rate compared with the comparison group. (

<.001). This difference refl ects national antibiotic prescribing trends, which show higher rates in the South.

Table 1 shows that all baseline characteristics were similar, except that the intervention group had a significantly lower percentage of members with a zip code—derived median income of >$50,000 (

 = .032). In addition, directional differences existed between the categories of infectious organisms (category 1: infections with drug resistant organisms specific to vancomycin, MRSA pneumonia, septicemia, or carrier status was found in 27.0% vs 39.1% of members; and category 2: infections due to undefined organisms found in 61.1% vs 50.7% of members, among intervention and comparison groups, respectively).

The unadjusted number of offi ce visits, hospitalizations, and ED visits are shown in 

. During the 30-day follow-up, the intervention group had an average of 3.0 office visits (standard deviation [SD] 2.1) and the comparison group 2.0 (SD 1.4), 

 = .332. There were no statistical differences in unadjusted hospitalizations (14.6% vs 17.4%) or ED visits (18.4% vs 14.5%) between the intervention and comparison groups, respectively.

During the 30-day follow-up, a paid claim for linezolid was found in 99 (53.5%) of 185 members initially denied linezolid coverage as a result of the PA (

). The mean time to linezolid claim was 2 days from the index date. The presence of any antibiotic claim, including linezolid, was found in 157 (84.9%) intervention group members, with an average time to first claim of 2 days. There were 28 (15.1%) intervention group members with no antibiotic claims during the 30-day follow-up. This subset of 28 members had baseline characteristics similar to those of the full intervention group (data not shown). There were 4 denials after a member had initiated the PA process. Denials were based on the approval criteria listed in the Methods section. The 4 members had culture information indicating that their respective organisms would be susceptible to other antibiotics, and in all cases, linezolid had not been started when the request came in. Also, a subanalysis comparing unadjusted counts of offi ce visits (2), hospitalizations (4 [14.3%]) and ED visits (5 [17.9%]) showed no statistical differences versus the comparison group during the 30-day follow-up.

The logistic regression model found no difference in hospitalization (

 = .332), or combined hospitalizations/ED visits (

 = .661) between the intervention and comparison groups (

). The generalized linear model showed the intervention group had 37% lower pharmacy costs (relative cost [RC] 0.63, 

 = .016) and 38% lower total cost of care (RC 0.62, 

 = .012) than the comparison group. Mean per member overall total costs of care after adjusting for covariates were $5868 lower in the intervention group, 

). There was no difference in adjusted medical costs (

 = .155) between groups (Table 5). The zip code—derived income difference between the 2 groups was significantly different and is consistent with the income differences between the Midwest and Southern United States that are found in the US Census data. Higher income may influence willingness to forgo insurance coverage and pay out of pocket for linezolid. Therefore, zip code–derived income was included in the multivariate model. Through inclusion of income in the multivariate model, the independent impact of the difference in income between the 2 groups on the study outcomes has been accounted for statistically.

In the 60-day sensitivity analysis, average member linezolid plus all other antibiotic costs remained signifi cantly lower, by $714 for the intervention group ($2083 vs $2847 for the comparison). The number of members with no evidence of any antibiotic claims in the 60-day follow-up dropped to 23 (12.4%), down from 15.1%. Overall, total adjusted costs remained lower in the intervention group; however, not statistically significantly lower. The logistic regression model continued to demonstrate no difference in hospitalizations (

 = .891) or combined hospitalizations/ED visits (

 = .851) between the intervention and comparison groups.

The differences in cost for the intervention group resulted in overall savings from the linezolid PA program. The average total cost per member for linezolid was $1303 higher in the comparison group, 

= .004 (Table 3). During the 30-day follow-up, mean member linezolid plus all other antibiotic costs were $1680 in the intervention group and $2595 in the comparison group, for a per patient $915 difference (

 <.001). Net antibiotic savings from the linezolid PA was $169,275 (185 patients per $915) or $0.024 per member per month (PMPM) ($169,275 divided by [1,167,888 members per 6 months]).

Per year, it takes approximately 15 hours to develop criteria for, 10 hours to implement, and 9 hours to maintain a PA program. Clinical review fees average $20 to $25 per case. Implementation costs for the intervention group were $2250 (15 + 10 hours per $90 per hour). Ongoing operational costs are $0.0005 PMPM [(9 hours per $90 per hour) + (332 cases per year per $20 per case)] / (1,167,888 covered lives / 12 months per year). Given that implementation occurred prior to our analysis, and that the ongoing costs are so low, the net savings would not be affected by administrative costs.

In April 2013, the geographic pattern of US outpatient antibiotic prescribing was highlighted, and researchers noted that up to 50% of antibiotic prescriptions may be unnecessary and contribute to resistance.

 We identified a diagnosis of drug-resistant microorganisms or MRSA in approximately one-third of members attempting to utilize linezolid; continued off-label use could further potentiate resistance. A health plan or PBM can influence appropriate use through implementation of a PA program. In this study, the linezolid PA resulted in no statistically significant differences in hospitalizations or ED visits. The intervention group appreciated a $0.024 PMPM antibiotic savings over a 30-day follow-up period with both clinical and economic findings maintained at 60 days. These results demonstrate that such a program aimed at the antibiotic linezolid could be applied without a concern for an increase in negative clinical consequences.

To our knowledge, few studies have been published examining the impact of a PA on medical outcomes, and none have focused specifi cally on linezolid. Published evaluations of PAs have been primarily focused on proton pump inhibitors, mental health medications (antipsychotics and antidepressants), cyclooxygenase-2 inhibitors, and diabetes medications.

 Additionally, the majority of PA research only reports economic outcomes and even less reports medical costs and utilization. Moreover, study participants are most often from Medicaid or Medicare Advantage populations, making comparisons with other market segments diffi cult, and some of the research lacks a comparison population altogether.

Given the paucity of PA data with which to compare and contrast our results, we chose to compare the impact of the PA program with studies involving members that had a reversed claim for linezolid. Both a linezolid PA claim and a reversed linezolid claim could result in treatment switching and/or delays. In 2010, researchers examined the impact on healthcare utilization by Medicare Advantage patients who were recently discharged from the hospital and who had experienced reversed linezolid claims.

The authors theorized that the high OOP linezolid costs, to which the member may be exposed, could result in treatment delays and hospital readmission. The patients with reversed linezolid claims experienced signifi cantly higher adjusted postdischarge medical expenditures ($10,594 [95% confi dence interval (CI), $8803-$12,705] vs $7953 [95% CI, $7292-$8673]) and lower adjusted postdischarge drug expenditures ($759 [95% CI, $630-$915] vs $2289 [95% CI, $2105-$2488]). The adjusted total costs were not signifi - cantly different. The impact on actual rehospitalizations, or outpatient and ED visits, was not reported. The authors noted that member cost share was the strongest predictor of claim reversal based on a propensity score model. Other research, published in poster form, also demonstrated signifi cantly higher healthcare costs in a Medicare Advantage group that was exposed to a coinsurance, resulting in OOP linezolid costs of more than $100 per claim.

 Members with reversed linezolid claims, presumably due to high OOP costs, experienced higher infection-related and 30-day allcause hospital readmissions than those without a reversal.

Our study results are in contrast to the results published by Ball et al

 The linezolid PA program described in the present analysis denied linezolid insurance coverage at the point of sale, requiring prescribers to submit clinical documentation demonstrating a need for linezolid. Upon PA approval, the linezolid claim was adjudicated as a formulary agent with cost shares of $15 to $35. In the current study, member cost share was $15 to $35 in both the intervention and comparison groups and therefore likely had no impact on linezolid utilization.

Two important characteristics of this study are worth noting. First, we studied a commercial population exposed to an appropriate-use PA program, while other research was focused on member OOP linezolid costs among Medicare Advantage Plan members. Population differences could account for discrepant results, in that our average age was lower and older adult members could have been at higher risk for incurring increased costs and higher hospitalization rates. Second, it is also possible that these populations had different indications for linezolid treatment, whereas the Medicare members may have had more advanced infections. Nonetheless, the implementation of a linezolid PA was without negative medical consequences over a period of 30 and 60 days, and showed cost savings for the intervention group.

The foremost limitation of this study is its quasi-experimental design comparing 2 commercially insured populations without randomization. Although the group characteristics were similar at baseline, claims analyses are limited in their ability to account for many possible differences among individuals and prescribers. Second, the primary internal validity concern regarding the findings is the possibility of changes that may have occurred at the same time as the implementation of the PA policy, or that a sentinel effect exists affecting regional variations in health insurance coverage. We are unaware of any effects that could have changed prescribing patterns independent of the PA program at the time of the study. Third, we may have overestimated the prevalence of patients without antibiotic therapy due to the use of physician samples or cash payment for linezolid and/or other antibiotic therapy. Fourth, the study is limited in the assessment of provider costs associated with the time spent addressing the denied claim, including possibly submitting a medical exception request or providing alternate pharmacotherapy. Fifth, the generalizability of the current study fi ndings is limited to continuously enrolled, commercially insured individuals in the South and Midwest. Lastly, this study utilized administrative claims data that are used for payment purposes only and may not be representative of actual medical diagnosis or healthcare utilization.

Clinical programs aimed at appropriate use of drugs will remain a primary function of health insurers in the future. The findings of this study demonstrated a signifi cant savings associated with a linezolid PA program and failed to identify any difference in clinical outcomes between members who were or were not exposed to the linezolid PA program. Furthermore, resistance to linezolid has occurred, but it is uncommon. We still have a chance to reduce the contribution of linezolid to the growing epidemic of antibiotic resistance, and the current results would suggest we can reduce the use of linezolid without harming patient care. Future research should be directed toward studying clinical and total direct healthcare cost outcomes of utilization management programs.

Articles

This study demonstrated that a linezolid PA program did not appear to be associated with a negative impact on medical outcomes and was associated with lower costs.