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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

To describe the effect of different exposure classification strategies for disease-modifying antirheumatic drugs (DMARDs) on drug-outcome associations.

Methods

We studied the association between DMARD initiation and all-cause hospitalizations in patients with rheumatoid arthritis (RA), 1995–2005. Initiators of DMARDs and oral glucocorticoids were followed for ≤180 days. We compared 2 strategies for exposure classification: a persistent exposure required (PER) approach, in which followup stopped when the regimen changed; and a persistent exposure ignored (PEI) approach, in which followup continued despite regimen changes. For PEI, adherence was assessed using the medication possession ratio. All-cause hospitalization risk was compared among RA regimen initiators using Cox models and methotrexate as the reference.

Results

We identified 28,906 episodes of medication initiation. In PER analyses, tumor necrosis factor α antagonists did not increase hospitalization risk compared with methotrexate, whereas leflunomide did (hazard ratio [HR] 1.36, 95% confidence interval [95% CI] 1.1–1.67). Glucocorticoids increased hospitalization risk (HR 1.29, 1.54, and 2.03 for low, medium, and high doses, respectively). PEI results were similar to PER except that infliximab initiation increased the risk of hospitalization compared with methotrexate (HR 1.46, 95% CI 1.19–1.8), and most other effects were closer to the null. In PEI, adherence ranged from 73% for etanercept to 6% for glucocorticoids and adherence to methotrexate was 59%.

Conclusion

Compared with methotrexate initiation, leflunomide or glucocorticoid initiation consistently increased all-cause hospitalizations in the first 180 days of use. Most PER and PEI estimates were similar; observed differences in risk between these methods were likely due to differences in adherence.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Although tumor necrosis factor α (TNFα) antagonists revolutionized the treatment of rheumatic diseases, their comparative safety relative to traditional disease-modifying antirheumatic drugs (DMARDs) has been questioned (1). Placebo-controlled trials indicated that TNFα antagonists increased infections among patients with rheumatoid arthritis (RA) (1). Observational studies indicated that TNFα antagonists increased the risk of infections and heart failure compared with methotrexate (MTX) in patients with RA (2–4).

Most medication effects are biologically plausible during the actual exposure to the medication, and sometimes during a period after the medication exposure has ended. Therefore, one approach to measuring medication exposure using administrative databases is to restrict the exposure person-time to the period with the medication supply available (i.e., persistent exposure required [PER] approach).

In an alternate approach, initiation of medication can by itself be considered an exposure of interest. This initiation identifies the exposure category in which the patient remains throughout followup. This persistent exposure ignored (PEI) approach is similar to the intent-to-treat analysis of randomized trials, except that exposures are not assigned through randomization.

In assessing the relative safety of TNFα antagonists in an observational setting, we recognized that DMARDs were often discontinued (5). We hypothesized that different exposure classification approaches could lead to conflicting results. Therefore, we compared these approaches during our assessment of the effects of RA medications on the risk of hospital admissions.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Study cohort.

We assembled a retrospective cohort of patients with RA enrolled in TennCare, Tennessee's Medicaid managed-care program. Enrollees met our RA definition with ≥1 RA-coded diagnosis and initiation of a DMARD or oral glucocorticoid regimen, defined as a filled prescription for a study medication after 180 days without exposure to that specific medication.

Initiation of medication determined the beginning of followup for each episode (T0). On T0, cohort members were age ≥18 years, had continuous TennCare enrollment during the previous 180 days (baseline), and had baseline use of pharmacy benefits. Because serious medical conditions could affect followup and outcomes, unrelated to medication exposure, we excluded patients with solid organ transplantation, human immunodeficiency virus/acquired immunodeficiency syndrome, cancer, and serious kidney, liver, or respiratory diseases, identified at baseline. We also excluded patients who had ≥2 baseline health care encounters for juvenile RA, systemic lupus erythematosus, Crohn's disease, or ulcerative colitis.

For each episode, followup continued from T0 through the first of date of death, end of study (December 31, 2005), date of hospitalization, or the 180th day of followup. Episodes were truncated because previous studies indicated that infection risk following initiation of TNFα antagonists was time dependent (2, 6), and that study medication use was intermittent, making the long-term classification of exposure challenging (5).

Study medications.

New episodes of DMARD or glucocorticoid use were identified applying an algorithm that maximized identification of newer and less-frequently used study DMARDs. Patients could contribute ≥1 non-overlapping DMARD episodes, using the following hierarchy: TNFα antagonists (etanercept, infliximab, and adalimumab), leflunomide (LEF), hydroxychloroquine (HCQ), sulfasalazine (SSZ), MTX, and glucocorticoids. Concurrent initiation of a DMARD and a glucocorticoid was considered DMARD initiation. Glucocorticoids were further classified based on the initial daily dosage in milligrams of prednisone equivalents: <7.5 mg (low), 7.5–30 mg (medium), or >30 mg (high) (7).

Exposure measurements.

We compared 2 approaches for exposure classification. For the PER approach, we classified each person-day of followup according to the days' supply of medication dispensed (8). Exposure started with the first filled prescription and continued through medication discontinuation (defined as 14 days without drug supply) or the change of the initial regimen (either by medication addition or switch to another regimen). For TNFα antagonist users, cotherapy with MTX was allowed; however, addition of a different TNFα antagonist or a DMARD other than MTX ended the episode. For other DMARDs, initiation of any new DMARDs, including TNFα antagonists, ended the episode. Initiation of oral glucocorticoids would not end a DMARD episode, but initiation of a DMARD ended a glucocorticoid episode. Therefore, exposure person-time included all person-days of continuous exposure after initiation of treatment including gaps ≤14 person-days.

For the PEI approach, within our defined episodes of use, we included all person-days, regardless of addition of or switching to other regimens or discontinuation of the initial regimen. To assess exposure misclassification in the PEI approach, we measured adherence using medication possession ratios expressed as the percentage of person-time exposed to the initial regimen during the episodes. Because the occurrence of an outcome or censoring event interferes with this assessment, we only calculated medication possession ratios for those episodes with 180 person-days of available followup.

Outcomes and potential confounders.

The study outcome was the first all-cause hospitalization, identified using TennCare inpatient claim files. We considered the first listed discharge diagnosis as the primary reason for hospitalization.

Covariates were measured during the 180-day baseline preceding each episode, including demographics (age, sex, race, place of residence, nursing home residency, and calendar year of the episode), markers of comorbidity (number of hospitalizations, outpatient and emergency room visits, enrollment on disability, number of different medication classes filled), surrogate markers of disease severity (extraarticular manifestations of disease, number of intraarticular and orthopedic procedures, number of tests ordered for inflammatory markers), and days of drug supply for other DMARDs, oral glucocorticoids, nonsteroidal antiinflammatory drugs, and narcotics (2, 6, 9).

Other risk factors assessed included previous hospitalization due to infection; chronic obstructive pulmonary disease (COPD); diabetes mellitus and cardiovascular diseases; and baseline prescriptions for antibiotics, anticonvulsants, antipsychotics, antidepressants, lipid-lowering agents, gastroprotective therapies, antiarrhythmics, anticoagulants, replacement estrogens, and oral contraceptives.

Among DMARD initiators, the average daily dosage of oral glucocorticoids used on T0 was categorized using ranges previously described (7). One patient could contribute ≥1 episode provided that the new-user definition was fulfilled. For these episodes, a new baseline period was defined and a new set of covariates measured.

Statistical analysis.

The units of analysis were the new episodes of medication use, and Cox proportional hazards regressions assessed the effect of medication exposure on the risk of hospital admission. Because patients could contribute one or more episodes of new use (with an updated set of covariates), we used patients' study numbers to define clusters and accounted for this additional intragroup correlation using the Huber-White sandwich variance estimator and calculated robust standard errors for all estimates (10). The proportional hazards assumption was verified using Schoenfeld residuals and log–log plots of survival functions. Models that used exposure propensity scores to summarize covariate information yielded almost identical results to those reported in this article and did not affect our conclusions. This study was approved by the Vanderbilt University Institutional Review Board and by the Bureau of TennCare. Statistical analyses were performed using Stata, version 10.1 (StataCorp).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Cohort description.

Overall, 14,586 patients with RA contributed 28,906 new episodes of medication use. Their median age was 55 years (interquartile range [IQR] 45–64 years) and 76% were women. Most patients were white (83%) and lived in major metropolitan areas (56%). Approximately 20% had orthopedic procedures performed during baseline. Manifestations of extraarticular disease were recorded in 1% of patients, 11% had diabetes mellitus, 14% had COPD, and 6% had an infection during baseline.

At baseline, 63% of patients were enrolled in a disability TennCare category and 2% were nursing home residents. During baseline, 39% had an emergency department visit and 22% had been hospitalized. The median number of different medications per patient was 13 (IQR 8–18). The median number of baseline days exposed to glucocorticoids and narcotics was 30 (IQR 0–128) and 30 (IQR 0–137), respectively.

There were 6,665 hospitalizations identified. Cardiovascular, respiratory, musculoskeletal, and gastrointestinal diseases (recorded as principal discharge diagnoses) accounted for 67% of all-cause hospitalizations.

PER approach.

The PER approach yielded 2,383 hospitalizations and 3,615 person-years of followup, or 659 hospitalizations per 1,000 person-years. Compared with initiation of MTX, initiation of TNFα antagonists, SSZ, or HCQ did not increase the risk of hospitalizations. Initiation of LEF increased this risk by 36% compared with MTX. There was a dose-response increase in hospitalization risk among glucocorticoid initiators (hazard ratio [HR] range 1.29–2.03) compared with MTX (Table 1). Baseline use of glucocorticoids was also associated with an increased risk of hospitalizations (HR 1.18, P = 0.009 and HR 1.16, P = 0.254 for medium and high doses, respectively), compared with no use or use of low doses at baseline.

Table 1. DMARD/GC initiation and the risk of hospitalization in a rheumatoid arthritis cohort, TennCare 1995–2005*
 Events, no.Rate/1,000 person-yearsCrude analysis, HR (95% CI)Adjusted analysis, HR (95% CI)
  • *

    DMARD = disease-modifying antirheumatic drug; GCs = glucocorticoids; HR = hazard ratio; 95% CI = 95% confidence interval; PER = persistent exposure required; MTX = methotrexate; PEI = persistent exposure ignored.

  • See Patients and Methods for the covariates for adjustment. Models included 48 variables (or 72 parameters) and 2,383 and 6,665 events for our PER and PEI models, respectively.

  • Low dose (<7.5 mg), medium dose (7.5–30 mg), and high dose (>30 mg) of prednisone equivalents.

PER    
 MTX460494.91.00 (reference)1.00 (reference)
 Etanercept ± MTX126464.10.95 (0.78–1.16)1.12 (0.90–1.4)
 Infliximab ± MTX45489.21.00 (0.74–1.35)1.21 (0.88–1.67)
 Adalimumab ± MTX55489.61.00 (0.76–1.32)1.09 (0.81–1.48)
 Leflunomide126654.11.32 (1.08–1.6)1.36 (1.10–1.67)
 Sulfasalazine98545.11.05 (0.85–1.31)1.16 (0.93–1.44)
 Hydroxychloroquine343492.80.99 (0.86–1.14)1.03 (0.90–1.19)
 Oral GCs, low171756.21.41 (1.18–1.69)1.29 (1.07–1.56)
 Oral GCs, medium687968.41.73 (1.52–1.97)1.54 (1.34–1.77)
 Oral GCs, high2721,322.22.32 (1.98–2.73)2.03 (1.72–2.41)
PEI    
 MTX899490.41.00 (reference)1.00 (reference)
 Etanercept ± MTX228435.20.89 (0.77–1.03)1.03 (0.88–1.21)
 Infliximab ± MTX101600.61.22 (0.99–1.49)1.46 (1.19–1.8)
 Adalimumab ± MTX110515.51.04 (0.86–1.27)1.17 (0.95–1.43)
 Leflunomide252549.71.12 (0.98–1.29)1.22 (1.05–1.41)
 Sulfasalazine249454.30.93 (0.81–1.07)1.06 (0.92–1.22)
 Hydroxychloroquine657457.80.93 (0.84–1.03)0.99 (0.89–1.09)
 Oral GCs, low487573.21.17 (1.05–1.30)1.12 (1.00–1.26)
 Oral GCs, medium2,766620.01.26 (1.17–1.36)1.21 (1.11–1.31)
 Oral GCs, high916698.31.41 (1.29–1.55)1.33 (1.20–1.47)

PEI approach.

Using the PEI approach, 6,665 hospitalizations were identified during 11,802 person-years of followup, or 565 per 1,000 person-years. Compared with initiation of MTX, initiation of etanercept, adalimumab, SSZ, or HCQ did not increase the risk of hospitalizations. Initiation of LEF increased this risk by 22% compared with MTX. There was a dose-response increase in hospitalization risk among glucocorticoid initiators (HR range 1.12–1.33). In the PEI approach, initiation of infliximab also increased the risk of hospitalizations by 46% compared with MTX (Table 1 and Figure 1). In this approach, baseline use of glucocorticoids was also associated with an increased risk of hospitalizations (HR 1.12, P = 0.015 and HR 1.18, P = 0.074 for medium and high doses, respectively), compared with no use or use of low doses at baseline.

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Figure 1. Adherence to rheumatoid arthritis (RA) regimens and the risk of hospitalization following initiation of disease-modifying antirheumatic drugs or glucocorticoids (GCs; in a low [<7.5 mg], medium [7.5–30 mg], or high [>30 mg] dose of prednisone equivalents) in an RA cohort, TennCare 1995–2005. Models included 48 variables (or 72 parameters) and 2,383 and 6,665 events for persistent exposure required (PER) and persistent exposure ignored (PEI) models, respectively. MPR = medication possession ratio (median [interquartile range]); HYD = hydroxychloroquine.

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Adherence to initial regimens (PEI).

Median medication possession ratios for TNFα antagonists ranged from 73% for etanercept to 68% for infliximab. Median medication possession ratios were 69% for LEF and 59% for MTX, the reference exposure. Median medication possession ratios were 49% and 33% for HCQ and SSZ, respectively. Glucocorticoid initiators had the lowest median medication possession ratios (6% overall, range 5–16% for medium and low doses) (Figure 1).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

In this large cohort of patients with RA, LEF and glucocorticoid initiation increased the risk of all-cause hospitalizations compared with MTX initiation. During short periods of followup, PER and PEI led to similar conclusions for most exposure effects. However, differences in some results were notable and likely related to differential adherence to the initial regimens. These differences might be even greater in studies with longer periods of followup.

The two approaches for exposure measurement differed in their complexity. The PER approach applied a strict day-by-day classification of exposure and allowed short gaps that were also considered exposed person-time. The simpler PEI approach classified exposure according to the initial regimen, disregarding subsequent changes. Because of more followup and events, confidence intervals were narrower in PEI than in PER. However, PEI HRs were consistently lower than PER estimates for glucocorticoids and LEF. The attenuation of an adverse effect with the PEI approach would be expected when exposure misclassification increases, provided the association between exposure and outcome is real. Therefore, the decrease in risk associated with lower adherence to LEF and glucocorticoids suggests that these drugs do increase hospitalization risk.

Although the PER approach minimized exposure misclassification (8), this approach over-represents patients with good adherence to therapies. Factors such as intent to comply with clinicians' directions, favorable experience in terms of effectiveness and safety, and the patient's own decision to continue on therapy are determinants of adherence. The effects of these selection factors might be magnified with longer durations of followup. However, these factors are difficult to ascertain and account for in administrative databases. The interpretation of results from PER approaches must consider these selection issues.

The PEI represents an alternative to the PER approach. Changes to the initial regimen are disregarded, reducing the possibility for selection bias. In placebo-controlled randomized trials, suboptimal adherence to the study medication attenuates the medication effects and biases the results toward the null. Outside of those experimental settings, adherence to medications may be lower and use of other cotherapies may be greater.

In our cohort, adherence to the initial regimen varied widely. Therefore, adherence to both the exposures of interest and the nonplacebo reference group must be considered when interpreting PEI results. The low adherence to glucocorticoid regimens suggests that these drugs were actually prescribed for intermittent use. Contrary to the PER analysis, infliximab initiation increased the risk of hospitalizations, compared with initiation of MTX in the PEI analysis. Discontinuation of infliximab was sometimes followed by initiation of other DMARDs or glucocorticoids, or continuation of glucocorticoid therapies (data not shown), which could increase the risk of hospitalization without regard to infliximab past exposure. Although adherence was lower in the reference MTX group than among infliximab initiators, rates of hospitalization were similar for MTX users in both analyses, whereas they increased for infliximab users in the PEI compared with the PER analysis (Table 1).

Our findings have implications for studies of patients with RA with severe disease who discontinued their TNFα antagonists due to lack of effectiveness or intolerance. This group of patients might require more aggressive or alternate treatments that could increase their risk of study outcomes. This would be one explanation for the increased risk of hospitalization observed for infliximab in the PEI approach compared with the PER strategy. However, although the PER approach considered short gaps after medication supply exhaustion as exposed person-time, hospitalizations following discontinuation of treatment may be residual effects of the medication that were missed by the PER approach (4).

Longer periods of followup will increase the possibility of suboptimal adherence and exposure misclassification. These changes will be missed by the PEI approach. PER will also be affected by selection issues increasing as followup expands, and patients with good adherence enrich the cohort with a subpopulation that is likely to differ from those who discontinued treatment early.

Discontinuation and lack of adherence to medication regimens are challenges for assessments of comparative effectiveness of medications. A medication proven to be highly efficacious in clinical trials might have little real-life effectiveness due to low adherence. In this scenario, assuming no effect of concurrent medications, the PEI approach would provide more useful effectiveness information than the PER approach, and could complement efficacy information. Nevertheless, use of concurrent medications is frequent and should be considered.

Our strategies attempted to determine the effects of individual treatments and to maximize sample size for examination of TNFα antagonists and other less-frequently used DMARDs. Although different DMARDs and glucocorticoids were often used in combination, many patients in our population used glucocorticoids alone, and we had sufficient sample size to examine this group separately. Because cotherapy with glucocorticoids was common in patients using DMARDs, we examined DMARD use, controlling for baseline use of glucocorticoids. However, initiation of glucocorticoids during a DMARD episode would not have been captured by our methods, and would result in misclassification of the episode as DMARD alone, rather than DMARD plus glucocorticoids. This would have made it more difficult to demonstrate differences between the DMARD and glucocorticoid groups. Our results suggest that baseline use of glucocorticoids was likely a predictor of subsequent use, and that baseline glucocorticoid use among DMARD initiators was associated with hospitalization, as were glucocorticoids when initiated alone.

For assessments of medication safety, for which clinical trial information is usually limited, misclassification introduced by the PEI approach in a low adherence setting could bias the results toward the null, potentially obscuring danger signals of interest. This is the likely explanation for the different results for glucocorticoids in our study, in which the PEI estimates were closer to the null than PER estimates. Regimen changes are problematic in this setting because their effects will be ignored and attributed to the initial regimen. Similar to confounding by disease severity, the probability of switching or adding medications to an ongoing regimen is likely differential with regard to the initial regimen.

Frequent discontinuation of medications complicates the assessment of the comparative safety of RA medications. Similar challenges will be faced in the forthcoming assessments of comparative effectiveness. Although most PER and PEI estimates were similar in the current study, some findings conflicted. The optimal approach to deal with these complexities should be based on a thorough assessment of medication utilization patterns.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Grijalva had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Grijalva, Mitchel, Griffin.

Acquisition of data. Grijalva, Mitchel, Griffin.

Analysis and interpretation of data. Grijalva, Kaltenbach, Arbogast, Mitchel, Griffin.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

We gratefully acknowledge the Tennessee Bureau of TennCare and the Tennessee Department of Health, which provided the study data.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES