Dose Escalation and Co-therapy Intensification Between Etanercept, Adalimumab, and Infliximab: The CADURA Study

2.1. Study Design and Data Source

This study was a retrospective chart review of biologic-naïve, adult patients who newly initiated ADA, ETN, or IFX between January 01, 2006 and December 31, 2012. The index date was defined as the date of treatment initiation (or prescription date if unknown) for the index medication, and the index anti-TNF was the first anti-TNF initiated during the study period. Medical records were obtained from 11 rheumatology clinics from private practice and teaching hospitals across Canada, representing 5 provinces (Ontario, Quebec, New Brunswick, Saskatchewan, and Newfoundland). Medical charts were abstracted 3 months prior to the index date and 12 and 18 months following and including the index date. Charts were selected based on reverse chronological order starting with patients treated with etanercept, adalimumab, or infliximab on December 31, 2011 and going backwards in time until enough charts were identified. The protocol and a waiver of patient consent were approved by Institutional Review Board Services and separate approvals were obtained at the facility level as needed. Confidentiality of all data was preserved.

2.2. Patient Identification

RA patients (≥18 years old) treated continuously with an initial biologic for at least 6 months following the index date who had at least 3 physician visits during the first year following the index date (with at least 1 visit in months 9-15 for the 12-month analysis and at least 1 visit in between months 15-21 for the 18-month analysis) were eligible; those with any prior biologic therapy or a concurrent diagnosis of Crohn’s disease, ulcerative colitis, juvenile idiopathic arthritis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, or ankylosing spondylitis were excluded, as were patients involved in any clinical trial or receiving any investigational drug within 28 days of the index date or throughout the study.

2.3. Study Outcomes

The primary outcome was dose escalation over 12 months follow-up, defined as the first occurrence of any upward adjustment in dose or dosing frequency of the index anti-TNF from the label/indicated dose and dose frequency (ETN 25 mg twice weekly or 50 mg once weekly, ADA 40 mg once every other week, or IFX 3 mg/kg every 8 weeks after the third infusion). Dose escalation was also measured over 18 months. Alternative definitions of dose escalation included the mean dose and dosing frequency and the last dose of the index anti-TNF exceeding the label/indicated dose and frequency. DMARD dose increases for titration and IFX dose increases due to weight gain were not considered escalations. The proportion of patients who switched to a different biologic, discontinued but did not switch, or intensified DMARD or glucocorticoid or both were also measured over 12 and 18 months. DMARD intensification was defined as any upward adjustment in dose or frequency, addition of a new DMARD, or a switch from an oral to subcutaneous or intramuscular (IM) DMARD 3 months after initiation of the anti-TNF. Similarly, glucocorticoid intensification was defined as an increase in dose or frequency, addition of a new glucocorticoid, or any IM or intra-articular (IA) glucocorticoid injections 3 months after initiation of the anti-TNF. Dose de-escalation was measured over 12 and 18 months and was defined as a decrease in initiating dose or a reduction in dosing frequency. The time to first dose escalation of the index anti-TNF was measured. The magnitude of dose escalation was calculated as the percent change from baseline dose to dose at first escalation. The baseline dose for IFX was the dose after the third infusion.

Drug and drug-related costs over the full 12 and 18 months were examined, including time after patients discontinued or switched index medication for those that did. All drug and drug-related costs were obtained from the province of Ontario and are reported in Canadian dollars. If 2015 costs were not available, earlier costs were adjusted to 2014 [28]. Medications were priced using the best available price for drugs listed on the Ontario Drug Benefit Formulary [29]. Drugs not listed on the formulary were obtained from the Ontario Exceptional Access Program [30]. An 8% markup was used for all prescription drug costs, not including the dispensing fee [31]. The cost of ETN was $195.31 for 25 mg and $390.74 for 50 mg, ADA $740.36 for 40 mg, and IFX $987.56 per 100 mg. A dispensing fee of $8.83 was added as applicable [32]. Healthcare professional fees for intravenous (IV) infusions of biologics and IM or IA injections of glucocorticoids and DMARDs were obtained from the Ontario Schedule of Benefits for Physician Services [33]. The administrative cost for each IV administration episode of IFX was $297.02 (based on $187 per hour [34] for 1.5 hours per infusion). No administration costs were included for subcutaneous injections, as they were assumed to be patient administered. Additional costs (e.g., saline, saline bags) were obtained from Surgo Surgical Supply [35]. Total drug costs were the sum of the direct drug costs and drug administration costs.

2.4. Statistical Analysis

A chi-square test (two-sided, α=0.05) was used to establish sample size based on the rates of dose escalation obtained from published literature to detect differences in the proportion of escalators. A total of 329 patients (137 ETN, 137 ADA, and 55 IFX) were expected to have 80% power to detect expected differences in escalation between ETN and ADA cohorts and 99% power to detect differences in escalation between ETN and IFX cohorts. To maintain the same power for the 18-month analysis with different estimates of escalation, the total increased to 445 patients (195 ETN, 195 ADA, and 55 IFX).

All statistical tests, unless otherwise noted, were 2-sided tests performed at a significance level of 0.05. For the primary analysis of no difference between treatment cohorts, sequential testing with fixed sequences was employed to preserve the family-wise error rate at α=0.05. All other p-values are descriptive. The null hypothesis of no difference in the proportion of patients with dose escalation between the ETN and IFX cohorts was tested using a chi-square test. If the null hypothesis was rejected, a conditional pair-wise comparison was implemented for the null hypothesis of no difference between ETN and ADA. Differences in other measures between ETN and IFX and between ETN and ADA were examined using chi-square tests (categorical variables) and t-tests (continuous variables). Subgroup analyses examined clinical and demographic factors related to dose escalation over 12 months with differences assessed by chi-square test. A generalized linear model (GLM) using gamma distribution with log link function was used to compare mean costs by cohort over 12 and 18 months. The model adjusted for Quan-Charlson comorbidity index score, age, duration of RA, gender, medication insurance, prior 3-month DMARD use, and initiation of anti-TNF monotherapy versus concomitant DMARD. Those with missing RA duration data were excluded from the model. A sensitivity analysis was conducted including patients with missing RA duration, setting the duration to 0-10 years, which matched the duration for 65% of patients who had duration data.

Kaplan-Meier curves were created to describe first dose escalation over time among the 3 cohorts without adjusting for confounders.

3.1. Patients

The final sample included 314 patients in the 12-months analysis and 217 who remained in the 18-month analysis (Fig. 1).

The three cohorts were balanced in regards to demographic and clinical characteristics (Table 1).

The population was predominantly female (76.8%), with a mean age of 56.3 years (range 21.0 to 90.0 years) and average disease duration of 9.0 years (range 2.0 to 26.0 years). The majority were receiving a concomitant DMARD (77.1%) at the time of anti-TNF initiation. More patients initiating ADA were taking a concomitant DMARD three months prior to (53.2%) and at anti-TNF initiation (83.3%) than patients initiating ETN [40.4% (p=0.041) and 72.4% (p=0.033), respectively]. Comparing patients initiating IFX to ETN, there were no differences in DMARDs three months prior to (31.3%; p=0.427) and at anti-TNF initiation (75.0%; p=0.833).

3.2. Anti-TNF Dose Escalation

No dose escalation was observed for ETN (95% confidence interval (CI) 0.0%, 2.3%), versus 37.5% (95% CI 21.1%, 56.3%) for IFX (p<0.001) and 1.6% (95% CI 0.2%, 5.6%) for ADA (p=0.199) over 12 months. (Table 2, Supplementary Figure A). Over 18 months, no dose escalation was observed for ETN (95% confidence interval (CI) 0.0%, 3.6%), versus 32.0% (95% CI 15.0%, 53.5%) for IFX (p<0.001) and 2.2% (95% CI 0.3%, 7.8%) for ADA (p=0.218).

Results were the same using the two alternative definitions, mean dose escalation and last dose escalation (data not shown). Subgroups provided no evidence of any differences of dose escalation patterns (data not shown).

3.3. Anti-TNF Dose Escalation/Co-Therapy Intensification

More IFX patients (40.6%) required dose escalation and/or intensification with a DMARD over 12 months compared to ETN (10.9%; p<0.001) (Table 2). While 14.3% of patients on ADA required dose escalation and/or intensification with a DMARD, the difference from ETN was not statistically significant (p=0.468). A higher proportion of patients receiving IFX (46.9%) or ADA (27.8%) required dose escalation and/or intensification with a DMARD and/or glucocorticoids over 12 months compared to patients initiating ETN (16.0%) (p<0.001 and p=0.019 respectively). Results over 18 months were similar.

3.4. Switching/Discontinuation

Discontinuation of index anti-TNF was similar between ETN and IFX and ETN and ADA over 12 months; however, by 18 months, fewer patients initiating ETN discontinued and switched to another biologic (5.9%) compared to ADA (22.2%; p=0.001) (Table 2).

3.5. Dose De-Escalation

Over 12 months, dose de-escalation was observed in 0.6% of patients who initiated ETN and in 0.0% of patients who initiated ADA or IFX (p=1.000). Over 18 months, slightly more ETN patients had evidence of dose de-escalation (2.0%) compared with ADA (1.1%) and IFX (0.0%), but the differences were not significant (p=1.000).

3.6. Magnitude and Time to Dose Escalation

Among patients requiring dose escalation, the mean dose of IFX, converted to a dose every 8 weeks, increased from 3.4 mg/kg after the third infusion to 4.5 mg/kg at first escalation, for a mean change of 32.9% (n=12). The mean dose of ADA increased from 40 mg every other week to 40 mg every week, for a mean change of 100% (n=2).

Patients initiating IFX began dose escalation between 4 and 7 months (Fig. 2). The mean (standard deviation) time to dose escalation within the subset of patients who dose escalated was 224 days (74 days) for IFX (n=12) and 248 days (88 days) for ADA (n=2). No further dose escalations were observed in the 18-month follow-up (data not shown).

3.7. Costs of Treatment

Over 12 months, mean drug costs (anti-TNFs, switched biologics, DMARDs, and glucocorticoids) were similar between patients initiating ETN ($22,234) versus those initiating IFX ($24,265, p=0.09) or ADA ($21,890, p=0.156). However, due mainly to the cost of IV infusions, the mean drug-related cost (health care professional fees for IV infusions, IM or IA injections) was higher in IFX patients ($2,682) than patients on ETN ($81, p<0.001) (Fig. 3). Over 18 months, drug costs for patients initiating ETN ($33,392) were higher than for patients initiating ADA ($31,912, p=0.009) (Fig. 3). The mean cost of switched biologics was higher for ADA initiators ($2,585) versus ETN ($570, p=0.005), as was the mean cost of DMARDs ($767 in ADA initiators versus $540 in ETN initiators, p=0.017); the mean index anti-TNF costs were $3,727 lower in ADA initiators ($28,529) compared to ETN initiators ($32,256, p<0.001).

The mean total unadjusted costs over 12 months were lower in ETN initiators ($22,315) compared to those initiating IFX ($26,947, p<0.001), but not significantly different from patients initiating ADA ($21,964, p=0.156) (Fig. 3). Over 18 months, total costs in ETN initiators ($33,478) remained lower than IFX ($38,323, p=0.044), but were higher than patients initiating ADA ($32,057, p=0.012). When the mean total costs were adjusted for confounders, the difference between patients initiating ETN and ADA over 18 months was no longer statistically significant (p=0.09 base case, p=0.059 sensitivity analysis) (Supplementary Table B).

Compared to no DMARD use in the 3 months prior to index medication, patients with more than one DMARD had higher 12-month mean total costs (cost ratio 1.082, p=0.007, sensitivity analysis) and higher 18-month total costs (cost ratio 1.093, p=0.045, sensitivity analysis) (Supplementary Tables A and B). Additionally, a one score increase in Charlson comorbidity score was associated with lower 18-month mean total costs (cost ratio 0.927, p=0.001, base-case analysis, cost ratio 0.941, p=0.005, sensitivity analysis) and compared to patients with government insurance (n=159), patients with no insurance (n=12) had lower 12-month mean total costs (cost ratio 0.899, p=0.004, sensitivity analysis).

Mean total costs over 12 months were $9,805 higher among dose escalators versus non-escalators taking IFX (p<0.001) (Table 3).

Over 18 months, the mean total costs were $16,126 and $13,599 higher in dose escalators versus non-escalators for patients initiating IFX (p<0.001) and ADA, respectively (p<0.001).