Overuse of corticosteroids in patients with immune thrombocytopenia (ITP) between 2011 and 2017 in the United States

Abstract Corticosteroids (CSs) are standard first‐line therapy for immune thrombocytopenia (ITP). Prolonged exposure is associated with substantial toxicity; thus guidelines recommend avoidance of prolonged CS treatment and early use of second‐line therapies. However, real‐world evidence on ITP treatment patterns remains limited. We aimed to assess real‐world treatment patterns in patients with newly‐diagnosed ITP, using two large US healthcare databases (Explorys and MarketScan) between January 1, 2011 and July 31, 2017. Adults with ITP, ≥12 months of database registration prior to diagnosis, ≥1 ITP treatment, and ≥1 month enrollment following initiation of first ITP treatment were included (n = 4066 Explorys; n = 7837 MarketScan). Information on lines of treatment (LoTs) was collected. As expected, CSs were the most common first‐line treatment (Explorys, 87.9%; MarketScan, 84.5%). However, CSs remained by far the most common treatment (Explorys ≥77%; MarketScan ≥85%) across all subsequent LoTs. Second‐line treatments such as rituximab (12.0% Explorys; 24.5% MarketScan), thrombopoietin receptor agonists (11.3% Explorys; 15.6% MarketScan), and splenectomy (2.5% Explorys; 8.1% MarketScan) were used much less frequently. CS use is widespread in the US in patients with ITP across all LoTs. Quality improvement initiatives are needed to reduce CS exposure and bolster use of second‐line treatments.

supplemented as needed with intravenous immunoglobulin (IVIg), IV anti-D immunoglobulin, and/or platelet transfusion [1][2][3]9]. The majority of patients experience an initial response to CSs, but the response is often transient [3,10]. Patients who do not respond to first-line treatment, or who relapse as it is tapered, are candidates for second-line treatment, including rituximab, thrombopoietin receptor agonists (TPO-RAs), fostamatinib, and splenectomy as well as other treatments [2,3,9].
Treatment guidelines have consistently recommended against prolonged or repeated exposure to CSs because of the substantial side-effect burden. Indeed, guidelines suggest avoiding steroids and using second-line therapies in patients with persistent or chronic ITP [2,3,11,12]. This reflects the imperative to avoid overuse of CSs, a recognized issue in ITP management for many years [2,3,11,12].
The 2010 international consensus report highlighted the adverse effects of CS use and advised that prednisone, for example, should be "rapidly tapered and usually stopped even in responders, and especially stopped in nonresponders after 4 weeks." [12] In 2011, the American Society of Hematology (ASH) guidelines recommended the use of second-line therapies, including TPO-RAs and splenectomy, for patients unresponsive to or who relapse after initial CS therapy [11].
This study sought to determine the extent to which such recommendations were followed in real-world practice by evaluating treatment patterns using data collected for the 2011-2017 period from the IBM Explorys Database and the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental Databases.  Table S1).

MATERIALS AND METHODS
Eligible patient records were partitioned by treatment type, lines of treatment (LoT), and the sequence of treatments received (full details on study population and selection criteria are available in Table S1).
All analyses were descriptive in nature and performed by IBM Watson Health using SAS version 9.4 (SAS Institute) -see Table S1 for full details on statistical methods used. Because Explorys and MarketScan include somewhat different patient populations and data fields, we report results separately for each database rather than pooling results. in MarketScan ( Figure 1C,D). Repeated courses of CSs were common.

Patient sample
In particular, repeated initiation of prednisone (monotherapy or in combination) across the first 3 LoTs (i.e., prednisone → prednisone → prednisone) was by far the most frequent of any treatment sequence among patients receiving at least 3 LoTs (Explorys, 33.0%; MarketScan, 17.8%).
Across all LoTs, second-line treatments were used much less frequently than CSs ( Figure 1C,D   Figure 2A). The mean ± SD time from LoT initiation to achieving a platelet count of ≥50 ⨯ 10 9 /L was shortest with LoT1 F I G U R E 2 Platelet counts per therapy type and LoT (Explorys database) and treatment regimens per LoT (MarketScan database). The proportion of patients per therapy type and LoT reaching a platelet count of ≥50 ⨯ 10 9 /L in the Explorys database. Patients receiving more than one treatment in a given LoT may be included more than once. (A) Treatment regimens in the MarketScan database, including type of regimen by LoT (B) and prednisone regimen by LoT (C). Regimen type (monotherapy or combination therapy) data were not available for the "Any CS" group. CS, corticosteroid; LoT, line of treatment. and longest with LoT4+, with durations of 10.3 ± 30.5 and 13.7 ± 34.2 days, respectively. In contrast, the median time to a platelet count response was 2 days during each LoT, showing that most patients responded rapidly to treatment.
Because prednisone was the most frequently prescribed treatment, prednisone regimen type was also analyzed. Among LoTs containing prednisone, prednisone was used as monotherapy in 32% (n = 1578/4918) and in combination with ≥1 agent in 68% (n = 3340/4918).
In LoT1, prednisone monotherapy was the most common regimen, with over half of LoT1 prednisone use occurring within a monotherapy regimen (57%; n = 2170/3779 patients). Prednisone monotherapy remained a frequently used regimen across all subsequent lines (range, 18%-28%; Figure 2C). CS use did not appear to be short-term or low dose. Patients with at least 12 months of continuous enrollment post-index (n = 5170; 66%) were prescribed CSs for a median ± interquartile range of 76 ± 190 days during the first year. Among patients treated with CSs in any given line of treatment (n = 5790), only 3.5% of patients were prescribed a prednisone dosage of <5 mg/day (or its equivalent).

Yearly evolution of treatment type: Explorys database
In the Explorys database, treatment patterns over time were examined. Overall, prednisone remained the most widely used treatment in the first, second, and third LoTs throughout the study period. However, between 2015 and 2017, the proportion of patients in Explorys who were treated with eltrombopag, romiplostim, and rituximab as secondline therapy increased, although patient numbers for these treatments remained low compared with the number of patients treated with CSs ( Figure S2).

DISCUSSION
CSs are an established, cost-effective first-line option for treatment of adults with ITP. The initial rate of response to CSs exceeds 70%; however, patients usually relapse upon cessation of treatment and prolonged exposure is associated with toxicity and tolerability issues [2,3,9,[12][13][14][15]. The well-documented side effects of long-term CS use are substantial and wide-ranging (e.g., mood disturbances, insomnia, weight gain, osteoporosis, opportunistic infections, hypertension); over time, the detrimental effects of CSs far outweigh their benefits [3,9,12]. This is reflected in patient experience, with lower overall treatment satisfaction and a greater burden of side effects reported by patients treated with CSs compared with other ITP therapies [16,17]. Accordingly, both the ASH 2019 guidelines and the International Consensus Report on the Management of ITP recommend against prolonged courses of CSs, with both expert panels urging treatment durations of 6 weeks or less as the preferred LoT1 approach, followed by progression to second-line options after either lack of response or relapse [2,3].
In spite of the ASH 2011 guidelines [11] and 2010 consensus report recommendations [12] [18]. Real-world patient data from a Korean Health Insurance Database between 2010 and 2014 showed that CSs were not only the most frequently used therapy after 3 months of treatment in patients with ITP but were also used in more than half of patients with ≥48 months of follow-up [19].
Why are CSs so consistently overused contrary to multiple sources of guidance? Perhaps because they are effective, inexpensive, easy to administer, and appear tolerable, at least in the short-term [2,10]. It is also important to acknowledge the role of medical insurance in shaping treatment decisions. Insurance approvals for second-line agents and appointments at infusion centers can take days or weeks to obtain, meaning that if a patient relapses after tapering CSs (and the physi-  [20][21][22][23]. While the results demonstrate overall prolonged CS use, some patients may have received only brief courses of CSs to limit side effects (such as infusion reactions) or to rapidly raise platelet counts while waiting for other treatment(s) to take effect. Given that only treatment prescription rather than treatment use was assessed, patients may not have used the full complement of prescribed medication (with CSs possibly being over-prescribed as a precautionary "backup" measure), potentially inflating CS and combination therapy usage rates in this study [3,11]. Of note, splenectomy was performed in LoT1 in 1%-2% of patients ( Figure S1D) suggesting that 1%-2% may be the approximate incidence of so-called refractory ITP at presentation. This is aligned with the ASH guidelines, which suggest delaying splenectomy for at least 1 year after diagnosis, if possible [2].

DATA AVAILABILITY STATEMENT
Novartis is committed to sharing with qualified external researchers' access to summary-level data. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are from IBM Watson Health.

ETHICS STATEMENT
The study uses only de-identified patient records fully compliant with United States patient confidentiality requirements and does not involve the collection, use, or transmittal of individually identifiable data.