Japanese database analysis: effectiveness of early initiation of TPO-RA treatment in tapering corticosteroid dose in ITP Open Access

Immune thrombocytopenia (ITP) is an acquired disease in which autoantibodies bind to platelets and megakaryocytes. This leads to platelet destruction and inhibits the production of platelets, thus resulting in thrombocytopenia and bleeding diathesis.¹ In Japan, corticosteroid therapy is primarily used as the first line of treatment for ITP according to the Japanese guidelines for the treatment of adult ITP.^2,3 Second-line treatments such as thrombopoietin receptor agonists (TPO-RA), rituximab, and splenectomy are used for patients who do not respond well to corticosteroids, require long-term high-dose corticosteroid treatment, or are unable to tolerate corticosteroids because of comorbidities or adverse events (AEs). According to a nationwide epidemiology survey of patients with ITP in Japan, in 2019, approximately 83% of patients received TPO-RA as a second-line treatment, whereas 9% received rituximab, and 8% underwent splenectomy.⁴ 

The timing of the initiation of second-line treatment in relation to the duration or dosage of corticosteroids is not specified in the Japanese guidelines. Most patients continue to receive corticosteroids even after initiating second-line TPO-RA therapy in real-world practice. However, the long-term use of corticosteroids has been associated with AEs such as hypertension and diabetes mellitus, and thus the dosage and duration of corticosteroid administration should be carefully managed.^5-7 

It is currently unknown how the timing of TPO-RA initiation affects the occurrence of corticosteroid-specific AEs such as diabetes, hypertension, insomnia, infection, gastroduodenal ulcer, and fracture, or the impact on the dosage and duration of corticosteroid administration and corticosteroid-related AEs in Japan.

Thus, this study aimed to investigate the impact of the timing of TPO-RA initiation on the dosage and duration of corticosteroid administration and corticosteroid-related AEs using real-world data of patients with ITP from the Japanese Diagnosis Procedure Combination (DPC) claim database. Specifically, treatment patterns were analyzed regarding the time from the initiation of corticosteroid (prednisolone) administration to the initiation of TPO-RA administration, the prednisolone dosage before and after TPO-RA initiation, and the effect of the timing of TPO-RA initiation on the dose and duration of prednisolone administration and on the occurrence of corticosteroid-specific AEs.

This was a longitudinal, descriptive study using real-world data in Japan. The study obtained data from 1 April 2008 through 30 September 2023. The data source was the Japan health claim database for acute care hospitals, provided by Medical Data Vision Co, Ltd (MDV). This database contains DPC data and health insurance claim data from over 450 hospitals, which covered approximately 28% of acute care hospitals registered as DPC hospitals in Japan (as of September 2023). In our analysis, we used data from 2008 onward. Patients must have had a record of ITP diagnosis before a specific date and must also have been registered in the database before that same date. We included the first prescription date of prednisolone after the diagnosis of ITP for patients after 2011 because eltrombopag, one of the TPO-RAs, was launched in December 2010, and another TPO-RA, romiplostim, in April 2011.

The date of the first prescription of prednisolone after the diagnosis of ITP was defined as the index date (day 0); the observation period was 365 days from the index date (supplemental Figure 1). Prednisolone is the most widely used corticosteroid for this indication in Japanese clinical practice.³ The aim of the present study was to investigate the long-term administration of corticosteroids. Methylprednisolone is used as steroid pulse therapy in emergency situations and before surgery, and dexamethasone is administered at high doses for 4 days per cycle^3,7; because both of these drugs are administered for only a short duration, they did not meet the objectives for the present study and were excluded from our analyses. Three cutoff values (60, 120, and 180 days) were set using the period from the index date to the start of TPO-RA treatment to classify patients receiving TPO-RA into early or late TPO-RA initiation groups at each cutoff value: <60 vs ≥60, <120 vs ≥120, and <180 vs ≥180 days.

Patients were divided into 3 groups according to the presence and timing of TPO-RA administration. The early TPO-RA initiation group included patients first administered TPO-RA <60, <120, and <180 days after the index date. The late TPO-RA initiation group included patients first administered TPO-RA ≥60, ≥120, and ≥180 days after the index date. The non–TPO-RA administration group included patients without a record of TPO-RA prescriptions during the observation period.

The study was conducted in compliance with the protocol and the ethical principles outlined in the Declaration of Helsinki. The data used in this study were anonymized and do not contain personal information. Therefore, the Ethics Review Committee of Saitama Medical University determined that no prior review was required. Similarly, the need for informed consent was waived.

The inclusion criteria were patients with records of a diagnosis of ITP (ICD-10 [International Classification of Diseases, 10th Revision] code D69.3 in the health insurance claim data), a record of the first prescription date for prednisolone after the initial ITP diagnosis, first prescription date for prednisolone after 2011, medical records for >365 days (the observation period), and a look-back period (ie, a washout period in the pre-observation period) of at least 60 days from the date of database registration to the first prednisolone prescription date. Patients whose first TPO-RA (romiplostim and eltrombopag) prescription date was before the first prednisolone prescription date were excluded.

The primary endpoints were the total prednisolone dose, duration of prednisolone administration, and average daily prednisolone dose by month for each group during the observation period. Total dose and duration of prednisolone administration were surrogate endpoints for long-term treatment tolerability.

The duration of prednisolone administration was established from the start date of administration (index date) to the end date of administration (ie, the earliest of either the end date of the last administration or the end of the observation period [1 year]). Total prednisolone dose included all prednisolone doses administered during the observation period. The dose of prednisolone was calculated by multiplying the unit dose by the daily dose and the number of days of administration for each prednisolone prescription record in the database.

The secondary endpoints were as follows: daily average prednisolone dose per month in each group during the observation period and daily average prednisolone dose per month in the 6 months before and after TPO-RA initiation. For patients in the early and late TPO-RA initiation group, the average daily prednisolone dose per month in the 6 months before and after TPO-RA initiation was calculated.

The incidence rate of prednisolone-specific AEs was calculated in each group. The AE rate was calculated using the number of patients with each comorbidity excluded as the denominator and the number of patients who experienced an AE during the observation period as the numerator.

Prednisolone-specific AEs were defined by ICD-10 code (disease code) and Anatomical Therapeutic Chemical code (drug code), and included the following diseases or conditions: diabetes (insulin-dependent), hypertension, insomnia, infection (pneumonia or sepsis), gastroduodenal ulcer, and fracture (ICD-10 code only). The definitions and disease codes of each AE are provided in supplemental Table 1. Given that in Japan, romiplostim and eltrombopag are indicated for chronic ITP (defined at the time of the clinical trial as lasting ≥6 months [≥180 days] from onset), we used a cutoff value of 180 days for the analysis of AEs.

Baseline variables and primary and secondary endpoints are presented using descriptive statistics. Categorical variables are displayed as counts and percentages of patients, and continuous variables are depicted using summary statistics.

The baseline variables assessed in each group were age, sex, comorbidity (diabetes, hypertension, insomnia, infection, gastroduodenal ulcer, fracture), year of first ITP diagnosis, year of index date, inpatient/outpatient at index date, and duration from the index date to the first TPO-RA dose.

Subgroup analyses by age and sex were conducted for primary and secondary analyses. All statistical analyses were conducted using SAS version 9.4 or higher (SAS Institute) or R version 4.1.0 or higher (R Foundation for Statistical Computing).

Of the 49 059 patients with ITP in the MDV database, 8495 were selected for this study (April 2008 to September 2023). Of these, 799 patients met the exclusion criteria, and 7696 patients were analyzed (supplemental Figure 2).

Although the groups had different sizes and characteristics, these were found to be similar across groups for underlying diseases (Table 1; supplemental Table 2). Overall, 57.7% of the study population was female. The median (minimum, maximum) age was 69.0 years (0, 100); 65.2% of patients were aged ≥60 years. Over half of the patients (58.5%) were hospitalized at the time of starting prednisolone administration. Patients tended to experience infections as the most frequently occurring comorbidities (45.7% of all comorbidities).

For any cutoff value (60/120/180 days) used, the early TPO-RA initiation group had a higher mean age and more frequent hospitalizations. The prevalence of comorbidities was slightly higher in the early group than in the late group.

The duration of prednisolone prescriptions and prednisolone total doses are shown in Table 2 and supplemental Table 3. The cutoff value was 180 days. The mean (standard deviation) duration of prednisolone prescriptions during the 1-year observation period was 244.8 (132.6), 319.0 (91.5), and 247.5 (139.2) days in the early TPO-RA initiation, late TPO-RA initiation, and non–TPO-RA administration groups, respectively. The mean (standard deviation) total prednisolone dose was 2831.7 (1846.9), 3409.5 (1929.4), and 2399.5 (1807.5) mg per year of observation period in the early TPO-RA initiation, late TPO-RA initiation, and non–TPO-RA administration groups, respectively (Table 2). A similar trend was also observed for the other cutoff values (120 and 60 days) (supplemental Table 3).

Regardless of the cutoff value used, the highest daily average prednisolone dose was initially observed in the early TPO-RA initiation group, followed by a rapid decrease in dose, which tended to be similar to that in the non–TPO-RA administration group (Figure 1; supplemental Figure 3). In the early TPO-RA initiation group, there was a long-term trend toward daily average prednisolone doses of ≤5 mg.

At 1 month, the median (minimum, maximum) prednisolone dose was 27.2 mg (0.2, 104.8), 27.3 mg (0.2, 104.8), and 28.1 mg (0.2, 104.8) in the early TPO-RA initiation groups within 180, 120, and 60 days from the index date, respectively. By approximately 10 to 11 months, the median dose was 0 mg for all cutoff values (Table 3; supplemental Tables 4 and 5).

The early TPO-RA initiation group showed a trend toward a gradual increase in prednisolone dose before TPO-RA administration, followed by a decrease (Figure 2; supplemental Figure 4). In the late TPO-RA initiation group, the prednisolone dose plateaued until the start of TPO-RA administration, followed by a gradual decreasing trend after TPO-RA initiation.

A cutoff value of 180 days was used for this analysis. Prednisolone-specific AEs included diabetes (insulin-dependent), hypertension, insomnia, infection (pneumonia or sepsis), gastroduodenal ulcer, and fracture. Diabetes (insulin-dependent) and hypertension tended to occur more frequently in the late TPO-RA initiation group (8.4% and 19.9%, respectively) than in the early TPO-RA initiation group (6.9% and 14.4%, respectively) and non–TPO-RA administration group (4.6% and 8.5%, respectively) (Table 4).

The incidence rates of infections in the late TPO-RA initiation group and the early TPO-RA initiation group were similar (7.2% vs 7.6%). Insomnia, gastroduodenal ulcer, and fracture were not observed in any groups.

The incidence of AEs by patient background was examined and was similar between male and female patients (Table 5). When analyzed by age, there was an overall trend toward a higher incidence of AEs in patients aged ≥60 years (Table 5).

To our knowledge, this report is the first to describe the effect of time from prednisolone initiation to TPO-RA on prednisolone duration and dose using real-world data from Japanese patients with ITP extracted from a database. Japanese guidelines recommend oral prednisolone 0.5 to 1 mg/kg per day for 2 to 4 weeks as initial therapy and ≤10 mg of prednisolone as the maintenance dose to preserve platelet count.^2,3 Second-line treatment should be selected if there is no response to treatment or a tendency toward exacerbation, or if first-line treatment is not tolerable because of AEs or comorbidities of the underlying disease. However, the timing of the initiation of second-line treatment in relation to the duration or dosage of corticosteroids is not specified in the Japanese guidelines. Each physician makes the decision according to their evaluation of the patient’s clinical situation. In general, the patient is advanced to second-line treatment not only when undesirable effects of corticosteroid therapy occur but also when corticosteroids are ineffective or high maintenance doses are required. This is in contrast with the American Society of Hematology ITP guidelines, which recommend stopping corticosteroids within 6 weeks and emphasize the importance of monitoring patients for AEs and the potential safety concerns associated with long-term corticosteroid use.⁸ 

In this study, the total prednisolone dose was higher in the TPO-RA groups than the non–TPO-RA group. This is suggestive of worse underlying disease in the former groups and is aligned with the recommendations stated in the 2019 revision of the Reference Guide for Management of Adult Immune Thrombocytopenia in Japan.³ 

The early TPO-RA initiation group, in particular, had a higher mean age and hospitalization frequency than the other groups. In this group, although the corticosteroid dose peaked shortly after the index date, there was an important decrease in the prednisolone prescription after the introduction of TPO-RA treatment. As time progressed after the first dose of prednisolone, the daily average doses of prednisolone in the early TPO-RA initiation group tended to be lower than those in the late TPO-RA initiation group and similar to those in the non–TPO-RA administration group. The incidence of AEs, such as insulin-dependent diabetes and hypertension, tended to be higher in the late TPO-RA initiation group than in the early TPO-RA initiation group. This may be a result of the increased exposure to prednisolone in the late TPO-RA initiation group compared with the early TPO-RA initiation group.

Corticosteroids, the first-line treatment for ITP, tend to be administered long-term in Japan. Such long-term use of corticosteroids may have undesirable effects.⁷ Nonetheless, this study revealed high exposure to corticosteroids in Japan, extending beyond first-line treatment. The risk of comorbidities increased in older patients, males, smokers, and those with prothrombotic comorbid conditions.^9,10 Of note, the early TPO-RA initiation group had a higher mean age and a higher proportion of patients hospitalized at the time of starting prednisolone administration. Additionally, the prevalence of comorbidities tended to be higher in the early TPO-RA initiation group than in the late TPO-RA initiation group, suggesting that the attending physicians might have tried to avoid the undesirable effects of corticosteroids.

These results (lower prednisolone daily average doses in the early TPO-RA initiation group than in the late TPO-RA initiation group) also suggest that early administration of TPO-RA can reduce the dose of prednisolone and shorten the duration of administration in the treatment of ITP in Japan. TPO-RAs are a treatment for chronic ITP, and an analysis using data from a phase 3 clinical trial of the TPO-RA romiplostim showed reduced corticosteroid doses or early discontinuation in the romiplostim group compared with the placebo group.¹¹ In addition, a study using real-world data in Germany reported corticosteroid administration patterns before and after initiation of TPO-RA and found a decrease in both the percentage of patients receiving corticosteroids and their doses after initiation of TPO-RA.¹² The proportion of patients treated with corticosteroids after starting TPO-RA treatment (index date) was 33.7%, as opposed to 43.9% immediately before the index date. This result shows that almost 25% of patients treated with corticosteroids at the end of the pre-TPO-RA phase stopped this treatment when they started TPO-RA therapy. Two years after the index date, the proportion of patients treated with corticosteroids had declined to 12.2%.¹² 

A retrospective observational study evaluating the actual use and AEs of TPO-RA in adult patients with ITP in the United Kingdom (the TRAIT study) reported that early use of TPO-RA after ITP diagnosis resulted in favorable response rates.¹³ Other studies have also reported that early initiation of TPO-RA has the potential to reduce corticosteroid use and improves platelet response outcomes in patients with ITP.⁷ 

The median prednisolone dose after approximately 10 to 11 months in the early TPO-RA initiation group was 0 mg, suggesting that more than half of the patients weaned off prednisolone within around 10 months. The median prednisolone dose at 12 months in the non–TPO-RA administration group was also low at 0.2 mg. This is considered to be primarily due to this group having well-controlled disease and symptoms that do not require TPO-RA administration, and thus being more likely to be weaned off corticosteroids.

It has been reported that most patients with ITP relapse^14,15 within a year of starting corticosteroid treatment and require additional therapy. Therefore, some patients are treated with corticosteroids on a long-term basis to avoid relapse. In clinical practice outside Japan, the duration of corticosteroid administration is generally limited, partly because of guideline recommendations.² Conversely, in Japan, prednisolone tends to be administered continuously at low doses of 5 to 10 mg, partly because of concerns about recurrence, as mentioned earlier.

No differences were observed between the early and late TPO-RA initiation groups in patient background or in the primary analysis results for prednisolone dose and duration of administration, regardless of the cutoff values used.

AEs with a higher frequency in the late TPO-RA initiation group included diabetes (insulin-dependent) and hypertension, consistent with previous reports of long-term corticosteroid use.^5-7 Some AEs did not show a particular trend, including insomnia, gastroduodenal ulcer, and fracture, because of their low incidence. The incidence of AEs in the non–TPO-RA administration group may have been lower than in the other 2 groups because the patients in this group had well-controlled disease and symptoms, and prednisolone was likely administered at a lower dose.

This study has some limitations that should be considered. First, given that the MDV database used in this study comprises mainly relatively large acute care DPC hospitals, it may tend to include patients with severe conditions requiring hospitalization compared with those treated in clinics and other facilities. However, because ITP treatment in Japan is received mostly at relatively large hospitals with acute care facilities, and patients may be hospitalized when high-dose corticosteroids are initiated, the potential selection bias in this study is likely small. Second, in database studies such as this one, when extracting patient information, it is not possible to link the information to the patient’s medical information at other hospitals. Thus, complete information on disease, treatment history, and clinical severity at other hospitals could not be ascertained during the observation period. Third, the endpoints of duration of prednisolone prescription and prednisolone dosage were defined using the date of prescription and the number of days prescribed. However, it was not possible to determine whether the patient was actually compliant with treatment. Fourth, it was not possible to confirm the diagnosis without linking to medical records. In particular, psychologic diagnosis such as insomnia may have been underreported because of inadequate patient assessments. Finally, some patients in the present study received other second-line therapies (splenectomy, rituximab) (supplemental Table 6). Because of the limited number of these patients, we did not perform stratified or other adjusted analyses; however, we believe that these data had minimal impact on the study results and were unlikely to have significantly affected the overall findings.

In conclusion, this study evaluated the effect of the timing of TPO-RA initiation on prednisolone dosing duration and dosage in Japanese patients treated for ITP. The results suggest that early initiation of TPO-RA administration can contribute to a reduction in total prednisolone dosage and duration of administration and, consequently, reduced AEs such as hypertension and insulin-dependent diabetes.

Statistical analysis was provided by Yuji Matsuo and Masashi Suzuki of I’cros Co, Ltd. Study design and statistical analysis support were provided by Takanobu Nomura of Kyowa Kirin Co, Ltd.

This study was funded by Kyowa Kirin Co, Ltd. The authors thank Keyra Martinez Dunn of Edanz for providing medical writing support, which was funded by Kyowa Kirin Co, Ltd, in accordance with Good Publication Practice (GPP 2022) guidelines.

Contribution: K.S., S.I., and Y.M. contributed to data analysis and interpretation; K.S. and S.I. prepared the first draft of the manuscript; K.S., S.C., M.S., S.H., and Y.M. critically reviewed the first draft; and all authors contributed to the study concept and design, commented on previous versions of the manuscript, and read and approved the final manuscript.

Conflict-of-interest disclosure: Y.M. received research funding from argenx Japan K.K., UCB Japan Co, Ltd, Zenyaku Kogyo Co, Ltd, Alexion Pharmaceuticals, Inc, BioMarin Pharmaceutical Inc, Chugai Pharmaceutical Co, Ltd, CSL Behring K.K., Janssen Pharmaceutical K.K., Novartis Pharma K.K., Novo Nordisk Pharma Co, Ltd, Pfizer Japan Inc, and Sanofi K.K.; received consulting or advisory fees from Kyowa Kirin Co, Ltd, Novartis Pharma K.K., Pfizer Japan Inc, and Sanofi K.K.; received honoraria from Alexion Pharmaceuticals, Inc, argenx Japan K.K., Sanofi K.K., Takeda Pharmaceutical Co, Ltd, and Novo Nordisk Pharma Co, Ltd; has participated in clinical trials for Sanofi K.K., Novartis Pharma K.K., and Pfizer Japan Inc; and has participated in both clinical trials and consulting for Argenx Japan K.K.. S.I., S.C., M.S., and S.H. are employees of Kyowa Kirin Co, Ltd. K.S. declares no competing financial interests.

Correspondence: Yoshitaka Miyakawa, Department of Hematology, Saitama Medical University Hospital, 38 Morohongo, Moroyama, Iruma District, Saitama 350-0495, Japan; email: [email protected].