This USA-based real-world study demonstrated that, overall, patients with PNH initiated on eculizumab had substantial unmet clinical needs and posed a considerable economic burden on the US healthcare system. Further, this clinical and economic burden was significantly greater among TD eculizumab users relative to TF eculizumab users. TD eculizumab users comprised 36% of the overall sample, indicating that the disease activity may not be well controlled and was consistent with prior studies, where between 36% to 49% of patients with PNH treated with eculizumab were still transfusion-dependent in the long term [8, 12, 23]. Moreover, these patients had more than four times the number of hospitalization days compared to TF eculizumab users, emphasizing the substantial unmet need despite treatment with eculizumab. On the basis of time between dosing intervals, more than 70% of eculizumab-treated patients with PNH in this study were not dosed per label, and two-thirds of patients discontinued eculizumab within an average of a 1.5-year timeframe. Discontinuation of eculizumab may be attributed to complications resulting in adverse events, the development of comorbid diseases (i.e., aplastic anemia, myelodysplastic syndrome) , or the high cost of the therapy , which in turn may have contributed to the lower number of infusions among TD eculizumab users (5 vs 8 infusions). Findings indicate that blood transfusion dependence added significantly to both the direct medical and medical-related absenteeism cost burden of patients with PNH initiated on eculizumab, particularly with respect to increased hospitalizations and related costs due to PNH, fever, and sepsis. For example, the present study reported over 2-fold higher annual direct medical costs among patients in the TD cohort compared to the TF cohort after treatment with eculizumab, which has implications for US payers since most commercially insured patients (82.7% in 2019)  are likely to maintain their coverage for a period of 1–3 years.
The present study provides novel additional insights into the characteristics and treatment patterns of the PNH population. To date, the International PNH Registry, the largest worldwide observational study of patients with PNH, has served as a comprehensive source of real-world information for researchers to draw upon [5, 6, 18]. Consistent with the present study, rates of PNH-related comorbidities and symptoms have been found to be high among the PNH Registry population, with aplastic anemia observed in approximately 50% of patients at baseline [5, 6]. The present study expanded upon these findings by showing that TD eculizumab users had higher rates of aplastic anemia than TF eculizumab users (63.6% vs 42.7%), suggesting that blood transfusion dependence is associated with a greater burden of disease relative to the general PNH population. Further, given the highly variable symptomatic presentation of PNH [3, 14], differences in blood transfusion dependence status may also partly explain the clinical heterogeneity of this patient population. Patients in the TD eculizumab user cohort also had higher rates of coagulopathy than TF eculizumab users (49.1% vs 30.2%), which may be attributed to the higher use of anticoagulants among TD eculizumab users (32.7% vs 21.9%). It is important to note that the PNH Registry population also differs from the present study population in certain respects. For instance, patients in the PNH Registry are older compared to patients in the present study (mean age 45 vs 37 years), which may in turn be associated with greater disease severity. Moreover, the PNH Registry includes patients across multiple countries unlike the current study, which was focused on patients in the USA, and may contribute to differences in treatment patterns. Further, the PNH Registry assessed patient characteristics and outcomes based on physician assessments and medical records whereas the present study utilized administrative claims data. Thus, results may vary between studies because of differences in the data sources and coding methods used.
Although real-world data on the treatment patterns of patients with PNH initiated on eculizumab is currently limited, available findings appear to corroborate the results obtained in the present study. In a prior retrospective study using Marketscan data , only a minority of patients newly diagnosed with PNH were initiated on eculizumab, and among these patients, at least 30% discontinued eculizumab within the first year of treatment. Similarly, in the present study, an estimated 61% of patients discontinued eculizumab treatment during a mean follow-up period of approximately 1.5 years. When stratifying patients by blood transfusion dependence status, the present study found that TD eculizumab users were less likely to be dosed per label (TD, 21%; TF, 33%) and went on to have a shorter median time to treatment discontinuation (TD, 0.5 years; TF, 0.9 years).
The current study helps to provide additional context to previous findings regarding the HRU burden of patients with PNH. Prior studies relying on the PNH Registry  and those relying on Marketscan data  have reported a substantial HRU burden among patients with PNH irrespective of treatment, particularly for hospitalizations. However, only one prior study to date has investigated the HRU burden among patients with PNH post-initiation of eculizumab compared to pre-initiation. Preliminary results shared at the European Hematology Association 22nd Annual Congress  showed that treatment with eculizumab failed to decrease the rate of healthcare provider visits and hospitalizations compared to before. Thus, treatment with eculizumab may not be sufficient to control disease among patients with PNH, although further studies are needed to confirm this. The present study expands upon these findings by providing evidence of a greater unmet clinical need among TD eculizumab users, as evidenced by approximately three times more all-cause hospitalizations and more than four times more all-cause hospitalization days compared to TF eculizumab users, which translates into higher all-cause hospitalization costs among TD eculizumab users.
Despite evidence of a high burden of disease, there is currently a dearth of information available on the direct medical costs associated with PNH, particularly among eculizumab users. The present study helps to close this knowledge gap by providing evidence of the significant direct medical costs incurred by TD eculizumab users, which are driven primarily by hospitalization costs, with blood transfusions representing a further cost burden. More specifically, the annual incremental medical costs to the healthcare system due to HRU, including blood transfusions, hospitalizations, and OP/ER visits, were an estimated average of $219,813 per year for every TD eculizumab user compared to TF eculizumab users, not including PNH-related drug costs for which TD eculizumab users had a shorter duration of treatment. In one recent study by Tomazos et al. , a cost model was used to quantify the economic burden of BTH management among patients with PNH receiving eculizumab. Consistent with the present study, substantial costs were estimated for eculizumab users due to the ongoing management of BTH (costs ranging from $51,716 to $186,107 PPPY), including expenses for eculizumab dosage adjustments, hospitalizations, and blood transfusions . However, given that this study relied on data modeling rather than empirical data analyses, certain underlying assumptions may not be generalizable to the real-world clinical setting. A further limitation of the model was that it did not account for differences in PNH management costs based on blood transfusion dependence status.
Patients with PNH are known to suffer from impaired quality of life and disease-related fatigue [5, 6]. Additionally, TD patients require intravenous treatment administration at infusion clinics, which may require a considerable amount of their time . As a result, it is not surprising that a substantial proportion of patients cite PNH as a major factor contributing to their workplace absenteeism [5, 18]. To our knowledge, the present study findings represent the first evidence of a significant increase in medical-related absenteeism costs among TD eculizumab users compared to TF eculizumab users, driven by greater hospitalization-related absenteeism costs and OP-related absenteeism costs.
Taken together, the substantial direct medical costs and medical-related absenteeism costs associated with PNH further suggest that disease activity may not be well controlled despite treatment with eculizumab, and that the burden of disease appears greater among TD eculizumab users relative to TF eculizumab users. However, some case studies have shown that treatment with eculizumab may contribute to a reduction of morbidity prior to and complications following allogeneic hematopoietic stem cell transplantation among patients with PNH [27, 28]. Additional research is needed to further delineate the use of eculizumab in the setting of transplantation.
The present study was subject to certain limitations. First, the ICD-9 diagnosis code for PNH is a broad code, encompassing other related diagnoses. To minimize imprecision in selecting patients with PNH into the study, the study cohort was selected on the basis of an inclusion by exclusion principle, in which patients were excluded if they had at least one diagnosis of another indication of eculizumab. As a result, the number of patients with PNH may be underestimated if a patient had a diagnosis for PNH as well as another indication of eculizumab. Another limitation of this study was the lack of available information in the data source regarding mortality and the reasons for discontinuation of eculizumab. Competing risk of death is an important consideration in time-to-event analyses of older patients (e.g., median age of 80 years)  and older age at enrollment is a risk factor for mortality among patients with PNH . However, the present study evaluated clinical outcomes (i.e., discontinuation of eculizumab) in a younger PNH population with a lower risk of near-term death. Therefore, mortality was likely to have a lesser impact on the analysis. Common limitations of administrative claims-based studies include the potential misclassification of clinical outcomes due to the misspecification of diagnosis, procedure, or drug codes, as well as billing inaccuracies and missing data due to miscoding of diagnoses. However, the aforementioned limitations were expected to affect all cohorts equally and, therefore, were not likely to have biased the comparative analyses. Additionally, definitions of visit types (e.g., IP, OP) vary among claim database analyses. The lack of standardization may add bias in the attribution of visit type-specific costs, but this limitation was unlikely to impact the total cost analysis presented. As in all observational studies, confounding adjustments can only account for factors that are observable and recorded in the database.