A Retrospective Claims Data Analysis on the Burden of COVID-19-Related Hospitalization in Adults at High Risk for Severe Disease Progression in Germany

Coronavirus disease 2019 (COVID-19) is associated with a variety of symptoms ranging from non-severe symptoms such as fever, loss of taste and smell, myalgias or respiratory symptoms such as cough, to severe symptoms such as decreased oxygen saturation, signs of severe respiratory distress and signs of pneumonia, up to life-threatening symptoms such as acute respiratory distress syndrome [1‐3]. Patients with severe symptoms often require hospitalization and treatment in an intensive care unit (ICU). The German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) Intensive Care Register records the free and occupied treatment capacities in intensive care medicine of around 1300 acute-care hospitals in Germany on a daily basis. As of January 1, 2022, during the end phase of the dominance of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) Delta variant (B.1.617.2), there were approximately 3823 patients treated within ICUs across Germany. Notably, 59% of these patients were undergoing invasive ventilation [4]. The severity of COVID-19 is also reflected in the high mortality rate among hospitalized patients. A German observational study showed a mortality rate of 17% increased to 29% for those admitted to the ICU, and further increased to 33% for patients who required ventilation [5].

Nirmatrelvir/ritonavir (NMV/r) is an antiviral drug for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for severe COVID-19 progression [6]. The aim of the drug treatment with NMV/r is to prevent severe courses of the disease and hospitalization [7]. Decision criteria for the use of NMV/r are primarily advanced age and the presence of multiple risk factors such as obesity, diabetes, immunodeficiency or immunosuppression [8‐10]. In addition, eligibility is gauged based on co-medications of the patient. Ritonavir, when co-administered as a pharmacokinetic enhancer, may lead to drug-drug interactions (DDIs) due to its interaction with various drug-metabolizing enzymes and transporters. As a result, there are specific medications that should not be administered alongside NMV/r. For other medications, the decision to prescribe is left to the physician, who is guided by the DDI risk as defined in the Liverpool list, which serves as a guidance for evaluating the potential risks associated with specific therapies and highlights which medications may need to be paused [11, 12].

High-risk patients (incl. those in older age groups) typically present with multiple comorbidities and medications. This complex health status necessitates careful consideration of risks and benefits with each additional therapy. The trade-off can be particularly challenging, as the simultaneous use of multiple treatments may increase the risk of adverse drug reactions. There is limited information on healthcare resource utilization and costs of hospitalized patients with COVID-19 at high risk for severe COVID-19 progression in Germany. To fill this gap, a retrospective database analysis was performed assessing the burden of hospitalized adult individuals with COVID-19 at high risk for severe COVID-19 progression in Germany during the period when the SARS-CoV-2 variant Delta was dominant (June 21, 2021 to December 31, 2021) [13]. As the co-administration of NMV/r needs to be carefully evaluated in high-risk patients, our study aimed to quantify these vulnerable groups, further investigate how the outcomes would present for these vulnerable subgroups overall and stratified according to eligibility criteria for NMV/r to support informed decision-making and improve the quality of care.

Of approximately 3.7 million individuals continuously observable in the InGef research database, about 60% were identified as being at high risk for severe COVID-19 progression. Among these high-risk individuals, 2938 patients were primarily hospitalized for COVID-19 between June 21, 2021, and December 31, 2021, i.e., in the period in which the Delta variant was the predominant SARS-CoV-2 variant. Advanced age (≥ 50 years) (86.3%) and cardiovascular conditions (83.9%) were the most prevalent of the predefined high-risk factors. Upon stratifying hospitalized patients based on the eligibility criteria for NMV/r treatment, approximately two-thirds were suitable for treatment with NMV/r, half of these patients without restrictions. Although the proportion of patients in each group may not remain consistent with the emergence of new virus variants, this data provides an initial indication of the group sizes observed. In future investigations, particularly those considering new virus variants, it will be valuable to monitor how these group sizes evolve to enable more informed decision-making and better preparedness for treating populations at high risk.

Among patients not eligible for NMV/r treatment, two-thirds had chronic liver and kidney disease, and half had diabetes mellitus as predefined risk factors for severe COVID-19 progression. These elevated percentages can be attributed to the contraindication of NMV/r treatment in patients with severe hepatic and renal impairment [22]. The high percentage of diabetic with diabetes might be linked to the high prevalence of renal impairment in those patients [23, 24].

The analysis found similarities and discrepancies compared to existing literature. The present analysis identified 2,225,743 individuals at high risk for severe COVID-19 progression, which extrapolates to about 50.7 million individuals in Germany. In contrast, Rommel et al. (2021) identified around 21.6 million high-risk individuals in Germany. However, this study used an earlier definition of high-risk group (e.g., classifying individuals ≥ 65 years as being high-risk) and was based on data of a nationwide cross-sectional telephone survey [25]. Despite methodological differences that introduce uncertainties when comparing the studies, the extrapolated patient numbers from the present analysis of 50.7 million are comparable with the 21.6 million by the RKI study, considering that, in contrast to the present study, the study by Rommel et al. did not include the age group of 51–65-year-olds, which would represent a potential plus of 19 million (as of 2021 in Germany) [17].

A German study of Bechmann et al. (2023) found that among all inpatients with COVID-19 whether they were diagnosed solely with COVID-19 or with a COVID-19-related respiratory main diagnosis, the mortality rate during the period when the SARS-CoV-2 variant Delta was dominant was 15.0% or 17.8%, respectively [26]. The present analysis yielded similar results with an overall mortality rate of 18.9%. However, when stratified by eligibility criteria for NMV/r, the figures varied significantly, ranging from 6.2% to 28.3%.

In the study conducted by Bechmann et al., the proportion of patients with a COVID-19-related respiratory main diagnosis during the period when the SARS-CoV-2 variant Delta was dominant was 75.9% [26]. The data from the present analysis reflects similar findings, with code J12 “Viral pneumonia, not elsewhere classified” recorded as primary diagnosis in 66.2% and J18 “Pneumonia, agent unspecified” in 7.2% of patients primarily hospitalized for COVID-19.

A systematic review and meta-analysis on hospital length of stay for COVID-19 patients revealed a mean stay of 14.5 days and a median of 13 days [27]. The present analysis demonstrated overall a slightly shorter mean stay of 11.3 days and a median of 9 days. When stratified by eligibility criteria for NMV/r, the length of stay ranged from 8.4 to 12.8 days, with a median of 7–10 days. In the context of Germany, Bechmann et al. demonstrated that the length of hospital stay during the period when the SARS-CoV-2 variant Delta was dominant, depending on whether they were diagnosed with COVID-19 or with COVID-19-related respiratory main diagnosis, was on average 10.2 or 11.6 days [26]. Despite a slightly shorter average length of stay compared to the meta-analysis and a slightly higher one depending on which stratification by eligibility criterion is considered, these results are in line with published literature.

A systematic review highlighted that routine service hospital bed/day costs are the predominant factor in COVID-19 hospital expenses, accounting for 39% of total costs, followed by treatment (27%), diagnostics (13%), and other costs (20%) [28]. A cross-sectional US study suggested that the average cost for providing inpatient treatment at hospitals during the COVID-19 pandemic experienced a 26% increase over a span of 2 years (March 1, 2020 to March 31, 2022), despite changes in care practices, rising vaccination rates, and the evolution of concerning variants [29]. A German study estimated the mean (median) costs for COVID-19 hospitalizations at €14,655 (€5103), including all patients with COVID-19 diagnosis, using administrative hospital data from the beginning of the pandemic until July 1, 2021 [30]. The present study covered a different time frame (June 21 to December 31, 2021) and restricted the study population to high-risk patients primarily hospitalized for COVID-19, which should be considered in a direct comparison.

Patients with high risk typically present with multiple comorbidities and medications so that careful evaluation of risks and benefits with each additional therapy (e.g., co-administration of NMV/r) is required. Other medications with similar or overlapping indications to NMV/r have different or fewer restrictions regarding comedications and comorbidities. This makes them potential treatment options in particular in the patients subgroups not eligible/eligible with restrictions for NMV/r.

However, few effective alternatives to prevent severe disease courses are available, as all monoclonal antibodies were found to have reduced or lost efficacy against emerging variants of SARS-CoV-2 [31, 32]. For this reason, they play a lesser role in daily clinical practice.

Age is an important risk factor for a severe course of COVID-19, which is also reflected in the results of the present study in that the eligible with restrictions and not eligible groups were on average older than the eligible group (68.2 and 76.0 vs. 58.3 years). Consequently, older patients, who often have more comorbidities and concomitant medications, are more likely to fall into the eligible with restrictions and not eligible categories and are at an increased risk of severe COVID-19 disease progression. Treatment with NMV/r may be beneficial for a subset of these patients, but the DDIs of NMV/r make it a complex treatment challenge. Therefore, our findings highlight the need for physicians to consider more nuanced treatment decisions for older patients.

Further, the complexity of decision-making for NMV/r use underscores the importance of considering the healthcare cost burden for these vulnerable groups. From the German SHI perspective, the average COVID-19-related hospitalization costs ranged from €4413 to €12,068 per hospitalization depending on the NMV/r treatment eligibility. Two US studies showed that NMV/r treatment can lead to substantial cost savings [33, 34]. Further cost-effectiveness analyses are needed to highlight the potential of NMV/r treatment to reduce or omit cost burden from the payer’s perspective in Germany.

Our research emphasizes the importance of awareness for timely and suitable treatment for patients with COVID-19 in order to prevent severe disease progression and reduce the number of related hospitalizations. According to our research, almost 70% of patients admitted to the hospital primarily for COVID-19 were suitable for treatment with NMV/r (half of which without restrictions). However, a US study showed that only 12.2% of outpatients eligible for NMV/r treatment received it [35]. Due to differences in healthcare systems the transferability to German setting is unknown.

The present work covers one part of a study that assessed the burden of hospitalized adult individuals with COVID-19 who were at high risk for severe COVID-19 progression between 2020–2021 in Germany. For this reason, the baseline period for determining of high-risk patients spanned from January 1, 2019 to December 31, 2019. In order to present the most up-to-date data possible, the presentation of the results was limited to the period in which the most recent virus variant (i.e., Delta) prevailed, which included June 21, 2021 to December 31, 2021 [13]. Therefore, the time gap between the identification of risk factors and the assessment of outcomes might have allowed for development of additional risk factors for the respective patients.

Another limitation of this study concerned the difficulty to assign the correct dominant Variant of Concern (VOC), as information on specific variants of COVID-19 (e.g., laboratory test results) was not available in the database. Therefore, the evaluation by time of the dominant VOCs was chosen as a proxy. The assumption was that in the period, in which a virus variant was dominant, the probability that the individual was hospitalized with that variant was high. The respective time periods of the dominant VOC were defined as those with a prevalence of > 50% for each virus variant and was based on published RKI data [13]. Therefore, it can occur that individuals in the study population were infected with the virus variant, which was not dominant in the respective study timeframe.

Further, patient identification in different groups was based on ICD-10-GM, ATC, PZN, OPS as well as aids and remedies codes. Although claims data are gathered for billing and reimbursement reasons, coding errors and data gaps cannot be completely avoided. Further, the claims data does not provide information on the actual intake of the medication and on the indication for which a drug has been prescribed.

The criteria for identifying patients primarily hospitalized for COVID-19 were adapted to the German perspective based on the US publication of the CDC [21]. The definition might be prone to misclassification due to its temporal variability and dependence on patient and contextual factors.

The identification of patients in the high-risk group for severe COVID-19 progression was derived from the epidemiological fact sheet of the RKI [19] (as of November 26, 2021) and is subject to uncertainties. The high-risk group definition of the RKI is based on the review of scientific literature. As the data landscape is developing fast, it cannot be ruled out that some publications were missing in the considered version of the epidemiological fact sheet. Moreover, as there is no approved list of risk factors for severe COVID-19 progression in Germany, the selection of risk factors varies between the published studies [25, 36, 37].

Further uncertainties exist in the classification of the identified patients into eligibility groups for NMV/r treatment, which was based on the SmPC of NMV/r (as of October 2022) [22] as well as based on the Interaction Checker of the University of Liverpool recommendation for the use of NMV/r (as of September 2022) [11, 12], i.e., list of respective contraindications and medications valid at the time the study was conducted. However, it cannot be guaranteed that the list of medicines was exhaustive, and it was also subject to changes, e.g., new co-medications were added, for example, cancer drug paclitaxel [38], that could lead to a change in the assignment of patients.

This study focused on in-hospital mortality, thereby not capturing individuals who died following hospital discharge. This limitation may lead to an underestimation of the true mortality rates associated with COVID-19, as adverse outcomes occurring post-discharge are not included in our analysis. Consequently, the findings do not reflect the overall mortality associated with COVID-19.

Since the present study focused on the Delta variant, the transferability of its results to newer variants is restricted. This limitation arises from the notable differences in transmissibility, severity, and treatment response observed among various variants [39], which could have influenced the characteristics of the hospitalized patients (e.g., more younger patients could be potentially identified), healthcare resource use and costs. Additionally, fluctuations in vaccination rates were not considered in this current study as vaccinations were not identifiable in the claims data and may have further impacted the results.

This is the first study reflecting the economic burden of hospitalized adult individuals with COVID-19 at high risk for severe disease progression from payer perspective, which is reflected in high number of hospitalizations, length of hospital stay, inpatient mortality and hospitalization costs. Overall, our findings highlight the need for early and appropriate treatment for patients with COVID-19 to prevent severe courses of the disease and associated hospitalizations to relieve healthcare systems regarding costs and resource allocation.