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Panos Stafylas¹ , Olga Siskou² , Petros Galanis³ , Olympia Konstantakopoulou³ , Iliana Karagkouni³ , Marianthi Karaiskou¹ , Argyro Tountopoulou⁴ , Ioanna Kouzi⁴ , Sofia Vasilopoulou⁴ , Ioannis Kalliontzakis⁵ , Christos Savopoulos⁶ , Efstathios Manios⁷ , Evangelos Tsampalas⁸ , Haralampos Milionis⁹ , Athanasios Protogerou¹⁰ , Daphne Kaitelidou³ , Eleni Korompoki^{7, 11} , George Ntaios^{11, 12} , Konstantinos Vemmos^{11, 13} ,

¹HealThink (Medical Research & Innovation PC), Thessaloniki, Greece

²Center for Health Services Management and Evaluation, Department of Nursing National and Kapodistrian University of Athens, Athens, and University of Piraeus, Piraeus Greece

³Center for Health Services Management and Evaluation, Department of Nursing National and Kapodistrian University of Athens, Athens, Greece

⁴1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.

⁵Department of Neurology, General Hospital of Chania, Creta, Greece.

⁶1st Medical Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece.

⁷Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece

⁸Department of Neurology, Panarkadikon General Hospital, Tripoli, Greece.

⁹Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece

¹⁰Cardiovascular Prevention & Research Unit in Laiko General Hospital of Athens at the Medical School of the National & Kapodistrian University of Athens, Greece

¹¹Hellenic Stroke Organization, Greece

¹²Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece

¹³Hellenic Cardiovascular Research Society, Athens, Greece

Corresponding Author Email: panos@healthink.info

DOI : https://doi.org/10.51470/AMSR.2024.03.01.30

Abstract

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INTRODUCTION

Stroke is one of the leading causes of morbidity, mortality and disability worldwide.^1,2 The most recent Global Burden of Disease (GBD) showed that in 2019 around the world, there were 12.2 million incident cases of stroke (one stroke every three seconds) and 101 million prevalent cases.^1,2 Recently, OECD reported that he average mortality rate over one year for ischaemic stroke was 14%, but there was a significant deviation among the different countries with a range from 5% to 25%. ³

Because of the high incidence and the subsequent disability, stroke constitutes a significant clinical, economic and social burden for the societies. In 2019, it was estimated that 143 million disability-adjusted life-years (DALYs) due to stroke², and the total estimated cost of stroke in 2017 was US$861 billion, about 1.2% of the global GDP.¹ Although, the last 30 years the age-standardised rates of stroke incidence decreased, the absolute number of incident strokes increased by 70% and stroke-related DALYs increased by 32%.In accordance with the World Stroke Organisation Global Stroke Fact Sheet 2022, one in four people will have a stroke in their lifetime, most of them an ischemic one.¹

Since all projections show that the burden of stroke in Europe will continue to increase⁴, it is urgent to identify and apply the most-effective methods for the primary prevention and management of stroke in each specific setting. Intravenous recombinant tissue plasminogen activator (rtPA) is an effective treatment for Acute Ischemic Stroke (AIS) if administered within 4.5 hours of symptoms onset.^5-7 In patients with AIS, rtPA administration within 4.5 hours of symptom onset, compared with placebo, significantly improved clinical outcome at 90 days after stroke onset, as assessed by the proportion of patients with modified Ranking scale (mRs) scores of 0 or 1.^5,7 Last years, several cost-effectiveness analyses showed that IV rtPA was a dominant or cost-effective strategy for the patients with AIS compared with conservative management without rtPA.^8-12 Despite of the above evidence, thrombolysis rates are still significantly low, with significant variations among EU countries but also among different regions in each country.¹³

Greece is one of the countries with a very low rate of thrombolysed ischemic stroke patients. ¹³It is estimated that approximately 30,000–35,000 new strokes occur each year, and represent one of the two leading causes of death, accounting for more than 10% of all deaths.^14-16 The total annual expenditure associated with strokes in Greece has been estimated at approximately 650 million Euros.¹⁷ In a recent study for the economic burden of stroke in Greece related with atrial fibrillation,¹⁵ it was estimated that the total cost per patient was 6,273 euros in 2018, regardless of the health state, i.e regardless of whether he/she is a survivor of a previous stroke episode or a new incident patient. The key cost drivers were productivity losses of informal caregivers (21.1%), productivity losses of patients (19.7%), hospitalizations (15.0%) and rehabilitation (14.1%), accounting for about 70% of the total cost.¹⁵

There are inadequate data on cost-effectiveness of rtPA in Greece. Because of differences in healthcare systems, costs and reimbursement methods, non-Greek data may not be relevant with the Greek setting and decision-makers hesitate to invest more resources on stroke units and thrombolysis of acute ischemic stroke.  The objective of this study is to assess the cost-effectiveness of rtPA for the management of AIS using real world data (RWD) from the Greek setting, and to provide the required evidence to the decision-makers.

METHODS

Study population

The study population derived retrospectively from the “Improving Stroke Care in Greece in Terms of Management, Costs and Health Outcomes – SUN4Patients” project. The SUN4P study is a prospective cohort multicenter study of patients with first ever acute stroke, hemorrhagic and ischemic, (ICD-10 codes: I61, I63 and I64) admitted within 48 hours of symptoms onset to nine National Health System and University hospitals. The study protocol has been registered in ClinicalTrials.gov (NCT04109612). Detailed data were prospectively recorded for each patient, including demographics, medical history and associated cardiovascular risk factors, stroke onset, length of hospital stay, stroke characteristics, clinical findings and vital signs on admission, laboratory investigations, and administered treatment. Body weight and height were measured by the stroke nurse on admission. For the needs of this analysis, all eligible patients were followed-up for 3 months. Data analysis included clinical outcomes and healthcare resources use. The study sample consisted of the 27 patients who have received thrombolysis with IV rtPA and 27 pairwise matched controls stratified by age, sex and severity on admission (NIHSS score), eligible for thrombolysis who have not been thrombolysed and blinded to 3 months patient’s outcomes. The primary clinical outcome of the analysis was the modified Rankin Scale (mRS, 0-6) at 3 months.¹⁸ A logistic regression analysis was performed to analyse the relationship between the mRS score at 3 months from admission after controlling for age, gender and NIHSS score at admission.

Cost-Effectiveness Analysis

A decision analytic model was used to compare health and economic outcomes of rtPA vs no-rtPA for the management of AIS (Figure 1). Possible states included: no symptoms (R0), no significant disability (R1), minimal disability (R2), moderate disability (R3), moderate to severe disability (R4), severe disability (R5) and death (R6). Utility values stratified by mRS category were derived from the literature(Table 1).¹⁹ Quality-adjusted life years (QALYs) were measured by multiplying years of life (days of life in the first three months) by the above utility scores.

The analysis was performed from a third-party payer perspective (EOPYY). EOPYY is the National Organization for Health Care Services Provision in Greece, covering more than 95% of the Greek population. This organisation provided the actual cost paid (by EOPYY) for the management of AIS and its consequences for all study participants, included initial and possible subsequent hospitalisations, medications, blood tests and imaging, outpatient management and rehabilitation. The time horizon of the model was 3 months, which was considered clinically appropriate. Discounting was not applicable due to the short duration of the analysis. The primary outcome of the economic evaluation was the incremental cost-effectiveness ratio (ICER) expressed in euros per QALY.

Uncertainty analyses

One-way sensitivity analyses (OWSA) as well as probabilistic sensitivity analyses (PSA) were performed to confirm the robustness of the cost-effectiveness results. OWSA were conducted by varying variables by +10/-10 % of their original (baseline) values to estimate their effect to the baseline ICER calculations. PSA was conducted by simulating the health and economic outcomes of 1,000 pairs of hypothetical individuals to assess the variability (robustness) of ICER. In each simulation all parameters varied randomly from the predefined distribution for each parameter.

RESULTS

Despite the non-randomized design of the study, there were no significant differences in the demographic and clinical characteristics of the two groups (rtPA vs no-rtPA) (Table 2). Most of the eligible patients were older than 70 years old (with a range from 36 to 95 years old), less than half of them female, 74% hypertensives, 17% diabetics, 30% with atrial fibrillation (one in four from patients with AF, newly diagnosed).

The analysis showed that rtPA is more effective than conservative treatment (non-rtPA) for the management of patients with AIS based on RWD from the Greek setting, gaining 0.009 incremental QALYs in the 3 months’ time horizon. This benefit has been gained with parallel savings of 302.79€ per patient. The average total cost paid by the social security system for the patients receiving rtPA in the first three months after admission was 2,196.65€ vs 2,499.45€ for the patients not receiving rtPA. The results indicate that rtPA is a dominant strategy for the management of AIS from a Greek third-party payer perspective because it is more effective and costs less than conservative treatment (Table 3).

OWSA confirmed the robustness of the conclusion and showed that index hospitalisation cost was the most important factor for the analysis. However, PSA showed that there is a significant variability in simulated ICER and that the probability of rtPA to be cost effective or dominant in the Greek setting is between 58.9%-74.1% within the threshold of one to three times the national GDP per capita (15,424€ is the last available Greek GDP per capita for 2020, reported by the Hellenic Statistical Authority). This variability is presented in the cost-effectiveness plane (Figure 2) and the cost-effectiveness acceptability curve (Figure 3).

DISCUSSION

Our analysis indicates that intravenous rtPA administered for the management of AIS in the Greek setting in less than 4.5 hours after symptoms onset is associated with better clinical outcomes and a lower cost for the national payer (EOPYY) indicating that it is a potentially dominant or cost-effective treatment strategy. The analysis was based on RWD collected prospectively in seven public and university hospitals in different Greek cities as part of the SUN4P project. Moreover, healthcare resources use, and total treatment cost were provided directly from the national payor, for each individual patient participating in the study, in accordance with study protocol as approved by Ethics Committee. As far as we know this study represents the first economic evaluation of stroke management in Greece based on RWD, prospectively collected, and the first economic evaluation for the Greek setting which has considered the actual burden for the national payor, with data provided directly by EOPYY.

Our findings are aligned with the international literature,^10,20,21 which clearly indicates that rtPA is a cost-saving or cost-effective treatment option compared with traditional treatment for patients with acute ischemic stroke.²² The broad range of the reported ICERs, from dominant to >70,000$/QALY in different studies can be explained by the fact that available evidence lacks generalizability because of limited data and various assumptions, including utilities used in the models.²²

Our study has also some limitations which have to be considered in the interpretation of the results. The study participants were only 54 (27 thrombolysed), which further indicates the urgency for action – it is obvious that in a total population of more than 750 ischemic strokes in the SUN4P project, someone would expect that more patients would be eligible and receive thrombolysis. However, we must mention that our study was conducted almost in parallel with the COVID-19 pandemic and that could be considered as a potential barrier for the administration of thrombolysis (e.g due to delays).

Another issue is the short duration of the follow-up but the results of our study can be confirmed by other relevant studies according to which most studies conducted for a year or less have a similar marginal difference in both costs and benefits between rtPA and no-rtPA arm.²² Moreover, although this was considered clinically relevant, for administrative issues more feasible and aligned with international literature, it is expected that a longer follow-up could demonstrate additional benefits in terms of QALYs because of the lower disability of the patients thrombolysed early.

Overall, patients that received thrombolysis had a better mRS score at 3 months. There was no difference in mortality in the 3 months’ time horizon, however it is well established that worse mRS scores are associated with an excess risk of death in the long-term.²³ This means that clinical effect of rtPA might be even more evident in the long-term, which can lead to a subsequent further improvement to its economic value. This hypothesis has been confirmed by previous studies in Europe, USA, and China.^20-22

Our analysis has partially considered rehabilitation costs. EOPYY has provided data for inpatient rehabilitation cost for 12 patients and for 8 out of 54 patients for outpatient rehabilitation, possibly because most of the other patients cover rehabilitation privately, due to administrative barriers in the reimbursement of stroke rehabilitation in Greece. A recent study by Vemmos et al. showed that 39% of direct healthcare costs for stroke in Greece were covered by the patients as out-of-pocket expenses and this percentage was even higher for rehabilitation.¹⁵

The perspective of the analysis was that of the national payor (EOPYY) and consequently indirect costs were not considered, although a recent study showed that indirect cost is a major driver of the total economic burden of stroke patients in Greece accounting for about 41% of the total cost.¹⁷

The main strength of our study is the use of RWD from the everyday clinical practice to estimate the cost-effectiveness of rtPA in Greece. To our knowledge, this is the first economic evaluation for the use of rtPA in patients with AIS in the Greek healthcare setting. Given the fact that, the accessibility in rtPA is as low as 6.9% ²⁴ of AIS patients in Greece, the results of the present study can be used to support decision-making and improve AIS management and patient’s accessibility to more advanced treatment. In any case, these findings must be interpreted with caution, considering that it is very likely that the study may have underestimated the potential benefits for rtPA and consequently may have contributed to the increased variability of the ICER, as presented in the acceptability curve.

CONCLUSION

In conclusion, intravenous rtPA represents a dominant or cost-effective strategy for the management of acute ischemic stroke in Greece, however with a significant variation in the PSA. Although this study provides additional evidence to decision-makers and the fact that  may have underestimated the potential benefits of rtPA, more data are required to improve the robustness of the conclusions. The systematic collection of RWD for stroke management at national level could support decision-making at clinical and administrative level, to use available resources with the most efficient way.

Funding

SUN4P project has received funding from the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT), under grant agreement Nb538.

Conflict of interest

Authors report no relationships that could be construed as a conflict of interest.

Acknowledgments

We thank Ms Alexopoulou H, Dr Dimas G., Ms Evaggelou H., Ms Fragkoulaki A., Ms Gamvroula A., Ms Garefou D., Ms Lypiridou M., Dr. Nick Kakaletsis, Ms Karagkiozi E., Ms Karapiperi A., Ms Kouridaki A., Mr Mavraganis G., Dr Myrou A., Ms Samara S., Mr Siopis G., Ms Vemmou A., for their efforts to collect clinical and follow up data of the under-study population. We also thank EOPYY for the provision of the economic data as well as Mr Christos Priftis for the interpretation of the data provided by EOPYY

TABLES

Abbreviations: mRS: Modified Rankin Scale; Data source: Ni et.al 2020 ¹⁹

Abbreviations: rtPA – indicates recombinant tissue-type plasminogen activator; SD – standard deviation; mRS – modified Rankin Scale; NIHSS – National Institute of Health Stroke Scale; BMI – Body Mass Index.

Table 3. Cost-Effectiveness analysis results

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