Cost-Utility of Venovenous Ecmo Associated with Protective Mechanical Ventilation in the Treatment of Patients with Acute Respiratory Distress Syndrome

Introduction

On December 31, 2019, the World Health Organization (OMS) was alerted to different cases of pneumonia in the city of Wuhan, People’s Republic of China. The reported cases were associated with a new strain of coronavirus not yet identified in humans, the SARS-CoV-2 that causes the disease COVID-19. A mass contamination began, which would soon turn into a Pandemic. On January 30, 2020, the WHO declared the outbreak a public health emergency of international concern, that is, an extraordinary event with great public health risk due to the international spread of diseases [1].

A race against time has begun for science to understand the mechanisms of the new virus, with regard to transmissibility, morbidity, pathophysiology, associated risk factors and mortality, in addition to the development and reviews of clinical protocols and therapeutic guidelines for the best possible assistance to hospitalized patients and for disease prevention. A daily work involving all members of the multidisciplinary team.

COVID-19 is an acute respiratory illness, which can progress to an acute respiratory distress syndrome (SDRA) [2]. Second Nishiura, et al. [3], the pathophysiological process of the disease results in destruction of the lung parenchyma, including extensive consolidation and interstitial inflammation, regardless of hypoxemia or respiratory distress, in addition to intravascular coagulopathy. Second Levi e Cate [4], intravascular coagulation is characterized by the diffuse activation of intravascular coagulation, leading to the formation and deposition of fibrin in the microvasculature.

We know that symptoms of COVID-19 can range from mild to severe. The latter are observed or can characterize ARDS, leading the patient to a severe clinical condition, with the need for hospitalization in Intensive Care Units (UTI), and not infrequently, mechanical ventilatory support, as an advanced life support measure, due to the acute respiratory failure that quickly sets in in those who develop the severe form of the disease. In the UTI, therefore, the patient will have the opportunity to be assisted by a specialized multidisciplinary team, increasing their chances of survival given the severity and lethality of the severe form of the disease. The SDRA caused by COVID-19 ends up leading the patient to a condition of Insufficiency Respiratória Aguda (IRA).

The IRA it is mainly characterized by the impairment of gas exchange caused by various clinical conditions, leading the patient to a potentially serious syndrome, so that it is necessary to hospitalize him in an intensive care unit [5]. It is always worth remembering that IRA is a consequence of a direct or indirect injury to the lung, such as SDRA caused by COVID-19.

Patients with Acute Respiratory Failure who require mechanical ventilation (VM) can benefit from UTI beds, which is undoubtedly the most appropriate place for hospitalization, especially due to the imminent need for mechanical ventilatory support, including invasive, due to the disease that impacts especially the respiratory function.

In 2019, before the Pandemic, the number of hospitalizations due to respiratory diseases in Brazil was 1.190.950, and 98.190 deaths [6]. However, in 2020, at the height of the pandemic, the number of hospitalizations was 760.929 and 92.828 deaths [7]. In 2021, the number of hospitalizations was 759.311 and 88.988 deaths [8].

With specific regard to hospitalizations of high complexity regardless of etiology, in 2019 in Brazil, 931.138 patients were admitted, and 27.944 deaths were recorded. In 2020, the numbers were 777.190 hospitalizations, and 26.638 deaths. Already in 2021, the numbers were 821.483 hospitalizations of high complexity and 28.356 deaths [6, 7, 8].

Although UTIs may have human and technological resources to provide advanced life support for patients who develop the severe form of the disease and have progressed to acute respiratory failure, specifically invasive mechanical ventilation (VMI), not all patients are able to benefit of this technology, requiring the need for other technological resources to ensure the survival of patients who do not respond clinically to VMI.

A study by Ranzani, et al. [9] analyzed the data of all patients aged 20 years or older, hospitalized due to COVID-19 in Brazil, in the period between 02/16/2020 and 08/15/2020, recorded in the Influenza Epidemiological Surveillance Information System (SIVEP-Gripe), totaling 254.288 individuals, which found a mortality in ICUs of 59% (47.002 / 79.687), and of the individuals who received mechanical ventilation, 80% (36.046 / 45.205) died.

Regarding the impacts of invasive mechanical ventilation on COVID-19 patients, the misuse of these resources can be considered as triggering lung injury or worsening the patient’s clinical condition, developing iatrogenic events such as barotrauma, as a result of flows, administration of large volumes and inadequate pressures during ventilatory support [10].

In this context, extracorporeal membrane oxygenation (ECMO) veno-venous (VV) has become indicated and used in some UTIs for patients with COVID-19 associated with refractory hypoxemic respiratory failure as an alternative to invasive mechanical ventilation (VMI) [11]. Although the scientific literature may suggest that the use of venovenous ECMO associated with protective VM results in some clinical benefit for patients with COVID-19 refractory to VMI [11], the costs of its use are high when compared to the costs of exclusive protective VM.

Faced with the uncertainties surrounding not only the clinical benefits of using veno-venous ECMO for these patients, but also the costs associated with its use, even though in theory this technology may be effective in reducing preventable deaths, improving the quality of life or reduction of disabilities caused by the severe form of the disease, the Ministry of Health (MS), through the National Commission for the Incorporation of Technologies in the SUS (CONITEC), based on Health Technology Assessment (ATS) studies, analyzes of cost-effectiveness and budgetary impact (CONITEC Recommendation Report nº. 636 of june 2021), evaluated the possibility of incorporating the technology, given the pressure exerted by stakeholders (term used in ATS studies to refer to interested people), including, the media, at a very troubled and critical moment of the pandemic, in which, the news that a famous Brazilian actor and comedian, with a serious condition of compromise the respiratory system due to the complications of COVID-19, was benefiting from a “new” technology that helped to maintain tissue oxygenation, helped to “popularize” the ECMO procedure and causing the Ministry of Health to take an official position regarding the possibility of incorporating and offering the procedure in the SUS.

The Scientific Technical Opinion (PTC) of the CONITEC Recommendation Report synthesized scientific evidence from six studies that evaluated the use of therapy with exclusive VMI and ECMO associated or not with ultra- protective mechanical ventilation. The meta-analysis showed a 33% gain in survival (RR=0,67; 95% IC: 0,57 to 0,79) for patients with Severe Acute Respiratory Syndrome (SRAG) or Severe Acute Respiratory Distress Syndrome (SARA) who received ECMO support in both the fixed and random effects models, but the odds of mortality were not significantly different between the two technologies (Estimate= 0,273; 95%CI: 0,06 to 1,111; I2= 0%, Q of Cochran, p value = 0,57) [12].

Among the six studies included in the systematic review to compose the set of evidence in the aforementioned CONITEC Report, two were published more than ten years ago, one in 1994 and the other in 2009 [13, 14]. Considering the possibility that new scientific evidence has been produced since the publication of this report, it should be considered reasonable and very timely to develop a new systematic review of the literature, in order to recover the most recent scientific evidence available about the clinical benefits of use of ECMO for patients with COVID, and that can be imputed in a mathematical model along the lines of a Markov model, for a new and more recent cost-effectiveness analysis, now at a more favorable moment due to the cooling of the pandemic, when it would be reasonable to believe that the costs related to the acquisition of equipment and inputs will probably be relatively lower.

Conitec members understood that despite the benefits of treatment, there is great difficulty in expanding and covering treatment for all patients who would eventually need therapy. The plenary also considered the moment of the pandemic as not favorable to the incorporation of ECMO, due to the existence of only nine centers belonging to the SUS registered in the Extracorporeal Life Support Organization (ELSO), being the majority in the Southeast region, which would lead to inequality of care, in addition to the impossibility of creating new centers at the time of the Pandemic [12].

ELSO is an international not-for-profit consortium that provides continuing education support, guidelines, original research, publications, and data recording of patients using ECMO to healthcare institutions, researchers, and industry partners.

With regard to economic aspects, the Report estimated that hospitalization costs with mechanical ventilation can reach R$ 78.750,34 to win 0,222±0,024 Quality-Adjusted Life Years (QALY) versus R$ 119.433,62 with ECMO to obtain 0,646±0,066 QALYs, resulting in the incremental difference of R$ 40.683,28/0,424±0,042 QALYs. In the incremental cost- effectiveness ratio, the Incremental Cost-Effectiveness Ratio (RCEI) was R$ 95.951,13 to obtain 1 year of life gained with quality (1 year of life without any disability) [12].

In terms of budgetary impact, the Report suggested that approximately 99% of critically ill patients with COVID-19 would respond clinically satisfactorily with conventional mechanical ventilation (VMI) and the remaining 1% would be refractory and require ECMO rescue therapy. Therefore, for Brazil, the Incremental Budgetary Impact with the ECMO intervention was estimated at R$ 15.703.746,08 in the 1st year and add R$ 80.816.036,09 with a 1% discount rate for the first five years [12].

Based on the scientific evidence presented in the PTC of the Report, the CONITEC Plenary decided that the matter should be made available in Public Consultation with a preliminary recommendation unfavorable to the incorporation of ECMO for the support of patients with severe acute respiratory syndrome due to viral infections, refractory to ventilation conventional mechanics within the SUS [12]. Later, a few months later, the CONITEC Plenary, in its 98th Ordinary Meeting, on June 10, 2021, decided by simple majority to recommend the non-incorporation of Extracorporeal Membrane Oxygenation (ECMO) as a therapy to support patients with respiratory failure severe and refractory in the SUS. To make this decision, the members of the Plenary of CONITEC considered that despite the benefits of the treatment, there is a great difficulty in expanding and covering the treatment for all the patients who might need the therapy, and that it would be unfeasible to create new centers in the country. current context.

The problem of this study is based on the premise that, with the expansion and consolidation of scientific knowledge about the disease, especially with regard to the clinical management of patients with the severe form of the disease and the advanced life support resources used, as well as the restructuring of the economic and industrial complex of health and the supply chain, significantly impacted at the height of the pandemic, contributing to a significant increase in the prices of inputs and medical-assistance equipment in the country and in the world, associated with the cooling of the pandemic in Brazil consequent reduction in demand, in a planned manner and outside a context of chaos in public health, CONITEC’s recommendation could be reconsidered, if new evidence, in view of the current context in which the pandemic is found, in Brazil and in the world, suggest that the use of veno-venous ECMO is cost-effective.

Given the above, the research question is whether the use of ECMO associated with protective mechanical ventilation in adult patients aged 18 years and over with SDRA is cost- effective as a therapeutic intervention to reduce mortality compared to exclusive protective mechanical ventilation.

Method

This is a Health Technology Assessment (HTA) study that can be defined as a process of analysis of the clinical, economic and social consequences of the use of health technologies. To compose the set of scientific evidence about the safety and efficacy of the interventions analyzed in this study, those already produced and presented in CONITEC Report nº 636 of June 2021 were considered, complemented by studies retrieved from a rapid systematic review carried out in October 2021, which consulted Medline databases, via PubMed, Embase, via Rede Cafe and Cochrane, which included randomized studies or with structured case-control pairing, prospective and even retrospective cohorts, in addition to systematic reviews with or without meta-analysis, including network meta-analyses.

Search strategies were guided by the following question structured by the acronym PICOS (population, intervention, comparator, outcome – outcome and type of studies – study):

Results

The proposed analytical model suggests that, in one year, exclusive invasive mechanical ventilation may represent a lower cost (R$ 144.984,36) although it may result in less effectiveness (0,215 QALY) when compared to ECMO + invasive mechanical ventilation, which, although it may represent higher cost, may also represent greater effectiveness (0,295 QALY), as suggested by the analytical model after Roll Back (Figure 4).

Click to enlarge

The cost-utility analysis chart (Figure 5), considering the willingness-to-pay threshold of R$ 120.000,00, shows that the ECMO intervention + protective VMI can offer around 0,295 AVAQ compared to 0,2015 AVAQ offered by the exclusive protective VMI.

Click to enlarge

The incremental cost of ECMO + protective VMI is R$ 12.519.94 for 0,397 effectiveness compared to 0,215 exclusive protective VMI (incremental effectiveness of 0,182).

For each quality-adjusted year of life gained, the amount of R$ 68.902,92 (ICER) would have to be disbursed, as shown in Table 4 below.

Discussion

Debates about the use of ECMO in patients with SDRA occurred on a large scale during the Pandemic period, with pressure exerted by the media and society on the acquisition of technology in the SUS for these cases, given the dissemination of information regarding the benefits of the its use. However, all acquisition of new technologies must follow a rigorous economic analysis in order to assess whether it is cost-effective for the SUS. That is, not only the possible benefits can be considered, but also the cost. In the case of ECMO, whether it is advantageous not only for the population, but also for the SUS, considering its additional cost for QALYs with its use.

The SDRA caused by COVID-19 causes inflammation of the lung parenchyma, making oxygenation difficult and leading the patient to hypoxemia. In this situation, there are two possible alternatives for rescue/treatment therapies, exclusive invasive mechanical ventilation and extracorporeal membrane oxygenation associated with mechanical ventilation. One of the criteria for ECMO contraindication is the risk of bleeding due to heparinization. Therefore, the choice of treatment depends on several clinical factors that need to be carefully evaluated by the medical team.

The effectiveness of ECMO in the treatment of patients with COVID-19 has been much questioned by health managers. Studies such as Peek’s, 2009, point out that the mortality of patients on MV in less than 6 months or before hospital discharge was 45%, while on ECMO it was 37%, suggesting a survival rate on ECMO of 63%. Most deaths of patients on MV were due to respiratory failure, while ECMO was due to multiple organ failure, in addition to leaving patients longer in intensive care. This study was included in CONITEC Report nº 636 of 2021, carried out precisely to answer health managers whether ECMO is cost-effective in the treatment of patients with SDRA.

The report pointed out that the mortality rate in patients with COVID-19 was 87,5% in patients with ECMO and 69,2% in patients with conventional therapy. The pooled odds of mortality on ECMO compared to conventional therapy were not significantly different (Estimate=0,273, 95%IC, 0,06 to 1,111; I2=0%, Cochran’s Q, p-value=0,57). Furthermore, due to the fact that the prices of equipment and inputs were higher during the Pandemic, and that there were few ECMO treatment centers in Brazil, it was not an opportune moment to include the technology in the SUS.

In the literature review of this dissertation, the 11

studies found evaluated mortality in patients with ARDS due to COVID-19 treated with VM and ECMO, but did not evaluate the costs and benefits of these technologies. Therefore, these data were extracted from the CONITEC report and the study by Conde, et al. [16].

According to the calculated variables in Table 4, the probability of a patient dying on MV was 0,408 while on ECMO it was 0,35 (DOMECQ, 2021). One of the unwanted effects of both technologies that may occur is sepsis, after all, both are composed of invasive devices, one for the pulmonary system (VM) and the other for the circulatory system (ECMO). In the study by Contrin, et al. [18], which evaluated the quality of life of patients who survived sepsis, the mortality rate was higher in patients with sepsis who were discharged from the hospital within one year, compared to those who were critically ill, however, no sepsis. A significantly higher prevalence of problems was also observed in older patients over 60 years of age with sepsis. And in this dissertation, the risks of developing sepsis and dying from sepsis in both technologies were analyzed.

According to the calculated variables in Table 4, the probability of a patient having sepsis on MV was 0,821 while on ECMO it was 0,448 [17]. Regarding quality of life, the report pointed to a trend in favor of ECMO. In the study by Nandasena [19], patients of advanced age, those with comorbidities, those admitted to the UTI, those who stayed in the UTI for a long time and those who were mechanically ventilated had a higher risk of poor quality of life after COVID-19.

Health professionals involved in this context need to be aware of economic evaluation methods and health technologies as a management tool for these technologies, so that it is possible to identify, among the available alternatives, the treatment that presents the best cost-effectiveness.

In this study, it was possible to demonstrate that both exclusive protective mechanical ventilation and ECMO associated with protective mechanical ventilation can be cost-effective alternatives for the treatment of SDRA, depending on the willingness to pay.

The results showed that there was no absolute dominance of one technology over the other, since, based on the estimated costs in the base case scenarios, as well as the probabilities of the clinical effects arising from the interventions and transition in the proposed analytical model, the results of the cost-utility analysis (Figure 5) showed that both exclusive VM and ECMO associated with protective VM could be cost-effective. From this perspective, considering the economic and financial condition of the SUS manager, a willingness-to-pay threshold is considered as a criterion for deciding on the best alternative. In this study, the amount of R$ 120.000,00 was considered as the willingness- to-pay threshold.

The analytical model proposed for the analysis of scenarios in the base case suggested that ECMO associated with protective VM in the SUS may result in an additional cost increase per AVAQ (effectiveness unit) of R$ 12.519,94 (Table 5). Since the willingness to pay threshold was approximately R$ 120,000.00, deciding to incorporate ECMO instead of exclusive VMI is supported by the argument that the greater the willingness to pay, the greater the effectiveness of ECMO. According to the acceptability curve chart (Figure 9), up to a limit of R$ 105,000.00 exclusive VMI is the most cost-effective alternative. And as the willingness to pay increases, that is, above R$ 105.000,00, ECMO associated with protective VM becomes the alternative most likely to be more cost-effective, considering a time horizon of 2 months with two Markov cycles lasting 30 days.

The model looks robust. Confidence in their results was attested by the deterministic multivariate sensitivity analysis and by the probabilistic sensitivity analysis, using 10.000 second-order Monte Carlo simulations, based on the acceptability curve and the incremental cost-effectiveness Scatterplot, which took into account consideration of the uncertainties of the values (parameters), demonstrating dispersion of both cost and effectiveness for each of the evaluated interventions.

Limitations

The proposed model was not concerned with knowing what happens to the patient after he is discharged, that is, the health status associated with this condition was also considered as an absorber, as well as death, which could impact the results found.

Conclusion

The analytical model suggested that ECMO associated with protective mechanical ventilation is more likely to be the most cost-effective alternative for treating patients with SDRA due to COVID-19 in the SUS, depending on willingness to pay. That is, if the manager is willing to pay for these patients to gain one more year of quality-adjusted life, an amount of R$ 68.902,92 (sixty-eight thousand, nine hundred and two reais and ninety-two cents), ECMO becomes more cost-effective, increasing the advantage over exclusive protective mechanical ventilation in terms of the probability of being cost-effective, the greater the willingness to pay, from R$ 120.000,00 (one hundred and twenty thousand reais).