FormalPara Key Points

We estimated the cost-effectiveness and budget impact of using this device versus standard practices to reduce the risk of perioperative bleeding during and after coronary artery bypass grafting from the US healthcare sector perspective.

This model found the hemoadsorption device to provide better clinical and economic outcomes compared with the standard of care in patients who required surgery within 2 days of ticagrelor discontinuation.

Given the increasing use of ticagrelor in patients with acute coronary syndrome, incorporating this novel device may represent an important part of any bundle to save costs and reduce harm.

1 Introduction

Over one million patients are hospitalized annually with an acute coronary syndrome (ACS) in the US [1]. Revascularization represents the mainstay treatment with approximately 10% of patients requiring coronary artery bypass grafting (CABG) surgery. However, the foundational role of antithrombotic therapy in ACS management can complicate the management of patients needing surgical revascularization due to the excess risk for perioperative bleeding that is associated with increased mortality and prolonged intensive care unit and overall hospital stays [2, 3].

Ticagrelor is an oral reversibly binding P2Y12 receptor antagonist indicated to reduce the risk of atherothrombotic events in adult patients with ACS or history of myocardial infarction [4]. The American College of Cardiology/American Heart Association guidelines recommend discontinuing ticagrelor at least 3 days prior to high-risk surgeries, including cardiac surgery, to allow for adequate washout; discontinuation of the P2Y12 inhibitors clopidogrel and prasugrel is recommended to be at least 5–7 days [5]. Patients who cannot complete the recommended washout are significantly more likely to experience a major perioperative bleed [6]. Available data suggest that a significant portion of cardiac surgery patients will end up having their indicated surgery before the recommended washout period is complete, with up to 20% operated within 2 days of their last ticagrelor dose [6].

Perioperative bleeding is currently managed with supportive measures, primarily the transfusion of blood products, such as red blood cells, platelets, or coagulation factors. The actual effectiveness of transfusions remains unclear, and several reports have shown them to be associated increased costs, morbidity, and mortality [7,8,9]. A sorbent-filled hemoperfusion cartridge that efficiently removes ticagrelor via hemoadsorption (DrugSorb-ATR system, CytoSorbents Corporation, Princeton, NJ, USA) presents a novel intervention to reduce the risk of perioperative bleeding by active intraoperative drug removal, thereby reducing the circulating drug levels in the patient’s blood. During cardiac surgery, the device is integrated as a parallel bypass circuit to the main flow circuit of any standard cardiopulmonary bypass setup. The hemoadsorption cartridge preferentially removes small hydrophobic molecules (up to 60 kDa) and does not adsorb larger molecules such as heparin. Benchtop data on the antithrombotic drug removal performance of this hemoadsorption device and early clinical experiences detailing the effect on perioperative bleeding in Europe, Asia, and the Middle East have already been published [10,11,12,13,14]. The device is currently being evaluated for the ability to reduce perioperative bleeding by removal of ticagrelor during cardiothoracic surgery in the investigational device exemption, double-blind, randomized, controlled “Safe and Timely Antithrombotic Removal-Ticagrelor (STAR-T)” trial (Registered Trial Number: NCT04976530) [15].

A previous economic evaluation completed from the UK’s National Health Service single-payer system presented favorable results for this technology compared with the standard of care [16]. However, the cost-effectiveness of the technology in the UK is likely ungeneralizable to the US healthcare system. Our study objective was to analyze the cost-effectiveness and budget impact of using this device to reduce the risk of moderate to massive perioperative bleeding in patients on ticagrelor undergoing cardiac surgery prior to completing the recommended washout from the US healthcare sector perspective.

2 Methods

2.1 Study Design

This study analyzed the cost-effectiveness of extracorporeal hemoadsorption in reducing moderate to massive bleeds, as defined by the Universal Definition of Perioperative Bleeding in Cardiac Surgery (UDPB) grading system in patients operated within 2 days of ticagrelor discontinuation. We examined two cohorts of patients based on their washout period and combined them in a third all-inclusive cohort. A Markov model was utilized to estimate the cost-effectiveness and budget impact of using this novel device compared with the current standard of care from the US healthcare sector perspective. Each cohort was modeled in daily cycles over a 1-year time horizon; therefore, neither clinical nor economic results were discounted.

Cost-effectiveness results was analyzed at a willingness-to-pay (WTP) threshold of $100,000 (USD) per quality-adjusted-life year (QALY). Model results included incremental cost-effectiveness ratios (ICERs) and net monetary benefits (NMBs). The budget impact was estimated by the difference in per-member-per-month spending. The overall cost difference for the health plan was determined by multiplying the 1-year cost difference per patient by the number of patients to have CABG with the use of the hemoadsorption device, as opposed to the standard of care. The cost difference per-member-per-month was estimated by dividing the total cost difference over the health plan population by 12 months. All data analyzed during this study were from published literature or publicly available datasets.

2.2 Study Cohorts

There were three patient cohorts of patients aged 18 years and older in the USA examined in this economic model: first, patients undergoing CABG within the first day of ticagrelor discontinuation (i.e., less than 1 day of washout); second, patients undergoing surgery between the first and second days of ticagrelor discontinuation (i.e., 1–2 days of washout); third, a combined cohort of all patients evenly split across the first two cohorts. The combined cohort was used to estimate the cost-effectiveness and budget impact for all prospective patients undergoing cardiac surgery with 2 days or less of ticagrelor washout. For the combined cohort, we assumed the target population is evenly split across the washout cohorts.

2.3 Model Structure

The same Markov model structure was used for all cohorts. The model consisted of eight mutually exclusive health states (Fig. 1). The modeled health states are listed in Appendix Table 1 and include CABG with no bleed or mild bleed, CABG with moderate to massive bleed, facility, home, home post-moderate to massive bleed, hospital readmission, and death. Patients in the health states following a moderate to massive bleed faced higher costs, higher risk of death, and lower health state utilities due to the bleed. Those in post-acute care facilities and with readmissions had higher costs and lower health state utility.

Fig. 1
figure 1

A 1-year Markov model following patients from coronary artery bypass graft surgery (CABG) and postoperative care with and without the use of the DrugSorb-ATR device to reduce risk of moderate-massive bleeds

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At the start of the models, patients underwent CABG either with standard care or with the use of the hemoadsorption device. Individuals followed different pathways based on moderate to massive bleed status. Patients stayed in the hospital for at least 4 days after surgery. Following the inpatient stay, individuals either died or were discharged home or to a post-acute care facility. Patients at a post-acute care facility could then transition to home. There were different home and facility health states dependent upon whether a moderate to massive bleed occurred (e.g., “home” versus “home post-moderate to massive bleed”). Patients could be readmitted from either home or a facility but were restricted to only one readmission during the 1-year time horizon. Individuals could transition to death from any health state.

2.4 Probabilities

Transition probabilities between health states were derived from published clinical literature and expert opinion (Table 1). Patients who received the hemoadsorption device were assumed to have a lower probability of experiencing a moderate to massive bleed compared with standard-of-care practices. Moderate to massive bleeds in the model were associated with higher mortality, longer total hospital stays, longer stays in the intensive care unit, and an increased utilization of blood products to manage bleeding. Patients who experienced moderate to massive bleeding were more likely to be discharged to a facility, have a readmission, or transition to death. Discharge, readmission, and mortality rates were converted to daily probabilities, given the 1-day model cycles.

Table 1 Model parameters
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The rate of moderate to massive bleeds under the standard of care was derived from the European Multicenter Registry on Coronary Artery Bypass Grafting [6]. The risk of bleed differed by length of the washout period: patients with less than 1 day of washout had a 71% probability and patients with 1–2 days of washout had a 60% probability of experiencing a moderate to massive bleed.

On the basis of published studies in Europe where the same technology was used in various types of cardiac surgery, we conservatively estimated that the use of this novel device would generate a 40% reduction in the risk of moderate to massive bleeds for each surgical cohort [12, 17].

2.5 Costs

Patients accrued costs on the basis of which health state they occupied. Costs were estimated by the healthcare resource utilization due to health states, treatment arm, and cohort (Table 1). We selected an illustrative cost of $5000 per single-use unit for the hemoadsorption device. Each patient in the intervention arm utilized one device. Costs generated during the 1-year time horizon were totaled and used to calculate the ICER, NMB, and budget impact. Costs were applied daily during each cycle. All costs were inflated to 2021 US dollars, when necessary.

2.6 Health Utilities

Health utility weights were derived from published literature and assigned to a health state in the model. The daily accumulated utility weights were added at the end of the time horizon to produce the resulting average QALYs per patient by cohort and treatment arm. Utility weights were determined on the basis of the presence of moderate to massive bleed, location of treatment, and discharge location (Table 1). Baseline post-CABG surgery utility reflected a postsurgical health state without the presence of a bleed. Health utility was estimated to be higher for individuals who were discharged home rather than to post-acute care facilities and higher as individuals become further removed from surgery. Individuals without bleeds and discharged home have the greatest health utility. Disutilities were applied for individuals who had a moderate to massive bleed from the time following surgery through discharge and for those with readmissions. There was no health state utility associated with death. Results were not discounted due to the 1-year time horizon.

2.7 Sensitivity Analyses

Uncertainty was estimated through deterministic and probabilistic sensitivity analyses for the cohorts of patients with less than 1 day washout and 1–2 days washout and a threshold analysis for the combined cohort. The sensitivity analyses were conducted using the parameter values’ standard error and designated distribution. If the standard error was not reported, it was assumed to be 10% of the baseline value. Gamma distributions were used for positive parameter values (> 0.0) with no upper bound (e.g., costs), and beta distributions were used for parameter values ranging from 0.0 to 1.0 (e.g., probabilities and utilities).

The one-way sensitivity analyses were conducted by varying the parameter values, one at a time, to upper and lower bounds. The results of the one-way sensitivity analysis are presented as a tornado diagram. We conducted a threshold analysis to explore where the assumed price of the hemoadsorption device would have to fall to exceed the WTP threshold. The probabilistic sensitivity analyses were estimated by varying the parameter values simultaneously on the basis of their designated distribution over 10,000 Monte Carlo simulations. Probabilistic sensitivity analyses results are presented as an ICER scatterplot and cost-effectiveness acceptability curve.

2.8 Assumptions

This model relied upon several assumptions. The model quantified the reduction in moderate to massive bleeds, as classified by the UDPB system in parallel to the design of the STAR-T trial [14]. The model assumed that the hemoadsorption device evenly reduces the occurrence of moderate to massive bleeds by 40% based on a small cohort study of patients undergoing urgent cardiac surgery conducted in Europe, which can be updated following the completion of STAR-T [14]. The hemoadsorption device is not currently available on the US market; thus, the $5000 price was illustrative and used for modeling purposes. For the budget impact analysis, it was assumed that patients with less than 1 day of washout and patients with 1–2 days of washout were evenly split and that 25% of all CABG patients were on ticagrelor prior to surgery.

3 Results

3.1 Cost-Effectiveness Analyses

The use of the extracorporeal hemadsorption device was a dominant strategy compared with the standard of care for CABG patients in all three cohorts as model results consistently reported increased QALYs at reduced costs (Table 2). In the cohort of CABG patients with less than 1 day of washout, the device arm gained 0.017 QALYs at a cost savings of $1748, equating to $3434 in NMB. In the cohort of patients with 1–2 days of washout, the device arm gained 0.014 QALYs at a cost savings of $151, equating to $1575 in NMB. In the combined cohort, use of the hemoadsorption device gained 0.016 QALYs at a cost savings of $950, equating to $2505 in NMB.

Table 2 Base-case cost-effectiveness and budget impact results
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3.2 Budget Impact Analysis

The budget impact of using the hemoadsorption device for all eligible CABG procedures was calculated assuming a one-million-member health plan. The rate of CABG surgery in 1 year was estimated to be 79 out of 100,000 patients, with an assumed 25% on ticagrelor prior to surgery [18]. This resulted in 198 total CABG patients during the 1-year time horizon. The use of the hemoadsorption device provided an overall cost savings to the healthcare system over a 1-year budget when used to remove ticagrelor during CABG surgeries. The per-member-per-month cost savings associated with device use was estimated to be $0.02 for a one-million-member health plan.

3.3 Sensitivity Analyses

The results of the deterministic sensitivity analysis in both cohorts showed that the use of the hemoadsorption device during CABG remained cost-effective across each varied parameter at a $100,000 per QALY WTP threshold (Fig. 2). The most sensitive parameters were device efficacy, the rate of moderate to massive bleeding with standard-of-care conditions, and the length of hospital stay following surgery with a moderate to massive bleed.

Fig. 2
figure 2

Univariate sensitivity analyses, tornado diagram. Results: patients with < 1 day of washout (a); patients with 1–2 days of washout (b)

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We conducted threshold analyses using the combined cohort of all patients with 2 or fewer days of washout to explore potential prices. Use of the hemoadsorption device was dominant over the standard of care at all prices below $5950 and cost-effective at a WTP threshold of $100,000/QALY up to $7505.

On the basis of the probabilistic sensitivity analyses, use of the device had a 91% likelihood of being dominant for patients with less than 1 day of washout, and a 99% likelihood of being cost-effective at a $100,000/QALY threshold (Fig. 3). For patients with 1–2 days of washout, use of the device had a 54% likelihood of being dominant and a 90% likelihood of being cost-effective at a $100,000/QALY threshold. Use of the hemoadsorption device had a greater than 50% likelihood to be cost-effective for both patient cohorts at any WTP threshold (Fig. 4).

Fig. 3
figure 3

Probabilistic sensitivity analyses, scatterplots. Results: patients with < 1 day of washout (a); patients with 1–2 days of washout (b)

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Fig. 4
figure 4

Probabilistic sensitivity analyses, cost-effectiveness acceptability curves. Results: patients with < 1 day of washout (a); patients with 1–2 days of washout (b)

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4 Discussion

Our cost-effectiveness analysis of this novel hemoadsorption device for CABG procedures found consistent cost savings and QALY gains across all ticagrelor washout periods. These findings were driven by the simple aversion of preventable harms in patients on ticagrelor undergoing surgery by avoiding moderate to massive bleeding. These serious bleeds lead to higher rates of blood product transfusions, longer hospital stays, increased likelihood of discharge to post-acute facilities, and higher risk of death. On the basis of the clinical indications for ticagrelor use (i.e., administered in patients presenting with ACS or those with history of prior myocardial infarction), it is anticipated that CABG would be the most frequent, but not the only, type of cardiac operation such patients may require. Given the pace with which facilities could obtain a return on investment for introducing this hemoadsorption device—less than 1 year—this technology could be installed into CABG bundles with little financial resistance.

The use of the hemoadsorption device provides specific savings to multiple stakeholders in the US healthcare sector, particularly for the hospital. Model results show that patients on ticagrelor treated with extracorporeal hemoadsorption during CABG had approximately one fewer inpatient day. Hospital providers typically deliver CABG for a bundled payment, so the sooner patients can be safely discharged, the more profitable the procedure becomes. In the USA, the average hospital expense per inpatient day for all cardiovascular causes is $3820 [19]. Thus, a hospital that performs 250 CABGs each year, would see a cost savings of nearly $1 million from shorter postoperative stays with the routine use of this device alone.

Many facilities already operate on slim profit margins. At the facility level, institutions that deliver the most CABG procedures would generate the largest decline in inpatient days and reap the greatest cost benefits from using this device. Intraoperative ticagrelor removal with extracorporeal hemoadsorption reduces adverse outcomes and associated expenses, thereby growing profit margins. Furthermore, there is added value for these complex bleeds because some result in 30-day readmissions. These readmissions are costly and not usually reimbursed for postsurgical patients. Thirty-day readmissions can also lead to penalties from Medicare if they occur in high frequencies, further increasing the device’s value proposition. Readmissions were not modeled for these added cost considerations; thus, the NMBs may represent lower bounds on potential value gained.

Payers too can realize substantial benefits by working with facilities to cover the cost of extracorporeal hemoadsorption. This technology would improve financial bandwidth for payers by reducing their liability to cover longer hospital stays and adverse events (e.g., acute myocardial infarction, stroke). By saving money as estimated in the budget impact analysis, payers could potentially reduce the cost of reimbursement for CABG and other urgent cardiac surgeries in the long term. Innovative payment models, such as cost-sharing with providers to deploy this novel device in a CABG bundle, could help providers overcome the initial upfront investment in the acquisition cost of the device. This is especially relevant for providers and payers with a patient population with high incidence of coronary artery disease and therefore a predictable need for CABG. Savings to payers can also be passed through to beneficiaries by reducing premiums or adding the coverage of other expensive medically necessary services (e.g., treatments for rare disease, curative therapies).

The presurgical period is a costly, high-risk time for patients as they wait for ticagrelor to wash out. During washout, patients are at increased risk for ischemic events as the protective antithrombotic qualities of ticagrelor wear off, all while incurring the added daily costs of remaining in the hospital, frequently in the intensive care unit, until surgery is performed. While our model only examined costs and resource utilization during and after CABG, use of this device also has the potential to expedite any patient on ticagrelor to surgery. Accelerating the washout period can eliminate the need for costly preoperative stays while reducing the risk of acute myocardial infarction or stroke.

Beyond the cost savings provided to the healthcare system, patients are provided meaningful clinical and utility benefits. Avoiding moderate to massive perioperative bleeds increases postsurgical survival, the likelihood of being discharged to home, and quality of life. In all, the evidence suggests that intraoperative extracorporeal hemoadsorption during CABG yields clinical and economic benefits to patients and the healthcare system, providing a win–win option for healthcare providers.

4.1 Limitations

There are several limitations of the model. The percentage reduction in moderate to massive bleedings by the hemoadsorption device when compared with standard of care is estimated on the basis of several nonrandomized clinical studies and might result in a conservative estimate of the device’s efficacy. An updated estimate can be derived upon completion of the STAR-T trial, at which time model inputs can be updated accordingly. Also, costs associated with bleeds were derived from published literature, which at times differed in bleed definitions from the UDPB classification. The analysis focused on CABG procedures, although intraoperative hemoadsorption can be utilized in all types of cardiac surgery with cardiopulmonary bypass, which, given the incidence of chronic ticagrelor use, likely leads to a conservative budget impact result. Similarly, an assumption was used that 25% of CABG patients had previous ticagrelor usage. The budget impact varies depending on the population size; however, the hemoadsorption device would represent a budget savings. The $5000 price of the device was illustrative and might not be generalizable to all health systems. Patients were limited to only one readmission following surgery and discharge. Given the relationship between bleeding severity and readmissions, this restriction likely results in a lower-bound base-case estimate for the hemoadsorption device. Finally, the budget impact utilized an even split between patients with less than 1 day of washout and patients with 1–2 days of washout, which might not reflect clinical practice. Nevertheless, use of the device saves costs across cohorts, thus yielding a negative budget impact regardless of the patient split.

The univariate sensitivity analysis and the probabilistic sensitivity analyses highlight the robustness of the results despite the noted limitations. Furthermore, the results are consistent with the cost-effectiveness analysis conducted in the UK [14]. The previous analysis found that the use of the device was dominant among emergent and urgent cardiac surgery patients and had a high probability of generating cost savings.

5 Conclusion

The use of intraoperative extracorporeal hemoadsorption is a dominant strategy compared with standard of care for CABG patients on ticagrelor with less than 2 days of washout. Thus, this novel device can be adopted for cardiac surgery patients on ticagrelor to provide better clinical outcomes at lower healthcare costs. Use of this device may be applicable to other surgery cohorts as well, the cost-effectiveness of which should be examined in future research.