Survival Benefit and Cost-Effectiveness Analysis of a Future Blood-Based Diagnostic Test to Detect Cerebral Aneurysm Formation: A hypothetical modeling study

doi:10.21203/rs.3.rs-2583583/v1

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Survival Benefit and Cost-Effectiveness Analysis of a Future Blood-Based Diagnostic Test to Detect Cerebral Aneurysm Formation: A hypothetical modeling study

https://doi.org/10.21203/rs.3.rs-2583583/v1

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IMPORTANCE: Cerebral aneurysms are typically diagnosed incidentally or upon rupture.

In this study we aimed to investigate cost-effectiveness of a hypothetical blood-based diagnostic test to detect cerebral aneurysm formation in the US healthcare model.

DESIGN: Markov decision analytic models were created for four different case studies to simulate management of cerebral aneurysm diagnosis within the US healthcare system over 50 years. To assess robustness, we performed sensitivity analyses. Further analysis was performed for different risk factors, patient groups, and aneurysm size.

INTERVENTIONS: Standard care, thrice-annually blood test monitoring, annual blood testing among high-risk groups.

RESULTS: A blood based diagnostic test pathway is more cost effective in patients undergoing watchful-waiting and as a screening tool in patients at a higher-risk of developing an aneurysm when compared to the traditional pathway. Our analysis demonstrated a greater than three-fold reduction in mortality compared to the standard of care (SOC) (15.71% vs 53.10%, respectively). The cost of using a blood test per additional QALY gained was estimated to be $34,515.13 among the watchful-waiting cohort. The threshold price for cost-effectiveness of a blood test was determined to be $3,951. Among patients with one family member with an aneurysm and smokers, we observed a near tenfold reduction in mortality compared to the SOC (0.21% vs 2.35%, and 0.27% vs 3.30 %, respectively) with a threshold at $865.23 and $1,078.48.

CONCLUSIONS: Introduction of a hypothetical blood-based diagnostic test to detect cerebral aneurysm formation would have a life-saving effect within the US healthcare system while remaining cost-effective.

intracranial aneurysm

cost-effectiveness

Markov model

blood test

Cerebral aneurysm (CA) development is a hemodynamic, inflammatory process with high morbidity and mortality.[1] Despite relatively high prevalence in the general population estimated at 2-5%, no blood-based test to detect CA formation, progression, or imminent rupture exists.[2] Current CA management is based on incidental discovery on advanced brain imaging, patient presentation during a rupture event, or interval surveillance based on a known lesion. The gold standard for CA diagnosis is digital subtraction angiography (DSA). However, DSA as a screening tool is disadvantageous due to cost, need for specialized equipment and personnel, and its inherent invasiveness.[3] Given ongoing advances in diagnostic clinical medicine and translational efforts by multiple research groups, we sought to investigate the impact that a hypothetical blood-based diagnostic test to detect CAs would have within the US healthcare system. A blood test can be used for diagnosis, follow-up and mass screening purposes depending on the price point. Cost analyses have been previously conducted to determine the best combination of conventional imaging methods to reduce costs and improve accuracy.[4, 5] However, no studies have measured the cost saving benefits of a hypothetical blood test for the diagnosis of CAs. It is hypothesized that an introduction of a blood-based diagnostic test to detect CA formation into the current practice model would have a life-saving effect within the US healthcare system, while being cost-effective as defined by willingness-to-pay (WTP) threshold of $50,000.

Markov Model Description

We constructed a Markov model from a healthcare payer perspective to examine cost-effectiveness of a hypothetical future blood-based diagnostic test using TreeAge Pro v 2022 (Williamstown, Massachusetts, USA). A Markov Model was chosen to mimic the real-world disease states of patients with known CA. Per national guidelines, costs and QALYs were discounted at a 3% rate.[6] In our model, patients exist in mutually exclusive statesand may transition between states at the end of the cycle. By default, the patients underwent the standard of care (SOC) which consists of three states of patients with known CA: active surveillance, treatment, or rupture. Terminal nodes of the model describe if the patient is alive and if alive what their health state is graded by the modified Rankin Scale (mRS). During active surveillance, patients’ CAs would then be treated, grow, rupture, or remain stable. Following treatment, patients would either be stable and receive further active surveillance or would progress to death. Following rupture, patients would either die or be hospitalized and treated. Patients that are hospitalized following rupture can experience different health states: healthy (mrs 0), mild disability (mRS 1-2), moderate to severe disability (mRS 3-5), or death (mRS 6). Similar pathway was constructed for the scenario model for a blood based diagnostic test. For this hypothetical pathway we assumed tri-annual blood testing. An illustration of the model can be found in Figure 1A. Average patient age was set at 30 years to reflect when CAs become more common as reported by the National Institute of Neurological Disorders and Stroke. More than 88% of all multiple CAs are detected in patients ≥30 years old.[7] Analysis was then performed over 50 year-cycles. Both values for patient age and number of cycles were specifically chosen in lieu of a typical average diagnosis of CA of 55 years. This was done to obtain more comparable results within the high risk-group analysis. We analyzed outcomes based on costs and quality-adjusted life years (QALYs).

Costs and Outcomes

The costs of DSA and other imaging included in the SOC were obtained from the 2022 National Medicare reimbursement rates. In agreement with prior literature, DSA was assumed to be a 6-vessel angiogram (bilateral internal carotid arteries, bilateral external carotid arteries, and bilateral vertebral arteries).[8] In order to allow for easier comparisons, cost of the hypothetical blood-test was assumed to be equivalent to the cost of DSA. The costs of complications, different health states, and vasospasm were obtained from available literature and adjusted for inflation to 2023. All costs and their descriptions are listed in Supplementary Table 1.

Model Parameters

Sensitivity and specificity of the SOC versus the blood test were used as input parameters in the decision model. Face validity of the model parameters was assessed by neurosurgery experts and prompted our inclusion of health states by modified Rankin Scale (mRS). We accounted for patients with no disability (mRS 0), mild disability (mRS 1-2), moderate to severe disability (mRS 3-5), and death (mRS 6). Associated probabilities of these health states were determined through the literature.[9-12] Associated costs were also obtained from the literature.[13-19] A weighted-average cost-probability value was then synthesized based on reported mRS grades for ruptured CA patients and used in the final analysis. We assumed all identified CAs were treated appropriately, because we could not account for individual case-specific management decisions. We assumed that 50% of the watchful waiting population for both model arms would be treated in the first year only. This assumption was made based on literature showing that 50% of patients end up in a watchful waiting state with 30%, 50%, and 90% intention-to-treat rates for radiologists, neurologists, and neurosurgeons, respectively, for small CAs.[20-22] Every year following (cycles 2-50) aneurysms in the watchful waiting population were treated at a rate of 6.7% based on the literature.[9]

Probabilities

All probabilities were found from past cohort studies or meta-analyses. Aubertin et al. reported on the initial probabilities of treatment and stable CAs as a result of watchful waiting.[9] The probability of rupture was reported by Cagnazzo et al. in a large systematic review.[10] The probability of sudden death following rupture was found by Huang and van Gelder in a large meta-analysis studying the probability of death following aneurysmal rupture.[11] The probability of different health states (death, no disability, mild disability, and moderate to severe disability) following treatment for CA rupture was reported in a systematic review by Nieuwkamp et al.[12] The probability of vasospasm was reported in a chapter by Singh et al.[23] The probabilities of complications from DSA were reported by a separate cost-effectiveness analysis by Jethwa et al., 2013.[13] All probabilities and their descriptions can be found in Supplementary Table 1.

Statistical Analysis

Incremental cost-effectiveness ratios (ICER) for our model illustrate the cost per QALY of each arm’s intervention. ICERs were calculated annually for each respective model arm and compared to determine the cost per QALY gained by use of a blood-based diagnostic test. One-way sensitivity analyses were run to determine the price point where a blood-based diagnostic test is dominant (cost saving with superior outcomes) compared to SOC. Further 1-way sensitivity analyses were run to generate a tornado diagram and determine which variables significantly influenced our model’s output.

High-Risk Markov Model

The blood test arm separates CAs by size (small <7mm, medium 7-12mm, Large 13+mm). Since previous studies have shown that CA growth is associated with increased risk of rupture, this model assumes that growing CAs are treated. CA growth rates based on size were obtained from existing literature.

A second Markov Model was created to determine the cost-effectiveness of an annual blood test for CA identification in high-risk groups. The high-risk Markov model (Figure 1B) illustrates the hypothetical screening utility of a blood based diagnostic test to detect CAs. This model is similar to the base model described above, except for annual rates of treatment and rupture for both arms (blood test vs SOC). Additionally, the blood test arm separates CAs by size (small [<7mm], medium [7-12mm], and Large [>13mm]). Previous studies have shown that CA growth is associated with increased risk of rupture, this model assumes that growing CAs are treated. Aneurysm growth rates based on size were obtained from existing literature.[24] Annual SOC cost was $0 based on the assumption that there would be no consistent active surveillance efforts in these populations. As in the previous model, it was assumed that these patients would either be undiscovered, present with rupture, or be discovered incidentally (probabilities and costs are presented in Supplementary Table 1). Hypothetical blood test sensitivity was assumed to be 95% with a specificity of 100%. These values were chosen based on similar test accuracies reported for high-sensitivity qualitative troponin (98%, 100%, respectively)[25] and Cologuard test for stage I colorectal cancer (98.2%, 95%, respectively).[26] Markov model analysis was also performed for three high-risk groups based on annual CA development rate. Annual rates of CA development were obtained from the literature for various high-risk groups.[27, 28] Markov model analyses were performed at annual CA development rates of 4%, 5%, and 9% to correspond with patients with one family member with an CA, patients who smoke, and patients with 2 or more family members with an CA, respectively. Price per test was calculated with a WTP of $50,000 per QALY, which is standard for cost effectiveness analyses.[29] One-way sensitivity analyses, cost-effectiveness analyses, and respective graphical output were performed similar to the base case.

Detection Rate of Aneurysms in High-Risk Populations

To estimate the average number of family members of patients with known aneurysms who could be screened, and who also happen to harbor an aneurysm, we used published demographic data and analysis available from the NIS database. We used the total number of treated aneurysm patients between 2004-2014 = 243,754 patients[30], and the average number of family members in the US (3.13) to arrive at 762,953 family members of which 30,518 (4%) could also harbor an aneurysm.[30] To estimate the number of new aneurysm diagnoses in smokers, we used published data for the prevalence of tobacco use in the US (12.5%) and CA rate in smokers (5%). The number of new aneurysm diagnoses was then calculated as the percent of screened population was varied.

Baseline Demographics and Calculations

For patients with known CA, the average incremental cost-effectiveness ratio (ICER) per year of a blood-based diagnostic test over a 50-year time horizon was $25,764.94. The average ICER per year for SOC over a 50-year time horizon was $24,568.93 (Figure 2). By year 50, the % dead of each cohort was 15.71% vs 53.09% for the blood test vs SOC arm, respectively, greater than a three-fold difference. (Figure 3A). Thus, patients treated with SOC had an absolute 37.38% greater incidence of death compared to patients monitored with the blood test pathway. When compared to SOC, the average cumulative cost of using a blood test per additional QALY gained is $34,515.13.

Sensitivity Derivation and Analysis

Our analysis shows that at a price point less than $3,951, the blood test is dominant (cost saving with better outcomes) compared to the SOC (Supplementary Figure 1 and 2) among watchful waiting patients. The cumulative result of the 1-way sensitivity analyses is illustrated in Supplementary Figure 1. All variables that did not significantly affect the base case were eliminated from this analysis. Variables that most significantly impacted the model include the total number of years (TotalCycles), the sensitivity of the blood test and subsequent rate of rupture (BloodTestSensitivity, pBloodTestRupture), SOC rate of rupture (pSOCRupture), and annual cost of blood-test monitoring (cBloodTestWatch).

High-Risk Population Analysis

For patients with a single family member with an CA (4% risk), the ICER of a blood-based diagnostic test was $6179.64. For patients who smoke (5% risk), the ICER of a blood-based diagnostic test was $6200.80. For patients with two or more family members with an CA (9% risk), the ICER of a blood-based diagnostic test was $6231.51. With a WTP per QALY of $50,000, a blood-based diagnostic test was cost effective at a price point of $865.23, $1,078.48, $1,979.51, for patients with a single family member with an CA, patients who smoke, and patients with two or more family members with CAs, respectively (Supplementary Figure 2B, 2C, and 2D). Survival curves comparing a blood-based diagnostic test to SOC are illustrated in Figure 3. In patients with one family member with an aneurysm, there was a greater than tenfold reduction in mortality compared to the SOC (0.21% vs 2.35%, respectively) (Figure 3B). In tobacco users, we observed a greater than tenfold reduction in mortality compared to the SOC (0.27% vs 3.30 %, respectively) (Figure 3C). In patients with two or more family members with an aneurysm, we observed a greater than tenfold reduction in mortality compared to the SOC (0.48% vs 5.85 %, respectively) (Figure 3D). The cumulative result of the 1-way sensitivity analyses is illustrated in Supplementary Figure 1 and 2. All variables that did not significantly affect the base case were eliminated from this analysis. Variables that most significantly impacted the model include the blood test sensitivity, annual chance of CA, the detection and treatment of CA using the blood test (pBloodTestTreat), and cost of the blood test.

Detection Rate of Aneurysms in High-Risk Populations

For patients with at least a single family member with a known CA (4% risk), we estimated that an average of 22,888 new aneurysms would be detected per year if family members were screened at 75% rate (Supplementary Figure 3A). For patients who smoke (5% risk), we estimated that an average of 31,116 new aneurysms would be detected per year if smokers were screened at 75% rate over a 50-year period (Supplementary Figure 3B).

In this study, we found that a blood based diagnostic test to detect CAs is a cost-effective measure that decreases mortality in watchful waiting patient segments and screening high risk groups. Among watchful waiting patients, a blood test leads to approximately a three-fold reduction in mortality at a cost per QALY of $34,515.13. The creation of a blood test for CA detection opens the door for screening of high-risk groups as a cost-efficient measure. Among all high-risk groups studied, a blood test used to screen high risk groups leads to a five-fold reduction in mortality. Cost-effectiveness was set at <$50,000/ICER to be comparable to that of other standard of care health maintenance interventions like colonoscopies. The model assumed annual blood test surveillance for all patients in these high-risk groups, therefore physician tailored recommendations would likely increase cost-effectiveness. For patients with small CAs that have no evidence of growth, annual surveillance may be unnecessary. In addition, previous mathematical models have shown that screening of the general population for intracranial aneurysms could result in QALY loss rather than gain due to several factors such as over-treatment, procedural complications, and others.[31] Increasing the time interval between surveillance tests would improve cost-effectiveness assuming the unchanged sensitivity, as shown by multiple modeling studies and reviews.[32]

Average annual rupture risk of CAs has been estimated around 1%, however, it is location- and size-dependent.⁴ Studies have also shown that CA have 3 % baseline chance of growth per year subject to increase depending on the comorbidities a patient may have.[33] Aneurysmal rupture is associated with up to 50% mortality rate.² Moreover, ruptured CAs are responsible for 85% of subarachnoid hemorrhage.[34] Of those patients who survive a ruptured CA, about one third will be physically dependent, while another one third will have mild-to-moderate neurologic deficits. Initial survivors of aneurysmal SAH are at increased risk of early mortality with additional 22- 32% patients dead at one year after and long-term follow up, respectively.[35] About 24,375 unruptured and ruptured aneurysms are surgically treated per year in the US.[30] Inpatient management and surgical treatment of ruptured CAs is expensive in terms of hospital resources, length of stay, and actual cost. In 2010, Hoh et al reported that total hospital cost for surgical clipping was estimated to be $80,894 ± 82,103 (max $1,122,476) in contrast to endovascular coiling at $68,648 ± 66,700 (max $1,023,440) for unruptured CAs, and $169,942 ± $130,462 (max $1,059,871) vs $174,296 ± $136,804 (max $1,018,972) for ruptured CAs, respectively.[36] Moreover, they reported inpatient length of hospital stay of 9 ± 10.4 days (min/max 1/182 days) for surgical clipping vs 4.5 ± 7.3 days (min/max 1/149 days) for patients who underwent endovascular coiling for unruptured CAs. For patients with ruptured CAs, inpatient length of hospital stay was twice as long at 19.7 ± 16 days (min/max 1/247 days) for clipping vs three times as long for endovascular coiling at 17.9 ± 14 days (min/max 1/134 days).[36] There is no doubt, that regardless of treatment modality, being able to detect, manage and treat CAs before they rupture would be a life- and cost-saving measure.

For small unruptured CAs, the American Heart Association recommends cross-sectional follow-up with imaging, but frequency, modality, and practices differ among neuroradiologists, neuro-interventionists, and neurosurgeons.[37] Cost-efficiency analysis of very small CAs (<3 mm) suggests that follow-up imaging rather than outright treatment might be more efficacious in terms of both cost and adverse events to patients.[38] Similarly, recent cost-effectiveness analysis in the US, UK, and the Netherlands, suggests that CA surveillance was most cost effective in the 1st and 5th year after initial diagnosis in patients older than 60 years and at increased risk of CA growth.[39]

Several opportunities exist within current CA management protocols and at-risk patient groups where introduction of an inexpensive blood-based diagnostic test would be advantageous. Specifically, targeted surveillance in family members of patients with CAs, patients undergoing watchful waiting, post-treatment in difficult to treat CAs, multiple CAs, or high-risk groups like tobacco-users would fill in the current gaps in the healthcare system.

When developing a diagnostic test, sensitivity or specificity of the test is usually prioritized depending on the target market and the harm of a false positive versus a false negative result. Specificity of the diagnostic test should be prioritized when used with the watchful waiting cohort. As these patients are already diagnosed with an CA, a negative result could be indicative of successful treatment and can be followed up with moderate fidelity imaging to reduce costs. Sensitivity should be prioritized when the test is used in a screening application with family members of those with known CAs or high-risk groups. Reducing false negatives would decrease the likelihood patients would rupture unknowingly following a negative test compared to the harm of obtaining at confirmatory DSA in the case of a false positive, which is more appropriate in a screening application of a diagnostic test.

We estimate that screening in high-risk groups with at least 75% catch rate would result in detection of 22,888 aneurysms in family members of patients with known aneurysms and 31,116 new aneurysm diagnoses per year in smokers (Supplementary Figure 3A and B). Screening rates for populations at risk for different conditions are variable but can range as high as 80% for cholesterol or 76.4% for breast cancer.[40] Efficacy of any screening strategy would hinge heavily on tailoring the target population and sensitivity of the test.

Quality-adjusted life-year (QALY) is a convenient way of quantifying disease burden and is a unit measure equivalent to one year of perfect health.[41] The Institute for Clinical and Economic Review defines new interventions within the US healthcare system as cost-effective if cost per QALY gained is less than $50,000 and as effective for select populations or cases between $50,000-$100,000.[42] Cost-saving measures are defined as having negative cost per QALYs. For the majority of new interventions in any healthcare system, most measures can be cost-effective despite adding cost to the overall system. Our analysis suggests a cost of $34,515.13 per QALY gained within the patient cohort with known CAs in our hypothetical blood test pathway (Supplementary Table 2). Typical QALY values for other interventions are conveniently summarized in Supplementary Table 3. The results shown here are more optimistic when one considers that the price for the blood-based diagnostic test was set in our models at the extreme value of the Medicare reimbursement rate for a typical DSA. More reasonable, patient-friendly, and forward-thinking pricing can result in cost per QALY less than $50,000 for all case studies discussed in this work.

Introduction of a hypothetical blood-based diagnostic test to detect CA formation and monitor patients with known lesions would have a life-saving effect within the US healthcare system while remaining cost-effective as defined by QALY. Those effects were even more pronounced in case studies of family members of patients with CAs, and high-risk groups. Future studies should focus on defining the estimated added cost to the healthcare system should such a blood-test be introduced.

COMPETING INTERESTS

None.

AUTHORS’ CONTRIBUTIONS

AM and KWN conceived the study, interpreted, analyzed data, and drafted the manuscript. RD performed statistical modeling and participated in drafting of the manuscript. AA reviewed the modeling data, results, and participated in drafting the manuscript. RMF, MJL, and BAG participated in designing the study, interpreting data and drafting the manuscript. All authors read and approved the final manuscript.

ACKNOWLEDGMENTS

None.

FOUNDING SOURCES

None.

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No competing interests reported.

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