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Introduction

Atrial fibrillation (AF), the most common persistent cardiac arrhythmia, has been estimated to affect approximately 350,000 Canadians [1]. AF is associated with an increased risk of morbidities and mortality [2-4]. Amongst its devastating complications is stroke. In the Framingham’s study [4], AF has been shown to increase the risk of stroke fivefold and mortality 1.5- to 1.9-fold after adjustment for related pre-existing cardiovascular conditions. This risk remains high even in AF patients at low stroke risk (CHADS₂ = 0). In this group, the annual risk of stroke has been estimated to be 0.49% and death to be 3.87% [5,6]. Symptoms of AF can also lead to temporary or permanent physical or mental disability which affects patients’ well-being and quality of life [7] and often results in increased health care resource use and costs [2,8,9].

Cognitive decline (CD) may be a consequence to AF. Among the proposed mechanisms behind the development of CD in AF patients are stroke [10-12], chronic cerebral hypoperfusion [11-14], silent cerebral ischemia due to microembolization [15,16] as well as traditional cardiovascular risk factors [11,17]. However, few longitudinal studies have shown the association between AF and dementia to be independent of stroke. Marzona, et al. [18], in a group of 31,546 AF patients, have found a 14% increased risk of cognitive decline and a 30% increased risk of new dementia, in presence or absence of stroke. Similarly, De Brujin et al. [17] reported a 34% increased risk of dementia in persistent AF patients (N = 6,514), even when censoring for stroke. This association between AF and CD or dementia has clinical implications where the efficacy of the treatment for AF can have direct effects on the risk of CD and dementia. In a study by Jacobs and colleagues, greater proportion of time outside the therapeutic range with vitamin K antagonist was associated with an increased risk of dementia [19]. Further, patients prescribed direct oral anticoagulants (DOACs) had a lower risk of cerebral ischemic events and new-onset dementia compared to warfarin [20].

DOACs (epixaban, dabigatran, apixaban, rivaroxaban) are currently used for the treatment of patients with NVAF at moderate or high risk of stroke [21]. For patients at low risk of stroke, the therapeutic guidelines recommend DOACs or ASA depending on the presence of additional risk factors and no antithrombotic therapy for those at the lowest risk in this category [21]. For this last group of patients with a CHADS₂ score of 0, the benefits of expanding anticoagulation with DOACs versus ASA or no treatment is poorly understood. It is hypothesized that a therapy with DOACs, despite potentially increasing the risk of bleeding, will help to prevent stroke and reduce silent cerebral ischemia and hence, the incidence of cognitive impairment, which is a known precursor of dementia.

The efficacy of rivaroxaban in lowering stroke and cognitive decline in the low-risk patients (CHADS₂ = 0) are being investigated in the “Brain-AF” trial, “Blinded Randomized trial of Anticoagulation to prevent Ischemic stroke and Neurocognitive impairment in Atrial Fibrillation” (NCT02387229). If the clinical outcomes of the “Brain-AF” trial are proven positives, then investigating the cost-effectiveness of adding anticoagulation to the treatment regimen of low stroke risk patients becomes important to inform decision-making. Therefore, the aim of the present study was to estimate the cost-effectiveness of rivaroxaban compared to ASA in a hypothetical cohort of non-valvular AF patients with low risk of stroke.

Methods

Type of Economic Analysis

This was a cost-utility analysis with cost-effectiveness assessed by the incremental cost per quality-adjusted life year (QALY) gained. The analysis adopted a single payer perspective relating to the Quebec Ministry of Health, and only direct medical costs were considered.

Target Population

The target population was a hypothetical cohort of patients, aged 30 – 62 years, with NVAF and vascular disease at low risk of stroke (CHADS₂ = 0) not requiring anticoagulation. Vascular disease was defined as coronary artery disease or peripheral artery disease.

Decision Model

A Markov cohort model was developed to conduct the economic analysis (Figure 1). Two strategies were considered: a strategy where patients received rivaroxaban 15 mg and placebo daily, and a second where patients were treated with ASA 100 mg and placebo daily.

The model simulated NVAF progression and the probabilities of patients experiencing health events depending on the treatment received. The outcomes were: systemic embolism, ischemic stroke (transient, minor, moderate, severe, fatal), intracranial hemorrhage (minor, major, fatal), myocardial infarction, other major bleed, clinically relevant minor bleed, cognitive decline (mild, moderate, severe, fatal), vascular death and non-vascular death. The Markov model allowed patients to move exclusively to one of the health states or die during each cycle. We assumed that patients could experience up to two events during the follow-up period. The health states were either permanent, indicating that patients remain in them until death, or transient, suggesting that patients only spend some time in that health state before returning to the NVAF well state.

At the end of each cycle, according to transition probabilities, the simulated patients could either stay healthy with NVAF, experience an event or die. Transition probabilities were built into the model and applied to the cohort during each cycle to calculate how the patients would be distributed between the health states at the end of the cycle. An event rate adjustment was incorporated in the model to account for an increased risk of recurrence after a first event of ischemic stroke (2.20), myocardial infarction (2.04) and bleeding (2.66) based on long-term prognosis and survival data from epidemiological studies [22-24]. The model assumed total compliance with the medication regimen and no change in the assigned medication for the whole follow-up period.

Time Horizon

The base-case analysis adopted a lifetime horizon (60 years) with a cycle length of three months. Sensitivity analyses were conducted with horizons of 10, 20 and 40 years and cycle lengths of 1 and 6 months. Future events were discounted at a rate of 1.5% per annum with sensitivity analysis using discounting rates of 0% and 3%.

Clinical Events and Mortality

For ASA, the rates of clinical event were obtained from a sub-analysis [25] of the “AVERROES” clinical trial [26] (Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K treatment). In this sub-analysis, Lip et al. [25] evaluated the event rates in a group of patients at low risk of stroke (38.2% of patients with CHADS₂ = 0 -1 or CHADS₂-VASC = 1 or higher) who were on either ASA or apixaban. The probabilities of transitioning from “NVAF well” to an event were based on an economic analysis [27] which used data from the “AVERROES” trial (Table 1).

For rivaroxaban, our literature search did not identify publications in similar patient population and with similar daily dosage regimen. Therefore, the rates of clinical events were obtained from the ROCKET-AF trial [28] (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). Given major differences between the ROCKET-AF trial and our model, mainly in terms of higher dosage regimen (20 mg vs 15 mg), older patient population (median age 73 vs 46) and higher stroke risk (average CHADS₂ = 3.5 vs CHADS₂ = 0), the event rates were reduced by an arbitrary 35% as an adjustment for those differences, with sensitivity analyses using adjustment rates of ± 25%. The probabilities of transitioning from “NVAF well” to an event were based on rates reported in an economic analysis comparing rivaroxaban to warfarin [29] and using the ROCKET-AF data (Table 1).

The rates of dementia were obtained from Friberg [30] who assessed the incidence of new dementia in patients with AF taking OACs compared to those not on OACs. The probabilities of new dementia observed in each group of patients were adjusted using the reported hazard ratio of dementia in the stroke low risk group (CHADS₂-VASC = 0 – 1) [30]. Transition probabilities, based on Spackman, et al. [31], were applied to account for changes in the severity of disease (Table 1).

Utility Values

Utility values were sourced from published studies in similar population [32,33] and applied whenever a patient experienced an event in a given cycle (Table 2). Given that patients had no history of stroke, a starting utility value of 0.81 was used, derived from the utility value for AF [32]. The analysis assumed no difference in utility values between the treatments. The utility values were assumed to apply from the cycle in which the event occurred until the end of the follow-up period or death. Upper and lower utility values (95% CI) (Table 2) were also obtained from the literature and applied in the sensitivity analyses [25,27,32-36].

Costs

One-time event and long-term costs of medical care and hospitalization were derived from the literature [37-40] and were based on the Ontario Case Costing Initiative, the Ontario Drug Benefit Formulary and the Canadian Institute for Health Information. The cost of medications was obtained from the “Régie de l’Assurance Maladie du Québec” price list [41] with inclusion of an $8.50 prescription fee and an 8% pharmacist’s markup (Table 3). The cost of drugs assumed daily use and no discontinuation. All costs were updated to 2020 Canadian dollars by using the Bank of Canada inflation calculator which is based on the Consumer Price Index (CPI) [42].

Analyses

The incremental cost-effectiveness ratio (ICER) was computed to determine the lifetime costs/QALYs of rivaroxaban 15 mg daily versus ASA 100 mg daily, at a Canadian willingness to pay of $50K (a commonly used threshold value) per added QALY.

Deterministic sensitivity analyses were conducted to examine the uncertainty in the model parameters. This was done by varying the base case value of one parameter at a time by a given amount and examining the impact that this change has on the model’s results. The base case value of clinical events and their costs were varied by ± 25%, the cost of treatments by ± 15% and utilities using high and low values (95% CI) except for cognitive decline (base case ± 25%).

Probabilistic sensitivity analysis (PSA), which allows all model parameters to be varied simultaneously, was also conducted to test the robustness of model parameter values and their impact on the ICERs. PSA was conducted using a Monte Carlo simulation. The analysis was run for 10,000 iterations where the value of each model parameter was randomly sampled from a probability distribution uniquely determined for each type of model parameter. Cost-effectiveness acceptability curves were derived to present the probability that each treatment is optimal at different values of willingness to pay per additional QALY gained.

The analyses were carried out using the TreeAgePro 2020 software® (TreeAge Software, Inc., MA, USA).

Results

Base Case Analysis

Among a hypothetical cohort of 1000 patients over a lifetime, use of rivaroxaban compared to ASA is predicted to result in 43 fewer first and 59 fewer second event ischemic strokes, 25 fewer systemic embolisms, 161 fewer cognitive declines, 29 fewer vascular deaths and 143 fewer non-vascular deaths. The model projected an additional 46 intracranial hemorrhages and 461 major bleeds with rivaroxaban.

Treatment with rivaroxaban 15 mg was more costly ($273,073) than treatment with ASA 100 mg ($75,086) while being more effective in terms of QALYs (20.7 with rivaroxaban versus 14.1 with ASA). The ICER per QALY gained over a lifetime was $29,900 (Table 4). This ratio is below the commonly accepted willingness-to-pay threshold [43] of $50K per QALY gained, indicating that rivaroxaban is cost-effective for this patient population (Figure 2). There was no dominance in the model given that the less costly treatment also had less QALYs.

Sensitivity Analyses

Table A1 in Data Supplement provides the results of the detailed deterministic sensitivity analysis. A tornado diagram (Figure 3) shows the top 20 parameters that had the most impact on the ICER value. Regardless of the variation in costs, utility/disutility values or event rates, the ICERs remained below the WTP threshold of $50K. The lowest ($23,578) and highest ($35,644) values observed were associated with a ± 25% variation in the base case value of major bleed with rivaroxaban.

The ICER also remained below the WTP threshold of $50 K with a time horizon of 10, 20 or 40 years ($29,298, $28,245 and $29,168, respectively) and with discount rates of 0% or 3% ($30,163 and $29,665, respectively). Similarly, varying the cycle length to 1-month or 6-month, despite having considerable impact on the ICER, resulted in values ($15,211 and $47,984, respectively) below the WTP threshold of $50 K.

Probabilistic Sensitivity Analysis

Figure 4 shows the results of the probabilistic sensitivity analysis. The cost-effectiveness acceptability curves (CEACs), shown in (A), present the probability that each treatment is optimal (cost-effective) over a range of WTP values. The scatter plot (Figure 4 (B)) illustrates the difference in the total aggregated costs between rivaroxaban and ASA on the y-axis versus the difference in QALYs accrued through a lifetime use of the drugs on the x-axis. The majority of the 10,000 Monte Carlo simulations showed rivaroxaban 15 mg to be more costly while being more effective than ASA 100 mg. At a WTP of $50K per QALY, when varying all the parameters (cost, utility/disutility and events) simultaneously by their defined ranges, rivaroxaban treatment was cost-effective (ICER < $50K per QALY gained) in 100% of the Monte Carlo simulations.

Discussion

The present cost-effectiveness evaluation of a hypothetical cohort of patients with NVAF, vascular disease and low risk of stroke, treated with either rivaroxaban or ASA, showed rivaroxaban to be associated with fewer strokes, systemic embolisms, cognitive declines and vascular and non-vascular deaths over a 60-year lifetime horizon. However, the drug caused additional intracranial hemorrhages and other major bleedings. Over a lifetime horizon, the net benefits in terms of reduction of clinical events with rivaroxaban yielded an incremental QALY of 6.6 at an incremental cost of $197,987 and an ICER below the WTP of $50K, deeming rivaroxaban to be cost-effective vs. ASA. The results were shown to be robust in deterministic and probabilistic sensitivity analyses.

Our study is the first to assess the cost-effectiveness of rivaroxaban 15 mg vs ASA 100 mg for patients with NVAF at low risk of stroke and to include cognitive decline as an adverse event in the model. Due to methodological differences, mainly relative to study design, patient population and drug dosage, it was impossible to place our results within the context of recent studies in this area. Nevertheless, several published economic evaluations have examined the value of DOACs in the treatment of AF patients with moderate to high stroke risk. Some of those studies found dabigatran [37,38,44-47] or apixaban [38,48-52] to be dominant vs. other DOACs or warfarin. A US study by Harrington, et al. found all DOACs to be cost-effective vs. warfarin [53], and a Canadian study, by Coyle, et al., showed rivaroxaban and warfarin to be dominated by apixaban and dabigatran 150 mg [38]. Two studies focused on the cost-effectiveness of rivaroxaban vs. warfarin from a US payer/Medicare perspective, in patients with AF at moderate or high risk of stroke. Lee, et al. [54] found an ICER for rivaroxaban of $27,498 per QALY and the drug was deemed cost-effective in >80% of the Monte Carlo iterations using a WTP of $50K and $100K. Also, Mensch, et al. [29] found an ICER of €15,207 per QALY and rivaroxaban to be a cost-effective alternative to warfarin from a German Statutory Health Insurance perspective.

There are a number of limitations to the underlying model structure and data. First, the rates of clinical events with rivaroxaban and ASA were drawn from RCTs [26,28] (ROCKET-AF and AVERROES) which used different drug dosages and involved patients with different characteristics, mainly older age and higher risk score. With ASA, this may have potentially led to an overestimation of the incidence of events and costs as well as an underestimation of the QALY. Nevertheless, looking at the impact a ± 25% variation in the rate of events with ASA had on the model, the results of the deterministic sensitivity analysis showed all the ICER values to remain below the WTP threshold. Similarly, with rivaroxaban, the 35% reduction of the ROCKET-AF data as an adjustment for differences in the populations was set arbitrarily and may have induced an underestimation or overestimation of the rates of events. Examining the uncertainty in these inputs, the deterministic sensitivity analyses results showed the model to be insensitive to a variation of ± 25% of the base case values. Second, these RCTs had limited follow-up period, an average of 1.1 years in the AVERROES [26] trial and a median of 1.9 years in ROCKET-AF [28] trial. By assuming a constant rate for most events through extrapolation over a lifetime follow-up period in the present study, the number of events and ICER may have been underestimated. Trials of DOACs in AF with longer follow-up periods would provide information on the long-term harms and benefits of these medication and would contribute to more precise economic evaluations. Third, the event rates inputted in the model may not reflect outcomes outside a RCT setting. Similarly, other data used in the model such as the patient’s age, dosage regimen, risk score, costs and the Canadian health-care system perspective make the results not necessarily generalizable to other settings. Finally, data on the incidence of different combination of clinical events in patients with NVAF at low risk of stroke would have certainly contributed to more precise calculations of the overall cost and benefits of rivaroxaban treatment. These data would be available once the Brain AF trial is completed.

Conclusion

Elevated costs associated with rivaroxaban compared to ASA were offset by an increased life expectancy for patients with NVAF and low risk of stroke. The present analysis demonstrates that treatment with rivaroxaban, when compared to the standard of care, was cost-effective for the prevention of stroke events and cognitive decline over a lifetime perspective. This finding suggests that rivaroxaban offers benefits to treating patients with a low-risk score from a clinical and economic perspective. The results from the BRAIN-AF trial will inform the analysis with observed event rates in this patient population.

Funding

This work was supported by The Montreal Heart Institute.

The Montreal Heart Institute received funding from the Health Collaboration Acceleration Fund (FACS) from the Government of Quebec.

Conflict of Interest

Drs. G. Nakhlé and J. Le Lorier report grants from Montreal Heart Institute for this project. The Montreal Heart Institute received funding from the Health Collaboration Acceleration Fund (FACS) from the Government of Quebec.

Drs. D. Roy, M. Samuel, A. Dubois have nothing to disclose.

Dr. J-C. Tardif reports grants from Amarin, grants and personal fees from Astra Zeneca, DalCor, Sanofi and Servier and grants from Esperion, Ionis and RegenXBio, outside the submitted work. In addition, Dr. Tardif has a patent “Genetic markers for predicting responsiveness to therapy with hdl-raising or hdl mimicking agent” pending, a patent “Methods for using low dose colchicine after myocardial infarction” pending, a patent “Methods of treating a coronavirus infection using Colchicine” pending, and a patent “Early administration of low-dose colchicine after myocardial infarction” pending.

Dr. L. Rivard reports grants from BAYER INC, during the conduct of the study; grants from the Montreal Heart Institute foundation, the Heart and stroke, and the Fonds de recherche du Québec – Santé (FRQS), outside the submitted work.

Authorship Statement

All persons who meet authorship criteria are listed as authors and all authors certify that they have approved the version of the manuscript to be published and take responsibility for the content of the manuscript.

Authorship Contributions:

Gisèle Nakhlé: Ideas, formulation of research question, statement of hypothesis, development and design of methodology, creation of models, programming and statistical analysis, data collection, writing the initial draft, finalizing manuscript for publication.

Jean-Claude Tardif, Denis Roy, Léna Rivard, Anick Dubois: Funding acquisition, commentary and revisions.

Michelle Samuel: critical review, commentary and revisions.

Jacques Le Lorier: Ideas, supervising of research, funding acquisition, critical review, commentary and revisions.