Novel antithrombotic regimen in patients with ischemic heart disease and peripheral arterial disease: can we identify those who derive the highest benefit?

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Economic burden of coronary artery disease or peripheral artery disease in patients at high risk of ischemic events in the French setting: a claims database analysis

The reduction in major adverse cardiovascular events (MACE), and their associated morbidity and mortality remains the primary target of several secondary prevention measures among patients with atherosclerotic cardiovascular disease (ASCVD). However, given the phenotypical variability and wide spectrum of patients with clinical ASCVD, it is important to identify patients at higher-than-average risk of MACE within this at-risk population. Based on prior large registry-based data, the presence of polyvascular atherosclerosis has been shown to bode a poorer prognosis with higher rates of recurrent ischemic events and death¹.

Furthermore, among this population, patients with the peripheral arterial disease (PAD) in particular remain at even higher risk for MACE and major adverse limb events (MALE)². These patients are not only at a heightened risk for cardiovascular morbidity and mortality but also contribute the greatest towards the healthcare economic burden^3,4. With the emergence of novel and highly effective secondary prevention therapies in the arena of lipid-lowering⁵ and atherothrombosis⁶, the identification of such a group of high-risk patients with ASCVD has become paramount⁷. Although the use of such therapies themselves pose an incremental cost burden to the healthcare system, this may be offset by the cost-savings derived from the proportionately higher absolute risk reduction in these very high-risk patients with ASCVD^7,8. Therefore, prior to the widespread dissemination of such therapies, it is essential to conduct a thorough assessment of the current financial burden of these patients on the healthcare system. In this editorial, we aimed to evaluate the recent publication by Emery and colleagues⁹ highlighting the economic burden of high-risk patients with PAD or ischemic heart disease (IHD), provide an assessment of the results, and discuss implications of the same.

Since the inception of the landmark trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE)¹⁰, multiple studies have investigated the combination of antithrombotic and antiplatelet agents for the reduction in MACE. Although some studies have shown no significant reduction in cardiovascular death with this strategy¹¹, data from trials such as the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events Thrombolysis in Myocardial Infarction 50 (TRA 2P TIMI 50) trial¹² have shown a significant reduction in MACE in patients with stable atherosclerosis. On the background of this data, the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was conducted to evaluate the addition of low-dose rivaroxaban to aspirin as compared to aspirin alone in patients with stable ASCVD⁶. At a mean follow up of 23 months, the COMPASS investigators demonstrated significant reductions in MACE and cardiovascular mortality among patients receiving low-dose rivaroxaban in addition to aspirin as compared to the aspirin only group.

In the May issue of the Journal of Medical Economics, Emery et al. examined the “Echantillon Généraliste de Bénéficiaires” (EGB) claims database to estimate healthcare costs of high-risk patients with IHD or PAD receiving care across France⁹. Using claims data from a 5-year period, the authors identified 29,888 patients with IHD or PAD. Additionally, the COMPASS trial eligibility and exclusion criteria were applied to identify 17,369 high-risk COMPASS-eligible patients. Among these patients, subgroup analyses were conducted consisting of patients with IHD ± PAD, PAD ± IHD, and IHD + PAD. These high-risk patients were compared against age and gender-matched controls (n = 52,104). The annual per capita healthcare expenditure was calculated for the entire cohort and represented as mean incremental cost for high-risk patients as compared to controls. The authors demonstrated that high-risk COMPASS-eligible patients accrued an additional €4,284 per capita per annum as compared to their matched controls. A major contributor to this cost was inpatient care and was largely driven by higher expenditure for the subgroup of patients with both IHD and PAD (mean per capita per annum incremental cost: €8,067) followed by patients with PAD ± IHD (mean per capita per annum incremental cost: €5,552).

These findings are consistent with prior healthcare expenditure data of patients with ASCVD demonstrating that the patients with polyvascular disease accrue an on average higher healthcare costs as compared to patients with atherosclerosis of a single vascular bed^3,4. Based on data from the REACH registry, analysis from the United States³, Canadian⁴, and European Union cohort¹³ have all demonstrated a greater cost accrued among patients with PAD and those with polyvascular atherosclerotic disease. However, the findings presented by Emery and colleagues go one step further and put this observation in context with the high-risk COMPASS-eligible patients with IHD or PAD. These results also highlight PAD as a foremost cost-generating domain within the spectrum of atherosclerotic cardiovascular diseases. The observations made in this study may be attributed to the overall higher illness severity of patients with PAD and especially those with concomitant IHD. Another explanation behind these results may be in part due to less aggressive treatment of patients with PAD which may stem from lack of recognition or knowledge regarding the true risk of cardiovascular morbidity and mortality in these patients¹⁴. As compared to their IHD counterparts, patients with PAD have varying symptomology and clinical presentation, which may result in delayed diagnosis and thereby higher disease severity and burden of complications at the time of treatment.

Consistent with the above, such high-risk patients with PAD and those with IHD + PAD also experience higher rates of recurrent ischemic events. This higher risk of ischemic events in these patients, although, contributes to greater overall healthcare expenditure, it may also bring about favorable implications in terms of the absolute risk reduction gained by application of secondary prevention therapies. For example, the use of novel lipid-lowering therapies such as the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors has shown to impart a larger absolute risk reduction in such high-risk patients¹⁵. Similarly, based on the results of a prespecified subgroup analysis of PAD patients from the COMPASS trial, the use of novel antithrombotic regimens in such patients was associated with a significant reduction in MACE and MALE¹⁶. An equal penetration and application of secondary prevention strategies, demonstrating significant relative risk reduction in all-comers with ASCVD, would lead to a higher absolute risk reduction in MACE among high-risk patients. Furthermore, even within this high-risk population, a subset of patients with multiple enrichment criteria have been predicted to derive the utmost benefit from secondary prevention therapies such as the COMPASS-based antithrombotic regimen^17,18. Lastly, although the cost-effectiveness of low-dose rivaroxaban was not the topic of evaluation by Emery and colleagues, analyses from other nations have demonstrated that the addition of low-dose rivaroxaban has a favorable incremental cost-effectiveness ratio (ICER). This was demonstrated by a UK-based analysis that used a Markov model to demonstrate the cost-effectiveness of rivaroxaban in addition to aspirin in patients with IHD and PAD¹⁹. The ICER was reported to be €16,360 per quality-adjusted life-year gained and €14,380 per life-year which remained below the ICER threshold (€20,000) regarded as cost-effective¹⁹. A similar analysis based on the Australian payer mix has yielded comparable results demonstrating a favorable ICER²⁰.

This study provides commendable evidence of cost estimates for high-risk French patients who would be eligible for low-dose rivaroxaban in addition to aspirin therapy for secondary prevention of ASCVD. The strength of the study lies in the large nationwide sample size and ability to gather information from both inpatient and outpatient patient settings. Despite these strengths, there are certain aspects of this study that limit its applicability. Firstly, the data presented in this study was extracted from the French claims database whereby cost estimates comprise of reimbursements acquired by the beneficiaries rather than true healthcare expenditures. Furthermore, given the lack of data on costs regarding post-acute care facilities and rehabilitation which consists of a substantial portion of overall healthcare expenditure, the results presented in this study may be at risk for measurement bias due to often varied use of these post-hospital care facilities among patients with IHD and PAD. The federal reimbursement claims data from France may lack generalizability as certain healthcare elements (diagnostic tests, physician visits, hospital stays, etc.) may be reimbursed differently in France than other nations worldwide. The lack of certain data elements such as renal function or presence of severe heart failure which were part of COMPASS exclusion criteria could not be ascertained by the claims data. This may have resulted in an overestimation in the number of COMPASS-eligible patients and introduced a potential selection bias. The retrospective nature of this study and the potential of illness-based dissimilarity in the construction of the control group may have amplified the incremental cost computed for the high-risk COMPASS-eligible group.

With recent advances in cardiovascular therapies, it is necessary to risk-stratify patients with ASCVD and identify patients who generate a higher healthcare expenditure, who may carry a higher illness burden, and who may subsequently derive the most benefit from such secondary prevention therapies. COMPASS-based antithrombotic strategy, the addition of low-dose rivaroxaban to aspirin therapy has been associated with a significant reduction in MACE. However, given the potential financial strain on pharmaceutical budget brought on by widespread use of low-dose rivaroxaban in all-comers with ASCVD and associated adverse events (i.e. bleeding), the use of such therapies could be targeted to a specific subset of high-risk patients based on a formal cost-effectiveness analysis. The fundamental to conducting such analyses is to first assess and understand the incremental cost generated by these high-risk patients as compared to their non-high-risk counterparts. Targeting a population with the highest risk and highest incremental cost would not only allow a higher number of adverse events averted by the use of such therapies but also prove the most cost-effective in the long term.

In summary, understanding the current patterns of healthcare utilization and medical expenditure of high-risk patients is essential prior to the implementation of newer secondary prevention therapies. The subset of patients with the greatest incremental healthcare cost burden and those at highest risk for recurrent MACE, such as patients with PAD and those with concomitant IHD, may derive the utmost benefit from such novel therapies. Findings from this study highlight such a subset of patients from the French population however, further studies are needed to confirm these findings on an international scale comprising of different healthcare systems and reimbursement models. Additionally, evaluation of ICER across different nations and payers- as well as patient-mix should be considered prior to widespread adoption and implementation of low-dose rivaroxaban as a complementary therapy in patients with IHD or PAD.

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Declaration of financial/other interests

Dhruv Mahtta: None. Salim S. Virani: Honorarium American College of Cardiology (Associate Editor for Innovations, aacc.org); Steering Committee Patient and Provider Assessment of Lipid Management (PALM registry) at the Duke Clinical Research Institute (no financial remuneration).

JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

The opinions expressed reflect those of the authors and not necessarily those of the Department of Veterans Affairs or the US government.

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