Journey to Anticoagulant Access Following Payer Rejection of Apixaban

ABSTRACT

Objectives: To investigate the journey to oral anticoagulant (OAC) access following formulary-related rejection of apixaban (Eliquis) and evaluate characteristics associated with failure to achieve OAC access among patients with atrial fibrillation (AF).

Study Design: Retrospective study using the Optum Market Clarity Data from January 2016 through February 2020.

Methods: Patients had at least 1 claim rejection for apixaban due to prior authorization (PA), formulary exclusion (FE), or quantity limit (QL) and at least 1 AF diagnosis on or before the rejected claim. Descriptive statistics summarized transaction journeys by type of formulary restriction. Multivariable regression assessed patient characteristics associated with not receiving an OAC within 60 days after initial rejection.

Results: Among 18,434 patients in the analytic sample, QL was the most common reason for rejection (68.7%), followed by PA (21.2%) and FE (10.2%). Most patients received a paid OAC claim within 60 days after rejection (82.2%-85.5% across restriction types). Mean time from rejection to paid claim ranged from 5.2 to 10.7 days among patients with a paid OAC claim and 12.4 to 17.6 days among those with multiple attempts before OAC receipt. Characteristics associated with higher odds of not receiving OAC treatment included being male, beingAfrican American, having Medicaid coverage, possessing a high stroke risk score, exhibiting no evidence of prior apixaban treatment, and being prescribed a low dose of apixaban on the initial rejected claim.

Conclusions: Most patients with a claim rejection for apixaban received approval for apixaban within 60 days, suggesting that initial rejection merely created a delay in treatment. Vulnerable populations were at greater risk of not receiving a paid OAC claim.

Am J Manag Care. 2023;29(11):e330-e338. https://doi.org/10.37765/ajmc.2023.89459

Takeaway Points

Limited evidence exists on the impacts of formulary restrictions on oral anticoagulant (OAC) access among patients with atrial fibrillation. This study assessed patients’ journey to OAC access following formulary-related claim rejection of apixaban (Eliquis) and found the following:

• The majority of patients subsequently received approval for apixaban within 60 days, suggesting that formulary restrictions may be overly stringent and delay treatment.
• Among patients who failed to receive treatment, many had unclaimed prescriptions that were subsequently reversed by the pharmacy, indicating that prior access restrictions may increase risk of prescription abandonment.
• Vulnerable populations such as Medicaid enrollees and African Americans were less likely to have a paid OAC claim.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the United States and is predicted to affect more than 12 million patients by 2030.^1,2 Among the complications associated with AF, stroke is the most debilitating. Without treatment, patients with AF face a 5-fold increased risk of stroke,³ and AF-related stroke is more likely to be recurrent and fatal than other stroke subtypes.^4,5 Despite the potential for significant consequences, many patients with AF do not receive consistent treatment with oral anticoagulants (OACs)—an efficacious therapy for stroke prevention in these patients.^6-11 For example, a 2020 US commercial claims analysis found that 33% of patients with AF were not treated with OACs despite having no contraindications.¹² A 2021 Medicare analysis found that more than half of patients with AF did not receive any OAC.¹³

Government and commercial payers in the United States have increasingly implemented more stringent formulary restrictions, including formulary exclusions (FEs), prior authorizations (PAs), step edits, and quantity limits (QLs), across many drug classes to help contain costs.^14-16 For instance, from 2014 to 2020, the number of medications removed from standard formularies of at least 1 of the 3 largest US pharmacy benefit managers increased by 676%.¹⁷ Additionally, a 2021 survey by the American Medical Association found that almost 1 in 5 prescriptions required a PA.¹⁴ Although access barriers created by formulary restrictions can, in some cases, play beneficial roles in curbing prescription misuse/abuse (such as with opioids^18,19), they also can create potentially harmful barriers to treatment, including treatment delays and prescription abandonment.^16,20,21 For medications like OACs that require consistent use to reduce risk of life-threatening events such as stroke, such barriers are especially concerning.

A recent study by Zhou et al found that formulary restrictions (PAs and step therapy) were associated with reduced use of non–vitamin K antagonists and higher stroke risk among Medicare patients with a new diagnosis of AF²²; however, little is known about potential impacts of formulary restrictions on patients’ transaction journey to OAC access. Our study aimed to address this knowledge gap by assessing the journey to OAC access among patients with AF who experienced a claim rejection triggered by a formulary restriction. Our analyses focused on patients with claim rejections for apixaban, given apixaban’s status as the most prescribed OAC in the United States.²³ To understand the extent to which these restrictions act as barriers to treatment, we quantified patterns of OAC approval, subsequent rejection, and reversals (prescription abandonment) within 60 days after initial apixaban claim rejection due to an FE, a PA, or a QL cap. We also assessed patient characteristics associated with failure to achieve eventual OAC treatment to evaluate potential disparities in treatment access.

DATA AND METHODS

Study Design and Data Source

Retrospective analyses were conducted using the Optum Market Clarity Data from January 2016 through February 2020. Market Clarity Data is a large US administrative claims and electronic health record database representing almost 32 million lives across multiple payer types. The database offers the unique feature of capturing pharmacy claims along with their transaction status (approved, rejected, reversed), allowing the transaction journey of patients’ pharmacy claims to be tracked. The data’s approved drug claims correspond to prescriptions that were approved and paid for by the patient’s plan (less patient co-pays or coinsurance contributions) and picked up by the patient. Rejected claims correspond to claims that were rejected by the patient’s plan. Reversed claims describe those that were reversed by the pharmacy after having been submitted and approved by the patient’s plan but not picked up by the patient (prescription abandonment).

Study Sample

Patients were selected if they were adults with at least 1 claim rejection for apixaban due to an FE, a PA, or a QL restriction between January 2016 and December 2019 (inclusive). (Step edits were not included because they were not observed in the data as rejection reasons for apixaban.) Patients were required to have at least 1 AF diagnosis on or before the first rejected claim for apixaban (eAppendix Table 1 [eAppendix available at ajmc.com]). The first rejected apixaban claim was defined as the patient’s index claim, and the claim date was defined as their index date. Patients were also required to have continuous medical and pharmacy health plan coverage for at least 6 months before the index date (baseline period) and continuous pharmacy coverage for at least 60 days after the index date (follow-up period). Patients were excluded if they were younger than 18 years at their index date or had an index claim with rejection reasons of FE in combination with PA or QL, likely reflecting a coding error. Patients meeting the selection criteria were categorized into 3 mutually exclusive strata based on the rejection reason on their index claim: FE, PA, or QL.

Outcomes and Patient Characteristics

The primary outcome related to patients’ transaction journey was paid OAC claim vs no paid claim over the 60-day follow-up period. Among patients with a paid OAC claim within the follow-up period, our analyses assessed (1) OAC drug for the first paid claim (apixaban or other OAC), (2) time from initial rejection (index date) to first paid OAC claim, and (3) patients with additional rejected or reversed OAC claims between initial rejection and first paid claim. Among patients with no paid claim for an OAC over the follow-up period, we assessed the percentage with additional rejected or reversed claims for an OAC and the corresponding OAC drug.

During the 6-month baseline period, patient characteristics were measured, including demographics, insurance type, index claim characteristics, clinical characteristics, and treatment history (Table 1, Table 2, and eAppendix Table 2).

Statistical Analyses

Descriptive statistics were used to summarize patient characteristics over the baseline period and outcomes related to patients’ transaction journey over the 60-day follow-up period. Results were reported for the full study sample and by strata. Multivariable logistic regression was used to identify baseline characteristics associated with failure to receive OAC treatment during the 60-day follow-up period.

RESULTS

Patient Characteristics

Among the 18,434 patients who met the eligibility criteria, QL restrictions were the most common reason for index claim rejection (68.7%), followed by PAs (21.2%) and FEs (10.2%). Patient baseline characteristics are presented in Table 1, Table 2, and eAppendix Table 2 and are further described in the eAppendix.

Patients’ Transaction Journey

The majority of patients in the study sample (82.2%-85.5% across the strata) had a paid OAC claim within 60 days after their initial rejected apixaban claim.

Patients with a paid OAC claim (Table 3). Among patients with a paid OAC claim over the 60-day follow-up period, the majority received apixaban as their first paid OAC claim (98.9%, 84.4%, and 77.6% in the QL, PA, and FE strata, respectively). For the FE and PA strata, the next most common paid OACs were rivaroxaban and warfarin. For these strata, 11.2% and 7.9% of patients received rivaroxaban, and 9.6% and 6.4% received warfarin, respectively.

Mean time from initial claim rejection to first paid OAC claim ranged from 5.2 days for the FE stratum to 6.9 days for the PA stratum to 10.7 days for the QL stratum (Figure 1). Across the strata, 82.3% of patients in the FE group, 75.1% in the PA group, and 58.3% in the QL group received their first paid OAC claim within 1 week.

For many patients, multiple attempts were made before finally receiving their first paid OAC. Approximately 45% of patients in the PA stratum and 26% in the FE and QL strata experienced additional rejections or reversals before receiving their first paid OAC. Specifically, additional rejections were experienced by 39.6% of patients in the PA group, 22.1% in the FE group, and 14.4% in the QL group. For most patients with additional rejections, these additional rejections corresponded to claim denials for apixaban (92.6% in the PA stratum, 85.8% in the FE stratum, and 98.8% in the QL stratum). Moreover, reversals were also experienced by many patients. Among patients with an eventual paid claim within the 60-day follow-up, reversals were experienced by 21.2% of patients in the PA group, 14.9% in the FE group, and 17.1% in the QL group before their first paid OAC claim. For patients with multiple attempts before finally receiving their first paid OAC, the mean time from index date to OAC receipt was nearly 2 weeks for the PA and FE strata and 2.5 weeks for the QL stratum (Figure 1).

Patients without a paid OAC claim (Table 3). Among patients with no OAC claim paid over the follow-up period, many patients did not make additional attempts to receive OAC treatment (Table 3). Nearly 40% of patients in the PA stratum and more than 50% in the FE stratum made no additional attempts to receive OAC treatment. As many as two-thirds of patients in the QL stratum made no additional attempts. Among patients in the PA and FE strata who had multiple attempts to receive OAC treatment after their initial claim rejection, the vast majority experienced additional rejections (92%). Among these patients, the majority faced additional claim denials for apixaban (94.1% and 88.7% in the PA and FE strata, respectively). Furthermore, many patients also experienced reversals. Among patients with multiple attempts, 25.1% and 22.1% in the PA and FE strata had both rejections and reversals. Among patients in the QL stratum who had multiple attempts to receive OAC treatment after initial claim rejection, almost 60% faced additional rejections and two-thirds experienced reversals. The vast majority of these rejections and reversals were for apixaban.

Factors Associated With Failure to Receive OAC Treatment After Index Claim Rejection

Several demographic and insurance characteristics were associated with higher odds of failure to receive OAC treatment within 60 days after initial claim rejection (Figure 2 and eAppendix Table 3). Specifically, being male (odds ratio [OR], 1.12; 95% CI, 1.02-1.22), being African American vs Caucasian (OR, 1.19; 95% CI, 1.03-1.38), having a Medicaid vs Medicare Advantage (MA) plan (OR, 1.18; 95% CI, 1.01-1.38), and having an index claim rejection in 2019 vs 2016 (OR, 1.13; 95% CI, 1.00-1.28) were associated with significantly higher odds of failure to receive OAC treatment when controlling for other characteristics. Among clinical characteristics, having a CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes, prior stroke/transient ischemic attack/thromboembolism, vascular disease, age 65-74 years, sex category) score of 5 or greater vs a score less than 2 was associated with higher odds of not receiving treatment (OR, 1.31; 95% CI, 1.05-1.64). Moreover, patients without prior apixaban treatment faced almost double the odds of failure to receive treatment (OR, 1.93; 95% CI, 1.75-2.13). Patients prescribed low vs standard doses of apixaban on their index claim had 14% higher odds of not receiving treatment (OR, 1.14; 95% CI, 1.01-1.27). By contrast, patients with previous use of angiotensin inhibitors, diuretics, and statins during the baseline period had 14% to 20% higher odds of receiving treatment (angiotensin inhibitors: OR, 0.88; 95% CI, 0.80-0.97; diuretics: OR, 0.84; 95% CI, 0.76-0.92; statins: OR, 0.83; 95% CI, 0.76-0.92).

DISCUSSION

This study assessed potential impacts of formulary restrictions on patients’ journey to OAC access and factors associated with failure to receive OAC treatment. We found that among patients with an initial claim rejection for apixaban, the majority received approval for apixaban within 60 days—suggesting that their initial rejection merely delayed the treatment that the patient ultimately received. This finding raises broader questions as to whether current formulary restrictions may be overly stringent. To this point, a 2022 report by the HHS Office of Inspector General found that 13% of denials for PA requests by MA plans actually fit within the Medicare coverage guidelines to which these plans must adhere.²⁴ These denials can delay or prevent medically necessary care for patients and can be particularly harmful for beneficiaries who are critically ill or cannot afford to pay for services/treatments themselves. In response to these concerns, federal legislation has been proposed with bipartisan support (Improving Seniors’ Timely Access to Care Act).^25-27 This act would mandate MA plans to standardize their PA requirements, increasing their transparency and aligning them with Medicare coverage guidelines to which plans must adhere. As our results suggest, opportunities exist to reduce inefficiencies from formulary restriction–related claim denials that are eventually countermanded by subsequent approvals.

Additionally, although some patients in the study sample received OAC approval upon their next attempt, many required multiple attempts before finally gaining OAC access (45% in the PA stratum and approximately 26% in the FE and QL strata). For these patients who faced additional hurdles to receiving treatment, their delay in treatment was substantial—nearly 2 weeks on average for the PA and FE strata and 2.5 weeks for the QL stratum. Moreover, a proportion of patients—10% in the FE stratum and 6% in the PA stratum—switched to warfarin, an OAC that has been shown to be clinically inferior to apixaban^7,28-31 and that presents a high burden to patients in its monitoring requirements, dietary restrictions, and potential for drug-drug interactions.^32,33 The psychological toll on patients from having to undergo such formulary-related treatment hurdles and nonmedical switching can be substantial. Patients may experience extreme stress and anxiety from the difficulties of navigating an administrative process that is not always transparent, the uncertainty of approval, and the potential for adverse health consequences from delays in care or having to switch to a less clinically appropriate treatment.³⁴

Although many patients had a paid OAC claim during the 60 days after their initial claim rejection, a sizable percentage did not (15% to 18% across the strata). Notably, a high percentage of these patients had no approval attempts within this 60-day period (39% in the PA stratum, 54% in the FE stratum, and 66% in the QL stratum). Moreover, 14% to 22% had reversals, signaling prescription abandonment. These findings suggest patient disengagement and are consistent with studies on other therapeutic drugs; systematic reviews have found that formulary restrictions have been associated with increased treatment discontinuation (measured with treatment utilization, medication possession ratio, and persistency).^35,36 These patterns are concerning given that premature discontinuation of OACs has been linked to increased risk of stroke^37,38 and mortality.³⁹ Moreover, studies have shown that patient engagement and activation—the willingness to actively manage their health and care—are important contributors to better health outcomes and lower costs.⁴⁰ Formulary restrictions that create barriers to critical, guideline-recommended treatments may discourage or even alienate patients, eroding their motivation for activation with additional negative effects.

Relatedly, our regression analyses found that patients failing to receive OAC treatment after initial claim rejection tended to be reflective of vulnerable populations—Medicaid enrollees and African American patients. Although it is unclear what the drivers may be, our results may reflect fragile support systems to care for these patients, potentially key facilitators for navigating the insurance process, overcoming approval hurdles, and receiving treatment. More specifically, vulnerable populations may be at greater risk of inadequate support systems to help with coordinating follow-ups with their physician after claim denial, handling communications with their insurance company, retrieving pharmacy prescriptions, and generally helping to persevere through the process.⁴¹ Given that medical mistrust—a key barrier to navigating the health care system—is particularly prevalent among racial and ethnic minority groups,⁴² formulary restrictions may further fuel mistrust in the health care system and lead to disproportionate prescription disengagement among vulnerable populations. These effects may, in turn, contribute to avoidable health inequities experienced by these patients.

Also concerning is that more medically challenged patients may be at increased risk of not receiving OAC treatment. Our regression results found that patients in the highest stroke risk category (CHA₂DS₂-VASc score ≥ 5) had 31% higher odds of failure to receive an OAC than those in the lowest category (score < 2). This finding is notable given that treatment guidelines recommend continued OAC use in patients with AF who have elevated CHA₂DS₂-VASc scores (ie, scores of ≥ 2 in men and ≥ 3 in women) to reduce stroke risk.⁴³

Finally, our regression results suggest a general trend over time of increased odds of not receiving treatment (index year 2017: OR, 1.07; 95% CI, 0.93-1.22; index year 2018: OR, 1.09; 95% CI, 0.96-1.24; index year 2019: OR, 1.13; 95% CI, 1.00-1.28, relative to 2016). Although the estimates for index years 2017 and 2018 did not reach significance, the results suggest that barriers to treatment may be intensifying.

Limitations

This study has several limitations. First, rejection codes to identify PAs, FEs, and QLs were selected based on code descriptions that most closely matched these formulary restrictions. To the extent that plans used other, nonspecific codes for these formulary restrictions, the results could be affected. To minimize potential noise that could attenuate the results, we opted to use rejection codes that most closely matched the formulary restrictions of interest. Second, comorbidities were identified using International Classification of Diseases, Tenth Revision, Clinical Modification codes, which are used for administrative billing purposes. Consequently, as with any claims analyses, comorbidities may be underestimated due to coding completeness issues. Third, although we adjusted for important variables, results of the multivariable regression analysis may be subject to unmeasured confounders. Additionally, it should be noted that the analyses are descriptive and not intended to establish causality. Finally, payment of drug claims does not guarantee that the dispensed drug was consumed by the patient.

CONCLUSIONS

Our findings reveal troubling issues with imposition of formulary restrictions on patients seeking apixaban treatment for AF. These include potential inefficiencies on the payer side that may inflate costs with unclear benefit—most patients with a formulary-related claim rejection for apixaban eventually received approval for apixaban within 60 days, highlighting that initial rejection merely delayed the treatment the patient ultimately received and introduced additional administrative overhead. These additional costs can be substantial. Howell et al estimated that payers spend at least $6.0 billion annually administering formulary restrictions and that physicians spend $26.7 billion interacting with payers on them (in 2019 US$).⁴⁴ More concerningly, we find evidence that the burden on patients may be large, with vulnerable populations at greater risk. Many patients had to undergo multiple attempts and notable delays before finally gaining OAC access after the initial claim rejection. Moreover, 15% to 18% of patients still did not have a paid OAC claim in the 60 days after initial rejection and tended to be reflective of Medicaid and African American populations, suggesting disparities in treatment access. Although formulary restrictions can play a valuable role in preventing medication misuse and promoting cost-effective treatments, our findings suggest that application of these restrictions might have negative impacts in this setting. 

Author Affiliations: Ochsner Health (SD), New Orleans, LA; Pfizer Inc (LX, DWH, MC, DMH), New York, NY; Analysis Group (ET), New York, NY; Bristol Myers Squibb (NA, AK), Lawrenceville, NJ.

Source of Funding: This study was sponsored by Pfizer and Bristol Myers Squibb (BMS).

Author Disclosures: Dr Deitelzweig was a paid consultant to Pfizer and BMS in connection with this study. Ms Xie was an employee of Pfizer at the time of this study. Dr Terasawa is an employee of Analysis Group, which received consultancy fees in connection with this study. Mr Hood was an employee and shareholder of Pfizer at the time of this study. Mr Cato was an employee of Pfizer at the time of this study. Dr Atreja and Ms Kang are employees and shareholders of BMS. Dr Hines is an employee and shareholder of Pfizer.

Authorship Information: Concept and design (SD, LX, DWH, MC, NA, AK, DMH); analysis and interpretation of data (SD, LX, ET, DWH, MC, NA, AK, DMH); drafting of the manuscript (SD, ET, NA, DMH); critical revision of the manuscript for important intellectual content (SD, LX, ET, DWH, AK, DMH); statistical analysis (SD, LX, DWH); administrative, technical, or logistic support (SD, ET, MC); and supervision (SD).

Address Correspondence to: Steven Deitelzweig, MD, Ochsner Health, 1514 Jefferson Hwy, New Orleans, LA 70121. Email: sdeitelzweig@ochsner.org.

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