AbstractBackground

Maintaining a steady medication supply during a public health crisis is a major health priority. We leveraged a large US pharmacy claims database to understand utilization of evidence-based therapies used in heart failure (HF) care during the coronavirus disease-2019 (COVID-19) pandemic.

Methods

We analyzed 27,027,650 individual claims from an all-payer pharmacy claims database across 56,155 chain, independent, and mail-order pharmacies in 14,164 zip codes in 50 states. Prescriptions dispensed (in 2-week intervals) of evidence-based HF therapies in 2020 were indexed to comparable timeframes in 2019. We normalized these year-over-year changes in HF medical therapies relative to those observed with a stable basket of drugs.

Results

Fills of losartan, lisinopril, carvedilol, and metoprolol all peaked in the weeks of March 2020 and demonstrated trajectories thereafter that were relatively consistent with the reference set of drugs. Fills of spironolactone (+4%) and eplerenone (+18%) showed modest trends towards increased relative use during 2020. Fills of empagliflozin (+75%), dapagliflozin (+65%), and sacubitril/valsartan (+61%) showed striking longitudinal increases throughout 2020 that deviated substantially from year-over-year trends of the overall basket of drugs. For all 3 therapies, fills of all quantity sizes relatively increased throughout 2020. For both generic and brand-name therapies, prescription fill patterns from mail order pharmacies increased substantially over expected trends beginning in March 2020

Conclusion

Prescription fills of most established generic therapies used in HF care were maintained, while those of sacubitril/valsartan and the sodium-glucose cotransporter-2 inhibitors steeply increased during the COVID-19 pandemic. These nationwide pharmacy claims data provide reassurance about therapeutic access to evidence-based medications used in HF care during a public health crisis.

KeywordsIntroductionMaintaining a steady medication supply during a public health crisis is a major health priority. Patients with chronic medical conditions such as heart failure (HF) face heightened risks with coronavirus disease 2019 (COVID-19) (1Bhatt AS Jering KS Vaduganathan M et al.Clinical Outcomes in Patients With Heart Failure Hospitalized With COVID-19.), but the pandemic may have indirect consequences for even non-infected individuals whose routine medical care and therapeutic access are disrupted (2Bhatt AS Moscone A McElrath EE et al.Fewer Hospitalizations for Acute Cardiovascular Conditions During the COVID-19 Pandemic.). Uncertainties regarding the safety of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) have further complicated routine HF care (3Vaduganathan M Vardeny O Michel T McMurray JJV Pfeffer MA Solomon SD. Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19.). However, in parallel to this global disruption, discovery science and care innovation in HF accelerated in 2020 and there is building support for initiation and maintenance of multi-drug regimens in slowing disease progression in HF with reduced ejection fraction. We leveraged a large US pharmacy claims database to understand utilization of evidence-based therapies used in HF care before and during the COVID-19 pandemic.MethodsWe analyzed data from an all-payer pharmacy claims database across 56,155 chain, independent, and mail-order pharmacies in 14,164 zip codes in 50 states (). Prescriptions dispensed (in 2-week intervals) of evidence-based HF therapies in 2020 (December 29, 2019 to December 26, 2020) were indexed to comparable timeframes in 2019 (December 30, 2018 to December 28, 2019). Only complete 2-week intervals were included and each period begins on a Sunday and ends on a Saturday. To further reduce noise due to short-term trends and cyclical seasonal variations and to address potential unobserved changes in the number of people covered in these pharmacy claims data (the denominator), we normalized these year-over-year changes in HF medical therapies relative to those observed with a reference set of 859 drugs used in general medical practice that excludes seasonal drugs (e.g. oseltamivir). Data are presented as % deviation from the expected year-over-year trends seen with this stable basket of drugs. Prescriptions of brand-name therapies were further evaluated by quantity of fills (60 tablets). Finally, prescription fill patterns were characterized based on pharmacy type (mail order or retail). Using the National Council for Prescription Drug Programs dataQ Pharmacy Database, we applied a broad definition for mail order pharmacies and considered any pharmacy that self-identified as such based on Primary, Secondary, and Tertiary Provider Type Code. To better understand shifts in pharmacy activity in relation to the COVID-19 pandemic, we additionally summarized overall % deviation from the expected year-over-year trends from the week the World Health Organization declared COVID-19 a global pandemic (March 11, 2020) and the US declared a national emergency (March 13, 2020) to the end of the study period. Analyses were performed using R Software Version 3.6.1 (Vienna, Austria).Results

In 2019 and 2020, we evaluated 27,027,650 individual claims for 9 therapies across 6 classes used in HF management: lisinopril, losartan, metoprolol (immediate-release or extended-release), carvedilol (immediate-release or extended-release), spironolactone, eplerenone, dapagliflozin, empagliflozin, and sacubitril/valsartan.

Fills of losartan, lisinopril, carvedilol, and metoprolol all peaked in the weeks of March 2020 and demonstrated trajectories thereafter that were relatively consistent with the reference set of drugs for the remainder of 2020 (deviating Figure 1. Fills of spironolactone (+4%) and eplerenone (+18%) showed modest trends towards increased relative use during 2020.

Figure 1Relative Prescription Fills of Evidence-Based Therapies Used in Heart Failure Care in 2020 in the United States. Prescription fills (in 2-week intervals) in 2020 were first indexed to 2019. These year-over-year changes were then normalized relative to those observed with a reference set of drugs. The percentages displayed in the figure represent deviation from the expected year-over-year trends seen with the reference set of drugs. Abbreviations: WHO = World Health Organization.

Fills of empagliflozin (+75%), dapagliflozin (+65%), and sacubitril/valsartan (+61%) showed striking longitudinal increases throughout 2020 that deviated substantially from year-over-year trends of the reference set of drugs (Figure 1). For all 3 therapies, fills of all quantity sizes relatively increased throughout 2020. For dapagliflozin and empagliflozin, fills 60 tablets (+116%) showed the greatest deviation.For all 9 therapies sampled, the prescription fill patterns from mail order pharmacies increased over expected trends beginning in March 2020 (Figure 2). These trajectories generally plateaued for generic therapies, while continued to increase through the end of 2020 for brand-name therapies (dapagliflozin, empagliflozin, and sacubitril/valsartan). From the week of March 8, 2020 (the week the World Health Organization declared pandemic status and US declared a national emergency) to the end of 2020, prescription fills of both brand-name therapies (range +112% to +173%) and generic therapies (range +59% to +81%) from mail order pharmacies showed substantial deviation from expected trends (Table 1). At retail pharmacies, prescription fills for generic therapies remained relatively stable compared with the reference set of drugs (deviating

Figure 2Relative Prescription Fills of Evidence-Based Therapies Used in Heart Failure Care at Mail Order and Retail Pharmacies. Prescription fills (in 2-week intervals) in 2020 were first indexed to 2019. These year-over-year changes were then normalized relative to those observed with a reference set of drugs. The percentages displayed in the figure represent deviation from the expected year-over-year trends seen with the reference set of drugs. Pharmacy type (mail order or retail) was based on self-identified designation in the National Council for Prescription Drug Programs dataQ Pharmacy Database.

Table 1Prescription Fill Patterns of Evidence-Based Therapies Used in Heart Failure Care During the COVID-19 Pandemic by Pharmacy Type.

Expected trends estimated based on a reference set of 859 drugs used in general medical practice that excludes seasonal drugs

Abbreviation = COVID-19 coronavirus disease-2019

DISCUSSION

These nationwide pharmacy claims data suggest that prescription fills of most established generic components of medical therapies used in HF care were maintained at use patterns consistent with many other common therapies during the COVID-19 pandemic. In contrast, use of newer brand-name therapies (sacubitril/valsartan and the sodium-glucose co-transporter-2 inhibitors) showed steep deviation from expected trends with increasing use throughout 2020. Prescription fills for all therapies from mail order pharmacies increased early as the COVID-19 pandemic evolved with initial lockdown phases.

Similar to observations with other therapies (5Vaduganathan M Van Meijgaard J Mehra MR Joseph J O'Donnell CJ Warraich HJ Prescription Fill Patterns for Commonly Used Drugs during the COVID-19 Pandemic in the United States.), ACEi, ARB, and β-blockers showed slight inflections in relative use in March 2020, which may represent stockpiling behavior in anticipation of the impending global pandemic and easing of restrictions to allow early and flexible prescription fills (). ACEi/ARB use was otherwise relatively stable suggesting limited perturbations from initial safety concerns voiced related to their use in COVID-19 (3Vaduganathan M Vardeny O Michel T McMurray JJV Pfeffer MA Solomon SD. Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19.). Prompt multi-society guidance and reassuring signals from interval trials may have supported their continued use (7Lopes RD Macedo AVS De Barros E Silva PGM et al.Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and out of the Hospital in Patients Admitted with COVID-19: A Randomized Clinical Trial., 8Cohen JB Hanff TC William P et al.Continuation versus discontinuation of renin–angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.).

Marked relative increased utilization of newer medical therapies provide reassurance that patients with HF and cardiometabolic illnesses are able to access latest advances in medical therapies, even during a public health crisis. Mail order pharmacies may have facilitated continued therapeutic access even during lockdown phases. Restructuring of HF care with virtual care pathways may have facilitated this uptake without necessitating in-person visitation. Increasing awareness around best practices in HF care and emerging supportive trial evidence and regulatory labels may have also contributed.

These findings need to be considered in the context of study limitations. We relied on pharmacy claims information and did not have access to patient-level characteristics. As such, we were unable to track whether therapies were titrated, continued, or discontinued in individual patients. Similarly, we could not distinguish between new versus refill prescriptions. While it is challenging to definitely ascertain the denominator of persons eligible for a prescription, we did attempt to normalize these observations to trajectories of fill patterns of over >800 common therapies. Strong divergence for certain medical therapies used in HF care from these expected patterns suggests that large influx of covered persons is unlikely to be responsible for this prescription growth. Importantly however, aside from sacubitril/valsartan, many of these therapies are indicated and commonly used in other medical conditions, and we cannot definitely attribute their prescription to HF care. We intentionally attempted to be inclusive in our analysis and included both immediate-release and extended-release formulations of a given therapy (for instance, metoprolol tartrate and metoprolol succinate), even though evidence may support one formulation preferentially. We excluded combination therapies for analytic purposes. Finally, this report does not characterize prescription fill patterns in relation to regional COVID-19 disease activity given the challenges in attributing prescription fills to a particular region. Mail-order pharmacies may be physically located in one geographic region, but prescriptions are often filled nationwide.

These contemporary data encompassing a large US pharmacy catchment area and over >27 million claims provide reassurance about therapeutic access to evidence-based medications used in HF care during the COVID-19 pandemic.

Disclaimer

This work represented an academic collaboration with GoodRx. The study was unfunded and no compensation was received. These analyses are based on a representative sample of US claims and not based on GoodRx transactions. The manuscript was drafted by the first author and revised based on input by all coauthors.

Funding/Support

None

Disclosures

Dr. Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Relypsa, and Roche Diagnostics, speaker engagements with Novartis and Roche Diagnostics, and participates on clinical endpoint committees for studies sponsored by Galmed and Novartis. Ms. Li and Dr. van Meijgaard are employees of GoodRx. Dr. Warraich has no relevant disclosures.

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Lopes RD Macedo AVS De Barros E Silva PGM et al.

Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and out of the Hospital in Patients Admitted with COVID-19: A Randomized Clinical Trial.

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Continuation versus discontinuation of renin–angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.

Lancet Respir Med. 9: 275-284Article InfoPublication History

Accepted: June 24, 2021

Received in revised form: June 24, 2021

Received: June 16, 2021

Publication stageIn Press Journal Pre-ProofIdentification

DOI: https://doi.org/10.1016/j.cardfail.2021.06.013

Copyright

© 2021 Elsevier Inc. All rights reserved.

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