https://orcid.org/0000-0003-1869-9721
Abstract
Aims
Cardiovascular disease (CVD) increases the risk of complications from respiratory viruses, including influenza. Moreover, respiratory viruses may increase the risk of CV events. Antiviral medication may reduce healthcare resource utilization (HRU), but more data is needed in CVD populations to explore relationships between influenza antiviral treatment, CVD-related complications, HRU, and costs.
Materials and methods
This retrospective claims analysis examined data extracted from IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases during three influenza seasons: 2016–2017, 2017–2018, or 2018–2019. Propensity score matching was used to compare HRU outcomes and costs among CVD patients treated with influenza antivirals and untreated patients.
Results
Across all influenza seasons, patients with CVD and influenza who received antiviral treatment had fewer all-cause emergency department (ED) visits (p < .01), respiratory-related HRU (p < .01), respiratory-related outpatient and ED visits (both p < .01), CVD-related HRU (p < .01), heart failure-related HRU visits (p < .01), and kidney failure-related HRU (p < .01) 180 days post-treatment fill date than CVD patients untreated for influenza. CVD patients treated with antivirals also had a lower mean number of all-cause inpatient, outpatient, and ED visits and days of stay (all p < .01) and fewer mean respiratory-related outpatient and ED visits (both p < .01). HRU patterns were generally consistent over time and across individual influenza seasons. Finally, treated CVD patients incurred lower all-cause outpatient costs 180 days post-treatment fill date (p < .05) than CVD patients untreated for influenza.
Conclusion
CVD patients who contract influenza and take antiviral medication have fewer short- and long-term influenza-related complications and less overall HRU compared with CVD patients who were not prescribed antiviral treatments. Antiviral treatment may be an important tool in reducing complications in CVD patients with influenza.
PLAIN LANGUAGE SUMMARY
People with heart disease are more likely to have complications from respiratory viruses, including influenza (flu). Moreover, respiratory viruses may increase the risk of damage to the heart muscle. We examined whether patients with heart disease who get the flu and take prescription medications called antiviral drugs have fewer short- and long-term flu-related complications and use fewer healthcare services than patients with heart disease who do not take antiviral drugs.
We examined commercial and Medicare databases during three influenza seasons (2016–2017, 2017–2018, and 2018–2019), and we compared outcomes and costs among heart disease patients who were treated or not treated with antiviral drugs. Patients with heart disease and the flu who received antiviral drugs had fewer visits to the emergency room, used fewer healthcare services for respiratory-related problems, used fewer heart disease-related healthcare services, and had fewer heart failure-related or kidney failure-related healthcare visits than heart disease patients who were not treated for the flu. Finally, patients with heart disease who were treated with antiviral drugs spent less money on outpatient services than patients with heart disease who were not treated with antiviral drugs.
We determined that patients who get the flu and take antiviral drugs have fewer short- and long-term flu-related complications and use fewer healthcare services than heart disease patients who do not receive antiviral drugs. Therefore, it may be important to treat heart disease patients with antiviral drugs in order to reduce the number of flu-related complications in these patients.
Introduction
People with cardiovascular disease (CVD) are at an increased risk of influenza complications, including a higher risk of acute myocardial infarction (AMI), stroke, myocarditis, decompensated heart failure, thromboembolism, and mortality, likely due to exacerbation of atherosclerosis, cardiac arrhythmias, and proinflammatory and prothrombotic alterationsCitation1,Citation2. About half of adults hospitalized for influenza during recent influenza seasons had CVDCitation3. In one case series of people hospitalized for AMI, the rate of hospital admissions within 7 days of influenza infection was 6-times higher than the rate of admissions during the year before and year after influenza infection (20 admissions per week vs 3.3 admissions per week, respectively)Citation4. Subgroup analyses showed a heightened risk of AMI after a confirmed influenza diagnosis for people >65 years and for those without a history of hospitalization for AMI. Moreover, in a sample of nearly 90,000 adults with a confirmed influenza diagnosis during the 2010–2011 through 2017–2018 influenza seasonsCitation5, the prevalence of acute cardiovascular events was about 12%, including acute heart failure (approximately 54%), acute ischemic heart disease (approximately 49%), hypertensive crisis (approximately 8%), and cardiogenic shock (approximately 3%).
Viral respiratory infections, including influenza, are known risk factors for CVD, including AMICitation2,Citation6,Citation7. Pre-existing CVD has been linked to an increased vulnerability to cardiac complications and worse outcomes following viral respiratory infections such as influenza; this increased vulnerability includes a greater risk of comorbid conditions, mortality, and healthcare resource utilization (HRU)Citation8. These patterns have been demonstrated in patients with seasonal influenza or with coronavirus disease 2019 (COVID-19)Citation6.
Influenza vaccination has been associated with a reduction in the risk of cardiovascular events and cardiovascular mortalityCitation9. In addition to vaccination, the Centers for Disease Control and Prevention (CDC) and The Infectious Diseases Society of America both recommend appropriate influenza antiviral treatment as soon as possible for individuals with confirmed or suspected influenza who are at an increased risk of medical complicationsCitation3,Citation10. Antiviral treatment that is administered early (i.e. 2 days before through up to 1 day after hospital admission for influenza) may help reduce the severity of CVD complications arising from influenzaCitation5. Previous research suggests that patients who receive antiviral treatment have significantly lower HRU (e.g. inpatient stays, emergency department [ED] visits, intensive care unit [ICU] admission, mechanical ventilation), lower all-cause costs, and lower medical costs than patients who do not receive antiviral treatmentCitation11. However, little research to date has assessed whether similar patterns are evident among patients with CVD who receive antiviral treatment for influenza. This retrospective cohort study explored whether patients with CVD who are diagnosed with influenza and receive antiviral treatment experience fewer influenza-related complications and have lower overall HRU and costs than patients with CVD who have influenza but do not receive antiviral treatment.
Methods
This study employed a retrospective claims analysis by influenza season (October to April of the following year). Because deidentified data were used, the study was exempt from Institutional Review Board review and approval. All aspects of the Health Insurance Portability and Accountability Act were followed.
Data source
Data for this study were extracted from IBM MarketScan Commercial Claims and Encounters (CCAE) and Medicare Supplemental and Coordination of Benefits (MDCR) databases (IBM Watson Health, Cambridge, MA). Medicare Fee-for-Service claims were not used in this study. Data for millions of US employees, as well as their spouses and dependents, who are insured with employer-sponsored commercial health insurance, are included in the CCAE database. Data covering retired US workers with Medicare supplemental insurance paid by employers, including Medicare-covered and employer-paid expenses, are included in the MDCR database. Inpatient and outpatient care, use of facilities and services, and payment information are included in the medical claims files. Individual outpatient prescription drug (pharmacy) claims are also available.
Study cohorts
The study cohorts included patients with CVD, identified as those with ≥1 inpatient or ≥2 outpatient claims for the same CVD condition at least 30 days apart (e.g. two separate diagnoses of myocardial infarction [MI] at least 30 days apart) as coded in the International Classification of Diseases, Tenth Revision (ICD-10). CVD conditions included MI (I21x), heart failure (I50x), atrial fibrillation (I48x), and stroke, including lacunar strokes (ICD-10 codes I60x–I62x [nontraumatic intracranial hemorrhage], I63x [cerebral infarctions], I65x–I66x [occlusion and stenosis of cerebral or precerebral vessels without infarction], I678x–I68x [other cerebrovascular disease], and I69x [sequelae of cerebrovascular disease]). For each influenza season, CVD patients were selected within a 2-year time frame – the year before and up to the end of the influenza season. For the 2016–2017 influenza season (selection period from October 2015 to April 2017), for instance, patients were included in the analysis for that season if they met the CVD inclusion criteria during that season.
Among those identified as having CVD, patients with influenza were selected if they had an outpatient or ED visit with influenza as a primary diagnosis (ICD-10 code J09–J11) between October 1 and April 30 (influenza season). The index influenza diagnosis date (index date) was the first influenza diagnosis date within each influenza season. Patients were included in the study if they were at least 18 years or older and were continuously enrolled in a health plan for 360 days before the index date (baseline period) and 30 days after the index date. Patients excluded from the analysis were those who received antiviral influenza treatment any time in the 30-day period before the index date.
Patients with CVD were divided into two cohorts of treated and untreated patients. Patients were assigned to the treated cohort if they received a prescription for antiviral influenza treatment (i.e. oseltamivir, baloxavir [as recommended by the CDC during at least one of the influenza seasons studied], rimantadine [not recommended by the CDC], or peramivir) within 2 days of their index date. The following patients were excluded: those who received prophylactic antiviral flu treatment with ≥10 days supply as their index treatment and those who were hospitalized during the period between their index date and their antiviral influenza prescription fill date (inpatient medication use could not be ascertained). Patients were assigned to the untreated cohort if they did not receive antiviral influenza treatment within 30 days after the index date. This study excluded patients who were hospitalized during the period between their index influenza diagnosis date and 2 days after their index date.
Propensity score matching (1:1 case:control) was used for treated and untreated patients using nearest neighbor matching (without replacement) and identical CVD flags. Baseline covariates (see Statistical analysis) were also included in propensity scores.
Outcomes
Two types of outcomes were analyzed: (1) number of patients with ED visits, inpatient stays (number of stays and number of days of stay), ICU admissions, outpatient visits, and outpatient antiviral influenza prescription refills; and (2) number of visits and associated costs for general all-cause visits and for respiratory-related visits. Respiratory-related HRU and costs were based on ED visits, inpatient stays (number of stays and number of days of stay), ICU admissions, and outpatient visits for relevant diagnosis codes (ICD-10 codes J00–J99). CVD-related HRU and costs were based on relevant diagnosis codes (IC-10 codes I21x [myocardial infarction]; I60x–I63x, I65x–I69x [stroke]; I50x [heart failure]; I49x [arrhythmia]; I16x [hypertensive crisis]; and N17x [acute kidney failure]) and were analyzed. Costs associated with HRU were adjusted to 2019 US dollars).
Treated patients were assessed for HRU and costs at 30, 60, 90, and 180 days post-antiviral treatment fill date (excluding the actual fill date). Untreated controls were assessed for HRU and costs at 30, 60, 90, and 180 days following the proxy fill date (excluding the actual proxy fill date). Proxy fill date was calculated using the number of days from the index date to the first antiviral treatment of matched cases. Because patients were required to be continuously enrolled in a health plan for 30 days after the index date, analysis on outcomes for 60, 90, and 180 days was only conducted for patients who had continuous enrollment up to those intervals.
Statistical analysis
Covariates for propensity score matching were identified during the baseline period (unless otherwise noted) and included Charlson comorbidity index (CCI) score, age at index date, sex, insurance plan type, region of the United States, month and year of index date, CVD conditions (as defined in Study cohorts), prior baseline influenza diagnosis (yes/no), evidence of chronic lung disease (including diagnostic codes for cystic fibrosis [E84], chronic lower respiratory diseases [J40x], lung diseases due to external agents [J6x–J7x], and other respiratory diseases principally affecting the interstitium, suppurative and necrotic conditions of the lower respiratory tract [J8x]), and evidence of pre-index HRU (flags within the 180 days before the index date for each of the following: at least one inpatient, ED, or outpatient visit at baseline) [yes/no]).
Descriptive statistics including percentages, means, and SDs were calculated. HRU and costs observed in the treated and untreated cohorts were compared using chi-square tests (for comparison of proportions) and t tests (for comparison of means).
Results
Study population
Over the study period, a total of 767,948 patients with a diagnosis of CVD were identified. Of these, 6,811 (1%) patients were diagnosed with influenza in an outpatient or ED setting during one of three influenza seasons (2016–2017, 2017–2018, or 2018–2019). Of these, 6,060 patients met the inclusion criterion of having at least one CVD diagnosis before the index date, and 5,124 met the additional inclusion criteria (≥18 years old and continuous health plan enrollment). Across all three influenza seasons, patients were included as cases if they received antiviral treatment within 2 days after the index date and were included as controls if they did not receive any antiviral treatment within 30 days after the index date. Of cases who received antiviral treatment within 2 days after the influenza index date, only those not hospitalized between the influenza index date and influenza treatment fill date were included. Similarly, control patients were only included if they were not hospitalized between the influenza index date and 2 days after the influenza index date. This yielded 4,332 cases and 4,332 control patients overall. Baseline descriptive characteristics of CVD patients with influenza who were treated or untreated with antivirals are shown in . Gender was predominantly male in both cohorts (51.4% vs 51.0%, respectively, p = .009). More patients were located in the southern region of the United States than in any other region and were continuously enrolled in a preferred provider organization plan (56.2% treated vs 55.6% untreated, respectively). Common CVD diagnoses included MI, heart failure, atrial fibrillation, and stroke, and mean (SD) CCI score was 1.41 (1.89) and 1.45 (1.93) in the treated and untreated cohorts, respectively. In the 180 days before the index date, all patients had outpatient visits during the baseline period; 24.8% treated vs 27.3% untreated, respectively, had inpatient visits; and 50.7% vs 54.4%, respectively, had ED visits.
Table 1. Baseline demographic and clinical characteristics of matched cohorts of cardiovascular disease patients with influenza who were treated or untreated with antivirals.
Healthcare resource utilization
At 60 days post-treatment/proxy fill date across all influenza seasons, fewer treated than untreated patients had all-cause ED visits (17.2% vs 22.0%, p < .01), as was respiratory-related HRU (30.6% vs 37.8%, p < .01), respiratory-related outpatient visits (30.4% vs 37.6%, p < .01), respiratory-related ED visits (5.0% vs 6.9%, p < .01), CVD-related outcomes overall (13.7% vs 17.4%, p < .01), and CVD outcomes of heart failure (5.6% vs 8.5%, p < .01) and acute kidney failure (0.9% vs 2.0%, p < .01). This pattern persisted at 90 days post-treatment/proxy fill date; fewer treated patients had all-cause ED visits (21.4% vs 25.9%, p < .01), respiratory-related HRU (34.5% vs 41.4%, p < .01), respiratory-related outpatient visits (34.3% vs 41.3%, p < .01), respiratory-related ED visits (5.4% vs 7.5%, p < .01), CVD-related outcomes in general (17.6% vs 21.4%, p < .01), and CVD outcomes of heart failure (7.3% vs 10.1%, p < .01), and acute kidney failure (1.0% vs 2.2%, p < .01).
HRU at 180 days post-treatment/proxy fill date for treated and untreated patients, respectively, was consistent with HRU patterns observed at 30, 60, and 90 days after the treatment/proxy fill date, across all three influenza seasons. Specifically, relative to treated patients, those in the untreated cohort frequently had more all-cause ED-related visits; more respiratory-related outpatient and ED visits; and more CVD-related outcomes for heart failure and acute kidney failure. At 30 days after treatment/proxy fill date, all-cause ED visits were 11.9% for treated vs 15.8% for untreated patients (p < .01), respectively. Respiratory-related HRU was more common in the untreated cohort (25.6% vs 33.1%, p < .01), as were respiratory-related outpatient visits (25.3% vs 32.9%, p < .01) and respiratory-related ED visits (4.2% vs 5.7%, p < .01). CVD outcomes were 8.5% in treated vs 12.4% in untreated patients, respectively (p < .01); heart failure was 3.7% and 6.7% (p < .01), and acute kidney failure was 0.7% and 1.7% (p < .01).
Across all three influenza seasons and time points, nearly all patients in both the treated (n = 3,664) and untreated cohorts (n = 3,664), respectively, had at least one all-cause HRU (99.5% and 99.4%) at 180 days post-treatment/proxy fill date. HRU was often significantly lower in treated vs untreated patients (). HRU at 60 and 90 days is shown in Supplementary Tables S1 and S2, respectively. Specifically, among all-cause HRU, 32.1% in treated vs 34.6% untreated patients (p = .02), respectively, had at least one ED visit. Almost 43% of treated patients reported any respiratory-related HRU, compared with almost 48% in the untreated cohort (p < .01). Among respiratory-related HRU, 42.4% in treated vs 47.8% in untreated patients (p < .01) had at least one outpatient visit and 6.6% vs 9.1% (p < .01) had at least one ED visit, respectively. CVD-related outcomes were also less common in the treated cohort (25.9% vs 29.0%, p < .01), particularly for the outcomes of heart failure (10.5% vs 12.6%, p < .01) and acute kidney failure (1.7% vs 2.8%, p < .01).
Table 2. HRU at 180 days post-treatment/proxy fill date in treated and untreated matched cohorts of cardiovascular disease patients with influenza who were treated or untreated with antivirals.
These patterns were generally consistent across the 2016–2017 and 2017–2018 influenza seasons but differed somewhat during the influenza season for 2018–2019 (). In the 2018–2019 season, the only statistically significant difference was for all-cause HRU involving at least one ICU admission (3.6% for treated vs 5.8% for untreated patients, respectively, p = .025). There were no statistically significant differences in respiratory-related HRU or in CVD-related outcomes.
The mean number of all-cause inpatient visits and days of stay, outpatient visits, and ED visits at 180 days post-treatment/proxy fill date across all three influenza seasons was significantly less for treated CVD patients than for untreated CVD patients (all p < .01; ; data for 60 and 90 days are shown in Supplementary Tables S3 and S4, respectively). The same pattern was observed for the mean number of respiratory-related outpatient visits and ED visits (both p < .01; ).
Table 3. Mean (SD) number of all-cause and respiratory-related days of inpatient stays and number of inpatient visits, outpatient visits, and ED visits for cardiovascular disease patients with influenza who were treated or untreated with antivirals.
Costs
Across all three influenza seasons, treated CVD patients incurred lower mean all-cause outpatient costs ($19,540 vs $23,919, p = .02) than untreated CVD patients at 180 days post-treatment/proxy fill date (; data for 60 and 90 days are shown in Supplementary Tables S5 and S6, respectively). This pattern was generally consistent across the 30-, 60-, and 90-day time points, with only outpatient costs reaching significance and only at 30 days ($3,887 vs $4,994, p = .02) and at 90 days ($10,142 vs $11,947, p = .04) post-treatment/proxy fill date. Across all three influenza seasons, all-cause inpatient stays were non-significant for all time points.
Table 4. Mean (SD) healthcare costs 180 days post-treatment/proxy fill date in matched cohorts of cardiovascular disease patients with influenza who were treated or untreated with antivirals.
At nearly all time points, mean respiratory-related costs were equivalent across the treated and untreated cohorts. However, at 180 days post-treatment/proxy fill date, the costs of respiratory-related outpatient treatment trended toward being lower for treated vs untreated CVD patients ($1,660 vs $2,338, p = .05). Respiratory-related inpatients costs were non-significant at all time points.
None of the CVD-related costs reached statistical significance at any time point other than the costs for heart failure-related HRU at 30 days, which was significantly lower for treated patients ($72 vs $392, p = .04).
Discussion
In our study, CVD patients with influenza who received antiviral treatment had lower HRU at 180 days post-treatment/proxy fill date than CVD patients who did not receive antiviral treatment. Specifically, all-cause ED visits, respiratory-related outpatient and ED visits, and HRU for CVD-related complications – particularly for heart failure and for acute kidney failure – were less common in antiviral-treated CVD patients. These patterns were generally consistent with those observed at 30, 60, and 90 days post-treatment/proxy fill date. Antiviral treatment was associated with fewer all-cause inpatient visits and days of stay, outpatient visits, and ED visits and fewer respiratory-related outpatient and ED visits. Additionally, CVD patients with influenza who received antiviral treatment incurred significantly lower all-cause outpatient costs at 180 days post-treatment/proxy fill date across all three influenza seasons than did CVD patients with influenza who did not receive antiviral treatment, with a trend toward lower respiratory-related outpatient costs as well. CVD patients who did not receive antiviral treatment also had higher baseline CCI scores.
CVD is among the most common conditions in adults hospitalized with influenzaCitation3. Multiple studies have documented the relationship between influenza and an increased risk of MI and strokeCitation4,Citation6,Citation12–14 as well as a higher risk of CVD-related mortalityCitation1. In a meta-analysis of case-control studies, patients who were recently infected with an influenza-like illness had a 2.29 greater odds of AMI compared with controlsCitation15.
Given that influenza is a known trigger of stroke and MI, influenza antiviral treatment is recommended for preventing or reducing the risk of CVD-related complications in patients with existing CVD. In one retrospective claims study of adults diagnosed with influenza, use of antiviral treatment was associated with a 28% lower risk of stroke/transient ischemic attack up to 6 months after influenza diagnosis and a 34% risk reduction at 6 months after influenza diagnosis in patients younger than age 65Citation16. Similarly, there was an 8.5% incidence of recurrent CV events over 30 days among 37,482 CVD patients with influenza who received antiviral treatment compared with a 21.2% incidence among these CVD patients who did not receive treatment – including a significantly lower risk of heart failure, MI, sudden cardiac arrest, and strokeCitation17. Additionally, use of antiviral treatment for influenza may result in significant reductions in HRU and spending compared with no treatment, including short- and long-term reductions in inpatient stays, ED visits, ICU admissions, and total costsCitation11. Further research is needed to better understand the role of antiviral treatment in preventing CVD complications. In addition, the cost of antiviral treatment for influenza in the United States vs the potential savings when clinical encounters for CVD complications are reduced should be explored.
Limitations
Because data were drawn from a claims database analysis, we were not able to account for diagnoses and HRU in the patient’s record that were not submitted for health insurance reimbursement, including diagnoses and treatments received outside the patient’s participating provider network. We were also not able to accurately account for influenza vaccination status. Additionally, data recorded in claims databases are primarily intended for billing purposes and may be subject to coding errors that could impact the accuracy of our findings.
Some patients categorized as having influenza may not have had laboratory-confirmed diagnoses because this study relied only on influenza diagnostic codes. Because we only included CVD patients who sought care for influenza, we were not able to capture non-treatment-seeking patients with CVD and influenza, which could result in an underestimate of the actual proportion of influenza cases among patients with CVD. Additionally, the number of patients diagnosed with influenza in each season was variable, which could reflect differences in severity of illness that we were not able to control for and could explain some of the variability in HRU and cost outcomes across the different influenza seasons.
Lastly, our results may not be generalizable beyond the study population, as data used in this analysis were limited to individuals covered with a US commercial insurance plan or Medicare and captured by the MarketScan databases.
Conclusions
In this large real-world sample of patients with CVD and influenza, CVD patients who received antiviral treatment had fewer CVD-related complications and lower HRU over 180 days than CVD patients who did not receive antiviral treatment. Patients with CVD and influenza who received antiviral treatment also incurred lower outpatient costs. Antiviral treatment for CVD patients could represent a viable strategy for reducing long-term CVD health-related costs attributed to all-cause complications.
Transparency
Declaration of funding
This study was sponsored and funded by Genentech, Inc., South San Francisco, CA.
Declaration of financial/other interests
MC, TMT, RCC, and JS are employees of Genentech/Roche, Inc. and hold Roche stock. SW is an employee of Genesis Research, and SA is a former employee of Genesis Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Author contributions
All authors were involved in study conception and design, acquisition, analysis, and interpretation of data; revising the article critically for important intellectual content; and reviewing and approving the final version to be submitted for publication.
Supplemental Material
Download MS Word (83.3 KB)Supplemental Material
Download MS Word (87.5 KB)Supplemental Material
Download MS Word (14.9 KB)Supplemental Material
Download MS Word (86.9 KB)Supplemental Material
Download MS Word (83.7 KB)Supplemental Material
Download MS Word (83.8 KB)Acknowledgements
Emily A. Kuhl and Esther Tazartes of the Global Outcomes Group provided editorial assistance; these services were funded by Genentech, Inc.
Data availability statement
The data that support the findings of this study are available from IBM MarketScan Research Databases. All relevant data are provided within the manuscript and supporting files.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
The Editor in Chief and Deputy Editor in Chief helped with adjudicating the final decision on this paper.
Previous presentations
Study results were previously presented at the 16th Annual Cardiometabolic Health Congress, 15–16 October 2021; National Harbor, MD.
Related Research Data
References
- Nguyen JL, Yang W, Ito K, et al. Seasonal influenza infections and cardiovascular disease mortality. JAMA Cardiol. 2016;1(3):274–281.
- Macias AE, McElhaney JE, Chaves SS, et al. The disease burden of influenza beyond respiratory illness. Vaccine. 2021;39:A6–14.
- Centers for Disease Control and Prevention. People at higher risk for flu complications; [cited 2021 May 18]. Available from: https://www.cdc.gov/flu/highrisk/index.htm.
- Kwong JC, Schwartz KL, Campitelli MA, et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med. 2018;378(4):345–353.
- Chow EJ, Rolfes MA, O’Halloran A, et al. Acute cardiovascular events associated with influenza in hospitalized adults: a cross-sectional study. Ann Intern Med. 2020;173(8):605–613.
- Chen L, Hao G. The role of angiotensin-converting enzyme 2 in coronaviruses/influenza viruses and cardiovascular disease. Cardiovasc Res. 2020;116(12):1932–1936.
- MacIntyre CR, Mahimbo A, Moa AM, et al. Influenza vaccine as a coronary intervention for prevention of myocardial infarction. Heart. 2016;102(24):1953–1956.
- Khan MS, Shahid I, Anker SD, et al. Cardiovascular implications of COVID-19 versus influenza infection: a review. BMC Med. 2020;18(1):1–3.
- Clar C, Oseni Z, Flowers N, et al. Influenza vaccines for preventing cardiovascular disease. Cochrane Database Syst Rev. 2015;2015(5):CD005050.
- Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis. 2019;68(6):e1–e47.
- Wallick C, Wu N, To TM, et al. Antiviral use is associated with a decrease in the rate of influenza-related complications, health care resource utilization, and costs. J Med Econ. 2021;24(1):386–393.
- Muscente F, De Caterina R. Causal relationship between influenza infection and risk of acute myocardial infarction: pathophysiological hypothesis and clinical implications. Eur Heart J Suppl. 2020;22(Suppl E):E68–72.
- Boehme AK, Luna J, Kulick ER, et al. Influenza‐like illness as a trigger for ischemic stroke. Ann Clin Transl Neurol. 2018;5(4):456–463.
- Kulick ER, Alvord T, Canning M, et al. Risk of stroke and myocardial infarction after influenza-like illness in New York State. BMC Public Health. 2021;21(1):1–8.
- Barnes M, Heywood AE, Mahimbo A, et al. Acute myocardial infarction and influenza: a meta-analysis of case–control studies. Heart. 2015;101(21):1738–1747.
- Madjid M, Curkendall S, Blumentals WA. The influence of oseltamivir treatment on the risk of stroke after influenza infection. Cardiology. 2009;113(2):98–107.
- Casscells SW, Granger E, Kress AM, et al. Use of oseltamivir after influenza infection is associated with reduced incidence of recurrent adverse cardiovascular outcomes among military health system beneficiaries with prior cardiovascular diseases. Cardiovascul Qual Outcomes. 2009;2(2):108–115.