Recurrent stroke admissions with vs without COVID-19 and associated in-hospital mortality: A United States nationwide analysis, 2020

Abstract

BACKGROUND

Coronavirus disease 2019 (COVID-19) has been shown to increase the risk of stroke. However, the prevalence and risk of recurrent stroke in COVID-19 patients with prior stroke/transient ischemic attack (TIA), as well as its impact on mortality, are not established.

AIM

To evaluate the impact of COVID-19 on in-hospital mortality, length of stay, and healthcare costs in patients with recurrent strokes.

METHODS

We identified admissions of recurrent stroke (current acute ischemic stroke admissions with at least one prior TIA or stroke) in patients with and without COVID-19 using ICD-10-CM codes using the National Inpatient Sample (2020). We analyzed the impact of COVID-19 on mortality following recurrent stroke admissions by subgroups.

RESULTS

Of 97455 admissions with recurrent stroke, 2140 (2.2%) belonged to the COVID-19-positive group. The COVID-19-positive group had a higher prevalence of diabetes and chronic kidney disease vs the COVID-19 negative group (P < 0.001). Among the subgroups, patients aged > 65 years, patients aged 45–64 years, Asians, Hispanics, whites, and blacks in the COVID-19 positive group had higher rates of all-cause mortality than the COVID-19 negative group (P < 0.01). Higher odds of in-hospital mortality were seen in the group aged 45-64 (OR: 8.40, 95%CI: 4.18-16.91) vs the group aged > 65 (OR: 7.04, 95%CI: 5.24-9.44), males (OR: 7.82, 95%CI: 5.38-11.35) compared to females (OR: 6.15, 95%CI: 4.12-9.18), and in Hispanics (OR: 15.47, 95%CI: 7.61-31.44) and Asians/Pacific Islanders (OR: 14.93, 95%CI: 7.22-30.87) compared to blacks (OR: 5.73, 95%CI: 3.08-10.68), and whites (OR: 5.54, 95%CI: 3.79-8.09).

CONCLUSION

The study highlights the increased risk of all-cause in-hospital mortality in recurrent stroke patients with COVID-19, with a more pronounced increase in middle-aged patients, males, Hispanics, or Asians.

Key Words: COVID-19; SARS-CoV-2; Recurrent stroke; Mortality; Hospitalization; Comorbidities; Acute ischemic stroke

Core Tip: This study underscores the enhanced all-cause in-hospital mortality risk among recurrent stroke patients who test positive for coronavirus disease 2019 (COVID-19). Notably, the increased mortality risk is most significant in middle-aged individuals (45-64 years), males, and ethnic minorities, including Hispanics and Asians. Data from the National Inpatient Sample in 2020 revealed that COVID-19 patients with prior stroke or transient ischemic attack exhibit higher mortality compared to non-COVID-19 counterparts, alongside a greater prevalence of comorbidities such as diabetes and chronic kidney disease. These findings emphasize the critical need for targeted management strategies in these high-risk groups.

INTRODUCTION

Stroke poses a substantial health burden, affecting around 795000 people annually in the United States and ranking as a leading cause of long-term disability. Nearly 1 in 4 of these occur in patients with a history of stroke[1] i.e., approximately 25% of all strokes are recurrent[2]. There are several preventive strategies to reduce the risk of recurrent stroke, including medication and mitigating the risk factors[3]. Despite these preventive practices, the 5-year cumulative incidence of recurrent stroke remains relatively high, ranging from 16% to 30%[4,5]. Mohan et al[4], reported the cumulative risk of recurrence after first event stroke to be 3.1% at 30 days, 11.1% at 1 year, 26.4% at 5 years, and 39.2% at 10 years. To compound this issue, the emergence of coronavirus disease 2019 (COVID-19) has introduced new challenges and is linked to an increased risk of acute ischemic stroke[6,7]. In our study, we investigated the influence of COVID-19 on in-hospital mortality rates among patients admitted for recurrent stroke, comparing those who tested positive for the virus to those who did not.

MATERIALS AND METHODS

Study design and setting

The data utilized in this investigation were obtained from the National Inpatient Sample (NIS) (2020) database, an organization sponsored by the Agency for Healthcare Research and Quality. The NIS was provided with discharge data for over 7 million hospitalizations spanning 48 states by over 1000 hospital facilities[3]. This study focused on hospitalized individuals with recurrent stroke diagnoses.

Study population and data collection

Our study population was primarily composed of recurrent stroke hospitalizations. We divided these patients into two cohorts based on their COVID-19 test results: The COVID-19 positive (+) and COVID-19 negative (-) cohorts. A recurrent stroke was defined as any new acute ischemic stroke occurring with an onset separate from that of the index stroke or transient ischemic attack history. The primary outcome was in-hospital mortality. In addition, we conducted a subgroup analysis of in-hospital mortality by age, gender, and race. We evaluated demographics and baseline characteristics.

Statistical analysis

Descriptive statistics were utilized to analyze the demographics and comorbidities of the study population. We evaluated differences in baseline characteristics between the two cohorts using χ² tests for categorical variables and the Mann-Whitney U test for continuous variables (non-normal distribution). The in-hospital mortality was determined using multivariable logistic regression analyses adjusted for potential confounders. The results were presented as adjusted odds ratios (aORs) with 95% confidence intervals (CI).

RESULTS

We found that there were 97255 hospitalizations due to recurrent strokes in the NIS database for the year 2020. Among recurrent stroke hospitalizations, 2140 (2.2%) belonged to the COVID-19 (+) cohort, and 95115 (97.8%) belonged to the COVID-19 (-) cohort. The COVID-19 (+) cohort predominantly comprised individuals aged 65 and above, accounting for 72.9% of cases. The proportion of COVID-19 + patients was greater in males (53.5%) compared to females (46.5%). When examining ethnicity, whites constituted the majority of the COVID-19 (+) cohort at 53.2%, blacks at 25.1%, Hispanics at 17.2%, and Asian/Pacific Islanders at 4.2%. Regarding socioeconomic status, those in the lowest income percentile (0–25) had the highest representation within the COVID-19 (+) cohort at 36.5%. Among healthcare facilities, urban teaching hospitals had the highest proportion of COVID-19 (+) cases at 75%, compared to urban non-teaching hospitals at 16.6% and rural hospitals at 8.4%. Moreover, patients with comorbidities such as diabetes (53.0%) and chronic kidney disease (CKD) (30.8%) were more frequently found within the COVID-19 (+) cohort compared to the COVID-19 (-) cohort (Table 1).

Table 1 Baseline characteristics, comorbidities and outcomes of recurrent/subsequent stroke admissions with vs without coronavirus disease 2019, 2020.

Variables		Total recurrent stroke (AIS with prior stroke/TIA) (n = 97255)		P value
		No COVID-19 (n = 95115), %	COVID-19 (n = 2140), %
Age in years at admission	Median (IQR)	72 (62-82)	73 (63-82)	0.001
	18-44	3.6	3.7
	45-64	27.0	23.4
	≥ 65	69.4	72.9
Sex	Male	51.0	53.5	0.023
	Female	49.0	46.5
Race	White	68.9	53.2	< 0.001
	Black	19.3	25.1
	Hispanic	8.6	17.2
	Asian/Pacific Islander	2.8	4.2
	Native American	0.4
Median household income national quartile for patient ZIP code	0-25th	31.3	36.5	< 0.001
	26-50th	27.1	30.1
	51-75th	23.1	18.0
	76-100th	18.4	15.4
Payer type	Medicare	72.8	74.6	0.118
	Medicaid	10.2	9.0
	Private	17.0	16.4
Hospital location & teaching status	Rural	6.7	8.4	0.001
	Urban Nonteaching	18.6	16.6
	Urban Teaching	74.7	75.0
Hospital region	Northeast	14.5	16.8	< 0.001
	Midwest	21.1	19.2
	South	45.2	47.9
	West	19.2	16.1
Comorbidities
Hypertension		89.5	85.7	< 0.001
Diabetes		43.2	53.0	< 0.001
Hyperlipidemia		66.8	61.4	< 0.001
Obesity		14.9	16.1	0.124
Peripheral vascular disease		11.7	8.6	< 0.001
Tobacco use disorder		28.9	28.3	0.535
Prior MI		10.3	5.8	< 0.001
Prior VTE		5.6	6.3	0.162
Cancer		5.0	3.7	0.009
Chronic kidney disease		22.7	30.8	< 0.001
Alcohol abuse		4.3	2.8	0.001
Drug abuse		3.1	2.1	0.007
Depression		11.8	9.6	0.001
Chronic pulmonary disease		17.3	15.0	0.004
Hypothyroidism		15.2	14.0	0.133
Other thyroid disorders		2.3	2.1	0.502
Valvular disease		2.7	1.6	0.002
Autoimmune conditions		3.2	2.8	0.283
Outcomes
All-cause in-hospital mortality		4.0	22.9	< 0.001
Disposition of patient	Routine	36.6	25.2	< 0.001
	Transfer to short-term hospital	2.8	3.4
	Transfer other: SNF, ICF, etc.	38.6	49.7
	Home health care	21.9	21.8
Length of stay (days)	Median (IQR)	3 (2-6)	7 (3-13)	< 0.001
Hospital charges (USD)	Median	$52662	$80888	< 0.001

P < 0.05 is noted to be statistically significant. MI: Myocardial infarction; VTE: Venous thromboembolism; SNF: Skilled nursing facility; ICF: Intermediate care facility; IQR: Inter-quartile range; TIA: Transient ischemic attack; COVID-19: Coronavirus disease 2019.

Patients in the COVID-19 (+) cohort showed poorer outcomes, with 49.7% requiring disposition to facilities like skilled nursing facility, intermediate care facility, etc., and 21.8% requiring home health care. The median length of stay was higher (7 days) for the COVID-19 (+) cohort compared to COVID-19 (-) (3 days). The median cost of hospitalization was also higher among the COVID-19 (+) cohort ($80888) compared to patients without COVID-19 ($52662) (all P-values < 0.005) (Table 1). Unadjusted all-cause mortality was substantially higher among recurrent stroke patients who belonged to the COVID-19 (+) cohort compared to COVID-19 (-) (22.9% vs 4.0%) (Table 1).

Using multivariate regression after adjusting for all factors and covariates, our analyses showed high in-hospital mortality among recurrent stroke patients with COVID-19 (+) (aOR: 7.01, 95%CI: 5.36–9.18). Subgroup analyses revealed higher odds among patients aged 45-64 (aOR: 8.4, 95%CI: 4.18-16.91) compared to age group 65 or greater (aOR: 7.04, 95%CI: 5.24-9.44); among males (aOR: 7.82, 95%CI: 5.38-11.35) compared to females (aOR: 6.15, 95%CI: 4.12-9.18). Although patients of all races exhibited significant adjusted odds of in-hospital mortality, Hispanics (aOR: 15.47, 95%CI: 7.61-31.44) and Asian Pacific Islanders (aOR: 14.93, 95%CI: 7.22-30.87) had almost three times more odds than Blacks (aOR: 5.73, 95%CI: 3.08-10.68), and White population (aOR: 5.54, 95%CI: 3.79-8.09) (All P value < 0.005) (Table 2).

Table 2 Multivariable logistic regression assessing impact of coronavirus disease 2019 on mortality following recurrent stroke admissions.

In-hospital mortality	COVID-19	Adjusted OR	95%CI		P value
			Lower Limit	Upper limit
Overall mortality	Yes vs No	7.01	5.36	9.18	< 0.001
In-hospital mortality by individual subgroup
Ages 45-64	Yes vs No	8.4	4.18	16.91	< 0.001
Ages 65 and above	Yes vs No	7.04	5.24	9.44	< 0.001
Male	Yes vs No	7.82	5.38	11.35	< 0.001
Female	Yes vs No	6.15	4.12	9.18	< 0.001
Whites	Yes vs No	5.54	3.79	8.09	< 0.001
Blacks	Yes vs No	5.73	3.08	10.68	< 0.001
Hispanics	Yes vs No	15.47	7.61	31.44	< 0.001
Asian/Pacific Islanders	Yes vs No	14.93	7.22	30.87	< 0.001

P < 0.05 indicates statistical significance. Multivariable regression models were adjusted for baseline demographics, hospital level characteristics and relevant comorbidities. COVID-19: Coronavirus disease 2019; OR: Odds ratio.

DISCUSSION

Hospitalizations for recurrent strokes in patients who also tested positive for COVID-19 were associated with higher mortality rates longer stays in the hospital and increased total healthcare costs. Within the COVID-19 (+) cohort, it was observed that men, individuals in middle age, as well as Hispanic and Asian patients, faced a greater risk of in-hospital mortality.

Our findings align with other studies indicating a significant increase in risk-associated deaths from heart disease and stroke among COVID-19 patients, particularly among ethnic and racial minorities[8]. The heightened mortality risk is intricately linked to the interplay between inflammation and endothelial dysfunction induced by COVID-19. Severe cases trigger a cytokine storm, leading to endothelial injury and thrombotic complications. The study by Lee et al[9]. further elucidates how COVID-19 antibody-mediated cytotoxicity against endothelial cells initiates vascular complications, exacerbating damage in patients with recurrent stroke. The severe stroke presentations in COVID-19 (+) patients[10] can be attributed to COVID-19-induced inflammation and immune dysregulation. Additionally, decreased emergency department visits and delayed hospital admissions due to the pandemic contributed to poor outcomes[11].

While our study revealed that most patients admitted with recurrent acute ischemic stroke and COVID-19 were in the older age group (> 60 years), the adjusted odds for in-hospital mortality were higher across all age groups. Interestingly, the middle-aged group exhibited higher odds compared to other age groups. These results are consistent with findings in other studies that suggested older adults were better protected due to fewer contacts with exposure. For instance, Malmgren et al[12] in Washington State reported a decline in COVID-19 among older individuals and an increase in younger patients, speculating that public warnings targeted those aged 60 and older. In contrast, younger adults had more social interactions. This finding also aligns with studies that hypothesized older adults were better protected[13]. Possible explanations for poorer outcomes in middle-aged include that they may have more subclinical chronic conditions like undiagnosed hypertension and poor metabolic health, leading to worse COVID-19 outcomes[14,15], and this age group may also have a dysregulated immune response leading to increased mortality[16].

Ethnic and racial disparities were evident, with Hispanics and Asian Pacific Islanders showing alarmingly higher odds of mortality. These results align with existing literature highlighting the disproportionate impact of COVID-19 on minority racial and ethnic groups, with hospitalizations being highest among Hispanic/Latino patients[17]. A multicenter case-control study conducted in England and Scotland during the first wave of the pandemic found that Asian ethnicity is strongly linked to COVID-19-related stroke, with the proportion of cases among Asians being more than twice the controls[18]. Annual United States mortality study of 2020 COVID-19-related deaths investigating the impact of socioeconomic position showed that low socioeconomic position and Hispanic ethnicity also stand out as risk factors for COVID-19-related mortality[19,20].

Adjusted subgroup analysis also showed that males had higher in-hospital mortality compared to females. Existing literature shows that there is a more significant burden of stroke deaths among women[21]. However, our study findings showed increased mortality in men compared to women. This finding could have resulted from poorer outcomes from COVID-19 disease among men. These worse outcomes among men suffering from COVID-19 could be attributed to inherent immune differences, an increased prevalence of unhealthy behaviors such as smoking and consuming alcohol, and a higher prevalence of metabolic risk factors among men[22-24].

Our study revealed an elevated prevalence of diabetes and CKD among patients with recurrent stroke and COVID-19. This finding can be attributed to the immunosuppressed nature of these conditions[25]. Diabetic and CKD patients exhibit worsened outcomes due to COVID-19 disease, including higher hospitalization rates, severe pneumonia, acute respiratory distress syndrome, the need for dialysis, and increased mortality[26,27]. Persistent hyperglycemia in diabetes hinders the immune response due to the pro-inflammatory state induced by elevated levels of inflammatory markers such as interleukin-6 and C-reactive protein, aggravating worse clinical outcomes[28]. Concurrently, CKD patients face increased thrombotic risk due to chronic inflammation and uremia[29]. Hypertension, a significant COVID-19 risk factor[30,31], predisposes infected individuals to severe disease through endothelial dysfunction-mediated hypercoagulability[32]. Exploring the impact of the COVID-19 pandemic on the management of chronic conditions reveals a pandemic-induced decline in doctor visits, particularly affecting vulnerable populations[33]. This decline exacerbates comorbidities, raising the risk of recurrent stroke as medication adherence and healthcare continuity wane[34,35]. Our study also highlights the increased risk of recurrent stroke among obese patients, consistent with current literature[36,37]. The pandemic-driven rise in average BMI and obesity prevalence, potentially stemming from decreased physical activity and a sedentary lifestyle, adds to the multifaceted challenges posed by COVID-19[38,39].

Recurrent stroke poses a significant burden on both patients and the healthcare system, with mortality ranging from 11.6% to 25.9% for in-hospital 30-day or 4-year periods[10]. Disability-adjusted life years (DALY) analysis by Hong et al[40] indicates a DALY loss of 3.82 after the index stroke, with an additional 0.84 DALY lost due to recurrent stroke. The average healthcare cost per person for stroke, including inpatient care, rehabilitation, and follow-up, is estimated at USD 140048[41]. Our study reports median in-hospital costs for recurrent stroke and COVID-19 at $80888, $28226 higher than those without COVID-19. Patients in the COVID-19 (+) cohort had a longer length of stay at seven days compared to those in the COVID-19 (-) cohort (3 days).

Clinical implications

Given this significant burden, our study has many future clinical implications. Rigorous management of risk factors and comorbid conditions is necessary. Timely screening, healthy behaviors, and equitable healthcare access are pivotal in reducing the disparities found in our study. Telemedicine and tailored prevention plans are crucial for achieving continuity of care and must be further explored for less severe cases.

Limitations

Through this study, we highlighted various risk factors for poor outcomes in patients admitted due to recurrent stroke and COVID-19. However, it is imperative to acknowledge the retrospective nature of our study and its inherent limitations. The observational nature of the study limits control over all potential confounders. Firstly, there might be administrative coding errors in the NIS database, which could over or underestimate COVID-19 and recurrent strokes. Variability in documentation and coding of comorbidities and outcomes across different healthcare facilities could influence the results. Secondly, our study only focuses on data from hospitalized patients, introducing potential sampling bias, as it overlooks undiagnosed or milder cases of COVID-19 not requiring hospitalization. Lack of outpatient data and long-term COVID-19 symptoms monitoring might impact results. An additional constraint of our study, stemming from its reliance on the NIS database for 2020, is the absence of vaccination status data for the subjects early in the pandemic. This limitation is particularly critical when assessing the potential mitigating impact of COVID-19 vaccines on the severe presentation of stroke, as demonstrated by Jiang et al[42], who found an association between even partial vaccination and a lower risk of major adverse cardiovascular events post-COVID-19 infection. Thirdly, data on the incidence of stroke among various ethnicities could have been influenced by reporting bias, as previous studies have shown a higher risk of stroke among African Americans. Finally, the data was not subclassified based on mechanisms of previous stroke, such as large vessel atherosclerosis or cardioembolic stroke. This subclassification is crucial for determining outcomes based on underlying mechanisms, and future prospective studies need to focus on incorporating this data to improve the management of these patients. In this context, future studies should focus on these limitations, and further prospective studies should be done with vaccination status data to understand the efficacy of vaccines in preventing severe manifestations and improving vaccination rates. Also, studies need to be done to understand the long-term implications of COVID-19 disease on patients with a history of stroke or TIA.

CONCLUSION

Our study shows increased in-hospital mortality after recurrent stroke and COVID-19, especially among the age group 45–64 years, Hispanics, and males. Given these findings, it is imperative to monitor risk factors such as diabetes rigorously, consistently screen them with HbA1c tests, and maintain strict glucose control, as such patients are at significant risk for recurrent stroke. Ensuring these patients stay compliant with secondary prevention strategies such as statin and antiplatelet agent use is paramount. Ethnic disparities evident in our study might be due to the lack of access and increased disease burden in these minority populations. Possible ways to reduce disparities include implementing evidence-based practices system-wide with quality improvement initiatives and encouraging best practices. New policies must address these disparities and reinforce existing policies to improve health equity among all ethnicities. Further prospective studies are essential to unraveling the mechanisms underlying the long-term consequences of COVID-19, particularly stroke incidence. Designing a comprehensive timeline for stroke occurrences and post-Covid-19 infection will contribute to a deeper understanding of this phenomenon. As more data on the long-term sequelae of COVID-19 evolves, the risk of stroke and other thromboembolic phenomena could be better understood.