Sex differences in comorbidities associated with exclusion from thrombolytic therapy in ischemic stroke patients with heart failure: A retrospective data analysis

Abstract

Objective

The objective of this study is to identify baseline risk factors in AIS-HF inclusion and exclusion from rtPA therapy and determine whether the baseline factors are different in male and female patients.

Methods

This is a retrospective data analysis of data from the PRISMA Health stroke registry. Logistic regression models were developed to generate odds ratios (OR) that predict risk factors that are associated with male and female AIS-HF patients excluded from rtPA.

Results

A total of 590 AIS-HF were identified. Of this, 76.78% were females while 23.22 were males. Male AIS-HF patients with carotid artery stenosis (CAS) (OR = 0.279, 95% CI, 0.083–0.944, P = 014), were more likely to be excluded from rtPA, while those with higher National Institutes of Health Stroke Scale (NIHSS) scores (OR = 1.096, 95% CI, 0.907–3.526, P < 0.001), were more likely to be included for rtPA. Female AIS-HF patients with chronic renal disease (CRD) (OR = 0.159, 95% CI, 0.050–0.503, P = 002), were likely to be excluded from rtPA therapy, while those on antidepressant use (OR = 5.322, 95%, CI 1.488–19.03, P < 0.001), that presents with higher NIHSS scores (OR = 3.336, CI 1.699–6.950, P < 0.001) were more likely to be included for rtPA.

Conclusions

Our results reveal that male AIS-HF patients with a history of CAS were more likely to be excluded from rtPA therapy, whereas, females who present with CRD were more likely to be excluded from rtPA. These findings indicate the need for the development of management strategies to improve the use of rtPA for male and female AIS-HF patients.

Keywords

acute ischemic stroke heart failure rtPA males females

Introduction

Heart failure (HF) poses a significant health risk to both females and males, especially at older age.¹ While the overall lifetime risk of HF is comparable for males and females, notable distinctions exist in the epidemiology, causes, development, risk factors, and prognosis based on sex.² Middle-aged females present with less likelihood of incident HF compared to middle-aged males; however, at older ages, females presented with increased risk than males.³ Males exhibited higher susceptibility to the onset of HF with reduced ejection fraction (HFrEF), conversely, females are predisposed to developing HF with preserved ejection fraction (HFpEF).⁴ This divergence can be attributed to the inclination of females toward coronary microvascular dysfunction and endothelial inflammation, as opposed to the propensity of males for macrovascular coronary artery disease and myocardial infarction. Important differences exist between males and females in traditional risk factors. For example, diabetes confers the most risk for HF development in females but not in males.⁵ Despite the similar prevalence of hypertension among males and females, HF risk was reported to be tripled for females with hypertension and doubled for males with hypertension,⁴ and the consequences of hypertension cause more severe effects in females when compared with males.⁴

Heart failure is a complicated condition associated with cardiac distress, resulting in increased intracardiac pressures.⁶ Ischemic stroke is caused by the occlusion of the cerebral artery resulting in a sudden loss of blood flow to specific regions of the brain, and loss of neurologic functions. Since HF contributes to the release of prothrombotic and proinflammatory mediators,⁷ HF may affect the efficacy of acute recanalization stroke therapies, including recombinant tissue plasminogen activator (rtPA).⁷ rtPA and endovascular therapy (EVT) are currently two available reperfusion therapies that have been shown to improve outcomes in AIS patients.⁸ Recombinant tissue plasminogen activator is used for thrombolysis /thrombolytic therapy, and it has been shown that less than 5% of AIS patients arriving at an emergency department within the time frame for the protocol are treated with rtPA.⁸ Many untreated patients are excluded based on some factors, and observational studies, indicate that some exclusion criteria are unnecessarily restrictive.⁹ For example, advanced age, rapidly improving or minor symptoms, severe hypertension, severe stroke or coma, combined history of prior stroke and diabetes, patients with unruptured intracranial aneurysms, the degree of thrombocytopenia, pregnancy, time from lumbar puncture, and recent surgery are all considered exclusion factors for rtPA.¹⁰ The data regarding the safety of rtPA for AIS patients with recent surgery are very few. Given the rarity of some of the contraindications or exclusion factors and unique aspects of individual cases, generalizing the results of some observational studies may be difficult when making decisions about rtPA.⁹ However, the lack of quality evidence regarding many of the risk factors that constitute contraindications for rtPA provides opportunities for future research on the risk factors or comorbidities associated with exclusion from rtPA.

The National Institutes of Health Stroke Scale (NIHSS) score is well known for assessing neurologic deficits after a stroke.¹¹ Patients with an NIHSS score of ≤7 at the time of admission are reported to be more likely to make positive neurologic progress, whereas AIS patients presenting with an NIHSS score of >7 are more likely to experience an initial worsening of neurologic functions after a hemispheric stroke.¹² Findings from existing studies reveal the strong predictive capability of initial or baseline NIHSS scores to help identify the early worsening neurologic functions in hemispheric stroke patients.

Therefore, stroke severity is anticipated to be greater in AIS patients with a history of chronic heart failure (AIS-HF) compared with AIS patients without HF.¹³ Females often present with worse baseline function, more comorbidities, poorer post-stroke outcomes, and an overall greater risk for stroke compared with males.¹⁴ Females treated with rtPA demonstrate an improvement in long-term self-efficacy, abolishing the usual sex difference in outcomes.¹⁵ Furthermore, there are no sex-based variations in the safety of rtPA therapy, both in terms of incidence and complications following rtPA.¹⁵ However, patients not receiving thrombolytic therapy exhibited worse outcomes among females compared with males,¹⁶ suggesting that females may represent a crucial clinical indicator of patients who may benefit from rtPA, especially later when the risk factors may or may not be equally distributed. Given that conventional risk factors including diabetes, obesity, tobacco use, socioeconomic status, and hypertension exert a more pronounced influence on the risk of HF in females than in males,¹⁷ HF in addition to other comorbidities that are associated with increased stroke severity may contribute to females’ increased likelihood of exclusion from thrombolytic therapy in comparison to males. This is because exclusion-associated risk factors may not be distributed in equal proportions between males and females in AIS patients with a history of HF. Therefore, our objective is to identify risk factors in AIS-HF populations with and without rtPA therapy and determine whether these baseline factors are different in male and female AIS-HF patients.

Methods

Study population

This is an observational study using retrospective data provided by the PRISMA Health stroke registry using data collected from January 2010 to December 2016. The study cohort included patients aged 18 to over 80 and represents a subset of data previously published.^13,18 The study was approved by the IRB of the PRISMA Health Ethics Committee. Classification of ischemic stroke was determined by neurological assessment with computed tomography (CT) or magnetic resonance imaging (MRI).

AIS and HF were based on the American Heart Association/American Stroke Association definition.¹⁹ Ischemic stroke was defined based on clinical and tissue criteria as brain death attributable to ischemia, based on neuropathological, neuroimaging, and clinical evidence of permanent injury, while HF was defined as a complex clinical syndrome with symptoms and signs that result from any structural or functional impairment of ventricular filling or ejection of blood.¹⁹

For inclusion for ischemic stroke, we focused on the main codes which are ICD-8 433/434 ICD-9 434 (occlusion of the cerebral arteries), and ICD-10 I63 (cerebral infarction). Inclusion criteria included both initial and recurrent ischemic strokes (ICD-10 code I63) with a prior history of HF. Advances in neuroimaging have resulted in many events that would previously have been labeled as TIA now being considered minor strokes. Since this is an area of ongoing controversy, we excluded data for patients solely evaluated for codes for TIA (ICD-9 435 or ICD-10 G45), by not considering episodes of TIA as acute stroke. Suspected or confirmed patients diagnosed with any form of hemorrhagic stroke were excluded from the data, and AIS patients with reported missing variables for HF were excluded.

Baseline characteristics of AIS-HF patients receiving rtPA and those excluded from rtPA were collected, including demographics, and relevant comorbidities. Information regarding sociodemographic characteristics, including age, sex, race, and ethnicity, as well as stroke risk factors such as prior stroke history, hypertension, ambulatory status prior to admission, at admission and discharge, heart failure, diabetes mellitus, atrial fibrillation, family history of stroke, obesity, smoking, and alcohol use were collected. Data regarding medications, blood pressure measurement, and laboratory values were extracted, and the values obtained nearest to the date of the index study established the baseline. Lastly, data on ischemic stroke severity was collected using the National Institutes of Health Stroke Scale (NIHSS).

Data analysis

Statistical Package for Social Sciences version 29.0 for Windows (SPSS, Chicago, IL) was used for the computation of all data. The data was tested for normal distribution with the Kolmogorov–Smirnov test. In our power analysis, 453 female AIS-HF patients produced 80% power and d = 0.20, while 137 male AIS-HF patients produced 72% power and d = 0.15. PASS 2023, version 23.0.2, was used for the power analysis. For the univariate analysis, demographic and clinical risk factor comparisons between AIS patients treated and those excluded from rtPA were performed using the student t-test for normally distributed data, the Mann–Whitney U-test for continuous variables, and the chi-square test were considered for categorical variables. Continuous variables results were presented as means ± standard deviation (SD) while discrete variables were presented as patient count and percentage in the population of interest. The two groups were then separated based on how male and female were treated and excluded from rtPA. After the univariate analysis of all variables, multivariate analysis was conducted to determine specific demographics and risk factors in male and female AIS patients that are associated with inclusion or exclusion from rtPA treatment.

Multivariable-adjusted logistic regression models determined associations between risk factors and exclusion from rtPA after correction for covariates. The regression models were developed to determine risk factors that are associated with males and females AIS-HF patients excluded from rtPA. We built logistic regression analyses using the established predictors from the univariate analysis. Variables were cross-tabulated to discard multicollinearity. In addition, we repeated the test for non-categorized continuous variables and separately performed the analysis to detect possible statistical bias. We intentionally chose factors with a p-value < 0.1 to identify independent predictors of exclusion or inclusion that were approaching significance and, theoretically, more likely to significantly contribute to the model. Moreover, it helped to minimize discrepancies due to non-comparable parameters. The logistic regression analysis was then performed by backward selection method using significant predicted variables from the univariate analysis. We chose the back selection method because it allowed us to include all the initially selected risk factors that were approaching significance in the model and then systematically remove them if they did not contribute to the overall significance of the model.

Two multivariate logistic models were developed. The first incorporated only risk factors for males AIS-HF patients while the second model included only risk factors for females AIS-HF patients. For the logistic models, inclusion, or exclusion from rtPA for males or females served as the dependent variable, and the demographics and risk factors of AIS-HF patients were used as independent variables. The adjusted odds ratios (ORs) for risk factors were calculated from their respective coefficients in the logistic regression models. Odds ratios and 95% confidence intervals (95% CIs) of outcome measures were obtained from this model with significance at P < 0.05. The odds ratios were used to predict variables that were significantly associated with inclusion and exclusion from rtPA for male and female AIS-HF patients. The logistic regression model's sensitivity, specificity, and accuracy were determined using the overall correct classification percentage and area under the Receiver Operating Curve (ROC). Multicollinearity and interactions among independent variables were analyzed using the Hosmer–Lemeshow test. The probability level for all tests was P < 0 .05.

Results

A total of 590 patients with HF who experienced AIS were identified. Among them, 453 were females, and 137 were males. The flowchart for male and female HF-AIS patients treated and excluded from rtPA is presented in Figure 1. Table 1 presents the demographic and clinical characteristics of AIS-HF patients categorized based on inclusion or exclusion from rtPA. AIS-HF patients excluded from rtPA therapy tended to be older, less likely to be of Hispanic origin, had lower BMI, less likely to be obese, had a history of previous stroke, and presented with higher NIHSS scores. Additionally, this group exhibited higher serum creatine levels, ambulated independently before the stroke, maintained improved ambulation at discharge, and was treated in the emergency unit. Table 2 presents the stratification of the AIS-HF patient population based on sex and their exclusion criteria for rtPA therapy. For the inclusion group, females were more likely to be older and with elevated serum creatine levels, lower diastolic pressure, CAD, alcohol use, and improved ambulation at discharge. Moreover, they showed higher rates of depression and the use of antidepressants. In the exclusion group, females were older, less likely to be smoking and take alcohol, had lower levels of elevated HDL, presented with CAS, and were more likely to exhibit elevated serum creatine levels and CAD. They were also inclined to take antidepressant medication, ambulate before the stroke event, and continue ambulation after discharge.

Figure 1.

Flowchart for male and female HF-AIS patients treated and excluded from rtPA.

Table 1.

Baseline risk factors in stroke patients with a history of heart failure stratified by exclusion or inclusion for rtPA therapy. Analyzed continuous variables are expressed as Mean ± SD, and discrete data are presented as percentage frequency.

Baseline risk factors	Inclusion	Exclusion	P-value
Age Group: No. (%)
<50	12 (31.6)	26 (68.4)	0.086^a
50–59	23 (32.4)	48 (67.6)
60–69	29 (25.4)	85 (74.6)
70–79	32 (22.2)	112 (77.8)
> = 80	41 (18.4)	182 (81.6)
Mean ± SD	69.31 ± 14.553	73.89 ± 13.539	<0.001*^b
Sex
Males	56 (40.88)	81 (59.12)	0.103
Females	112 (24.72)	341 (75.28)	0.001*
Race: No (%)
White	97 (22.2)	339 (77.8)	0.622
Black	36 (26.3)	101 (73.7)	0.622
Other	4 (23.5)	13 (76.5)	0.622
Hispanic Ethnicity: No. (%)	3 (0.021)	0 (0.0)	0.002*
BMI: Mean ± SD	29.975 ± 7.924	28.213 ± 7.724	0.021*^b
Medical History: No. (%)
Atrial Fib	50 (20.2)	197 (79.8)	0.146^a
Coronary Artery Disease	71 (21.3)	263 (78.7)	0.197^a
Carotid Artery Stenosis	16 (14.3)	36 (85.7)	0.155^a
Depression	26 (26.3)	73 (73.7)	0.432^a
Diabetes	64 (22.1)	226 (77.9)	0.515
Drugs or Alcohol	19 (29.0)	32 (71.0)	0.431^a
Dyslipidemia	80 (22.7)	272 (77.3)	0.730
Stroke Family History	13 (32.5)	27 (67.5)	0.150
Chronic Heart Failure	168 (28.47)	422 (71.53)	0.051^a
Hypertension	396 (75.9)	126 (24.1)	0.144^a
Migraine	5 (100.0)	0 (0.0)	0.217^a
Obesity	177 (71.4)	71 (28.6)	<0.008*
Previous Stroke	162 (83.1)	33 (16.9)	0.011*
Previous TIA (> 24 h)	36 (72.0)	14 (28.0)	0.066
Prosthetic Heart Valve	11 (84.6)	2 (15.4)	0.499
Peripheral Vascular Disease	45 (77.6)	13 (22.4)	0.878
Chronic Renal Disease	92 (83.6)	18 (16.4)	0.059
Sickle Cell	1 (100.0)	0 (0.0)	0.582^a
Medication History: No (%)
HTN medication	123 (23.5)	401 (76.5)	0.6821^a
Cholesterol Reducer	79 (23.1)	263 (76.9)	0.935^a
Diabetic Medication	52 (23.1)	173 (76.9)	0.961
Antidepressant	30 (29.1)	73 (70.9)	0.118^a
Initial NIHSS Score: No (%)
0–9	58 (20.8)	221 (79.2)	0.008*^a
10–14	26 (38.8)	41 (61.2)
15–20	19 (26.9)	49 (72.1)
21–25	16 (35.6)	29 (64.4)
Mean ± SD	7.63 ± 7.84	8.90 ± 8.56	<0.001*^b
Lab values: Mean ± SD
Total cholesterol	161.69 ± 51.88	160.70 ± 47.58	0.844^b
Triglycerides	131.84 ± 93.37	132.66 ± 114.40	0.942
HDL	39.20 ± 13.85	40.51 ± 14.23	0.370^b
LDL	99.52 ± 45.59	96.13 ± 37.02	0.405^b
Lipids	6.52 ± 1.78	6.71 ± 1.92	0.324
Blood Glucose	158.86 ± 96.02	153.06 ± 81.49	0.486
Serum Creatinine	1.41 ± 0.97	1.49 ± 1.06	0.441^b
INR	1.14 ± 0.17	1.31 ± 0.77	<0.001*
Vital Signs: Mean ± SD
Heart Rate	83.70 ± 17.26	82.05 ± 19.49	0.343^b
Blood Pressure Systolic	152.32 ± 26.55	148.00 ± 29.21	0.105
Blood Pressure Diastolic	82.58 ± 19.81	80.17 ± 20.54	0.218^b
Ambulation Status Prior to Event: No. (%)
Ambulate Independently	122 (26.4)	340 (73.6)	0.004*^a
Ambulate with Assistance	5 (11.9)	37 (88.1)
Unable to Ambulate	8 (16.7)	40 (83.8)
Not Documented	2 (5.4)	35 (94.6)
Ambulation Status on Admission: No. (%)
Ambulate Independently	13 (14.6)	76 (85.4)	0.024^a
Ambulate with Assistance	28 (19.7)	114 (80.3)
Unable to Ambulate	67 (24.8)	203 (75.2)
Not Documented	29 (32.6)	60 (67.4)
Ambulation Status on Discharge: No. (%)
Ambulate Independently	43 (27.6)	113 (72.4)	0.343^a
Ambulate with Assistance	39 (19.6)	160 (80.4)
Unable to Ambulate	42 (24.3)	131 (75.7)
Not Documented	1 (33.3)	2 (66.7)
First Care Received: No. (%)	30 (31.9)	64 (68.1)
Emergency Department	106 (21.6)	384 (78.4)	0.031*
Direct Admission	30 (31.9)	64 (68.1)
Improved Ambulation: No. (%)	57 (30.6)	129 (69.4)	0.005*^a

Pearson's Chi-Squared test

Student's T test

* P-value < 0.05

Table 2.

Baseline risk factors of stroke patients with and without heart failure stratified by inclusion or exclusion from rtPA therapy, and categorized by sex. Analyzed continuous variables are presented as Mean ± SD, and discrete data are presented as percentage frequency.

	Inclusion			Exclusion
Baseline risk factors	Men	Women	P value	Men	Women	P value
Age Group
<50 yrs	6 (50.0%)	6 (50.0%)		15 (57.7%)	11 (42.3%
50–59 yrs	18 (78.3%)	5 (21.7%)		29 (60.4%)	19 (39.6%)
60–69 yrs	20 (69.0%)	9 (31.0%)		38 (44.7%)	47 (55.3%)
70–79 yrs	14 (43.8%)	18 (56.3%)		47 (42.0%)	65 (58.02%)
>80 yrs	16 (39.0%)	25 (61.0%)		42 (23.1%)	140 (76.9%)
Age	66.58±13.80	72.52±14.87	0.010*	69±.39	76.62±12.66	<0.001*
Total Cholesterol	161.90±51.12	161.45±53.17	0.961	155.20±48.16	164.07±46.82	0.092
Triglycerides	129.99±94.38	133.98±92.94	0.809	130.13±107.74	136.77±124.82	0.599
HDL	37.86±11.04	40.74±16.46	0.238	43.10±14.76	36.29±12.26	<0.001*
LDL	100.61±46.60	98.27±44.77	0.772	96.51±35.23	95.49±39.92	0.803
Lipids	5.60±1.71	6.43±1.86	0.589	6.70±1.87	6.74±2.01	0.872
Blood Glucose	159.29±70.85	158.37±119.35	0.956	155.90±79.88	84.2	0.345
Serum Creatinine	1.61±1.22	1.18±0.46	0.01	1.37±0.92	1.68±1.25	0.003*
Platelet Count on Arrival	176929.69±105068.79	148425.00±147438.77	0.477	74499.62±119903.51	28104.58±65139.79	0.247
INR	1.14±0.18	1.14±0.16	0.79	1.27±0.50	1.39±1.06	0.15
Heat Rate	83.77±17.80	83.62±16.74	0.959	82.85±20.34	80.73±17.98	0.26
Pressure Systolic	155.05±24.65	149.11±28.496	0.193	149.91±29.32	144.87±28.84	0.075
Pressure Diastolic	85.84±19.20	78.75±20.00	0.036	79.75±20.89	80.86±19.99	0.577
BMI	29.60 ± 7.34	30.41±8.59	0.544	28.10±8.11	28.39±7.06	0.7
Race (Black)	23 (63.9%)	13 (36.1%)	0.353	40 (39.6%)	61 (60.4%)	0.759
Atrial Fib	24 (48.0%)	26 (52.0%)	0.284	65 (33.0%)	132 (67.0%)	0.067
CAD	44 (62.0%)	27 (38.0%)	0.053	113 (43.0%)	150 (57.0%)	0.007*
CAS	4 (66.7%)	2 (33.3%)	0.525	19 (52.8%)	17 (47.2%)	0.053*
Depression	9 (34.6%)	17 (65.4%)	0.027	24 (32.9%)	49 (67.1%)	0.349
Diabetes	38 (59.4%)	26 (40.6%)	0.238	87 (385%)	139 (61.5%)	0.743
Alcohol use	8 (88.9%)	1 (11.1%)	0.03	18 (81.8%)	4 (18.2%)	<0.001
Dyslipidemia	46 (57.5%)	34 (42.5%)	0.332	106 (39.0%)	166 (61.0%)	0.511
HRT	0 (0.0%)	2 (100%)	0.123	0 (0.0%)	4 (100.0%)	0.118
Hypertension	67 (53.2%)	59 (46.8%)	0.504	144 (36.4%)	252 (63.6%)	0.109
Obesity	34 (47.9%)	37 (52.1%)	0.136	69 (39.0%)	108 (61.0%)	0.664
Previous Stroke	20 (60.6%)	13 (39.4%)	0.383	62 (38.4%	100 (61.7%)	0.864
Previous TIA	7 (50.0%)	7 (50.0%)	0.75	14 (38.9%)	22 (61.1%)	0.883
Prosthetic Heart valve	1 (50.0%)	1 (50.0%)	0.909	4 (36.4%)	7 (63.6%)	0.924
PVD	5 (38.5%)	8 (61.5%)	0.237	14 (31.1%)	31 (68.9%)	0.33
Renal-Chronic	13 (72.2%)	5 (27.8%)	0.096	41 (44.6%)	51 (55.4%)	0.131
Sleep Apnea	7 (63.6%)	4 (36.4%)	0.504	13 (56.5%)	10 (43.5%)	0.057
Smoker	20 (69.0%)	9 (31.0%)	0.069	42 (54.5%)	35 (45.6%)	<0.001*
Antihypertensive medication	63 (51.2%)	60 (48.8%)	0.052	143 (35.7%)	258 (64.3%)	0.011*
Cholesterol reducer prior	45 (57.0%)	34 (43.0%)	0.419	98 (37.3%)	165 (62.7%)	0.802
Diabetic meds prior	30 (57.7%)	22 (42.3)	0.499	69 (39.9%)	104 (60.1%)	0.461
Antidepressant Prior	9 (30.0%)	21 (70.0%)	0.003	23 (31.5%)	50 (68.5%)	0.23
Race (other)	2 (50.0%)	2 (50.%)	0.383	3 (23.1%)	10 (76.9%)	0.512
First Care	17 (56.7%)	13 (43.3%)	0.71	25 (39.1%)	39 (60.9%)	0.842
Telestroke	9 (56.3%)	7 (43.8%)	0.905	23 (35.9%)	41 (64.1%)	0.189
NIHSS	46 (52.3%)	42 (47.7%)	0.566	55 (32.9%)	112 (67.1%)	0.06
Race (White)	49 (50.5%)	49 (49.5%)	0.353	128 (37.8%)	211 (62.2%)	0.512
NIH Group			0.812			0.506
0–9	31 (53.4%)	27 (46.6%)		92 (41.6%)	129 (58.4%)
10–14	16 (61.5%)	10 (38.5%)		16 (39.0%)	25 (61.0%)
15–20	9 (47.4%)	10 (52.6%)		15 (30.6%)	34 (69.4%)
21–21	9 (56.3%)	7(43.8%)		10 (34.5%)	19 (65.5%)
Ambulatory Prior			0.268			0.044*
0	0 (0.0%)	2 (100.0%)		8 (22.9%)	27 (77.1%)
1	3 (37.5%)	5 (62.5%)		11 (27.5%)	29 (72.5%)
2	2 (40.0%)	3 (60.0%)		11 (29.7%)	26 (70.3%)
3	69 (56.6%)	53 (43.4%)		141 (41.5%)	199 (58.5%)
Ambulatory Admission			0.841			0.066
0	17 (58.6%)	12 (41.4%)		27 (45.0%)	33 (55.0%)
1	34 (50.7%)	33 (49.3%)		63 (31.0%)	140 (69.0%)
2	15 (53.6)	13 (46.4%)		48 (42.1%)	66 (57.9%)
3	8 (61.5)	5 (38.5%)		33 (43.4%)	43 (56.6%)
Ambulatory Discharge			0.032*			0.013*
0	1 (100.0%)	0 (0.0%)		1 (50.0%)	1 (50.0%)
1	15 (35.7%)	27 (64.3%)		42 (32.1%)	89 (67.9%)
2	25 (64.1%)	14 (35.9%)		54 (33.8%)	106 (66.3%)
3	26 (60.5%)	17 (39.5%)		57 (50.4%)	56 (49.6%)

Table 3 shows risk factors associated with the inclusion or exclusion of males in the AIS-HF population receiving rtPA therapy. In the adjusted analysis, males with AIS-HF and CAS (OR = 0.279, 95% CI, 0.083–0.944, P = 014), were more likely to be excluded from rtPA, while those with higher NIHSS scores (OR = 1.096, 95% CI, 0.907–3.526, P < 0.001) were more likely to be included for rtPA. The logistic regression model demonstrated robust predictive power with AUROC = 0.7132 (95% CI, 0.7012–0.752).

Table 3.

Risk factors of males AIS-HF stratified by inclusion or exclusion from thrombolytic therapy. Adjusted OR < 1 denotes factors that were associated with exclusion from rtPA, while OR > 1 denotes factors that are associated with inclusion from rtPA therapy. Hosmer-Lemeshow test (P < 0.001*), Cox & Snell (R² = 0.105). *Indicates statistical significance (P < 0.05) with a 95% confidence interval. A backward stepwise model based on the likelihood ratio was applied. Model assumptions were fulfilled. Multicollinearity and interactions among independent variables were checked and no significant interactions were found.

Variables	B values	Wald	Odds Ratio	Lower	Upper	P Value
CAS	−1.275	4.212	0.279	0.083	0.944	0.014*
NIHSS1	0.092	16.139	1.096	1.048	1.146	<0.001*
Improvement	0.582	2.820	1.789	0.907	3.526	0.93

Risk factors of females with AIS-HF stratified by inclusion or exclusion from thrombolytic therapy are presented in Table 4. For females, AIS-HF patients presenting with CRD (OR = 0.159, 95% CI, 0.050–0.503, P = 002) were more likely to be excluded from rtPA therapy. On the other hand, AIS-HF patients with a history of antidepressant use (OR = 5.322, 95%, CI 1.488–19.03, P < 0.001) and higher NIHSS scores (OR = 3.336, CI 1.699–6.950, P < 0.001) were more likely to be treated with rtPA. The model's discriminative capability was robust (AUC = 0.756, 95% CI, 0.739–0.813, P < 0.001).

Table 4.

Risk factors of females with AIS-HF stratified by inclusion or exclusion from thrombolytic therapy. Adjusted OR < 1 denotes factors that were associated with exclusion from rtPA, while OR > 1 denotes factors that are associated with inclusion from rtPA therapy. Hosmer-Lemeshow test (P < 0.001*), Cox & Snell (R² = 0.107). *Indicates statistical significance (P < 0.05) with a 95% confidence interval. A backward stepwise model based on the likelihood ratio was applied. Model assumptions were fulfilled. Multicollinearity and interactions among independent variables were checked and no significant interactions were found.

Variables	B Values	Wald	Odds Ratio	Lower	Upper	P value
Age	–1576	8.678	0.972	0.948	0.997	0.002*
Chronic renal disorder(CRD)	–1.840	9.796	0.159	0.050	0.503	<0.001*
Antidepressant	1.672	6.613	5.322	1.488	19.03	0.006*
Improvement	1.175	7.530	3.237	1.399	7.489	0.006*
Ambulation prior independently	0.629	0.270	1.875	0.175	20.064	0.603*
Ambulation prior with assistance	1.372	1.086	3.944	0.299	52.085	0.297
Ambulation prior Unable	2.095	3.703	8.129	0.962	68.70	0.054*
NIHSS	3.034	5.874	3.336	1.699	6.950	<0.001*
Depression	–1.156	3.046	0.315	0.086	1.153	0.081
Obesity	0.931	5.964	2.537	1.202	5.355	0.051

Discussion

HF is a complex disorder caused by cardiac distress, resulting in increased intracardiac pressures.²⁰ HF is a risk factor for AIS as well as a risk factor for a worse outcome after stroke.¹¹ In addition, HF causes the release of prothrombotic mediators resulting in poor cerebral tissue. In addition, HF is a predictor for worse functional stroke outcomes but does not affect the efficacy and safety of intravenous thrombolysis and mechanical recanalization oxygenation.²¹ Consequently, HF may affect the effectiveness and safety of rtPA. Options for reperfusion therapy that are proven effective include rtPA and mechanical thrombectomy.²² Intravenous thrombolysis is the mainstay of treatment for acute ischemic stroke, especially if treatment is administered within a 4.5-h protocol.²³ The safety of rtPA implies that ischemic stroke patients treated with rtPA are not associated with complications including systemic hemorrhage.⁷

In this study, we investigated risk factors contributing to the exclusion of AIS-HF patients from rtPA. First, we observed that among male AIS-HF patients, CAS increased the likelihood of exclusion from rtPA, while higher NIHSS scores were associated with inclusion for rtPA. Second, among female AIS-HF patients, those presenting with CRD were more prone to exclusion from rtPA therapy. Conversely, a history of antidepressant use and higher NIHSS scores were associated with an increased likelihood of rtPA inclusion in females with AIS-HF.

In our study, male AIS-HF patients with CAS exhibited a higher likelihood of exclusion from thrombolytic. Watershed /border-zone infarctions are about 10% of all infarcts.¹² Although CAS accounts for more than 10% of the AIS not all CAS-related strokes are watershed infarctions (WS).¹² The mechanisms underlying CAS-related strokes involve hemodynamic impairment in significant stenosis and thromboembolism from an atherosclerotic plaque, regardless of the degree of stenosis.¹² The latter is predominantly attributed to the embolization process of a vulnerable atherosclerotic plaque and propagation of thrombus distally in the carotid artery. This process may lead to downstream infarcts within the territory of a major cerebral artery or in the WS area between two territories, with micro embolism being implicated in the infarction process.²³ Therefore, both mechanisms may act synergistically to promote the process of WS infarction in carotid artery stenosis.

Patients with carotid stenosis–associated stroke regardless of the mechanism, often experience high rates of poor outcomes.²¹ Severe carotid stenosis, especially in carotid athero-thrombotic occlusion, results in low efficacy of rtPA with successful recanalization achieved in less than 30% of cases.²¹ Therefore, our male AIS-HF patients may have presented with severe carotid stenosis, potentially contributing to unsuccessful rtPA recanalization. Therefore, determining the degree of carotid stenosis in AIS-HF patients could inform the selection and application of rtPA. Regardless of whether ischemic strokes in AIS-HF patients are associated with carotid artery disease from hypoperfusion, or a related embolism from a vulnerable plaque, a deeper understanding of ischemic stroke pathogenesis in carotid stenosis holds the potential to enhance the management of AIS-HF patients, optimizing eligibility for rtPA therapy.

In our adjusted analysis, we observed that female AIS-HF patients presenting with CRD were more prone to exclusion from rtPA therapy. Renal failure is a major risk factor for stroke,²⁴ reflecting the intricate interplay between vascular co-morbidities directly linked with renal impairment.²³ The elevated stroke risk is prominent in CRD patients, especially among those on dialysis.²³ Thrombolytic therapy in stroke patients with CRD has been associated with an increased risk of symptomatic intracranial hemorrhage or serious systemic hemorrhage.²⁵ While atherosclerotic risk factors such as smoking, hyperlipidemia, and HF contribute to the overall risk of ischemic stroke, the prevalence of HF in the CRD population is more than twice that in the general population, conferring a greater thromboembolic risk.²⁶ Therefore, the increased risk of hemorrhage may have contributed to the exclusion of female AIS-HF patients with a baseline CRD from rtPA in our current study. Further research is imperative to gain a comprehensive understanding of the management of CRD patients, aiming to improve the care provided to AIS-HF patients who present with CRD.

The finding that the use of antidepressants was associated with inclusion for rtPA among female AIS-HF patients aligns with reports from other studies focused on AIS.²⁷ Even after successful treatment with rtPA, successfully alleviating the burden of disability resulting from a stroke often involves a combination of behavioral therapies, such as physical and occupational therapy, along with pharmacologic interventions.²⁸ Antidepressants are emerging as a promising pharmaceutical means for actively reducing the burden of disability following stroke.²⁶ Patients treated with antidepressants exhibit better recovery from disability compared to those who did not receive antidepressant therapy,²⁷ a result that supports our current findings regarding the inclusion of AIS-HF patients for rtPA therapy. Furthermore, early initiation of antidepressant therapy, even in non-depressed stroke patients, may mitigate the risk of post-stroke depression development and enhance cognitive and functional recovery after stroke. Therefore, future studies exploring potential drug interaction between rtPA, and antidepressants hold promise in advancing the safe recovery of AIS-HF patients.

In our adjusted analysis, for male and female AIS-HF patients, we observed that individuals with higher NIHSS scores were more likely to be included for rtPA therapy. Generally, individuals with severe stroke symptoms and major anterior circulation occlusions tend to experience improved outcomes when treated with rtPA compared to their counterparts who do not receive this intervention.²⁹ This benefit has been reported in a subset of patients, with NIHSS scores exceeding 10 and anterior circulation occlusions who received rtPA.²⁹ Notably, severe stroke (e.g. NIHSS > 25) serves as a relative exclusion criterion for intravenous alteplase within 3 to 4.5 h from symptom onset.³⁰ Among our AIS-HF patients treated with rtPA, the majority exhibited NIHSS scores of ≤ 20 with anterior circulation occlusion. Similar NIHSS scores have been linked to favorable outcomes following treatment with rtPA in other studies.³⁰ The initial severity of a stroke, as measured by NIHSS, serves as a predictive factor for mortality and adverse outcomes after stroke, providing important insights into a patient's short-term mortality risk.³⁰ The NIHSS emerges as a pivotal predictor for various stroke outcomes, including recurrent stroke, complications following administration or rtPA, and the likelihood of achieving a favorable functional outcome. These observations strengthen our current findings of an association between NIHSS score and the inclusion of AIS-HF patients for thrombolytic therapy.

Limitation

We acknowledge several limitations in this retrospective study. Firstly, although the logistic regression model aimed to control for differences in patients and disease characteristics, we lacked information on the treatment history of various risk factors including diabetes, hypertension, dyslipidemia, and atrial fibrillation. Obtaining such data is often challenging and may introduce inherent errors. Additionally, as this is a hospital-based study that relies on data from a single medical center, the characteristics of the present subjects may differ from those of the larger community. Despite these limitations, our study has notable strengths. We successfully identified risk factors associated with the exclusion of both male and female AIS-HF patients from rtPA therapy. These findings suggest the need for future studies on sex-specific differences in risk factors. Findings from such studies could provide valuable insights for clinicians to enhance the care of AIS-HF patients to improve their eligibility for rtPA therapy.

Conclusion

Females presented with a lower risk of incident HF than males, in middle-aged to older individuals, but females presented with a higher HF risk than males in the older age groups. Despite this, females often present with more significant baseline functional impairments, increased comorbidities, poorer post-stroke outcomes, and an overall greater risk for stroke compared to males. When administered according to protocols, thrombolytic treatment improves the AIS outcome. In our study, female AIS patients excluded from rtPA demonstrated poorer outcomes compared with males, suggesting the influence of several risk factors on stroke severity and sex-specific differences in the exclusion and inclusion of AIS-HF patients in the use of rtPA therapy.

Safety of rtPA implies that ischemic stroke patients treated with rtPA are not associated with complications related to rtPA including symptomatic intracranial hemorrhage, and major systemic hemorrhage. Therefore, despite having a favorable risk/benefit profile, intravenous thrombolysis for AIS has risks. Our findings indicate that male AIS-HF patients who present with CAS, are more likely to be excluded from rtPA therapy. Conversely, female AIS-HF patients that present with CRD were more likely to be excluded from rtPA. Furthermore, female AIS-HF patients with a history of antidepressant use, and higher NIHSS scores were associated with rtPA inclusion. These findings emphasize the need to develop management strategies targeting both male and female AIS-HF patients to enhance their eligibility for rtPA therapy. Our study shows the importance of further research and the development of effective interventions to optimize the use of rtPA and improve outcomes in this AIS-HF patient population.

Footnotes

Abbreviations

Acknowledgment

We thank the stroke unit of Greenville Health System for helping with data collection.

Authors’ contribution

JJ, RS,MF, SIN, AIN, and TIN, developed the concept, data collection and data analysis. JJ,RS,MF, and TIN participated in writing the manuscript, data collection, and editing the manuscript. All co-authors provided critical reviews on different drafts of the manuscript. All authors read and approved the final manuscript for publication.

Availability of data and materials

Materials are available on request from the corresponding author.

Consent for publication

Not applicable

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

This study was approved by the Institutional Review Board of PRISMA Health institutional committee for ethics (approval number: 00052571). All data were fully anonymized before they were accessed. Data used in our retrospective analysis were from the PRISMA Health stroke data registry.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institute of Health Sciences, (grant number 5R25AG067934-04).

ORCID iD

Thomas I. Nathaniel

References

Butrous

Hummel

. Heart failure in older adults. Can J Cardiol 2016; 32: 1140–1147.

Lam

CSP

Arnott

Beale

, et al. Sex differences in heart failure. Eur Heart J 2019; 40: 3859–368c.

Bozkurt

Khalaf

. Heart failure in women. Methodist Debakey Cardiovasc J 2021; 13: 216–223.

Azad

Kathiravelu

Minoosepeher

, et al. Gender differences in the etiology of heart failure: a systematic review. J Geriatr Cardiol 2011; 8: 15–23.

Ohkuma

Komorita

Peters

SAE

, et al. Diabetes as a risk factor for heart failure in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million individuals. Diabetologia 2019; 62: 1550–1560.

Mene-Afejuku

Pernia

Ibebuogu

, et al. Heart failure and cognitive impairment: clinical relevance and therapeutic considerations. Curr Cardiol Rev 2019; 15: 291–303.

Poupore

Strat

Mackey

, et al. Thrombolytic therapy in ischemic stroke patients with a preceding transient ischemic attack in telestroke and non-telestroke settings. Neurol Clin Neurosci 2020; 8: 298–308.

Bhaskar

Stanwell

Cordato

, et al.

Reperfusion therapy in acute ischemic stroke: dawn of a new era?

BMC Neurol 2018; 18: 8.

Fugate

Rabinstein

. Absolute and relative contraindications to IV rt-PA for acute ischemic stroke. Neurohospitalist 2015; 5: 110–121.

10.

Magoufis

Safouris

Raphaeli

, et al. Acute reperfusion therapies for acute ischemic stroke patients with unknown time of symptom onset or in extended time windows: an individualized approach. Ther Adv Neurol Disord 2021; 14: 17562864211021182.

11.

Kim

. Heart failure as a risk factor for stroke. J Stroke 2018; 20: 33–45.

12.

Mechtouff

Rascle

Crespy

, et al. A narrative review of the pathophysiology of ischemic stroke in carotid plaques: a distinction versus a compromise between hemodynamic and embolic mechanism. Ann Transl Med 2021; 9: 1208.

13.

Lawson

Brown

Westerkam

, et al. Tissue plasminogen activator (rt-PA) in acute ischemic stroke: outcomes associated with ambulation. Restor Neurol Neurosci 2015; 33: 301–308.

14.

Synhaeve

Arntz

van Alebeek

, et al. Women have a poorer very long-term functional outcome after stroke among adults aged 18–50 years: the FUTURE study. J Neurol 2016; 263: 1099–1105.

15.

Fang

, et al. No sex difference was found in the safety and efficacy of intravenous alteplase before endovascular therapy. Front Neurol 2022; 13: 989166.

16.

Kent

Buchan

Hill

. The gender effect in stroke thrombolysis: of CASES, controls, and treatment-effect modification. Neurology 2008; 71: 1080–1083.

17.

Mehta

Wei

Wenger

. Ischemic heart disease in women: a focus on risk factors. Trends Cardiovasc Med 2015; 25: 140–151.

18.

Nathaniel

Cochran

Chaves

, et al. Co-morbid conditions in use of recombinant tissue plasminogen activator (rt-PA) for the treatment of acute ischaemic stroke. Brain Inj 2016; 30: 1261–1265.

19.

Sacco

Kasner

Broderick

, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44: 2064–2089.

20.

Lee

Conners

Cutting

, et al. Elevated international normalized ratio as a manifestation of post-thrombolytic coagulopathy in acute ischemic stroke. J Stroke Cerebrovasc Dis 2014; 23: 2139–2144.

21.

Siedler

Sommer

Macha

, et al. Heart failure in ischemic stroke: relevance for acute care and outcome. Stroke 2019; 50: 3051–3056.

22.

Imran

Mohamed

Nahab

. Acute Reperfusion Therapies for Acute Ischemic Stroke. J Clin Med 2021; 10: 1–12. doi:10.3390/jcm10163677

23.

Nayak-Rao

Shenoy

. Stroke in patients with chronic kidney disease…: how do we approach and manage it? Indian J Nephrol 2017; 27: 167–171.

24.

Wyld

Webster

. Chronic kidney disease is a risk factor for stroke. J Stroke Cerebrovasc Dis 2021; 30: 105730.

25.

Modrego

. The risk of symptomatic intracranial hemorrhage after thrombolysis for acute stroke: current concepts and perspectives. Ann Indian Acad Neurol 2019; 22: 336–340.

26.

Elzib

Pawloski

Ding

, et al. Antidepressant pharmacotherapy and poststroke motor rehabilitation: a review of neurophysiologic mechanisms and clinical relevance. Brain Circ 2019; 5: 62–67.

27.

Zerriaa

Moula

Ben Saadi

, et al. Benefits of antidepressant treatment after a stroke. Eur Psychiatry 2017; 41: S315.

28.

Yan

Chen

, et al. Prevention, management, and rehabilitation of stroke in low- and middle-income countries. eNeurologicalSci 2016; 2: 21–30.

29.

González

Furie

Goldmacher

, et al. Good outcome rate of 35% in IV-tPA-treated patients with computed tomography angiography confirmed severe anterior circulation occlusive stroke. Stroke 2013; 44: 3109–3113.

30.

Fugate

Rabinstein

. Contraindications to intravenous rtPA for acute stroke: a critical reappraisal. Neurol Clin Pract 2013; 3: 177–185.