Sage Journals: Discover world-class research

Abstract

Background

First-pass effect (FPE) in endovascular thrombectomy (EVT) is strongly associated with clinically favorable outcomes. Atrial fibrillation (AF)-related strokes have been shown to be associated with greater rates of FPE in acute large vessel occlusions (LVOs). In this study, we aimed to assess the association between AF and achieving FPE in medium vessel occlusions (MeVOs).

Methods

A prospectively maintained registry of adult ischemic stroke patients at a comprehensive stroke center between October 2019 and October 2023 was retrospectively screened for inclusion. Patients undergoing EVT for a MeVO were included. Univariable and multivariable logistic regressions with 2500 bootstrap iterations for FPE and mFPE was performed using covariables that were clinically and/or statistically significant. Adjusted odds ratios with 95% confidence intervals (CIs) were reported. Regression performance was assessed using area under the curve (AUC) from receiver operating characteristics curve analysis.

Results

34.4% of patients with MeVO achieved FPE and 58.2% achieved mFPE. In multivariable logistic regression models, AF was independently associated with lower likelihood of FPE, and AF and prior antiplatelet/anticoagulant use were independently associated with lower likelihood of mFPE. Models for FPE and mFPE had AUCs of 0.80 (95% CI [0.75–0.85]) and 0.86 (95% CI [0.78–0.94]), respectively.

Conclusion

AF was associated with a significantly lower likelihood of FPE and mFPE in EVT of MeVOs. This may suggest a need to prepare for additional passes and rescue intraprocedural strategies for MeVO in patients with AF.

Keywords

atrial fibrillation thrombectomy reperfusion medium vessel ischemic stroke

Introduction

Endovascular thrombectomy (EVT) is the standard of care for acute ischemic stroke (AIS) treatment.¹ The first-pass effect (FPE), or the ability to achieve complete reperfusion following a single pass, is a valuable indicator of clinically favorable outcomes following EVT, associated with improved functional outcomes, lower rates of symptomatic intracranial hemorrhage, and mortality.² Similar benefits of FPE have also been seen in medium vessel occlusions (MeVOs).^3–5

The rate of FPE for large vessel occlusions (LVOs) and MeVOs in multicenter registries have ranged from around 20% to 60%.^3,6–11 Numerous factors, including clot composition, interventional approach, patient comorbidities and vasculature impact the ability to achieve FPE. Predictors of complete FPE in LVO have been found to be older age, female gender and use of balloon guide catheters.⁶ However, factors influencing the rate of FPE in MeVOs are not as well-characterized.

Atrial fibrillation (AF) is a major risk factor for cerebrovascular stroke, with the relative risk of stroke in patients with AF ranging from 5.6 to 17.6 of that observed in patients without AF.^12–14 Although AF is commonly associated with LVOs, MeVOs can also be seen with AF.^15–17 In a recent study analyzing DIRECT-SAFE data, AF-related strokes were associated with significantly higher rates of FPE in LVO AIS.¹⁸ In this study, we assess the association between AF and achieving FPE in MeVOs treated with EVT.

Methods

Deidentified data are available from the corresponding author upon reasonable request. This analysis was approved by the institutional review board with waiver of informed consent, and results were reported in accordance with the Studies in Epidemiology guidelines.

Patients

Patients receiving care at a comprehensive stroke center between October 2019 and October 2023 were retrospectively screened for inclusion from a prospectively maintained database of consecutive adult ischemic stroke patients. Patients were included if they had evidence of an MeVO in a middle cerebral artery segment on computed tomography (CT) angiography and were treated with thrombectomy.

Data collection

Demographic data collected included age, sex, and comorbid conditions. Stroke-related data collected included Alberta Stroke Program Early CT Score (ASPECTS) from noncontrast CT, relative occlusion location (proximal: distal M2 branches, distal: M3/M4 branches), and laterality of occlusion from CT angiography. Decision to pursue thrombolytic treatment and thrombectomy treatment was per multidisciplinary stroke team consensus. First-line thrombectomy approach (i.e. aspiration-only or combination of aspiration and stent-retriever) and devices used intraprocedurally was per the neurointerventionalist's discretion. Clinical outcomes collected included discharge and 90-day modified Rankin Score (mRS).

Outcomes

The primary outcome was FPE, defined as achieving modified Treatment in Cerebral Infarction (mTICI) 2C or 3 after the first thrombectomy pass. The secondary outcome was the modified FPE (mFPE), defined as achieving mTICI 2B, 2C, or 3 after the first thrombectomy pass.

Statistical analysis

Continuous data were summarized as medians with interquartile ranges (IQR); categorical data were summarized as frequencies. Baseline demographics were analyzed with the entire cohort, and then when stratified by FPE and mFPE. Univariable and multivariable logistic regressions with 2500 bootstrap iterations were performed for the outcome of FPE and mFPE using covariables that were clinically and/or statistically significant: age, sex, hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, AF, prior stroke, tobacco use, antiplatelet/anticoagulant use, premorbid mRS, admission National Institutes of Health Stroke Scale, ASPECTS, laterality of occlusion, relative occlusion location, thrombolytic administration, and thrombectomy approach (combination aspiration/stent-retriever vs aspiration-only). Adjusted odds ratios (aORs) with 95% confidence intervals (CI) were reported. Regression performance was assessed using area under the curve (AUC) from receiver operating characteristics curve analyses. Missing data was minimal and not imputed. Significance was prespecified at p ≤ .05. Statistics were conducted in JMP v18.0.0 (SAS Institute, Inc., Cary, NC).

Results

Of 67 patients meeting inclusion, the median age was 70 years (IQR 63–82), and 49.3% (33/67) were female (Table 1). The most common comorbid condition was hypertension (82.1%, 55/67) (Table 1). Approximately one-third of patients had AF (34.3%; 23/67) (Table 1). Most patients had proximal MeVOs (88.1%; 59/67) (Table 1). Thrombolytics were administered in 34.3% (23/67) of patients, and most patients were treated with aspiration-only thrombectomy (61.2%; 41/67) (Table 1).

Table 1.

Baseline demographics.

Variable	All (n = 67)	By first-pass effect		By modified first-pass effect
Variable	All (n = 67)	FPE (n = 23)	No FPE (n = 44)	mFPE (n = 39)	No mFPE (n = 28)
Age (years), median (IQR)	70 (63–82)	69 (63–82)	71 (62–82)	69 (59–82)	71 (65–81)
Female, No. (%)	33 (49.3%)	10 (43.5%)	23 (52.3%)	17 (43.6%)	16 (57.1%)
Past medical history, No. (%)
Hypertension	55 (82.1%)	20 (87.0%)	35 (79.5%)	33 (84.6%)	22 (78.6%)
Hyperlipidemia	40 (59.7%)	15 (65.2%)	25 (56.8%)	24 (61.5%)	16 (57.1%)
Diabetes mellitus	23 (34.3%)	6 (26.1%)	17 (38.6%)	13 (33.3%)	10 (35.7%)
Coronary artery disease	12 (17.9%)	6 (26.1%)	6 (13.6%)	7 (17.9%)	5 (17.9%)
Atrial fibrillation	23 (34.3%)	5 (21.7%)	18 (40.9%)	10 (25.6%)	13 (46.4%)
Prior stroke	8 (11.9%)	4 (17.4%)	4 (9.1%)	7 (17.9%)	1 (3.6%)
Tobacco use, No. (%)	38 (56.7%)	13 (56.5%)	25 (56.8%)	22 (56.4%)	16 (57.1%)
Antiplatelet/anticoagulant use, No. (%)	29 (43.3%)	11 (47.8%)	18 (40.9%)	20 (51.3%)	9 (32.1%)
Premorbid mRS, median (IQR)	0 (0–1)	0 (0–1)	0 (0–1)	0 (0–1)	0 (0–1)
Stroke characteristics
Admission NIHSS, median (IQR)	12 (7–20)	12 (6–19)	13 (7–21)	14 (7–20)	11 (6–22)
ASPECTS, median (IQR)	9 (8–10)	10 (9–10)	9 (8–10)	9 (8–10)	9 (8–10)
Left-sided laterality, No. (%)	40 (59.7%)	15 (65.2%)	25 (56.8%)	24 (61.5%)	16 (57.1%)
Relative occlusion location, No. (%)
Proximal	59 (88.1%)	20 (87.0%)	39 (88.6%)	34 (87.2%)	25 (89.3%)
Distal	8 (11.9%)	3 (13.0%)	5 (11.4%)	5 (12.8%)	3 (10.7%)
Thrombolysis, No. (%)	23 (34.3%)	9 (39.1%)	14 (31.8%)	18 (46.2%)	5 (17.9%)
Thrombectomy approach, No. (%)
Aspiration-only	41 (61.2%)	13 (56.5%)	28 (63.6%)	25 (64.1%)	16 (57.1%)
Combination (aspiration and stent-retriever)	26 (38.8%)	10 (43.5%)	16 (36.4%)	14 (35.9%)	12 (42.9%)
Postthrombectomy outcomes
Discharge mRS, median (IQR)	4 (3–5)	4 (3–4)	4 (3–5)	4 (3–5)	4 (3–5)
90 Day mRS, median (IQR)	3 (1–6), n = 62	2 (1–3), n = 19	3 (1–6), n = 43	2 (1–6), n = 35	3 (1–6), n = 27
90 Day mRS 0–2, No. (%)	30 (48.4%), n = 62	12 (63.2%), n = 19	18 (41.9%), n = 43	18 (51.4%), n = 35	12 (44.4), n = 27
90 Day mortality, No. (%)	17 (27.4%), n = 62	3 (15.8%), n = 19	14 (32.6%), n = 43	9 (25.7%), n = 35	8 (29.6%), n = 27

Abbreviations: ASPECTS, Alberta Stroke Program Early Computed Tomography Score; FPE, first-pass effect; IQR, interquartile range; mFPE, modified first pass effect; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; No. = number.

First-pass effect

One-third of MeVO patients achieved FPE (34.3%; 23/67) (Table 1). In a multivariable logistic regression model, only AF (Yes vs No (Reference), aOR 0.08, 95% CI [0.01–0.63], p = .02) was significantly associated with FPE (Table 2). The multivariable regression had AUC of 0.80 (95% CI [0.75–0.85]).

Table 2.

Logistic regression for first pass effect in medium vessel occlusion thrombectomy.

	Univariable logistic regression		Multivariable* logistic regression
Variable	Unadjusted odds ratio [95% CI]	p-value	Adjusted odds ratio [95% CI]	p-value
Age (per year)	1.00 [0.97–1.05]	.81	1.02 [0.95–1.10]	.61
Sex (female vs male)	0.70 [0.25–1.93]	.49	0.58 [0.15–2.33]	.45
Past medical history
Hypertension (no vs yes)	0.58 [0.12–2.22]	.44	0.33 [0.04–3.17]	.34
Hyperlipidemia (no vs yes)	0.70 [0.24–1.97]	.50	0.61 [0.12–3.00]	.54
Diabetes mellitus (yes vs no)	0.56 [0.17–1.65]	.30	0.21 [0.04–1.21]	.08
Coronary artery disease (no vs yes)	0.45 [0.12–1.62]	.22	0.43 [0.06–3.21]	.41
Atrial fibrillation (yes vs no)	0.40 [0.12–1.22]	.11	0.08 [0.01–0.63]	.02
Prior stroke (no vs yes)	0.48 [0.10–2.20]	.33	0.19 [0.02–2.17]	.18
Tobacco use (no vs yes)	1.01 [0.36–2.80]	.98	0.51 [0.10–2.58]	.41
Antiplatelet/anticoagulant use (no vs yes)	0.76 [0.21–2.10]	.59	0.61 [0.11–3.47]	0.57
Premorbid mRS (per point)	1.11 [0.66–1.85]	.67	1.05 [0.46–2.33]	0.91
Admission NIHSS (per point)	0.98 [0.91–1.04]	.45	0.96 [0.88–1.04]	0.30
ASPECTS (per point)	1.42 [0.96–2.35]	.12	1.92 [1.00–4.53]	0.06
Laterality (right vs left)	0.70 [0.24–1.97]	.50	0.78 [0.21–2.87]	0.70
Relative occlusion location (distal vs proximal)	1.17 [0.22–5.27]	.84	0.81 [0.13–4.93]	0.82
Thrombolysis (no vs yes)	0.73 [0.25–2.11]	.55	1.25 [0.30–5.27]	0.76
Thrombectomy approach (combination vs aspiration-only)	1.35 [0.48–3.78]	.57	1.03 [0.23–4.56]	0.97

Abbreviations: ASPECTS, Alberta Stroke Program Early Computed Tomography Score; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale.

*Multivariable regression was performed with the following covariables: age, sex, hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, atrial fibrillation, prior stroke, tobacco use, antiplatelet/anticoagulant use, premorbid mRS, admission NIHSS, ASPECTS, laterality of occlusion, relative occlusion location, thrombolysis administration, and thrombectomy approach.

Modified FPE

Over half of MeVO patients achieved mFPE (58.2%, 39/67) (Table 1). In a multivariable logistic regression model, AF (Yes vs No (Reference), aOR 0.04, 95% CI [0.01–0.49], p = .01) and prior antiplatelet/anticoagulant use (No vs Yes (Reference), aOR 0.05, 95% CI [0.01–0.71], p = .03) were significantly associated with mFPE (Table 3). The multivariable regression had AUC of 0.86 (95% CI [0.78–0.94]).

Table 3.

Logistic regression for modified first-pass effect in medium vessel occlusion thrombectomy.

	Univariable logistic regression		Multivariable* logistic regression
Variable	Unadjusted odds ratio [95% CI]	p-value	Adjusted odds ratio [95% CI]	p-value
Age (per year)	0.99 [0.95–1.03]	.69	1.01 [0.95–1.09]	.68
Sex (female vs male)	0.58 [0.21–1.54]	.27	0.59 [0.14–2.51]	.48
Past medical history
Hypertension (no vs yes)	0.67 [0.19–2.39]	.53	0.68 [0.07–6.44]	.74
Hyperlipidemia (yes vs no)	1.20 [0.44–3.24]	.72	1.18 [0.25–5.67]	.83
Diabetes mellitus (yes vs no)	0.90 [0.32–2.53]	.84	0.26 [0.05–1.49]	.13
Coronary artery disease (yes vs no)	1.01 [0.29–3.77]	.99	0.34 [0.04–2.96]	.33
Atrial fibrillation (yes vs no)	0.40 [0.14–1.11]	.08	0.04 [0.01–0.49]	.01
Prior stroke (no vs yes)	0.17 [0.01–1.04]	.06	0.05 [0.01–1.62]	.09
Tobacco use (no vs yes)	1.03 [0.39–2.77]	.95	0.29 [0.06–1.50]	.14
Antiplatelet/anticoagulant use (no vs yes)	0.45 [0.16–1.22]	.12	0.05 [0.01–0.71]	.03
Premorbid mRS (per point)	0.79 [0.47–1.30]	.35	0.51 [0.17–1.40]	.19
Admission NIHSS (per point)	1.01 [0.95–1.08]	.66	1.01 [0.93–1.11]	.81
ASPECTS (per point)	1.13 [0.82–1.59]	.47	1.28 [0.79–2.39]	.35
Laterality (right vs left)	0.83 [0.31–2.25]	.72	0.67 [0.16–2.74]	.57
Relative occlusion location (distal vs proximal)	1.23 [0.27–6.42]	.79	0.55 [0.07–4.25]	.57
Thrombolysis (no vs yes)	0.25 [0.07–0.76]	.01	0.25 [0.05–1.23]	.09
Thrombectomy approach (combination vs aspiration-only)	0.75 [0.27–2.03]	.56	0.20 [0.04–1.13]	.07

Abbreviations: ASPECTS, Alberta Stroke Program Early Computed Tomography Score; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale.

Discussion

FPE is strongly associated with improved clinical outcomes following AIS for patients treated with EVT, correlated with better functional outcomes, less vascular injury, lower risk of clot fragments, and decreased time to reperfusion.^2,6,19 Previous studies have shown an association between AF and achieving FPE during EVT for LVO, however, this association has yet to be widely investigated for MeVOs.¹⁸ In our study, AF was significantly associated with lower odds of FPE and mFPE in MeVOs treated with EVT. Clinically, this may suggest a need to prepare for additional passes and rescue intraprocedural strategies to achieve reperfusion in EVT of MeVO patients with AF.

Our results contrast with previous studies showing a positive association between AF and achieving FPE during EVT for LVOs. This suggests that the intraprocedural course in MeVOs may differ from that in LVOs in patients with AF, including aspects such as clot composition, location, and size. Erythrocyte-rich clots are associated with higher rates of successful recanalization than fibrin-rich clots; however, studies investigating the composition of cardioembolic clots have yielded heterogeneous results.^20–22 A substudy of the DIRECT-SAFE trial hypothesized that the higher rate of FPE achieved in LVO patients with AF was due to mature, fibrin-rich, cardioembolic clots that are less likely to disintegrate or embolize.¹⁸ In contrast, we postulate that these physical properties of cardioembolic thrombi associated with AF may predispose to more difficult thrombectomy courses when targeting MeVOs in comparatively narrower, more distal cerebrovasculature.

Limitations

Limitations of this study include factors inherent to the retrospective study design, including selection bias and confounding. The study was conducted at a single center, which limits generalizability. Future multicenter studies in a larger, diverse cohort are necessary to validate these results.

Conclusion

AF is associated with lower odds of FPE and mFPE in MeVOs treated with EVT. This may suggest a need to prepare for additional passes and rescue intraprocedural strategies for MeVO in patients with AF.

Footnotes

Acknowledgments

We would like to acknowledge the Cooper Acute Stroke Registry team, including stroke coordinators, research coordinators, physicians, medical students, technicians, and nurses, for their contributions.

Consent to participate

Requirement for informed consent has been waived by the IRB.

Data availability statement

Deidentified data may be made available upon reasonable request.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TGJ is a consultant for Anaconda, Route 92 Medical, Viz.Ai, FreeOx, Blockade Medical, and MeThinks. He serves in an advisory capacity for Cerenovus and Contego Medical. He has equity in Corindus. He receives research support from Medtronic and Stryker. All other authors have no relevant disclosures to declare.

Ethical approval

This study was approved by the Cooper Hospital Institutional Review Board with waiver of informed consent (IRB# 20-371).

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Hamza A. Shaikh

Manisha Koneru

References

Powers

Rabinstein

Ackerson

, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019; 50(12): e344–e418. https://doi.org/10.1161/STR.0000000000000215

Zaidat

Castonguay

Linfante

, et al. First pass effect: a new measure for stroke thrombectomy. Stroke 2018; 49(3): 660–666. https://doi.org/10.1161/STROKEAHA.117.020315

Radu

Costalat

Fahed

, et al. First pass effect as an independent predictor of functional outcomes in medium vessel occlusions: an analysis of an international multicenter study. Eur Stroke J 2024; 9(1): 114–123. https://doi.org/10.1177/23969873231208276

Zhao

Koneru

Siegler

, et al. Single center experience using 3 mm Trevo stent retrievers in medium vessel occlusion thrombectomy. Interv Neuroradiol 2023; 0(0): 15910199231199880. https://doi.org/10.1177/15910199231199880

Ospel

Nguyen

Jadhav

, et al. Endovascular treatment of medium vessel occlusion stroke. Stroke 2024; 55(3): 769–778. https://doi.org/10.1161/STROKEAHA.123.036942

Bai

Zhang

Wang

, et al. Factors influencing recanalization after mechanical thrombectomy with first-pass effect for acute ischemic stroke: a systematic review and meta-analysis. Front Neurol 2021; 12: 628523. https://doi.org/10.3389/fneur.2021.628523

Jadhav

Desai

Zaidat

, et al. First pass effect with neurothrombectomy for acute ischemic stroke: analysis of the systematic evaluation of patients treated with stroke devices for acute ischemic stroke registry. Stroke 2022; 53(2): e30–e32. https://doi.org/10.1161/STROKEAHA.121.035457

Huang

Sun

Nguyen

, et al. Impact of first pass effect in endovascular treatment of large core stroke: a post-hoc analysis of the ANGEL-ASPECT trial. J Neurointerv Surg. 2025; 0(0): jnis-2024-021728. https://doi.org/10.1136/jnis-2024-021728

Tonetti

Bhattacharyya

Koneru

, et al. Novel Tenzing 7 delivery catheter for thrombectomy in acute stroke: a clinical multicenter experience. Stroke Vasc Interv Neurol 2023; 3(6): e000940. https://doi.org/10.1161/SVIN.123.000940

10.

Tonetti

Koneru

Bhattacharyya

, et al. Tenzing 7 delivery catheter with or without a leading microwire for single pass aspiration thrombectomy: a multicenter experience. Interv Neuroradiol 2023; 0(0): 15910199231216765. https://doi.org/10.1177/15910199231216765

11.

Koneru

Badger

Settecase

, et al. Tenzing 7 delivery catheter performance across tortuosity indices. Stroke Vasc Interv Neurol 2024; 4(4): e001351. https://doi.org/10.1161/SVIN.124.001351

12.

Jørgensen

Nakayama

Reith

, et al. Acute stroke with atrial fibrillation: the Copenhagen stroke study. Stroke 1996; 27(10): 1765–1769. https://doi.org/10.1161/01.STR.27.10.1765

13.

Elsheikh

Hill

Irving

, et al. Atrial fibrillation and stroke: state-of-the-art and future directions. Curr Probl Cardiol 2024; 49(1 Pt C): 102181. https://doi.org/10.1016/j.cpcardiol.2023.102181

14.

Choi

Sagris

Hill

, et al. Atrial fibrillation and stroke. Expert Rev Cardiovasc Ther 2023; 21(1): 35–56. https://doi.org/10.1080/14779072.2023.2160319

15.

Koneru

Hoseinyazdi

Wang

, et al. Pretreatment parameters associated with hemorrhagic transformation among successfully recanalized medium vessel occlusions. J Neurol 2024; 271(4): 1901–1909. https://doi.org/10.1007/s00415-023-12149-4

16.

Yedavalli

Koneru

Hoseinyazdi

, et al. Low cerebral blood volume index, thrombectomy, and prior stroke are independently associated with hemorrhagic transformation in medium-vessel occlusion ischemic stroke. Stroke: Vascular and Interventional Neurology 2024; 4(3): e001250. https://doi.org/10.1161/SVIN.123.001250

17.

Sepp

Petzsche

MRH

Zarth

, et al. Mechanical thrombectomy of distal cerebral vessel occlusions of the anterior circulation. Sci Rep 2023; 13(1): 5730. https://doi.org/10.1038/s41598-023-32634-0

18.

Pillai

Bush

Kusuma

, et al. Atrial fibrillation is associated with higher first pass effect following thrombectomy for large vessel occlusion. J Neurointerv Surg 2024; 16(7): 652–656. https://doi.org/10.1136/jnis-2023-020512

19.

Anadani

Alawieh

Vargas

, et al. First attempt recanalization with ADAPT: rate, predictors, and outcome. J Neurointerv Surg 2019; 11(7): 641–645. https://doi.org/10.1136/neurintsurg-2018-014294

20.

Shin

Jeong

Kwon

H-J

, et al. High red blood cell composition in clots is associated with successful recanalization during intra-arterial thrombectomy. PLoS One 2018; 13(5): e0197492. https://doi.org/10.1371/journal.pone.0197492

21.

Maekawa

Shibata

Nakajima

, et al. Erythrocyte-rich thrombus is associated with reduced number of maneuvers and procedure time in patients with acute ischemic stroke undergoing mechanical thrombectomy. Cerebrovasc Dis Extra 2018; 8(1): 39–49. https://doi.org/10.1159/000486042

22.

Vandelanotte

Staessens

François

, et al. Association between thrombus composition and first-pass recanalization after thrombectomy in acute ischemic stroke. J Thromb Haemost 2024; 22(9): 2555–2561. https://doi.org/10.1016/j.jtha.2024.05.034

Atrial fibrillation is associated with lower likelihood of first-pass effect in thrombectomy for medium vessel occlusion acute ischemic strokes

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Patients

Data collection

Outcomes

Statistical analysis

Results

First-pass effect

Modified FPE

Discussion

Limitations

Conclusion

Footnotes

Acknowledgments

Consent to participate

Data availability statement

Declaration of conflicting interests

Ethical approval

Funding

ORCID iDs

References