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Alkhouli, Mohamad

https://orcid.org/0000-0003-3847-0959

Mayo Clinic

Mayo Clinic

Citations 151

Invasive Versus Conservative Strategy in Older Adults ≥75 Years of Age With Non–ST‐segment–Elevation Acute Coronary Syndrome: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Rout, Amit , Moumneh, Mohamad Bahij , Kalra, Kriti , Singh, Sahib , Garg, Aakash , Kunadian, Vijay , Alkhouli, Mohamad , Batchelor, Wayne , Biscaglia, Simone , Alkhouli, Mohamad , Rymer, Jennifer A , Batchelor, Wayne B , Nanna, Michael G , Damluji, Abdulla A , Kunadian, Vijay , Nanna, Michael G.

Journal of the American Heart Association | November 4, 2024 | Volume: 13 | Issue: 21 | Pages: No page available

10.1161/jaha.124.036151 Get It

Background Older adults with non–ST‐segment–elevation acute coronary syndrome are less likely to undergo an invasive strategy compared with younger patients. Randomized controlled trials traditionally exclude older adults because of their high burden of geriatric conditions. Methods and Results We searched for randomized controlled trials comparing invasive versus medical management or a selective invasive (conservative) strategy for older patients (age≥75 years) with non–ST‐segment–elevation acute coronary syndrome. Fixed effects meta‐analysis was conducted to estimate the odds ratio (OR) with 95% CI for the composite of death or myocardial infarction (MI) and individual secondary end points of all‐cause death, cardiovascular death, MI, revascularization, stroke, and major bleeding. Nine studies with 2429 patients (invasive: 1228 versus control: 1201) with a mean follow‐up of 21 months were included. An invasive strategy was associated with a significantly decreased risk of a composite of death and MI (OR, 0.67 [95% CI, 0.54–0.83], P <0.001), MI (OR, 0.56 [95% CI, 0.45–0.70], P <0.001) and subsequent revascularization (OR, 0.27 [95% CI, 0.16–0.48], P <0.001). There was no difference in all‐cause death (OR, 0.84 [95% CI, 0.65–1.10], P =0.21), cardiovascular death (OR, 0.85 [95% CI, 0.63–1.15], P =0.30), stroke (OR, 0.74 [95% CI, 0.38–1.47], P =0.39), or major bleeding (OR, 1.24 [95% CI, 0.42–3.66], P =0.70). Conclusions In older patients ≥75 years old with non–ST‐segment–elevation acute coronary syndrome, an invasive strategy reduced the risk of a composite of death and MI, MI, and subsequent revascularization compared with a conservative strategy alone. Older adults with higher burden of geriatric conditions should be included in future trials to improve generalizability to this growing population.
Antiplatelet Strategy for Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A Systematic Review and Network Meta‐Analysis
Ullah, Waqas , Sandhyavenu, Harigopal , Taha, Amro , Gowda, Smitha Narayana , Mukhtar, Maryam , Polam, Aravind Reddy , Zahid, Salman , Fischman, David L. , Savage, Michael P. , Rao, Sunil V. , Reddy Polam, Aravind , Alkhouli, Mohamad , Mukhtar, Maryam , Rao, Sunil V , Fischman, David , Sandhyavenu, Harigopal , Alkhouli, Mohamad

Journal of the American Heart Association | October 11, 2024 | Volume: 13 | Issue: 20 | Pages: No page available

10.1161/jaha.122.032490 Get It

Background Optimal duration and choice of antiplatelet therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention remain controversial. Methods and Results Digital databases (PubMed, Cochrane, and Embase) were queried to select all randomized controlled trials on a post–percutaneous coronary intervention population with acute coronary syndrome. Dual‐antiplatelet therapy (DAPT) with aspirin and clopidogrel for 12 months was compared with 4 major strategies: high‐potency, high‐ to low‐potency, low‐dose, and short‐duration DAPT. A network meta‐analysis was performed to compare the safety and efficacy of different antiplatelet strategies. This study was the second updated manuscript under the International Prospective Register of Systematic Review registration (CRD42021286552). Thirty‐two randomized controlled trials comprising 103 459 (51 750 experimental, 51 709 control) patients were included. Compared with DAPT with aspirin and clopidogrel for 12 months, high‐ to low‐potency DAPT (risk ratio [RR], 0.69 [95% CI, 0.52–0.92]) and aspirin+prasugrel containing DAPT for 12 months (RR, 0.84 [95% CI, 0.72–0.98]) had a significantly lower, whereas DAPT for 1 month followed by clopidogrel only (RR, 1.59 [95% CI, 1.06–2.39]) had a higher, incidence of major adverse cardiovascular events at 1 year (median follow‐up). Prasugrel (RR, 1.35 [95% CI, 1.09–1.66]) and ticagrelor (RR, 1.38 [95% CI, 1.17–1.62]) containing DAPT for 12 months had significantly higher rates, whereas high‐ to low‐potency DAPT (RR, 0.85 [95% CI, 0.63–1.15]) had no significant risk of major bleeding. Conclusions Aspirin and ticagrelor for 3 months, followed by aspirin and clopidogrel for the remaining duration, can be considered the optimal strategy for treating post–percutaneous coronary intervention patients with acute coronary syndrome because of a significantly reduced risk of major adverse cardiovascular events without increasing the risk of bleeding.
Left Atrial Appendage Occlusion vs Standard of Care After Ischemic Stroke Despite Anticoagulation
Seiffge, David , Group, STR-OAC LAAO, Macha, Kosmas , Takagi, Masahito, Arihiro, Shoji , Polymeris, Alexandros A. , Yoshimura, Sohei , Venti, Michele , Thilemann, Sebastian , Altavilla, Riccardo , Peters, Nils , Inoue, Manabu, Bobinger, Tobias , Agnelli, Giancarlo , Acciarresi, Monica, Jager, Hans, Bovi, Paolo, Schwab, Stefan , Registry, RAF, RAF-DOAC, CROMIS-2, SAMURAI, NOACISP, Erlangen Registry, and Verona, Aarnink, Errol W. , Fierro, Nicolai, Tondo, Claudio , Zieliński, Kamil , Korsholm, Kasper , Nielsen-Kudsk, Jens Erik, Caneiro‐Queija, Berenice, Benito‐González, Tomás , Holmes, David R. , Almakadma, Abdul H., Álvarez, Xavier Millán, Alla, Venkata , Agarwal, Himanshu , Paitazoglou, Christina , Freixa, Xavier , Cepas‐Guillén, Pedro , Chothia, Rashaad , Badejoko, Solomon O. , Bergmann, Martin , Spoon, Daniel B., Maddux, James T., Ram, Pradhum , Branca, Luca , Dijk, Vincent F. van , Rensing, Benno J. , Paciaroni, Maurizio , Kallmünzer, Bernd , Wilson, Duncan , Jäger, Hans Rolf , Korsholm, Kasper , Seiffge, David , Jäger, Hans Rolf , Cepas-Guillen, Pedro , Maarse, Moniek , Werring, David J. , Boersma, Lucas V.A. , Group, STR-OAC LAAO, Tsivgoulis, Georgios , Bonetti, Bruno , Alberti, Andrea , Ambler, Gareth , Bonati, Leo H. , Muir, Keith W. , Yamagami, Hiroshi, Inoue, Manabu , Brown, Martin M. , Sato, Shoichiro , Lyrer, Philippe A. , Marchis, Gian Marco De , Peper, Joyce , Simard, Trevor , Alkhouli, Mohamad , Registry, RAF, RAF-DOAC, CROMIS-2, SAMURAI, NOACISP, Erlangen Registry, and Verona, Mazzone, Patrizio , Beneduce, Alessandro , Gasperetti, Alessio , Pracoń, Radosław , Demkow, Marcin , Backer, Ole De , Nielsen‐Kudsk, Jens Erik , Estévez‐Loureiro, Rodrigo , Prado, Armando Pérez de , Nombela‐Franco, Luis , Salinas, Pablo , Berti, Sérgio , Romeo, Maria Rita , Arzamendi, Dabit , Eitel, Ingo , Bergmann, Martin W., El‐Chami, Mikhael F. , Adamo, Marianna , Suradi, Hussam , Zietz, Annaelle , Caso, Valeria , Koga, Masatoshi , Toyoda, Ḱazunori , Cappellari, Manuel , Engelter, Stefan T. , Swaans, Martin John

JAMA Neurology | September 23, 2024 | Volume: 81 | Issue: 11 | Pages: 1150

10.1001/jamaneurol.2024.2882 Get It

ImportancePatients with atrial fibrillation (AF) who have ischemic stroke despite taking oral anticoagulation therapy (OAT) have a very high risk of recurrence. Left atrial appendage occlusion (LAAO) is a mechanical stroke prevention strategy that may provide additional protection in patients with thromboembolic events under OAT.ObjectiveTo compare percutaneous LAAO with continuing OAT alone regarding stroke prevention in patients with AF who had a thromboembolic event despite taking OAT.Design, Setting, and ParticipantsThis cohort study was a propensity score–matched comparison of the STR-OAC LAAO cohort, an international collaboration of 21 sites combining patients from multiple prospective registries of patients who underwent LAAO between 2010 and 2022. STR-OAC LAAO cohort patients who had follow-up longer than 3 months were propensity score–matched to a previously published control cohort comprising patients from an established international collaboration of investigator-initiated prospective studies. This control cohort included patients with nonvalvular AF, recent ischemic stroke or transient ischemic attack, and follow-up longer than 3 months who were taking OAT before the index event. Analyses were adjusted for imbalances in gender, age, hypertension, diabetes, and CHA2 DS2-VASc score.ExposureLeft atrial appendage occlusion vs continuation of oral anticoagulation therapy alone (control group).Main Outcomes and MeasuresThe primary outcome was time to first ischemic stroke.ResultsFour hundred thirty-three patients from the STR-OAC LAAO cohort (mean [SD] age, 72 [9] years; 171 [39%] females and 262 [61%] males; mean [SD] CHA2 DS2-VASc score, 5.0 [1.6]) were matched to 433 of 1140 patients (38%) from the control group. During 2-year follow-up, 50 patients experienced ischemic stroke: an annualized event rate of 2.8% per patient-year in the STR-OAC LAAO group vs 8.9% per patient-year in the control group. Left atrial appendage occlusion was associated with a lower risk of ischemic stroke (hazard ratio, 0.33; 95% CI, 0.19-0.58; P &amp;lt; .001) compared with the control group. After LAAO, OAT was discontinued in 290 patients (67%), and the remaining 143 patients (33%) continued OAT after LAAO as an adjunctive therapy.Conclusions and RelevanceIn patients with nonvalvular AF and a prior thromboembolic event despite taking OAT, LAAO was associated with a lower risk of ischemic stroke compared with continued OAT alone. Randomized clinical trial data are needed to confirm that LAAO may be a promising treatment option for this population with a very high risk of stroke.
Reproducibility of cardiac computed tomography classifications of hypoattenuated thickening and peridevice leak following left atrial appendage closure
Kramer, Anders , Russo, Gerardo Lo , Alarouri, Hasan S. , Collins, Jeremy D. , Jensen, Jesper Møller , Nielsen‐Kudsk, Jens Erik , Alkhouli, Mohamad , Korsholm, Kasper , Lo Russo, Gerardo , Møller Jensen, Jesper , Alkhouli, Mohamad , Collins, Jeremy , Korsholm, Kasper , Kramer, Anders Dahl

European Heart Journal - Cardiovascular Imaging | September 2, 2024 | Volume: 26 | Issue: 1 | Pages: 62-71

10.1093/ehjci/jeae236 Get It

Abstract Aims To assess the reproducibility of interpreting hypoattenuated thickening (HAT) and peridevice leak (PDL) using cardiac computed tomography (CT) imaging following Watchman FLX left atrial appendage closure (LAAC). Methods and results In this multicentre retrospective reproducibility study, 100 anonymized post-LAAC cardiac CT scans were evaluated within the same cardiac phase by an experienced and a novice rater blinded to prior evaluations. All scans were evaluated twice by each rater, assessing overall HAT and PDL categories as well as specific associated findings based on suggested algorithms for post-LAAC interpretation. Inter- and intra-rater agreement and reliability were evaluated using absolute agreement, Cohen’s kappa, and Kendall’s tau for categorical variables, and mean difference, Bland–Altman plots, limits of agreement (lower and upper), and intra-class correlation coefficients (ICCs) for continuous variables. Within overall categories of both HAT and PDL, substantial agreement (kappa ≥0.61) and reliability (Kendall’s tau-b ≥ 0.75) were observed. Specifically, identifying high-grade HAT (kappa ≥0.78) and distal patency (kappa ≥0.85) displayed the highest agreement within HAT and PDL interpretation. Meanwhile, measuring the height of the proximal screw hub cove represented the least reliable HAT assessment among both inter- and intra-rater comparisons (ICC &lt; 0.75), while suspected leak mechanism represented the least reproducible PDL measure. Conclusion Despite only minimal training of one rater, overall high levels of inter- and intra-rater agreement and reliability were observed across the chosen algorithms for interpretation of HAT and PDL following Watchman FLX LAAC. The prognostic implications of the included variables are to be explored in future trials and registries.
Impact of transcatheter edge to edge repair in functional mitral regurgitation and cardiac resynchronization‐therapy nonresponders
Abraham, Bishoy , Suppah, Mustafa , Elbanna, Mostafa , Kaldas, Sara, Fortuin, F. David , Sweeney, John , Ayoub, Chadi , Sell-Dottin, Kristen, Megaly, Michael S. , Alsidawi, Said , Alkhouli, Mohamad , Sell‐Dottin, Kristen , Chao, Chieh‐Ju , Arsanjani, Reza

Catheterization and Cardiovascular Interventions | August 15, 2024 | Volume: 104 | Issue: 4 | Pages: 829-836

10.1002/ccd.31190 Get It

AbstractBackgroundDespite optimal medical therapy and cardiac resynchronization therapy (CRT), significant functional mitral regurgitation (MR) persisted in 30% of the patients and labeled as CRT nonresponders.AimsWe sought to study the impact of transcatheter edge‐to‐edge repair (TEER) in patients with symptomatic grade III and IV functional MR despite CRT.MethodsA retrospective analysis was conducted of all patients who had prior CRT for at least 6 months and underwent TEER for significant residual functional MR (grade ≥3) and symptomatic heart failure (HF) at our institution. The primary outcomes were the change in New York Heart Association classification (NYHA), MR grade, echo parameters, and NT‐ProBNP from baseline to 1‐year post‐procedure.ResultsA total of 28 patients were identified, mean age of 73 ± 6.7 years and 89% males. Procedure success was achieved in all patients. At 1‐year follow‐up, patients had lower MR grade (median 2, IQR 1 [1,2] vs. 4, IQR 1 [3,4]; p < 0.001), NYHA class (median 2, IQR 1 [2,3] vs. 3, IQR 1 [3,4]; p < 0.001), and NT‐ProBNP (7658 ± 11322 vs. 3760 ± 4431; p = 0.035) compared to before the TEER procedure. The left ventricular end‐diastolic volume (255 ± 59 vs. 244 ± 66 mm; p = 0.016) and the right ventricular systolic pressure (52 ± 14 mmHg vs. 37 ± 13 mmHg, <0.001) decreased.ConclusionPatients who remain symptomatic after CRT with severe functional MR had improved functional status and MR grade at 1‐year following TEER. There was a signal toward reverse remodeling.
Over Flexing of the WATCHMAN FLX Muscles in the Real World
Alkhouli, Mohamad , Alkhouli, Mohamad

Circulation: Cardiovascular Interventions | July 26, 2024 | Volume: 17 | Issue: 9 | Pages: No page available

10.1161/circinterventions.124.014465 Get It

Understanding the role of the left atrial appendage on the flow in the atrium
Bshennaty, Ahmad , Vogl, Brennan , Bavo, Alessandra , Kramer, Anders , Jia, Yuheng, Beule, Matthieu De , Nielsen‐Kudsk, Jens Erik , Backer, Ole De , Alkhouli, Mohamad , Bavo, Alessandra Maria , Sularz, Agata , Kramer, Anders Dahl , De Backer, Ole , Hatoum, Hoda , Sularz, Agata , Alkhouli, Mohamad , Hatoum, Hoda

Catheterization and Cardiovascular Interventions | July 21, 2024 | Volume: 104 | Issue: 6 | Pages: 1290-1298

10.1002/ccd.31153 Get It

Abstract Background The exclusion/occlusion of the left atrial appendage (LAA) is a treatment option for atrial fibrillation (AF) patients who are at high risk of stroke and high risk of bleeding. As the role of the LAA is not well understood or explored, this study aims to assess its role on flow dynamics in the left atrium. Methods Computational fluid dynamics (CFD) simulations were carried out for nine AF patients before and after LAA exclusion. The flow parameters investigated included the LA velocities, Time Averaged Wall Shear Stress (TAWSS), Oscillatory Shear Index (OSI), Relative Residence Time (RRT), and Pressure in the LA. Results This study shows that, on average, a decrease in TAWSS (1.82 ± 1.85 Pa to 1.27 ± 0.96 Pa, p < 0.05) and a slight increase in OSI (0.16 ± 0.10 to 0.17 ± 0.10, p < 0.05), RRT (1.87 ± 1.84 Pa −1 to 2.11 ± 1.78 Pa −1 , p < 0.05), and pressure (−19.2 ± 6.8 mmHg to −15.3 ± 8.3 mmHg, p < 0.05) were observed in the LA after the exclusion of the LAA, with a decrease in low‐magnitude velocities. Conclusion The exclusion of the LAA seems to be associated with changes in LA flow dynamics. Further studies are needed to elucidate the clinical implications of these changes.
Transcatheter vs. surgical mitral valve interventions in patients with prior coronary artery bypass grafting
Ismayl, Mahmoud , Ahmed, Hasaan , Goldsweig, Andrew M. , Alkhouli, Mohamad , Eleid, Mackram F. , Rihal, Charanjit S. , Goldsweig, Andrew M , Ismayl, Mahmoud , Alkhouli, Mohamad , Rihal, Charanjit S. , Guerrero, Mayra

European Heart Journal - Quality of Care and Clinical Outcomes | July 18, 2024 | Volume: 11 | Issue: 5 | Pages: 539-553

10.1093/ehjqcco/qcae060 Get It

Abstract Background A significant proportion of patients requiring mitral valve (MV) intervention have undergone prior coronary artery bypass grafting (CABG). Reoperative heart surgery is associated with increased risk. Aims To evaluate the utilization and outcomes of transcatheter vs. surgical MV interventions in patients with prior CABG. Methods We queried the Nationwide Readmission Database (2016–21) to identify adults with prior CABG hospitalized for transcatheter or surgical MV intervention. In-hospital outcomes were compared using multivariable regression and propensity-matching analyses. Readmissions were compared using Cox proportional hazards regression model. Results Of 305 625 weighted hospitalizations for MV intervention, 23 506 (7.7%) occurred in patients with prior CABG. From 2016Q1–2021Q4, the use of transcatheter MV interventions increased among patients with prior CABG (72 to 191 for repair and 6 to 45 for replacement per 100 000 hospitalizations, both ptrend &lt; 0.001). Compared with surgical MV repair and replacement, transcatheter MV repair and replacement were associated with similar in-hospital mortality (adjusted odds ratio [aOR] 0.44, 95% confidence interval [CI] 0.20–1.03 for repair; aOR 0.61, 95% CI 0.38–1.02 for replacement) and 180-day heart failure (HF) readmissions (adjusted hazard ratio [aHR] 1.56, 95% CI 0.85–2.87 for repair; aHR 1.15, 95% CI 0.63–2.09 for replacement) and lower stroke, acute kidney injury, permanent pacemaker placement, length of stay, and non-home discharges, respectively. Vascular complications were higher with transcatheter vs. surgical MV replacement. Conclusion Transcatheter MV interventions are increasingly used as the preferred modality of MV intervention in patients with prior CABG and are associated with similar in-hospital mortality and 180-day HF readmissions compared with surgical MV interventions.
Lipoprotein(a) and long-term in-stent restenosis after percutaneous coronary intervention
Mahmoud, Ahmed , Awad, Kamal , Ali, Nima Baba , Pereyra, Milagros , Scalia, Isabel G. , Allam, Mohamed, Kamel, Moaz, Rmilah, Anan Abu , Chao, Chieh-Ju, Barry, Timothy, Lester, Steven J., Pollak, Peter , Sweeney, John P., Fortuin, David, Arsanjani, Reza , Mahmoud, Ahmed K , Allam, Mohamed N , Kamel, Moaz A, Alsidawi, Said , Pollak, Peter M, Alkhouli, Mohamad A, Lee, Richard W, Fortuin, David F, Arsanjani, Reza , Pereyra, Milagros , Scalia, Isabel G , Awad, Kamal , Farina, Juan M. , Abbas, Mohammed Tiseer , Allam, Mohamed N, Chao, Chieh‐Ju , Alsidawi, Said , Alkhouli, Mohamad , Lee, Kwan , Yang, Eric H. , Lee, Richard

European Journal of Preventive Cardiology | June 20, 2024 | Volume: 31 | Issue: 15 | Pages: 1878-1887

10.1093/eurjpc/zwae212 Get It

Abstract Aims Lipoprotein(a) [Lp(a)] has demonstrated its association with atherosclerosis and myocardial infarction. However, its role in the development of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is not clearly established. The aim of this study is to investigate the association between Lp(a) and ISR. Methods and results A retrospective study of adult patients who underwent successful PCI between January 2006 and December 2017 at the three Mayo Clinic sites and had a preprocedural Lp(a) measurement was conducted. Patients were divided into two groups according to the serum Lp(a) concentration [high Lp(a) ≥ 50 mg/dL and low Lp(a) &lt; 50 mg/dL]. Univariable and multivariable analyses were performed to compare risk of ISR between patients with high Lp(a) vs. those with low Lp(a). A total of 1209 patients were included, with mean age 65.9 ± 11.7 years and 71.8% were male. Median follow-up after baseline PCI was 8.8 [interquartile range (IQR) 7.4] years. Restenosis was observed in 162 (13.4%) patients. Median serum levels of Lp(a) were significantly higher in patients affected by ISR vs. non-affected cases: 27 (IQR 73.8) vs. 20 (IQR 57.5) mg/dL, P = 0.008. The rate of ISR was significantly higher among patients with high Lp(a) vs. patients with low Lp(a) values (17.0% vs. 11.6%, P = 0.010). High Lp(a) values were independently associated with ISR events (hazard ratio 1.67, 95% confidence interval 1.18–2.37, P = 0.004), and this association was more prominent after the first year following the PCI. Conclusion Lipoprotein(a) is an independent predictor for long-term ISR and should be considered in the evaluation of patients undergoing PCI.
Racial, ethnic, and sex disparities in the utilization and outcomes of tricuspid valve surgery
Ahmed, Hasaan , Alkhouli, Mohamad , Ismayl, Mahmoud , Goldsweig, Andrew M. , Alkhouli, Mohamad , Guerrero, Mayra

Annals of Medicine & Surgery | June 18, 2024 | Volume: 86 | Issue: 8 | Pages: 4368-4376

10.1097/ms9.0000000000002203 Get It

Background: Data on racial/ethnic and sex disparities in the utilization and outcomes of tricuspid valve surgery (TVS) in the United States are scarce. The authors aimed to evaluate the impact of race/ethnicity and sex on the utilization and outcomes of TVS. Methods: The authors analyzed the National Inpatient Sample database from 2016 to 2020 to identify hospitalizations for TVS. Racial/ethnic and sex disparities in TVS outcomes were determined using logistic regression models. Results: Between 2016 and 2020, 19 395 hospitalizations for TVS were identified. The utilization rate (number of surgeries/100,000 hospitalizations) was lower in Black and Hispanic patients compared with White patients for surgical tricuspid valve repair (STVr) (331 versus 493 versus 634, P<0.01) and surgical tricuspid valve replacement (STVR) (312 versus 601 versus 728, P<0.01). Similarly, the utilization rate was lower for women compared with men for STVr (1021 versus 1364, P<0.01) and STVR (930 versus 1,316, P<0.01). Compared to White men undergoing TVS, all women had lower odds of acute kidney injury [adjusted odds ratio (aOR) 0.65, 95% CI 0.55–0.78] and higher odds of blood transfusion (aOR 1.30, 95% CI 1.07–1.59), and Black men had higher odds of blood transfusion (aOR 1.59, 95% CI 1.08–2.35). In-hospital mortality and other surgical complications were similar between all groups (all P>0.05). Conclusions: Significant racial/ethnic and sex disparities exist in the utilization of TVS in the United States. Further studies are needed to understand the reasons for these disparities and to identify effective strategies for their mitigation.