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Ghozy, Sherief

0000-0001-5629-3023

Mayo Clinic

Mayo Clinic

Citations 115

The Utilization of Systematic Reviews and Meta-Analyses in Stroke Guidelines
Ghozy, Sherief , Amoukhteh, Melika , Kadirvel, Ramanathan , Brinjikji, Waleed , Carpenter, Christopher R. , Kallmes, David F. , Amoukhteh, Melika , Carpenter, Christopher R , Ghozy, Sherief , Kobeissi, Hassan , Rabinstein, Alejandro A.

Brain Sciences | July 23, 2024 | Volume: 14 | Issue: 7 | Pages: 728

10.3390/brainsci14070728 Get It

Background: Stroke guideline statements are important references for clinicians due to the rapidly evolving nature of treatments. Guideline statements should be informed by up-to-date systematic reviews (SRs) and meta-analyses (MAs) because they provide the highest level of evidence. To investigate the utilization of SRs/MAs in stroke management guidelines, we conducted a literature review of guidelines and extracted relevant information regarding SRs/MAs. Methods: A literature review was conducted in PubMed with supplementation using the Trip medical database with the term “stroke” as the target population, followed by using the filter “guidelines”. We extracted the number of included SRs/MAs, the years of publication, the country of origin, and other characteristics of interest. Descriptive statistics were generated using the R software version 4.2.1. Results: We included 27 guideline statements. The median number of overall SRs or MAs within the guidelines was 4.0 (interquartile range [IQR] = 2–9). For MAs only, the median number included in the guidelines was 3.0 (IQR = 2.0–5.5). Canadian guidelines had the oldest citations, with a median gap of 12.0 (IQR = 5.2–18.0) years for the oldest citation, followed by European (median = 12; IQR = 9.5–13.5) and US (median = 10.0; IQR = 5.2–16) guidelines. Conclusions: Stroke guideline writing groups and issuing bodies should devote greater effort to the inclusion of up-to-date SRs/MAs in their guideline statements so that clinicians can reference recent data with the highest level of evidence.
Symptomatic intracerebral hemorrhage in proximal and distal medium middle cerebral artery occlusion patients treated with mechanical thrombectomy
Yedavalli, Vivek , Salim, Hamza , Musmar, Basel , Adeeb, Nimer, Essibayi, Muhammed Amir , Naamani, Kareem El , Henninger, Nils , Sundararajan, Sri Hari , Kuhn, Anna Luisa, Khalife, Jane, Tan, Benjamin YQ, Heit, Jeremy J. , Regenhardt, Robert W, Cancelliere, Nicole M , Rouchaud, Aymeric , Sheth, Sunil A, Puri, Ajit S, Dyzmann, Christian , Colasurdo, Marco , Barreau, Xavier, Renieri, Leonardo, Filipe, Joo Pedro, Harker, Pablo, Marotta, Thomas R. , Spears, Julian, Jabbour, Pascal , Biswas, Arundhati , Clarenon, Frdric, Varela, Ricardo, Baker, Amanda, Altschul, David , Gonzalez, Nestor R. , Mhlenbruch, Markus A, Costalat, Vincent, Gory, Benjamin, Stracke, Paul, Aziz-Sultan, Mohammad Ali, Shaikh, Hamza , Liebeskind, David S. , Pedicelli, Alessandro, Alexandre, Andrea M, Tancredi, Illario, Faizy, Tobias D, Kalsoum, Erwah, Lubicz, Boris, Patel, Aman B, Guenego, Adrien , Regenhardt, Robert W. , Tan, Benjamin Yong‐Qiang , Varela, Ricardo , Alexandre, Andrea , Pulli, Benjamin , Yedavalli, Vivek S , Salim, Hamza , ElNaamani, Kareem , Ghozy, Sherief , Scarcia, Luca , Cancelliere, Nicole M , Rouchaud, Aymeric , Fiehler, Jens , Colasurdo, Marco , Alexandru Radu, Răzvan , Ota, Takahiro , Jabbour, Pascal , Siegler, James E , Nguyen, Thanh N , Altschul, David J , Gonzalez, Nestor R , Hecker, Constantin , Shaikh, Hamza A , Liebeskind, David S. , Mendes Pereira, Vitor , Guenego, Adrien , Dmytriw, Adam A , Heit, Jeremy J , Musmar, Basel , Regenhardt, Robert W , Essibayi, Muhammed Amir , Henninger, Nils , Tan, Benjamin Yq , Alexandre, Andrea M , Pulli, Benjamin , Varela, Ricardo , Adeeb, Nimer , Kühn, Anna Luisa , Khalife, Jane , Ghozy, Sherief , Bernstock, Joshua D. , Fiehler, Jens , Sheth, Sunil A , Puri, Ajit S , Barreau, Xavier , Renieri, Leonardo , Harker, Pablo , Radu, Răzvan Alexandru , Spears, Julian , Mowla, Ashkan , Jabbour, Pascal , Siegler, James E. , Nguyen, Thanh N. , Baker, Amanda, Costalat, Vincent , Gory, Benjamin , Aziz‐Sultan, Mohammad Ali , Hecker, Constantin , Pedicelli, Alessandro , Tancredi, Illario , Faizy, Tobias D. , Kalsoum, Erwah , Lubicz, Boris , Patel, Aman B. , Dmytriw, Adam A.

Journal of NeuroInterventional Surgery | July 8, 2024 | Volume: 17 | Issue: 8 | Pages: 803-810

10.1136/jnis-2024-021879 Get It

Background Acute ischemic stroke (AIS) caused by distal medium vessel occlusions (DMVOs) represents a significant proportion of overall stroke cases. While intravenous thrombolysis (IVT) has been a primary treatment, advancements in endovascular procedures have led to increased use of mechanical thrombectomy (MT) in DMVO stroke patients. However, symptomatic intracerebral hemorrhage (sICH) remains a critical complication of AIS, particularly after undergoing intervention. This study aims to identify factors associated with sICH in DMVO stroke patients undergoing MT. Methods This retrospective analysis utilized data from the Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. Middle cerebral artery (MCA) DMVO stroke patients were included. The primary outcome measured was sICH, as defined per the Heidelberg Bleeding Classification. Univariable and multivariable logistic regression were used to identify factors independently associated with sICH. Results Among 1708 DMVO stroke patients, 148 (8.7%) developed sICH. Factors associated with sICH in DMVO patients treated with MT included older age (adjusted odds ratio (aOR) 1.01, 95% confidence interval (95% CI) 1.00 to 1.03, P=0.048), distal occlusion site (M3, M4) compared with medium occlusions (M2) (aOR 1.71, 95% CI 1.07 to 2.74, P=0.026), prior use of antiplatelet drugs (aOR 2.06, 95% CI 1.41 to 2.99, P<0.001), lower Alberta Stroke Program Early CT Scores (ASPECTS) (aOR 0.75, 95% CI 0.66 to 0.84, P<0.001), higher preoperative blood glucose level (aOR 1.00, 95% CI 1.00 to 1.01, P=0.012), number of passes (aOR 1.27, 95% CI 1.15 to 1.39, P<0.001), and successful recanalization (Thrombolysis In Cerebral Infarction (TICI) 2b-3) (aOR 0.43, 95% CI 0.28 to 0.66, P<0.001). Conclusion This study provides novel insight into factors associated with sICH in patients undergoing MT for DMVO, emphasizing the importance of age, distal occlusion site, prior use of antiplatelet drugs, lower ASPECTS, higher preoperative blood glucose level, and procedural factors such as the number of passes and successful recanalization. Pending confirmation, consideration of these factors may improve personalized treatment strategies.
Comparative meta-analysis of endovascular strategies for intracranial dissecting aneurysms: Flow diverters versus stents with or without coiling
Amoukhteh, Melika , Hassankhani, Amir , Jannatdoust, Payam , Valizadeh, Parya , Ghozy, Sherief , Bilgin, Cem , Kallmes, David F. , Ghozy, Sherief , Bilgin, Cem

Interventional Neuroradiology | June 14, 2024 | Volume: 32 | Issue: 4 | Pages: 1669-1679

10.1177/15910199241262070 Get It

Background Intracranial dissecting aneurysms present a challenging subset linked to considerable morbidity and mortality, necessitating effective therapeutic strategies to prevent complications. Traditional treatments face technical limitations, while emerging endovascular modalities like stent-assisted coiling, multiple stenting, and flow-diverting devices (FDDs) offer promise in reducing periprocedural risks and enhancing patient outcomes. The aim of this study is to compare the safety and efficacy outcomes of endovascular treatment for intracranial dissecting aneurysms using FDDs versus stents (with or without coiling). Methods A systematic review and meta-analysis were conducted following established guidelines. The search included PubMed, Scopus, Web of Science, and Embase databases up to July 30, 2023. Eligible studies reporting outcomes of interest in both FDD and stent-treated groups were included, and the data was extracted and analyzed using STATA software. Results Six studies were analyzed, involving 131 patients in the FDD group and 199 patients in the stent group. The pooled rates for favorable functional outcomes (86.8% vs. 86%), mortality (3.9% vs. 6%), adequate occlusion (79.7% vs. 86.3%), aneurysm recurrence (1.3% vs. 13.3%), in-stent stenosis/thrombosis (7% vs. 6.9%), ischemic events/infarctions (6.7% vs. 7.8%), retreatment (7% vs. 8.6%), and technical success (100% vs. 98.7%) were comparable in individuals treated with FDDs and stents (p > 0.05 in all cases). Additionally, complete occlusion rates were not significantly different between FDD (62.7%) and stent-treated patients (75.2%) (p = 0.06). However, after excluding one study in a leave-one-out analysis of the random effects meta-analysis, a significant difference in the pooled rates of this outcome was observed between the FDD (59.2%) and stent (75.2%) groups (p = 0.034). Conclusion FDDs present a promising approach for the treatment of intracranial dissecting aneurysms, yielding outcomes that are roughly comparable to stent-based methods. However, the absence of randomized trials and data limitations highlight the need for further research to enhance treatment strategies.
Contour Neurovascular System for endovascular embolization of cerebral aneurysms: a multicenter cohort study of 10 European neurovascular centers
Griessenauer, Christoph J. , Ghozy, Sherief , Biondi, Alessandra , Hecker, Constantin , Wodarg, Fritz , Liebig, Thomas , Patankar, Tufail , Lamin, Saleh , Martínez‐Galdámez, Mario , Cognard, Christophe , Fiehler, Jens , Dmytriw, Adam A , Killer-Oberpfalzer, Monika , Martínez-Galdámez, Mario , Ghozy, Sherief , Cognard, Christophe , Hecker, Constantin , Griessenauer, Christoph J , Fiehler, Jens , Dorn, Franziska , Dmytriw, Adam A.

Journal of NeuroInterventional Surgery | May 17, 2024 | Volume: 17 | Issue: 4 | Pages: 399-404

10.1136/jnis-2023-021378 Get It

Background Intrasaccular devices have become increasingly popular in the treatment of cerebral aneurysms, particularly at the bifurcation. Here we evaluate the Contour Neurovascular System, an intrasaccular device for the endovascular treatment of cerebral aneurysms, in a multicenter cohort study, the largest to the best of our knowledge. Methods Consecutive patients with intracranial aneurysms treated with the Contour Neurovascular System between February 2017 and October 2022 at 10 European neurovascular centers were prospectively collected and retrospectively reviewed. Patient and aneurysm characteristics, procedural details, and angiographic and clinical outcomes were evaluated. Results During the study period, 279 aneurysms (median age of patients 60 years, IQR 52–68) were treated with Contour. In 83.2% of patients the device was placed electively, whereas the remaining patients were treated in the setting of acute subarachnoid hemorrhage. The most common locations were the middle cerebral artery (26.5%) followed by the anterior communicating region (26.2%). Median aneurysm dome and neck size were 5.2 mm (IQR 4.2–7) and 3.9 mm (IQR 3–5). Contour size 7 (39%) and 9 (25%) were most used. Thromboembolic and hemorrhagic complications occurred in 6.8% and 0.4% of aneurysms, respectively. Raymond-Roy 1 and 2 occlusions at last follow-up were achieved in 63.2% and 28.3%, respectively, resulting in adequate occlusion of 91.5% of aneurysms. Conclusion This is the largest multicenter study reporting the outcome on the Contour Neurovascular System. At 1 year, the self-evaluated data on safety and efficacy are comparable to data of existing intrasaccular devices. Contour is a promising technology in the treatment of cerebral aneurysms.
Correspondence on ‘Transradial versus transfemoral access for diagnostic cerebral angiography: frequency of acute MRI findings in 500 consecutive patients at a single center’
Ghozy, Sherief , Brinjikji, Waleed , Cloft, Harry J. , Kallmes, David F. , Ghozy, Sherief

Journal of NeuroInterventional Surgery | May 17, 2024 | Volume: 17 | Issue: 2 | Pages: 229-229

10.1136/jnis-2024-021894 Get It

Endovascular Treatment for Basilar Artery Occlusion: Revisiting Evidence From Randomized Clinical Trials
Ghozy, Sherief , El‐Ghanem, Mohammad , Gandhi, Chirag D. , Ghozy, Sherief , El‐Qushayri, Amr Ehab , Elfil, Mohamed , Dicpinigaitis, Alis J. , Amuluru, Krishna , Al‐Mufti, Fawaz

Stroke: Vascular and Interventional Neurology | April 23, 2024 | Volume: 5 | Issue: 1 | Pages: No page available

10.1161/svin.122.000655 Get It

Background Acute ischemic stroke attributed to basilar artery occlusion is known to be associated with high rates of mortality and disability. However, the previous clinical trials did not provide evidence to support the efficacy of endovascular treatment (EVT) in patients with basilar artery occlusion. The purpose of this study was to provide updated evidence about EVT's benefits and safety profile with the recent update from both the Endovascular Treatment for Acute Basilar Artery Occlusion (ATTENTION) and the Basilar Artery Occlusion Chinese Endovascular Trial (BAOCHE) trials. Methods We searched for eligible articles from inception to November 1, 2022, in 5 databases and included all randomized controlled trials with no restrictions on the publication date or language. Meta‐analysis statistics were performed using R software version 4.2.1. Results The rate of modified Rankin scale score of 0 to 3 was significantly higher in the EVT group compared with best medical treatment (risk ratio [RR], 1.54 [95% CI, 1.16–2.04]; P value = 0.002), and the same was observed for the rate of modified Rankin scale score 0 to 2 (RR, 1.83 [95% CI, 1.08–3.08]; P value = 0.024). Moreover, there was a significant reduction in the 90‐day mortality in the EVT group (RR, 0.76 [95% CI, 0.65–0.89]; P value = 0.002). However, there was a significantly higher rate of symptomatic intracerebral hemorrhage in the EVT group compared with best medical treatment (RR, 7.48 [95% CI, 2.27–24.61]; P value <0.001). Conclusions EVT may confer a clinical benefit to patients with acute ischemic stroke caused by basilar artery occlusion. Because of the small number of included studies and because all of them were conducted in the Chinese population, further trials might be needed to confirm and further investigate the generalizability of these results.
eCLIPs bifurcation remodeling system for treatment of wide-neck bifurcation aneurysms: A systematic review and meta-analysis of safety and efficacy
Ghozy, Sherief , Ramzan, Abdullah , Motawei, Ahmed Sallam, Abdelghaffar, Mariam , Dmytriw, Adam A. , Kallmes, David F. , Kadirvel, Ramanathan , Dmytriw, Adam A , Ghozy, Sherief , Kobeissi, Hassan

The Neuroradiology Journal | April 15, 2024 | Volume: 37 | Issue: 6 | Pages: 699-704

10.1177/19714009241247463 Get It

Background Wide neck bifurcation aneurysms (WNBAs) are a subtype of aneurysms that are especially complex to treat. We aim to conduct a systematic review and meta-analysis to synthesize the available literature on the safety and efficacy of employing endovascular clip system (eCLIPs) in the treatment of WNBAs. Methods We report this study in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. PubMed, Embase, Web of Science, and Scopus were queried for this review. Screening and extraction were performed by at least two authors to ensure accuracy and completeness, and a senior author arbitrated any discrepancies. All data were analyzed using R software version 4.3.0. and random-effects model. Results Four studies were finally included, of which three were prospective and one was retrospective. Successful adjunctive coiling occurred in 91.38% (95% CI = 70.71–97.9) of cases and overall technical success was achieved in 88.61% (95 CI = 75.54–95.15) of cases. The pooled complete occlusion (Raymond-Roy Class I) was 50.65% (95% CI = 39.63–61.60) and adequate occlusion (Raymond-Roy Class I/II) was 84.42% (95% CI = 74.53–90.93). Thrombo-embolic complication had a pooled rate of 1.22% (95% CI = 0.17–8.15), retreatment rate was 6.10% (95% CI = 2.56–13.83), and mortality reported in 3.66% (95% CI = 1.18–10.74) of patients. Conclusion The use of eCLIPs may be a safe and efficacious treatment for WNBAs. Future randomized controlled trials are needed for further validation of the findings.
Differences in outcome between left-sided and right-sided mechanical thrombectomy for acute ischemic stroke: A systematic review and meta-analysis
Ramzan, Abdullah , Ghozy, Sherief , Bilgin, Cem , Kadirvel, Ramanathan , Kallmes, David F. , Kadirvel, Ram , Kallmes, David F , Ghozy, Sherief , Bilgin, Cem , Rabinstein, Alejandro A.

Interventional Neuroradiology | March 1, 2024 | Volume: 32 | Issue: 4 | Pages: 1594-1600

10.1177/15910199241236329 Get It

Background Mechanical thrombectomy (MT) is a safe and effective treatment option for acute ischemic stroke due to large vessel occlusion. To investigate differences in outcomes between patients receiving left-sided and right-sided MT, we performed a systematic review and meta-analysis. Methods A systematic literature review was performed using Embase, PubMed, Scopus, and Web of Science databases. Additional literature was searched for manually. Studies reporting safety and efficacy metrics for MT were included. Data regarding the modified Rankin scale (mRS), thrombolysis in cerebral infarction (TICI), symptomatic intracranial hemorrhage (sICH), and 90-day mortality were included. A random-effects model was used to calculate pooled odds ratios (ORs), mean differences (MDs), and 95% confidence intervals (CIs). Results The literature search yielded 13 reports consisting of 19 studies ranging from 98 to 5590 patients. Patients presenting with left-sided stroke had a National Institutes of health stroke scale score 2.89 greater than patients presenting with right-sided stroke (MD = 2.89; 95% CI = 2.09–3.68; P -value < 0.001). There were no differences between left-sided and right-sided MT patients for mRS 0–2 (OR = 0.94; 95% CI = 0.85–1.04; P -value = 0.224), TICI 2b–3 (OR = 1.05; 95% CI = 0.88–1.25; P -value = 0.598), sICH (OR = 0.83; 95% CI = 0.61–1.14; P -value = 0.255), or 90-day mortality (OR = 1.06; 95% CI = 0.84–1.33; P -value = 0.610). Conclusions There does not appear to be a difference in outcomes for patients undergoing left-sided or right-sided thrombectomy.
Factors Affecting Selection of TraineE for Neurointervention (FASTEN)
Elfil, Mohamed , Ghozy, Sherief , Elmashad, Ahmed , Al‐Bayati, Alhamza R , Alaraj, Ali , Brook, Allan , Kam, Anthony W. , Waldau, Ben , Altschul, David , Parrella, David Turkel, Tóth, Gábor , Jindal, Gaurav , Shaikh, Hamza , Dolia, Jaydevsinh , Thomas, Justin, Kim, Louis J. , Harrigan, Mark R. , Kole, Max , Mokin, Max, Janjua, Nazli , Zaidat, Osama O. , Youssef, Patrick , Khandelwal, Priyank , Wang, Qingliang Tony, Szeder, Viktor , Tanweer, Omar , Jankowitz, Brian T. , Heit, Jeremy J. , Williamson, Richard , Kass‐Hout, Tareq , Crowley, R. Webster , El‐Ghanem, Mohammad , Kam, Anthony , Ghozy, Sherief , Siddiqui, Adnan H , Al-Bayati, Alhamza , Alaraj, Ali , Kam, Anthony W , Matouk, Charles , Schirmer, Clemens M , Altschul, David J , Shaikh, Hamza A , Amuluru, Krishna , Grandhi, Ramesh , Hanel, Ricardo A , Ortega-Gutierrez, Santiago , Nguyen, Thanh N , Szeder, Viktor , Heit, Jeremy J , Al-Mufti, Fawaz , Elfil, Mohamed , Dolia, Jaidevsinh , Morsi, Rami Z. , Siddiqui, Adnan H. , Chatterjee, Arindam R , Patsalides, Athos T , Prestigiacomo, Charles Joseph , Matouk, Charles , Schirmer, Clemens M. , Fifi, Johanna T , Fraser, Justin F , Kim, Louis J. , Amans, Matthew R. , Abraham, Michael G. , Jumaa, Mouhammad , Grandhi, Ramesh , Hanel, Ricardó A. , Kellogg, Ryan Thomson , Sheth, Sunil A , Nguyen, Thanh N. , Hu, Yin , Yoo, Albert J. , Al‐Mufti, Fawaz

Interventional Neuroradiology | February 23, 2024 | Volume: 32 | Issue: 4 | Pages: 1253-1260

10.1177/15910199241232726 Get It

Background and importance Neurointervention is a very competitive specialty in the United States due to the limited number of training spots and the larger pool of applicants. The training standards are continuously updated to ensure solid training experiences. Factors affecting candidate(s) selection have not been fully established yet. Our study aims to investigate the factors influencing the selection process. Methods A 52-question survey was distributed to 93 program directors (PDs). The survey consisted of six categories: (a) Program characteristics, (b) Candidate demographics, (c) Educational credentials, (d) Personal traits, (e) Research and extracurricular activities, and (f) Overall final set of characteristics. The response rate was 59.1%. As per the programs’ characteristics, neurosurgery was the most involved specialty in running the training programs (69%). Regarding demographics, the need for visa sponsorship held the greatest prominence with a mean score of 5.9 [standard deviation (SD) 2.9]. For the educational credentials, being a graduate from a neurosurgical residency and the institution where the candidate's residency training is/was scored the highest [5.4 (SD = 2.9), 5.4 (SD = 2.5), respectively]. Regarding the personal traits, assessment by faculty members achieved the highest score [8.9 (SD = 1)]. In terms of research/extracurricular activities, fluency in English had the highest score [7.2 (SD = 1.9)] followed by peer-reviewed/PubMed-indexed publications [6.4 (SD = 2.2)]. Conclusion Our survey investigated the factors influencing the final decision when choosing the future neurointerventional trainee, including demographic, educational, research, and extracurricular activities, which might serve as valuable guidance for both applicants and programs to refine the selection process.
Mechanical thrombectomy for the treatment of large vessel occlusion due to cancer-related cerebral embolism: A systematic review
Toruno, Michelle A. , Ghozy, Sherief , Şenol, Yiğit Can , Kobeissi, Hassan , Kadirvel, Ramanathan , Ashdown, B C, Kallmes, David F. , Toruno, Michelle , Ghozy, Sherief , Senol, Yigit Can , Kobeissi, Hassan , Kadirvel, Ram , Ashdown, Boyd, Kallmes, David F , Al‐Janabi, Omar , Karaman, İrem

Interventional Neuroradiology | February 9, 2024 | Volume: 32 | Issue: 4 | Pages: 1560-1568

10.1177/15910199241230356 Get It

Background Cancer-related cerebral embolism due to direct tumor embolization results in a rare acute ischemic stroke with large vessel occlusion (LVO). Despite the established status of mechanical thrombectomy (MT) in LVO management, its effectiveness and safety remains inadequately explored in this specific patient group. Methods We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the Nested Knowledge AutoLit software, encompassing databases like Embase, PubMed, Scopus, and Web of Science, from their inception up to 9 May 2023. Results In the review of 35 studies encompassing 37 cases, mean patient age was 52 years, and 30% were female. Cardiac myxoma (29.7%), cardiac papillary fibroelastoma (16.2%), and squamous cell carcinoma of the lung (8.1%) were the most frequent underlying cancers. The left middle cerebral artery was the most commonly affected occlusion site (24.3%). Of the patients, 67.5% underwent MT alone, while 32.5% received MT combined with intravenous thrombolysis. Successful reperfusion (thrombolysis in cerebral infarction (TICI) 2b–3) was achieved in 89.1% of cases, with 59.4% reaching TICI 3. Functional independence was observed in 29.7% of patients. Conclusion While limitations exist, this comprehensive study highlights the potential benefits of MT in a patient group historically excluded from major trials, warranting further investigation.