Complete vs Culprit-Only Revascularization in Older Patients With Myocardial Infarction and High Bleeding Risk: A Randomized Clinical Trial.

Importance: Patients with high bleeding risk (HBR) have a poor prognosis, and it is not known if they may benefit from complete revascularization after myocardial infarction (MI). Objective: To investigate the benefit of physiology-guided complete revascularization vs a culprit-only strategy in patients with HBR, MI, and multivessel disease. Design, Setting, and Participants: This was a prespecified analysis of the Functional Assessment in Elderly MI Patients With Multivessel Disease (FIRE) randomized clinical trial data. FIRE was an investigator-initiated, open-label, multicenter trial. Patients 75 years or older with MI and multivessel disease were enrolled at 34 European centers from July 2019 through October 2021. Physiology treatment was performed either by angiography- or wire-based assessment. Patients were divided into HBR or non-HBR categories in accordance with the Academic Research Consortium HBR document. Interventions: Patients were randomized to either physiology-guided complete revascularization or culprit-only strategy. Main Outcomes and Measures: The primary outcome comprised a composite of death, MI, stroke, or revascularization at 1 year. Secondary outcomes included a composite of cardiovascular death or MI and Bleeding Academic Research Consortium (BARC) types 3 to 5. Results: Among 1445 patients (mean [SD] age, 81 [5] years; 917 male [63%]), 1025 (71%) met HBR criteria. Patients with HBR were at higher risk for the primary end point (hazard ratio [HR], 2.01; 95% CI, 1.47-2.76), cardiovascular death or MI (HR, 1.89; 95% CI, 1.26-2.83), and BARC types 3 to 5 (HR, 3.28; 95% CI, 1.40-7.64). The primary end point was significantly reduced with physiology-guided complete revascularization as compared with culprit-only strategy in patients with HBR (HR, 0.73; 95% CI, 0.55-0.96). No indication of interaction was noted between revascularization strategy and HBR status for primary and secondary end points. Conclusions and Relevance: HBR status is prevalent among older patients with MI, significantly increasing the likelihood of adverse events. Physiology-guided complete revascularization emerges as an effective strategy, in comparison with culprit-only revascularization, for mitigating ischemic adverse events, including cardiovascular death and MI. Trial Registration: ClinicalTrials.gov Identifier: NCT03772743.

Periprocedural myocardial infarction after percutaneous coronary intervention and long-term mortality: a meta-analysis.

BACKGROUND AND AIMS: Conflicting data are available regarding the association between periprocedural myocardial infarction (PMI) and mortality following percutaneous coronary intervention. The purpose of this study was to evaluate the incidence and prognostic implication of PMI according to the Universal Definition of Myocardial Infarction (UDMI), the Academic Research Consortium (ARC)-2 definition, and the Society for Cardiovascular Angiography and Interventions (SCAI) definition. METHODS: Studies reporting adjusted effect estimates were systematically searched. The primary outcome was all-cause death, while cardiac death was included as a secondary outcome. Studies defining PMI according to biomarker elevation without further evidence of myocardial ischaemia ('ancillary criteria') were included and reported as 'definition-like'. Data were pooled in a random-effect model. RESULTS: A total of 19 studies and 109 568 patients were included. The incidence of PMI was progressively lower across the UDMI, ARC-2, and SCAI definitions. All PMI definitions were independently associated with all-cause mortality [UDMI: hazard ratio (HR) 1.61, 95% confidence interval (CI) 1.32-1.97; I2 34%; ARC-2: HR 2.07, 95% CI 1.40-3.08, I2 0%; SCAI: HR 3.24, 95% CI 2.36-4.44, I2 78%]. Including ancillary criteria in the PMI definitions were associated with an increased prognostic performance in the UDMI but not in the SCAI definition. Data were consistent after evaluation of major sources of heterogeneity. CONCLUSIONS: All currently available international definitions of PMI are associated with an increased risk of all-cause death after percutaneous coronary intervention. The magnitude of this latter association varies according to the sensitivity and prognostic relevance of each definition.

Prognostic Value of Microvascular Resistance Reserve Measured Immediately After PCI in Stable Coronary Artery Disease.

BACKGROUND: Microvascular resistance reserve (MRR) has been proposed as a specific metric to quantify coronary microvascular function. The long-term prognostic value of MRR measured in stable patients immediately after percutaneous coronary intervention (PCI) is unknown. This study sought to determine the prognostic value of MRR measured immediately after PCI in patients with stable coronary artery disease. METHODS: This study included 502 patients with stable coronary artery disease who underwent elective PCI and coronary physiological measurements, including pressure and flow estimation using a bolus thermodilution method after PCI. MRR was calculated as coronary flow reserve divided by fractional flow reserve times the ratio of mean aortic pressure at rest to that at maximal hyperemia induced by hyperemic agents. An abnormal MRR was defined as ≤2.5. Major adverse cardiac events (MACEs) were defined as a composite of all-cause mortality, any myocardial infarction, and target-vessel revascularization. RESULTS: During a median follow-up of 3.4 years, the cumulative MACE rate was significantly higher in the abnormal MRR group (12.5 versus 8.3 per 100 patient-years; hazard ratio 1.53 [95% CI, 1.10-2.11]; P<0.001). A higher all-cause mortality rate primarily drove this difference. On multivariable analysis, a higher MRR value was independently associated with lower MACE and lower mortality. When comparing 4 subgroups according to MRR and the index of microcirculatory resistance, patients with both abnormal MRR and index of microcirculatory resistance (≥25) had the highest MACE rate. CONCLUSIONS: An abnormal MRR measured immediately after PCI in patients with stable coronary artery disease is an independent predictor of MACE, particularly all-cause mortality.

Ten-Year Outcome of Recanalization or Medical Therapy for Concomitant Chronic Total Occlusion After Myocardial Infarction.

BACKGROUND: The EXPLORE (Evaluating Xience and Left Ventricular Function in PCI on Occlusions After STEMI) trial was the first and only randomized trial investigating chronic total occlusion (CTO) percutaneous coronary intervention (PCI) early after primary PCI for ST-segment-elevation myocardial infarction, compared with medical therapy for the CTO. We performed a 10-year follow-up of EXPLORE to investigate long-term safety and clinical impact of CTO PCI after ST-segment-elevation myocardial infarction, compared with no-CTO PCI. METHODS AND RESULTS: In EXPLORE, 302 patients post-ST-segment-elevation myocardial infarction with concurrent CTO were randomized to CTO PCI within ≈1 week or no-CTO PCI. We performed an extended clinical follow-up for the primary end point of major adverse cardiac events, consisting of cardiovascular death, coronary artery bypass grafting, or myocardial infarction. Secondary end points included all-cause death, angina, and dyspnea. Median follow-up was 10 years (interquartile range, 8-11 years). The primary end point occurred in 25% of patients with CTO PCI and in 24% of patients with no-CTO PCI (hazard ratio [HR], 1.11 [95% CI, 0.70-1.76]). Cardiovascular mortality was higher in the CTO PCI group (HR, 2.09 [95% CI, 1.10-2.50]), but all-cause death was similar (HR, 1.53 [95% CI, 0.93-2.50]). Dyspnea relief was more frequent after CTO PCI (83% versus 65%, P=0.005), with no significant difference in angina. CONCLUSIONS: This 10-year follow-up of patients post-ST-segment-elevation myocardial infarction randomized to CTO PCI or no-CTO PCI demonstrated no clinical benefit of CTO PCI in major adverse cardiac events or overall mortality. However, CTO PCI was associated with a higher cardiovascular mortality compared with no-CTO PCI. Our long-term data support a careful weighing of effective symptom relief against an elevated cardiovascular mortality risk in CTO PCI decisions. REGISTRATION: URL: https://www.trialregister.nl; Unique identifier: NTR1108.

Acute Kidney Injury in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention: The Role of Vascular Access Site.

Background: in patients undergoing percutaneous coronary interventions (PCI), radial access should be favoured over femoral access as it reduces the risk of vascular complications and bleeding. Furthermore, a preventive role of radial access in the occurrence of acute kidney injury (AKI), mainly mediated by the reduction of bleeding and cholesterol crystal embolization into renal circulation, has been investigated in several studies, yielding conflicting results. Methods: we designed a retrospective study to appraise the effect of the use of a vascular access site on the occurrence of AKI in a cohort of 633 patients with acute myocardial infarction treated by PCI at our centre from 2018 to 2020. Results: after propensity score adjustment, radial access was associated with a reduced, albeit statistically not significant, incidence of AKI (14.7% vs. 21.0%; p = 0.06) and major bleeding (12.5% vs. 18.7%; p = 0.04) as compared to femoral access. At multivariate analysis, femoral access was an independent predictor of AKI, together with in-hospital occurrence of BARC 3-5 bleeding, Killip class >1 at presentation, female gender, baseline eGFR <60 mL/min, and baseline haemoglobin <12 g/dL. Conclusions: although limited by the observational design, our study supports the hypothesis that radial access may exert a protective role on the occurrence of AKI in patients with acute myocardial infarction undergoing PCI.

Systematic Review Article: New Drug Strategies for Treating Resistant Hypertension-the Importance of a Mechanistic, Personalized Approach.

Resistant hypertension (RHT) is characterized by persistently high blood pressure (BP) levels above the widely recommended therapeutic targets of less than 140/90 mmHg office BP, despite life-style measures and optimal medical therapies, including at least three antihypertensive drug classes at maximum tolerated dose (one should be a diuretic). This condition is strongly related to hypertension-mediated organ damage and, mostly, high risk of hospitalization due to hypertension emergencies or acute cardiovascular events. Hypertension guidelines proposed a triple combination therapy based on renin angiotensin system blocking agent, a thiazide or thiazide-like diuretic, and a dihydropyridinic calcium-channel blocker, to almost all patients with RHT, who should also receive either a beta-blocker or a mineralocorticoid receptor antagonist, or both, depending on concomitant conditions and contraindications. Several other drugs may be attempted, when elevated BP levels persist in these RHT patients, although their added efficacy in lowering BP levels on top of optimal medical therapy is uncertain. Also, renal denervation has demonstrated to be a valid therapeutic alternative in RHT patients. More recently, novel drug classes and molecules have been tested in phase 2 randomised controlled clinical trials in patients with RHT on top of optimal medical therapy with at least 2-3 antihypertensive drugs. These novel drugs, which are orally administered and are able to antagonize different pathophysiological pathways, are represented by non-steroid mineralocorticorticoid receptor antagonists, selective aldosterone synthase inhibitors, and dual endothelin receptor antagonists, all of which have proven to reduce seated office and 24-h ambulatory systolic/diastolic BP levels. The main findings of randomized clinical trials performed with these drugs  as well as their potential indications for the clinical management of RHT patients are summarised in this systematic review article.

Guideline-Directed Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Incident Cancer.

BACKGROUND: It has been postulated that cancer hampers the delivery of guideline-directed medical therapy (GDMT) for heart failure (HF). However, few data are available in this regard. METHODS: We performed a retrospective analysis from the HF Outpatient Clinic of the IRCCS Ospedale Policlinico San Martino in Genova, Italy. All HF patients evaluated between 2010 and 2019, with a left ventricular ejection fraction <50% and at least two visits ≥3 months apart with complete information about GDMT were included in the study. We assessed the prescription of GDMT-in particular, beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid antagonists (MRA)-at the time of the last HF evaluation and compared it between patients with and without incidental cancer. For those with incidental cancer, we also evaluated modifications of GDMT comparing the HF evaluations before and after cancer diagnosis. RESULTS: Of 464 HF patients, 39 (8%) had incidental cancer. There were no statistical differences in GDMT between patients with and without incidental cancer at last evaluation. In the year following cancer diagnosis, of 33 patients with incidental cancer on BB, none stopped therapy, but two had a down-titration to a dosage <50%; of 27 patients on RASi, two patients stopped therapy and three had a down-titration to a dosage <50%; of 19 patients on MRA, four stopped therapy. CONCLUSIONS: Although HF patients with incidental cancer may need to have GDMT down-titrated at the time of cancer diagnosis, this does not appear to significantly hinder the delivery of HF therapies during follow-up.

Obesity: the perfect storm for heart failure.

Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi-imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost-effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium-glucose co-transporter-2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF.

International evaluation of an artificial intelligence-powered electrocardiogram model detecting acute coronary occlusion myocardial infarction.

Aims: A majority of acute coronary syndromes (ACS) present without typical ST elevation. One-third of non-ST-elevation myocardial infarction (NSTEMI) patients have an acutely occluded culprit coronary artery [occlusion myocardial infarction (OMI)], leading to poor outcomes due to delayed identification and invasive management. In this study, we sought to develop a versatile artificial intelligence (AI) model detecting acute OMI on single-standard 12-lead electrocardiograms (ECGs) and compare its performance with existing state-of-the-art diagnostic criteria. Methods and results: An AI model was developed using 18 616 ECGs from 10 543 patients with suspected ACS from an international database with clinically validated outcomes. The model was evaluated in an international cohort and compared with STEMI criteria and ECG experts in detecting OMI. The primary outcome of OMI was an acutely occluded or flow-limiting culprit artery requiring emergent revascularization. In the overall test set of 3254 ECGs from 2222 patients (age 62 ± 14 years, 67% males, 21.6% OMI), the AI model achieved an area under the curve of 0.938 [95% confidence interval (CI): 0.924-0.951] in identifying the primary OMI outcome, with superior performance [accuracy 90.9% (95% CI: 89.7-92.0), sensitivity 80.6% (95% CI: 76.8-84.0), and specificity 93.7 (95% CI: 92.6-94.8)] compared with STEMI criteria [accuracy 83.6% (95% CI: 82.1-85.1), sensitivity 32.5% (95% CI: 28.4-36.6), and specificity 97.7% (95% CI: 97.0-98.3)] and with similar performance compared with ECG experts [accuracy 90.8% (95% CI: 89.5-91.9), sensitivity 73.0% (95% CI: 68.7-77.0), and specificity 95.7% (95% CI: 94.7-96.6)]. Conclusion: The present novel ECG AI model demonstrates superior accuracy to detect acute OMI when compared with STEMI criteria. This suggests its potential to improve ACS triage, ensuring appropriate and timely referral for immediate revascularization.

Validation of a new non-hyperemic physiological index: the constant-resistance ratio (cRR).

OBJECTIVES: The instantaneous wave-free ratio (iwFR) has limited availability. A new resting index called the constant-resistance ratio (cRR), which dynamically identifies cardiac intervals with constant and minimum resistance, has been developed; however, its diagnostic performance is unknown. The aim of this study was to validate the cRR by retrospectively calculating the cRR values from raw pressure waveforms of 2 publicly available datasets and compare them with those of the iwFR. METHODS: Waveform data from the CONTRAST and VERIFY 2 studies were used. The primary endpoint was Bland-Altman bias between cRR and iwFR. Secondary endpoints included diagnostic agreement, correlation, receiver operating characteristic (ROC) analysis, and success rates of cRR and iwFR. RESULTS: Among the 1036 waveforms, 871 were successful in determining paired cRR and iwFR values, while cRR was 6% more successful than iwFR (P less than .0001). The mean bias between cRR and iwFR was 0.003, with 95% limits of agreement [-0.021,0.028]. These 2 indices were highly correlated (r = 0.991; P less than .0001). Using an iwFR of 0.89 or less as the reference standard, the optimal cRR cutoff was 0.89, with an area under the ROC curve of 0.991 (P less than .001) and a diagnostic accuracy of 96.9% (95% CI [96%, 98%]). CONCLUSIONS: The cRR, a new resting index for identifying dynamic cardiac intervals with constant and minimum resistance, demonstrated high numerical agreement, diagnostic consistency, and a higher success rate than the iwFR based on the 2 publicly available datasets.

Systematic review and meta-analysis of randomized and nonrandomized studies on fractional flow reserve-guided revascularization.

INTRODUCTION AND OBJECTIVES: Several studies have investigated the effectiveness of fractional flow reserve (FFR) guidance in improving clinical outcomes after myocardial revascularization, yielding conflicting results. The aim of this study was to compare clinical outcomes in patients with coronary artery disease following FFR-guided or angiography-guided revascularization. METHODS: Both randomized controlled trials (RCTs) and nonrandomized intervention studies were included. Coprimary endpoints were all-cause death, myocardial infarction, and major adverse cardiovascular events (MACE). The study is registered with PROSPERO (CRD42022344765). RESULTS: A total of 30 studies enrolling 393 588 patients were included. FFR-guided revascularization was associated with significantly lower rates of all-cause death (OR, 0.63; 95%CI, 0.53-0.73), myocardial infarction (OR, 0.70; 95%CI, 0.59-0.84), and MACE (OR, 0.77; 95%CI, 0.70-0.85). When only RCTs were considered, no significant difference between the 2 strategies was observed for any endpoints. However, the use of FFR was associated with reduced rates of revascularizations and treated lesions. Metaregression suggested that the higher the rate of revascularized patients the lower the benefit of FFR guidance on MACE reduction compared with angiography guidance (P=.012). Similarly, higher rates of patients with acute coronary syndromes were associated with a lower benefit of FFR-guided revascularization (P=.039). CONCLUSIONS: FFR-guided revascularization was associated with lower rates of all-cause death, myocardial infarction and MACE compared with angiographic guidance, with RCTs and nonrandomized intervention studies yielding conflicting data. The benefits of FFR-guidance seem to be less evident in studies with high revascularization rates and with a high prevalence of patients with acute coronary syndrome.

Asymptomatic Aortic Stenosis: From Risk Stratification to Treatment.

Our understanding of the natural history of aortic stenosis has significantly increased over the last decade. There have been considerable advances in the diagnosis and risk stratification of patients with aortic stenosis and in surgical and anesthetic techniques. In addition, transcatheter aortic valve replacement has established itself as a viable alternative to surgical management. Inevitably, these developments have raised questions regarding the merits of waiting for symptom onset in asymptomatic patients with severe aortic stenosis before offering treatment. Recent observational and randomized trial data suggest that early intervention in asymptomatic patients with severe aortic stenosis and normal left ventricular function may confer a prognostic advantage to a watchful waiting strategy. In this review, we highlight advances in the management and risk stratification of patients with asymptomatic severe aortic stenosis with particular consideration of recent findings supporting early valvular intervention.

Impact of pre-admission physical activity on benefits of physiology-guided complete revascularization in older patients with myocardial infarction: insights from the FIRE trial.

AIMS: The present analysis from the Functional Assessment in Elderly Myocardial Infarction Patients with Multivessel Disease (FIRE) trial aims to explore the significance of pre-admission physical activity and assess whether the benefits of physiology-guided complete revascularization apply consistently to sedentary and active older patients. METHODS AND RESULTS: Patients aged 75 years or more with myocardial infarction (MI) and multivessel disease were randomized to receive physiology-guided complete revascularization or culprit-only strategy. The primary outcome was a composite of death, MI, stroke, or any revascularization within a year. Secondary endpoints included the composite of cardiovascular death or MI, as well as single components of the primary endpoint. Pre-admission physical activity was categorized into three groups: (i) absent (sedentary), (ii) light, and (iii) vigorous. Among 1445 patients, 692 (48%) were sedentary, whereas 560 (39%) and 193 (13%) performed light and vigorous physical activity, respectively. Patients engaging in light or vigorous pre-admission physical activity exhibited a reduced risk of the primary outcome compared with sedentary individuals [light hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.55-0.91 and vigorous HR 0.14, 95% CI 0.07-0.91, respectively]. These trends were also observed for death, cardiovascular death, or MI. When comparing physiology-guided complete revascularization vs. culprit-only strategy, no significant interaction was observed for primary and secondary endpoints when stratified by sedentary or active status. CONCLUSION: In older patients with MI, pre-admission physical activity emerges as a robust and independent prognostic determinant. Physiology-guided complete revascularization stands out an effective strategy in reducing ischaemic adverse events, irrespective of pre-admission physical activity status. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03772743.

The Functional Assessment in Elderly Myocardial Infarction Patients with Multivessel Disease (FIRE) trial has shown that physiology-guided complete revascularization reduces ischaemic adverse events in older patients with myocardial infarction (MI) and multivessel disease. Older patients who engage in light or vigorous physical activity before hospitalization for MI have a reduced risk of the primary composite outcome of death, MI, stroke, or ischaemia-driven revascularization. These benefits extend to all secondary cardiovascular outcomes as well. In the present subanalysis of the FIRE trial, we find that the positive prognosis associated with physiology-guided complete revascularization holds true even for patients with a sedentary lifestyle. This means that this type of revascularization can effectively reduce ischaemic adverse events in older patients with MI and multivessel disease, regardless of their physical activity levels.

Association between Immune Checkpoint Inhibitors and Atherosclerotic Cardiovascular Disease Risk: Another Brick in the Wall.

In recent years, immune checkpoint inhibitors have significantly changed the field of oncology, emerging as first-line treatment, either alone or in combination with other regimens, for numerous malignancies, improving overall survival and progression-free survival in these patients. However, immune checkpoint inhibitors might also cause severe or fatal immune-related adverse events, including adverse cardiovascular events. Initially, myocarditis was recognized as the main immune checkpoint inhibitor-related cardiac event, but our knowledge of other potential immune-related cardiovascular adverse events continues to broaden. Recently, preclinical and clinical data seem to support an association between immune checkpoint inhibitors and accelerated atherosclerosis as well as atherosclerotic cardiovascular events such as cardiac ischemic disease, stroke, and peripheral artery disease. In this review, by offering a comprehensive overview of the pivotal role of inflammation in atherosclerosis, we focus on the potential molecular pathways underlying the effects of immune checkpoint inhibitors on cardiovascular diseases. Moreover, we provide an overview of therapeutic strategies for cancer patients undergoing immunotherapy to prevent the development of cardiovascular diseases.

Microplastics and Nanoplastics in Atheromas and Cardiovascular Events.

BACKGROUND: Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking. METHODS: We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis-gas chromatography-mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs. RESULTS: A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 µg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 µg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001). CONCLUSIONS: In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. (Funded by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale and others; ClinicalTrials.gov number, NCT05900947.).